diff --git a/.gitignore b/.gitignore index fb35a33..7a38ccf 100644 --- a/.gitignore +++ b/.gitignore @@ -1,3 +1,6 @@ +.idea +.env + literature/ /cellsem_agent/graphs/cl_validation/resources/val_annotations.json diff --git a/Claude.md b/Claude.md new file mode 100644 index 0000000..cfc87a3 --- /dev/null +++ b/Claude.md @@ -0,0 +1,11 @@ +You are an experienced developer of agentic workflows in Python. You write well documented code with good test coverage. You build carefully and incrementally, making sure any user can run tests for each element of the workflows you build as well as for the whole workflow. + +This repo features agentic workflows structure using the Pydantic library with graphs specifying how agents are orchestrated into workflows. + +Current aim: + - A workflow, 'contextual_gene_list_annotation', for annotating gene lists with predicted functional implications for cells that express genes on the list in some given cell-type/tissue/disease context. This workflow has three steps: + 1. A deepsearch query that takes a gene list and a context statement as input. Output will be structured according to a provided JSON schema. This step uses the openAI deepsearch API. It DOES NOT USE AN AGENT. The prompts for this have already been written and tested in open-AI chat. The output (as described by these prompts) consists of a set of ranked list of composite functions. + 2. The output of step 2 is passed to an agent that decomposes terms into atomic processes, components, cell types etc and relates them to each other. The results are used to update the JSON outputed from step 1. + 3. A third step uses an agent to map these atomic terms to ontolgy terms, updating the JSON again. + + diff --git a/Progress.md b/Progress.md new file mode 100644 index 0000000..e8527dc --- /dev/null +++ b/Progress.md @@ -0,0 +1,17 @@ +Starting point and progress log: + +In this repo you will find: + - A command line runner: gene_list_annotation_cli.py for contextual_gene_list_annotation + - This is not yet linked to any workflow + - A utilities package with code for running openai deepsearch & one shot LLM queries via the API: cellsem_agent/utils/openai/ + - An ontology mapping agent at cellsem_agent/agents/ontology_mapping/ + - A working service for running deepsearch queries --> structured gene list annotation + - This has been tested and includes examples + - An untested service for decomposing compound functions from step one into components and updating the schema + +TODO: + - [ ] Write workflow as new graph combining components + - [ ] Hook workflow up to CLI runner + - [ ] Refine prompts and schema + - [ ] Extend examples - focussing on things we can use as objective tests. + diff --git a/cellsem_agent/__init__.py b/cellsem_agent/__init__.py index e69de29..3a11cf7 100644 --- a/cellsem_agent/__init__.py +++ b/cellsem_agent/__init__.py @@ -0,0 +1 @@ +"""Utility modules for cellsem-agent.""" \ No newline at end of file diff --git a/cellsem_agent/agents/annotator/annotator_agent.py b/cellsem_agent/agents/annotator/annotator_agent.py index 7a8256b..2912f73 100644 --- a/cellsem_agent/agents/annotator/annotator_agent.py +++ b/cellsem_agent/agents/annotator/annotator_agent.py @@ -1,7 +1,6 @@ """ Ontology based Annotator Agent. """ - import logging from typing import List, Optional diff --git a/cellsem_agent/agents/ontology_mapping/__init__.py b/cellsem_agent/agents/ontology_mapping/__init__.py new file mode 100644 index 0000000..e69de29 diff --git a/cellsem_agent/agents/ontology_mapping/ontology_mapping_agent.py b/cellsem_agent/agents/ontology_mapping/ontology_mapping_agent.py new file mode 100644 index 0000000..b653f38 --- /dev/null +++ b/cellsem_agent/agents/ontology_mapping/ontology_mapping_agent.py @@ -0,0 +1,101 @@ +""" +Ontology Mapping Agent for mapping terms to multiple ontologies. +""" +import logging +from typing import List, Optional + +from pydantic import BaseModel +from pydantic_ai import Agent + +from .ontology_mapping_config import OntologyMappingDependencies +from .ontology_mapping_tools import search_go, search_cl, search_uberon, search_chebi, search_multi_ontology + +ontology_mapping_logger = logging.getLogger(__name__) +ontology_mapping_logger.setLevel(logging.INFO) +console = logging.StreamHandler() +console.setLevel(logging.INFO) +formatter = logging.Formatter('%(asctime)s - %(name)s - %(levelname)s - %(message)s') +console.setFormatter(formatter) +ontology_mapping_logger.addHandler(console) + +ontology_mapping_logger.propagate = False + +ONTOLOGY_MAPPING_SYSTEM_PROMPT = """ +You are an expert bioinformatics specialist and ontology curator focused on mapping biological terms to standardized ontologies. + +You will be provided with a JSON array where each item represents a biological term that may include atomic functions, cellular components, or other relevant biological concepts. +Your task is to map atomic functions, cellular components, and other biological terms to appropriate terms in multiple ontologies including: + +- **GO (Gene Ontology)**: For molecular functions, biological processes, and cellular components +- **CL (Cell Ontology)**: For cell types and cellular structures +- **UBERON**: For anatomical structures and tissues +- **ChEBI**: For chemical compounds and molecular entities + +**For each input term, you must**: +1. **Search multiple ontologies** using the available search tools +2. **Select the best match** based on semantic similarity and biological accuracy +3. **Assign confidence scores** (0.0-1.0) based on match quality +4. **Document the mapping method** used (e.g., "exact_match", "partial_match", "synonym_match") + +**Guidelines for high-quality mappings**: +- Prioritize exact matches over partial matches +- Use the most specific term available (child terms over parent terms when appropriate) +- Consider biological context when multiple matches are available +- For compound terms, try searching individual components if no direct match is found +- Convert plurals to singular before searching +- Try alternative phrasings (e.g., "X of Y" vs "Y X") + +**Search Strategy**: +- Always start with the most relevant ontology for the term type +- Try multiple search strategies if the initial search fails: + - Search for synonyms or related terms + - Break down compound terms into components + - Try different word orders and phrasings +- If no suitable match is found in any ontology, set cl_id to "NO MATCH found" + +**Output Format**: +For each input term, create a MappingResult object with: +- `original_term`: The input term exactly as provided +- `ontology_id`: The matched ontology term ID (e.g., "GO:0008150", "CL:0000000") +- `ontology_label`: The official label from the ontology +- `ontology_source`: The ontology name (GO, CL, UBERON, ChEBI) +- `confidence_score`: Float from 0.0 to 1.0 +- `mapping_method`: Description of how the match was found + +Available tools: +- `search_go`: Search Gene Ontology +- `search_cl`: Search Cell Ontology +- `search_uberon`: Search UBERON anatomy ontology +- `search_chebi`: Search ChEBI chemical ontology +- `search_multi_ontology`: Search multiple ontologies at once +""" + +class MappingResult(BaseModel): + """ + A mapping result is a span of text and the ontology ID and label for the term it mentions. + Use `original_term` for the source text, and `ontology_id` and `ontology_label` for the ID and label of the entity in the ontology. + """ + original_term: str + ontology_id: Optional[str] = None + ontology_label: Optional[str] = None + ontology_source: Optional[str] = None + confidence_score: Optional[float] = None + mapping_method: Optional[str] = None + +class MappingResults(BaseModel): + mappings: List[MappingResult] + +ontology_mapping_agent = Agent( + model="openai:gpt-4o-2024-11-20", + deps_type=OntologyMappingDependencies, + output_type=MappingResults, + system_prompt=ONTOLOGY_MAPPING_SYSTEM_PROMPT, + defer_model_check=True, +) + +# Register tools +ontology_mapping_agent.tool(search_go) +ontology_mapping_agent.tool(search_cl) +ontology_mapping_agent.tool(search_uberon) +ontology_mapping_agent.tool(search_chebi) +ontology_mapping_agent.tool(search_multi_ontology) \ No newline at end of file diff --git a/cellsem_agent/agents/ontology_mapping/ontology_mapping_config.py b/cellsem_agent/agents/ontology_mapping/ontology_mapping_config.py new file mode 100644 index 0000000..f4b6ed7 --- /dev/null +++ b/cellsem_agent/agents/ontology_mapping/ontology_mapping_config.py @@ -0,0 +1,42 @@ +""" +Configuration for the Ontology Mapping agent. +""" +from dataclasses import dataclass +import os +from typing import List, Optional +from pathlib import Path + + +@dataclass +class OntologyMappingDependencies: + """ + Configuration for the Ontology Mapping agent. + + Maps atomic functions and cellular components to terms in OLS ontologies. + Target ontologies include GO, CL, UBERON, and others as appropriate. + """ + workdir: Optional[Path] = None + target_ontologies: Optional[List[str]] = None + + def __post_init__(self): + """Initialize the config with default values.""" + if self.workdir is None: + workdir_path = os.environ.get("WORKDIR", "./workdir") + self.workdir = Path(workdir_path) + # Create workdir if it doesn't exist + self.workdir.mkdir(parents=True, exist_ok=True) + + if self.target_ontologies is None: + # Default ontologies for functional and anatomical mapping + self.target_ontologies = [ + "GO", # Gene Ontology (molecular functions, biological processes, cellular components) + "CL", # Cell Ontology + "UBERON", # Uber-anatomy ontology + "CHEBI", # Chemical Entities of Biological Interest + "PR" # Protein Ontology + ] + + +def get_config(target_ontologies: Optional[List[str]] = None) -> OntologyMappingDependencies: + """Get the Ontology Mapping configuration from environment variables or defaults.""" + return OntologyMappingDependencies(target_ontologies=target_ontologies) \ No newline at end of file diff --git a/cellsem_agent/agents/ontology_mapping/ontology_mapping_tools.py b/cellsem_agent/agents/ontology_mapping/ontology_mapping_tools.py new file mode 100644 index 0000000..22f16b2 --- /dev/null +++ b/cellsem_agent/agents/ontology_mapping/ontology_mapping_tools.py @@ -0,0 +1,136 @@ +""" +Tools for the Ontology Mapping agent. +""" +import os +import logging +from typing import List, Tuple, Dict, Any + +from oaklib import get_adapter +from pydantic_ai import RunContext + +logger = logging.getLogger(__name__) + + +def search_go(ctx: RunContext[str], term: str) -> List[Tuple[str, str]]: + """ + Search the Gene Ontology for a term. + + Args: + ctx: The run context + term: The term to search for. + + Returns: + A list of tuples, each containing a GO ID and a label. + """ + try: + adapter = get_adapter("ols:go") + results = adapter.basic_search(term) + labels = list(adapter.labels(results)) + logger.info(f"GO search for '{term}' returned {len(labels)} results") + return labels + except Exception as e: + logger.error(f"Error searching GO for term '{term}': {e}") + return [] + + +def search_cl(ctx: RunContext[str], term: str) -> List[Tuple[str, str]]: + """ + Search the Cell Ontology for a term. + + Args: + ctx: The run context + term: The term to search for. + + Returns: + A list of tuples, each containing a CL ID and a label. + """ + try: + adapter = get_adapter("ols:cl") + results = adapter.basic_search(term) + labels = list(adapter.labels(results)) + logger.info(f"CL search for '{term}' returned {len(labels)} results") + return labels + except Exception as e: + logger.error(f"Error searching CL for term '{term}': {e}") + return [] + + +def search_uberon(ctx: RunContext[str], term: str) -> List[Tuple[str, str]]: + """ + Search the UBERON anatomy ontology for a term. + + Args: + ctx: The run context + term: The term to search for. + + Returns: + A list of tuples, each containing a UBERON ID and a label. + """ + try: + adapter = get_adapter("ols:uberon") + results = adapter.basic_search(term) + labels = list(adapter.labels(results)) + logger.info(f"UBERON search for '{term}' returned {len(labels)} results") + return labels + except Exception as e: + logger.error(f"Error searching UBERON for term '{term}': {e}") + return [] + + +def search_chebi(ctx: RunContext[str], term: str) -> List[Tuple[str, str]]: + """ + Search the ChEBI chemical ontology for a term. + + Args: + ctx: The run context + term: The term to search for. + + Returns: + A list of tuples, each containing a ChEBI ID and a label. + """ + try: + adapter = get_adapter("ols:chebi") + results = adapter.basic_search(term) + labels = list(adapter.labels(results)) + logger.info(f"ChEBI search for '{term}' returned {len(labels)} results") + return labels + except Exception as e: + logger.error(f"Error searching ChEBI for term '{term}': {e}") + return [] + + +def search_multi_ontology(ctx: RunContext[str], term: str, ontologies: List[str] = None) -> Dict[str, List[Tuple[str, str]]]: + """ + Search multiple ontologies for a term. + + Args: + ctx: The run context + term: The term to search for. + ontologies: List of ontology prefixes to search (e.g., ['GO', 'CL', 'UBERON']) + + Returns: + A dictionary mapping ontology names to lists of (ID, label) tuples. + """ + if ontologies is None: + ontologies = ['GO', 'CL', 'UBERON', 'ChEBI'] + + results = {} + search_functions = { + 'GO': search_go, + 'CL': search_cl, + 'UBERON': search_uberon, + 'ChEBI': search_chebi + } + + for ont in ontologies: + if ont in search_functions: + try: + results[ont] = search_functions[ont](ctx, term) + except Exception as e: + logger.error(f"Error searching {ont} for term '{term}': {e}") + results[ont] = [] + else: + logger.warning(f"Ontology {ont} not supported") + results[ont] = [] + + return results \ No newline at end of file diff --git a/cellsem_agent/graphs/cxg_annotate/cxg_annotate_graph_v2.py b/cellsem_agent/graphs/cxg_annotate/cxg_annotate_graph_v2.py index 3921e5c..93d6363 100644 --- a/cellsem_agent/graphs/cxg_annotate/cxg_annotate_graph_v2.py +++ b/cellsem_agent/graphs/cxg_annotate/cxg_annotate_graph_v2.py @@ -28,7 +28,7 @@ ANNOTATIONS_BATCH_SIZE = 5 -IS_TEST_MODE = False +IS_TEST_MODE = True TEST_ANNOTATIONS_COUNT = 4 # Number of annotations to process in test mode CURRENT_DIR = os.path.dirname(os.path.abspath(__file__)) @@ -158,7 +158,7 @@ async def run(self, ctx: GraphRunContext[State]) -> GetGroundings: cc_labels = [{"cc.label": ann['annotation_text']} for ann in batch] if not os.path.exists(dataset_cache): - full_text_path = os.path.join(EXPANSIONS_DIR, f"{normalise_file_name(article_pmc)}.txt") + full_text_path = os.path.join(PUBLICATIONS_DIR, f"{normalise_file_name(article_pmc)}.txt") if os.path.exists(full_text_path): with open(full_text_path, 'r', encoding='utf-8') as f: paper_full_text = f.read() diff --git a/cellsem_agent/graphs/gene_annotator/__init__.py b/cellsem_agent/graphs/gene_annotator/__init__.py new file mode 100644 index 0000000..e69de29 diff --git a/cellsem_agent/graphs/gene_annotator/gene_annotate_graph.py b/cellsem_agent/graphs/gene_annotator/gene_annotate_graph.py new file mode 100644 index 0000000..06d5b2e --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/gene_annotate_graph.py @@ -0,0 +1,241 @@ +# To reduce the cost, we cache the results of each step in the output folder. +# +# Delete the cached files to re-run the steps. +# - DeepSearch cache: input_file_name_ds.json +# - Decompose cache: input_file_name_decompose.json +# - Annotate cache: input_file_name_result.json + +import asyncio +import os.path +import json +from typing import Any +import pandas as pd + +import logfire +import logging + +from dataclasses import dataclass +from dotenv import load_dotenv +from pydantic_graph import BaseNode, End, Graph, GraphRunContext + +from cellsem_agent.agents.ontology_mapping.ontology_mapping_agent import ontology_mapping_agent +from cellsem_agent.services.gene_list_contextual_deepsearch.gene_list_contextual_deepsearch import run_contextual_deepsearch +from cellsem_agent.services.gene_list_contextual_deepsearch.decomposer import decompose + +gene_annotate_logger = logging.getLogger(__name__) +gene_annotate_logger.setLevel(logging.INFO) +console = logging.StreamHandler() +console.setLevel(logging.INFO) +formatter = logging.Formatter('%(asctime)s - %(name)s - %(levelname)s - %(message)s') +console.setFormatter(formatter) +gene_annotate_logger.addHandler(console) + +gene_annotate_logger.propagate = True +logfire.configure() + +IS_TEST_MODE = False + +CURRENT_DIR = os.path.dirname(os.path.abspath(__file__)) +DATASETS_DIR = os.path.join(CURRENT_DIR, "../../", "services/gene_list_contextual_deepsearch/examples") +OUTPUT_DIR = os.path.join(CURRENT_DIR, "output") +OUTPUT_DS_DIR = os.path.join(OUTPUT_DIR, "deepsearch") +OUTPUT_ANNOT_DIR = os.path.join(OUTPUT_DIR, "mappings") + +@dataclass +class GeneData: + cell_type: str + genes: list[str] + context: str + description: str + file_name: str + deep_search_result: dict = None + # decompose_result: dict = None + +@dataclass +class State: + gene_data: list[GeneData] + is_test_mode: bool = IS_TEST_MODE + +@dataclass +class AnnotateData(BaseNode[State, None, str]): + + async def run(self, ctx: GraphRunContext[State]) -> End: + os.makedirs(OUTPUT_ANNOT_DIR, exist_ok=True) + + gene_data = ctx.state.gene_data + for j in gene_data: + output_file = os.path.join(OUTPUT_DIR, j.file_name.replace(".json", "_result.json")) + # don't re-run existing results for cost reasons + if not os.path.exists(output_file): + print("Ontology mapping for file: ", j.file_name) + if j.deep_search_result: + programs = j.deep_search_result.get("programs", []) + all_mappings = [] + iteration = 1 + for program in programs: + print("Processing program: ", iteration, " of ", len(programs)) + await self.annotate_properties(program["atomic_biological_processes"], all_mappings) + await self.annotate_properties(program["atomic_cellular_components"], all_mappings) + iteration += 1 + await self.save_all_mappings(all_mappings, output_file) + else: + print("No decompose result to annotate for file: ", j.file_name) + await write_json(j.deep_search_result, output_file) + return End("Results saved to the output folder.") + + async def save_all_mappings(self, all_mappings: list[Any], output_file: str): + file_name = os.path.basename(output_file).replace(".json", ".csv") + mapping_file = os.path.join(OUTPUT_ANNOT_DIR, file_name) + df = pd.DataFrame(all_mappings) + df.to_csv(mapping_file, index=False) + + async def annotate_properties(self, properties, all_mappings): + names = json.dumps([atomic_item["name"] for atomic_item in properties]) + agent_response = await ontology_mapping_agent.run(names) + await self.update_with_mappings(properties, agent_response.output.mappings, all_mappings) + + async def update_with_mappings(self, atomic_terms, result, all_mappings): + for atomic_term in atomic_terms: + item_results = [r for r in result if r.original_term == atomic_term["name"]] + if not item_results: + atomic_term["ontology_label"] = "" + atomic_term["ontology_id"] = "" + all_mappings.append({ + "original_term": atomic_term["name"], + "ontology_id": "", + "ontology_label": "", + "ontology_source": "", + "confidence_score": 0.0, + "mapping_method": "" + }) + else: + if "ontology_label" in atomic_term: + del atomic_term["ontology_label"] + atomic_term["ontology_label"] = item_results[0].ontology_label + atomic_term["ontology_id"] = item_results[0].ontology_id + all_mappings.append({ + "original_term": atomic_term["name"], + "ontology_id": item_results[0].ontology_id, + "ontology_label": item_results[0].ontology_label, + "ontology_source": item_results[0].ontology_source, + "confidence_score": item_results[0].confidence_score, + "mapping_method": item_results[0].mapping_method + }) + + +# @dataclass +# class DecomposeProcess(BaseNode[State, None, str]): +# +# async def run(self, ctx: GraphRunContext[State]) -> AnnotateData: +# gene_data = ctx.state.gene_data +# for j in gene_data: +# output_file = os.path.join(OUTPUT_DIR, j.file_name.replace(".json", "_decompose.json")) +# if not os.path.exists(output_file): +# if j.deep_search_result: +# print("Decomposing deep search results for file: ", j.file_name) +# out_text = decompose(j.deep_search_result) +# if out_text and out_text.strip(): +# print("Decompose result obtained for file: ", j.file_name) +# try: +# rj = json.loads(out_text) +# with open(output_file, "w") as f: +# json.dump(rj, f, indent=4) +# j.decompose_result = rj +# except Exception as e: +# print("Error parsing JSON from out_text:") +# print(out_text) +# print("Exception:", e) +# else: +# print(f"No output_text returned from decompose for '{j.file_name}'; see status/error above.") +# else: +# # read the existing file as cache +# with open(output_file, "r") as f: +# j.decompose_result = json.load(f) +# print("Using cached decompose result for file: ", j.file_name) +# return AnnotateData() + +@dataclass +class DeepSearchGene(BaseNode[State, None, str]): + + async def run(self, ctx: GraphRunContext[State]) -> AnnotateData: + gene_data = ctx.state.gene_data + os.makedirs(OUTPUT_DS_DIR, exist_ok=True) + + for j in gene_data: + output_file = os.path.join(OUTPUT_DS_DIR, j.file_name.replace(".json", "_ds.json")) + if not os.path.exists(output_file): + print("Deep searching for genes in file: ", j.file_name) + result = run_contextual_deepsearch(gene_list=','.join(j.genes), context=j.context) + if result: + print("Deep search result obtained for file: ", j.file_name) + result = result.replace("```json", "").replace("```", "").strip() + rj = json.loads(result) + await write_json(rj, output_file) + j.deep_search_result = rj + else: + print(f"No result returned from deepsearch for '{j.file_name}'; see status/error above.") + else: + # read the existing file as cache + with open(output_file, "r") as f: + j.deep_search_result = json.load(f) + print("Using cached deep search result for file: ", j.file_name) + + return AnnotateData() + +@dataclass +class ReadGeneData(BaseNode[State, None, str]): + + async def run(self, ctx: GraphRunContext[State]) -> DeepSearchGene: + # iterate the json files in the examples folder and read them into the state + for file in os.listdir(DATASETS_DIR): + if file.endswith(".json"): + file_path = os.path.join(DATASETS_DIR, file) + with open(file_path, "r") as f: + data = json.load(f) + + # Handle both old format (single example) and new format (multiple examples) + if "examples" in data: + # New format with multiple examples + for i, example in enumerate(data["examples"]): + gene_data = GeneData( + cell_type="", + genes=example["genes"], + context=example.get("context", ""), + description=example.get("description", ""), + file_name=f"{file}_{example.get('id', i)}" + ) + ctx.state.gene_data.append(gene_data) + if ctx.state.is_test_mode: + # run only one example in test mode + break + else: + # Old format with single example + gene_data = GeneData( + cell_type="", + genes=data["genes"], + context=data.get("context", ""), + description=data.get("description", ""), + file_name=file + ) + ctx.state.gene_data.append(gene_data) + + if ctx.state.is_test_mode: + # run only one example in test mode + break + print("Total datasets loaded: ", len(ctx.state.gene_data)) + return DeepSearchGene() + +async def write_json(data: Any, output_file: str): + with open(output_file, "w") as f: + json.dump(data, f, indent=4) + +async def main(): + state = State(list(), is_test_mode=IS_TEST_MODE) + validation_graph = Graph(nodes=(ReadGeneData, DeepSearchGene, AnnotateData)) + result = await validation_graph.run(ReadGeneData(), state=state) + print(result.output) + # print(validation_graph.mermaid_code()) + +if __name__ == "__main__": + load_dotenv() + asyncio.run(main()) \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/README.md b/cellsem_agent/graphs/gene_annotator/output/README.md new file mode 100644 index 0000000..9b8d26e --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/README.md @@ -0,0 +1,8 @@ +Agentic graph outputs and cache data will be stored here. + +If you want to clear the cache and reproduce the data, you can delete the contents of this folder. + +- DeepSearch cache: input_file_name_ds.json +- Decompose cache: input_file_name_decompose.json [DEPRECATED] +- Annotate cache: input_file_name_result.json + input_file_name_result.csv \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/AT2_combined_input_result.json b/cellsem_agent/graphs/gene_annotator/output/experiment1/AT2_combined_input_result.json new file mode 100644 index 0000000..a2a54e7 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/AT2_combined_input_result.json @@ -0,0 +1,244 @@ +{ + "context": { + "cell_type": "alveolar type II epithelial cell", + "disease": "Pulmonary alveolar proteinosis", + "tissue": "lung" + }, + "input_genes": [ + "ABCA3", + "CTSH", + "NAPSA", + "SFTPB", + "SFTPC" + ], + "programs": [ + { + "program_name": "Surfactant Homeostasis and Lamellar Body Assembly", + "theme": "Surfactant metabolism", + "description": "In alveolar type II cells, these genes coordinate pulmonary surfactant production, processing, and secretion. ABCA3 is a lamellar body membrane transporter that shuttles phospholipids into surfactant storage organelles ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=al,While%20the%20complete%20substrate%20repertoire)). SFTPB and SFTPC encode major hydrophobic surfactant proteins, whose precursors (proSP-B/C) are proteolytically processed by enzymes like Napsin A and Cathepsin H within the multivesicular body ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=Napsin%20was%20localized%20to%20multivesicular,whereas%20cathepsin%20H%20cleaved%20the)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2586979/#:~:text=proSP,More%20importantly%2C%20RNAi%20experiments%20showed)). This proteolysis is essential to generate mature SP-B and SP-C before they are packaged into lamellar bodies and secreted into the alveolar space ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12972403/#:~:text=blot%20analysis%20of%20human%20type,In)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=Napsin%20was%20localized%20to%20multivesicular,whereas%20cathepsin%20H%20cleaved%20the)). Proper lamellar body biogenesis (dependent on ABCA3) and surfactant secretion maintain alveolar stability and lower surface tension ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=The%20lipid%20transporter%2C%20ATP%20binding,More%20than%20200%20ABCA3)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=al,While%20the%20complete%20substrate%20repertoire)). In diseases such as pulmonary alveolar proteinosis (PAP), increased NAPSA/CTSH activity in bronchoalveolar fluid indicates dysregulated surfactant turnover ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18216060/#:~:text=the%20bronchoalveolar%20lavage%20fluid%20,was%20increased%20in%20PAP%20patients)).", + "atomic_biological_processes": [ + { + "name": "Proteolytic processing of surfactant protein precursors", + "citation": [ + { + "reference": "Ueno T et al., J Biol Chem 2004", + "id": "DOI:10.1074/jbc.M312029200", + "type": "DOI", + "notes": "Napsin A and Cathepsin H cleave proSP-B to an intermediate form in type II cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=Napsin%20was%20localized%20to%20multivesicular,whereas%20cathepsin%20H%20cleaved%20the))" + } + ], + "Genes": [ + "NAPSA", + "CTSH", + "SFTPB" + ], + "ontology_label": "protein processing", + "ontology_id": "GO:0016485" + }, + { + "name": "Phospholipid transport into lamellar bodies", + "citation": [ + { + "reference": "Beers MF & Mulugeta S, Cell Tissue Res 2016", + "id": "PMID:28025703", + "type": "PMID", + "notes": "ABCA3 transports phosphatidylcholine and other lipids into lamellar bodies in AT2 cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=al,While%20the%20complete%20substrate%20repertoire))" + } + ], + "Genes": [ + "ABCA3" + ], + "ontology_label": "phospholipid transport", + "ontology_id": "GO:0015914" + }, + { + "name": "Lamellar body biogenesis", + "citation": [ + { + "reference": "Beers MF & Mulugeta S, Cell Tissue Res 2016", + "id": "PMID:28025703", + "type": "PMID", + "notes": "ABCA3 is critical for lamellar body formation and surfactant packaging ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=The%20lipid%20transporter%2C%20ATP%20binding,More%20than%20200%20ABCA3))" + } + ], + "Genes": [ + "ABCA3" + ], + "ontology_label": "lamellar body", + "ontology_id": "GO:0042599" + }, + { + "name": "Surfactant secretion to alveolar space", + "citation": [ + { + "reference": "Dobbs LG et al., J Appl Physiol 1984", + "type": "DOI", + "id": "10.1152/jappl.1984.56.5.1246", + "notes": "Mature surfactant proteins are transported together to lamellar bodies and secreted to maintain alveolar surface tension ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12972403/#:~:text=blot%20analysis%20of%20human%20type,In))" + } + ], + "Genes": [ + "SFTPB", + "SFTPC" + ], + "ontology_label": "surfactant secretion", + "ontology_id": "GO:0160069" + }, + { + "name": "Extracellular protease activity in alveoli", + "citation": [ + { + "reference": "Brasch F et al., Respir Res 2007", + "type": "PMID", + "id": "PMID:18216060", + "notes": "NAPSA and CTSH are active in bronchoalveolar lavage fluid and are upregulated in alveolar proteinosis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18216060/#:~:text=the%20bronchoalveolar%20lavage%20fluid%20,was%20increased%20in%20PAP%20patients))" + } + ], + "Genes": [ + "NAPSA", + "CTSH" + ], + "ontology_label": "serine-type peptidase activity", + "ontology_id": "GO:0008236" + } + ], + "atomic_cellular_components": [ + { + "name": "Lamellar body", + "citation": [ + { + "reference": "Dobbs LG et al., Am J Physiol Lung Cell Mol Physiol 2000", + "type": "DOI", + "id": "10.1152/ajplung.2000.279.4.L631", + "notes": "Mature SP-B and SP-C, along with lipids, accumulate in lamellar bodies for secretion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12972403/#:~:text=blot%20analysis%20of%20human%20type,In))" + } + ], + "Genes": [ + "ABCA3", + "SFTPB", + "SFTPC" + ], + "ontology_label": "lamellar body", + "ontology_id": "GO:0042599" + }, + { + "name": "Multivesicular body (MVB)", + "citation": [ + { + "reference": "Dobbs LG et al., J Cell Biol 2000", + "type": "DOI", + "id": "10.1083/jcb.200005033", + "notes": "ProSP-B processing intermediates and sorting of surfactant components occur in MVBs ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12972403/#:~:text=propeptide,with%20immunoelectron%20microscopy%20and%20Western)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=,network%20to%20LB%20and%20plasma))" + } + ], + "Genes": [ + "SFTPB", + "ABCA3" + ], + "ontology_label": "multivesicular body", + "ontology_id": "GO:0005771" + }, + { + "name": "Golgi apparatus", + "citation": [ + { + "reference": "Dobbs LG et al., Am J Physiol 1998", + "type": "DOI", + "id": "10.1152/ajplung.1998.275.3.L428", + "notes": "ProSP-B intermediates are present in Golgi vesicles prior to lamellar body trafficking ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12972403/#:~:text=propeptide,with%20immunoelectron%20microscopy%20and%20Western))" + } + ], + "Genes": [ + "SFTPB" + ], + "ontology_label": "Golgi apparatus", + "ontology_id": "GO:0005794" + }, + { + "name": "Endoplasmic reticulum", + "citation": [ + { + "reference": "Dobbs LG et al., Am J Physiol 1998", + "type": "DOI", + "id": "10.1152/ajplung.1998.275.3.L428", + "notes": "Initial translation and early processing of proSP-B occur in the ER of AT2 cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12972403/#:~:text=propeptide,with%20immunoelectron%20microscopy%20and%20Western))" + } + ], + "Genes": [ + "SFTPB" + ], + "ontology_label": "endoplasmic reticulum", + "ontology_id": "GO:0005783" + }, + { + "name": "Alveolar space (bronchoalveolar fluid)", + "citation": [ + { + "reference": "Brasch F et al., Respir Res 2007", + "type": "PMID", + "id": "PMID:18216060", + "notes": "Active NAPSA and CTSH are detected in lung alveolar fluid in health and increased in proteinosis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18216060/#:~:text=the%20bronchoalveolar%20lavage%20fluid%20,was%20increased%20in%20PAP%20patients))" + } + ], + "Genes": [ + "NAPSA", + "CTSH" + ], + "ontology_label": "bronchoalveolar duct junction", + "ontology_id": "UBERON:0004903" + } + ], + "predicted_cellular_impact": [ + "Enhanced lamellar body lipid loading and surfactant secretion, supporting low surface tension", + "Efficient conversion of pro-surfactant proteins to mature SP-B/C, promoting alveolar stability", + "Maintenance of alveolar patency and gas-exchange capacity through robust surfactant pool", + "Dynamic protease activity regulating surfactant turnover (e.g. protease/inhibitor imbalance in PAP may affect clearance)" + ], + "evidence_summary": "These genes are well-established markers of alveolar type II cells and surfactant function. ABCA3 deficiency abolishes lamellar bodies and causes surfactant deficiency ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=The%20lipid%20transporter%2C%20ATP%20binding,More%20than%20200%20ABCA3)). SFTPB/C are essential surfactant components; mice lacking SP-B die of respiratory failure. Napsin A and cathepsin H have been shown to cleave pro-SP-B in AT2 cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=Napsin%20was%20localized%20to%20multivesicular,whereas%20cathepsin%20H%20cleaved%20the)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2586979/#:~:text=proSP,More%20importantly%2C%20RNAi%20experiments%20showed)), and loss of Ctsh in mice reduces mature SP-B and impairs surfactant activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3192174/#:~:text=,reducing%20function%20of%20lung%20surfactant)). In pulmonary alveolar proteinosis patients, elevated NAPSA/CTSH in bronchoalveolar fluid indicates disturbed surfactant turnover ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18216060/#:~:text=the%20bronchoalveolar%20lavage%20fluid%20,was%20increased%20in%20PAP%20patients)). Collectively, this evidence indicates that these genes cooperatively drive surfactant biogenesis, processing, and secretion in the lung", + "citations": [ + { + "reference": "Johnen G et al. Involvement of Napsin A in SP-B processing. J Biol Chem 2003;278:49006\u201349014.", + "id": "DOI:10.1074/jbc.M306844200", + "type": "DOI", + "notes": "Demonstrated Napsin A cleaves pro-SP-B in AT2 cells (supports proteolytic processing) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2586979/#:~:text=proSP,More%20importantly%2C%20RNAi%20experiments%20showed))" + }, + { + "reference": "Ueno T et al. Processing of SP-B by napsin and H. J Biol Chem 2004;279:16178\u201316184.", + "id": "DOI:10.1074/jbc.M312029200", + "type": "DOI", + "notes": "Showed Napsin and Cathepsin H both generate SP-B intermediates in AT2 cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=Napsin%20was%20localized%20to%20multivesicular,whereas%20cathepsin%20H%20cleaved%20the))" + }, + { + "reference": "B\u00fchling F et al. Cathepsin H gene targeting impairs surfactant. PLoS One 2011;6:e26247.", + "id": "DOI:10.1371/journal.pone.0026247", + "type": "DOI", + "notes": "Ctsh\u2010knockout mice have reduced mature SP-B in alveoli and surfactant dysfunction ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3192174/#:~:text=,reducing%20function%20of%20lung%20surfactant))" + }, + { + "reference": "Beers MF & Mulugeta S. Biology of ABCA3 in lung disease. Cell Tissue Res 2016;367:481\u2013493.", + "id": "DOI:10.1007/s00441-016-2554-z", + "type": "DOI", + "notes": "Reviews ABCA3 regulation of surfactant lipid transport and lamellar body formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=al,While%20the%20complete%20substrate%20repertoire)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=The%20lipid%20transporter%2C%20ATP%20binding,More%20than%20200%20ABCA3))" + }, + { + "reference": "Guttentag SH et al. Post-transcriptional regulation of SP-B. Am J Physiol Lung Cell Mol Physiol 2008;295:L0\u2013L0.", + "id": "PMID:18929160", + "type": "PMID", + "notes": "Describes AT2-specific proteases (Napsin A, Cathepsin H) processing proSP-B and effects of Napsin A knockdown ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2586979/#:~:text=proSP,More%20importantly%2C%20RNAi%20experiments%20showed))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "ABCA3", + "CTSH", + "NAPSA", + "SFTPB", + "SFTPC" + ], + "supporting_gene_count": 5, + "required_components_present": true + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/README.md b/cellsem_agent/graphs/gene_annotator/output/experiment1/README.md new file mode 100644 index 0000000..de5b727 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/README.md @@ -0,0 +1,4 @@ + +Deepsearch model: "o4-mini-deep-research-2025-06-26" +Annotator agent model: "openai:gpt-4o-2024-11-20" +Schema: https://github.com/Cellular-Semantics/cellsem-agent/blob/4a9aef6f9c6402ec321380b1044f57e2a400cf09/cellsem_agent/services/gene_list_contextual_deepsearch/schema/deepsearch_results_schema.json \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/astrycytoma_1_result.json b/cellsem_agent/graphs/gene_annotator/output/experiment1/astrycytoma_1_result.json new file mode 100644 index 0000000..df06a62 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/astrycytoma_1_result.json @@ -0,0 +1,1116 @@ +{ + "context": { + "cell_type": "Astrocyte (IDH-mutant astrocytoma malignant subset)", + "disease": "IDH-mutant diffuse astrocytoma", + "tissue": "Brain (central nervous system white/gray matter)" + }, + "input_genes": [ + "FAM189A2", + "OGFRL1", + "MAP3K5", + "ITPR2", + "ETNPPL", + "NRG3", + "CD38", + "FMN2", + "LINC01088", + "KCNN3", + "DAAM2", + "AC002429.2", + "OBI1-AS1", + "NTRK2", + "SYTL4", + "WDR49", + "ADGRV1", + "LIFR", + "AQP4", + "ID3", + "OSBPL11", + "DPP10", + "SERPINI2", + "TLR4", + "NAA11", + "MGAT4C", + "AC026316.5", + "EEPD1", + "RASSF4", + "AL392086.3", + "SLC4A4", + "EDNRB", + "SLC39A11", + "ATP1A2", + "SLCO1C1", + "AHCYL2", + "SPON1", + "SLC1A3", + "GRAMD2B", + "DTNA", + "AC012405.1", + "NKAIN3", + "NTM", + "SLC14A1", + "DCLK2", + "DCLK1", + "ID4", + "AC124854.1", + "LINC01094", + "PCDH9", + "GABBR2", + "PARD3B", + "PDE8A", + "LRIG1", + "C5ORF64", + "RNF19A", + "SPARCL1", + "AC093535.1", + "FADS2", + "PLEKHA5", + "ASTN2", + "ADAMTS9", + "AC073941.1", + "SLC24A4", + "PAPPA", + "AC068587.4", + "FARP1", + "SORL1", + "ARHGAP26", + "CADPS", + "ST3GAL6", + "ITPKB", + "GABRB1", + "FAM107A", + "MIR99AHG", + "ANK2", + "AC107223.1", + "PPP2R2B", + "LPL", + "AL589935.1", + "MRVI1", + "TNIK", + "AL160272.1", + "AC016766.1", + "RANBP3L", + "ARHGEF4", + "ADCY2", + "NPL", + "KCNQ5", + "AC079352.1", + "LIX1", + "APOE", + "SLC25A48", + "ADCYAP1R1", + "AHCYL1", + "RASL12", + "GINS3", + "PTPRG", + "AL096709.1", + "BMP2K", + "MCF2L2", + "RBMS3", + "SLCO3A1", + "AL445426.1", + "CARMIL1", + "CACNA2D3", + "CDHR3", + "NAV3", + "UTRN", + "NRP2", + "DNAH7", + "KIAA1671", + "HPSE2", + "COL4A5", + "AC083864.5", + "L3MBTL4", + "AC092131.1", + "PCSK6", + "AC097450.1", + "ANOS1", + "SYNPO2", + "LINC00836", + "MAPK4", + "AL365259.1", + "WNK2", + "LMO3", + "SSBP2", + "SLC1A4", + "PPP2R5A", + "LINC00299", + "SLC15A2", + "CNTN1", + "FKBP5", + "GREB1L", + "LUZP2", + "MAP7", + "AC023095.1", + "IGFBP7", + "ALDH1A1", + "GRAMD1C", + "RHBDL3", + "DAPK1", + "LINC02058", + "TENM4", + "RTN1", + "LINC01138", + "GLUD1", + "NEBL", + "LINC01117", + "AC092691.1", + "TJP2", + "PCDH9-AS2", + "YAP1", + "ABCC9", + "LAMA1", + "AL137024.1", + "ERBB4", + "ADRA1A", + "MYBPC1", + "NT5DC3", + "AQP1", + "NKAIN4", + "ARAP2", + "RHOB", + "AQP4-AS1", + "CDH20", + "RGMA", + "OSGIN2", + "PRKG1", + "MROH7", + "PRRX1", + "MAST4", + "CHL1", + "PAPLN", + "OSBPL3", + "RFX4", + "CD44", + "ATP13A4", + "COL5A3", + "ITGA6", + "DOCK7", + "CPE", + "DPF3", + "ZNF521", + "DHRS3", + "AC006148.1", + "LMNTD1", + "AC092924.2", + "LHFPL6", + "AC024145.1", + "LIMCH1", + "SRPX2", + "AL590999.1", + "ADCY8", + "AC008957.2", + "TTYH2", + "GJA1", + "SHROOM3", + "USH1C", + "AC007262.2" + ], + "programs": [ + { + "program_name": "Astrocyte-vascular coupling", + "description": "This program encompasses classic astrocytic functions that regulate the brain microenvironment, particularly water and ion balance at vascular and synaptic interfaces. Malignant astrocytoma cells expressing these genes retain an astrocyte-like capability for K+ buffering, water transport, and gap junction coupling, positioning themselves at blood vessels and around neurons. In the tumor context, this may help malignant cells modulate extracellular K+ and glutamate levels, sustain local blood flow (neurovascular coupling), and survive hypoxic stress by efficiently clearing excess ions and preserving osmotic balance. The program mirrors normal astrocyte roles in supporting neurons and vessels but in a dysregulated tumor setting, it could influence peritumoral edema, seizure propensity, and adaptation of tumor cells to metabolic demands.", + "atomic_biological_processes": [ + { + "name": "K+ buffering and spatial ion distribution", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytic endfeet use channels (AQP4, Kir4.1) to remove K+ and water, maintaining ionic balance in brain ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=the%20CNS%2C%20AQP4%20is%20predominantly,cell)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in))." + } + ], + "Genes": [ + "AQP4", + "SLC1A3", + "ABCC9", + "SLC4A4", + "KCNQ5" + ], + "ontology_label": "regulation of potassium ion transport", + "ontology_id": "GO:0043266" + }, + { + "name": "Water transport and edema regulation", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "AQP4 water channels in astrocyte endfeet facilitate fluid clearance and are crucial for neurovascular fluid exchange ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Polarized%20expression%20of%20AQP4%20in,49%5D.%20Furthermore%2C%20AQP4))." + } + ], + "Genes": [ + "AQP4", + "AQP1" + ], + "ontology_label": "water transport", + "ontology_id": "GO:0006833" + }, + { + "name": "Gap junction intercellular communication", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes form networks via gap junctions (connexin 43) allowing ion and metabolite sharing to buffer activity and metabolic stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": [ + "GJA1" + ], + "ontology_label": "gap junction-mediated intercellular transport", + "ontology_id": "GO:1990349" + }, + { + "name": "Neurovascular coupling", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocyte endfeet with AQP4 and K+ channels at capillaries regulate blood flow in response to neural activity, matching perfusion to metabolic demand ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=reciprocal%20regulation%20involves%20coordinated%20actions,in%20astrocytic%20endfeet%2C%20whereas%20some)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=regulatory%20effects%20at%20both%20blood,vessels%20and%20synapses))." + } + ], + "Genes": [ + "AQP4", + "ABCC9", + "EDNRB" + ], + "ontology_label": "neurovascular bundle", + "ontology_id": "UBERON:0016630" + } + ], + "atomic_cellular_components": [ + { + "name": "Perivascular astrocyte endfoot", + "citations": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "AQP4 and Kir channels are highly concentrated in astrocytic endfeet abutting blood vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=the%20CNS%2C%20AQP4%20is%20predominantly,their%20functional%20role%20in%20this)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in))." + } + ], + "Genes": [ + "AQP4", + "AQP1", + "ABCC9" + ], + "ontology_label": "astrocyte end-foot", + "ontology_id": "GO:0097450" + }, + { + "name": "Astrocyte gap junction (connexin 43 complex)", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes are coupled by connexin-43 gap junctions, enabling intercellular signaling and distribution of ions across the glial network ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": [ + "GJA1" + ], + "ontology_label": "connexin complex", + "ontology_id": "GO:0005922" + }, + { + "name": "Glial limitans and basement membrane contacts", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes form the glial limiting membrane and contact basement membranes via specialized endfeet enriched in AQP4 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses))." + } + ], + "Genes": [ + "AQP4", + "TJP2", + "ITGA6", + "LAMA1" + ], + "ontology_label": "glial limiting membrane", + "ontology_id": "UBERON:0018687" + } + ], + "predicted_cellular_impact": [ + "Enhanced clearance of extracellular K+ and glutamate, reducing hyperexcitability", + "Efficient removal of excess water, potentially mitigating peritumoral edema", + "Coupling of tumor cells into functional networks via gap junctions", + "Ability to modulate local blood flow in response to neuronal activity and metabolic needs" + ], + "evidence_summary": "Multiple genes in this program encode hallmark astrocytic channels and transporters that maintain CNS homeostasis. AQP4 is localized to astrocyte endfeet and greatly increases water permeability at the blood\u2013brain interface, facilitating fluid clearance and K+ siphoning ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses)). Co-expressed K+ handling mechanisms (e.g., KCN channels and transporters) allow astrocytic processes to buffer extracellular K+ from active neurons, preventing neuronal hyperexcitability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in)). Connexin-43 (GJA1) gap junctions electrically and metabolically couple astrocytoma cells, enabling the distribution of ions and signaling molecules through tumor cell networks ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339)). Expression of EDNRB (endothelin B receptor) in these cells suggests they can respond to vascular endothelin signals, potentially constricting or dilating nearby vessels and participating in neurovascular coupling, akin to reactive astrocytes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Correspondingly%2C%20patient%20glioblastoma%20tissues%20express,were%20those%20involved%20in%20cytoskeleton)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=role%20of%20autocrine%20EDN3%2FEDNRB%20system,mediated%20tumor%20recurrence)). Overall, this program indicates that a subset of malignant cells retains an astrocyte-like supportive phenotype, regulating ions and water to influence neuronal activity and blood flow around the tumor.", + "citations": [ + { + "reference": "Jukkola & Gu (2014) Regulation of Neurovascular Coupling in Autoimmunity to Water and Ion Channels, Autoimmun Rev.", + "id": "PMC4303502", + "type": "PMID", + "notes": "Details AQP4, Kir4.1 channel localization in astrocyte endfeet and their roles in water & K+ homeostasis." + }, + { + "reference": "Shao et al. (2011) Autocrine EDN3/EDNRB signaling maintains GSC properties, Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Shows EDNRB supports glial stem-like cells, implying astrocytoma cells with EDNRB can influence survival and migration in a radial glial-like manner." + } + ], + "confidence_score": 0.9, + "significance_score": 0.6, + "supporting_genes": [ + "AQP4", + "AQP1", + "GJA1", + "SLC1A3", + "SLC4A4", + "ABCC9", + "EDNRB", + "KCNQ5", + "TJP2" + ], + "supporting_gene_count": 9, + "required_components_present": false + }, + { + "program_name": "Mesenchymal Transformation & ECM Remodeling", + "description": "This program reflects a shift of tumor cells toward a reactive, mesenchymal-like phenotype with enhanced motility, stress response, and extracellular matrix (ECM) interaction. Genes in this cluster encode cell-surface receptors and signaling molecules (e.g., TLR4, CD44, integrin \u03b16, YAP1, PRRX1) that collectively promote an inflammatory and migratory state. Malignant astrocytes with this program secrete and remodel ECM components (e.g., SPARC-like 1, ADAMTS9, papilin, collagens) and upregulate cytoskeletal regulators (Rho GTPase regulators and actin-binding proteins) to acquire fibroblast-like morphology and invasive behavior. Functionally, this enables tumor cells to invade surrounding brain tissue (often along blood vessels via integrin \u03b16-laminin interactions), resist apoptosis, and communicate with immune cells through cytokine and Toll-like receptor pathways. It mirrors aspects of reactive astrogliosis and epithelial\u2013mesenchymal transition: cells become highly migratory, secrete matrix, and activate NF-\u03baB and YAP/TAZ signaling to sustain proliferation and survival in a hostile microenvironment.", + "atomic_biological_processes": [ + { + "name": "Extracellular matrix deposition and remodeling", + "citations": [ + { + "reference": "Ferr\u00e1ndez et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "TLR4 activation in differentiating glioma cells triggers NF-\u03baB and upregulates genes like IL-6 and likely ECM modifiers, linking inflammatory signaling to a mesenchymal gene expression profile ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=an%20important%20event%20in%20tumor,cells%20has%20been%20poorly%20studied))." + }, {}, {}, {}, {} + ], + "Genes": [ + "SPARCL1", + "ASTN2", + "LAMA1", + "COL4A5", + "COL5A3", + "PAPLN", + "ADAMTS9" + ], + "ontology_label": "extracellular matrix organization", + "ontology_id": "GO:0030198" + }, + { + "name": "Cell migration and invasion", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Integrin \u03b16 on glioma stem cells mediates adhesion to laminin in perivascular niches, promoting self-renewal and invasion along blood vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Immunostaining%20of%20GBM%20surgical%20biopsies,varying%20overlap%20with%20CD133%20expression))." + } + ], + "Genes": [ + "ITGA6", + "DOCK7", + "ARHGEF4", + "ARHGAP26", + "CARMIL1", + "SYNPO2", + "LIMCH1" + ], + "ontology_label": "cell migration", + "ontology_id": "GO:0016477" + }, + { + "name": "Inflammatory signaling (NF-\u03baB activation)", + "ontology_label": "", + "citation": [ + { + "reference": "Ferr\u00e1ndez et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "Hyaluronic acid produced by glioma cells engages TLR4 to activate NF-\u03baB, preventing full differentiation and maintaining proliferation of these cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=transcriptional%20activation%20of%20NF%CE%BAB%2C%20which,and%20consequently%20their%20tumorigenic%20capacity))." + } + ], + "Genes": [ + "TLR4", + "CD44" + ], + "ontology_id": "" + }, + { + "name": "Mechanotransduction and Hippo pathway signaling", + "citation": [ + { + "reference": "Guo et al. (2020) J. Neurosci.", + "id": "32066583", + "type": "PMID", + "notes": "YAP is upregulated in reactive astrocytes after injury, driving astrocyte proliferation and scar formation via RhoA-p27^Kip1 signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytes%20of%20C57BL%2F6%20male%20mice,Finally%2C%20bFGF)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytic%20proliferation%2C%20impaired%20the%20formation,findings%20suggest%20that%20YAP%20promotes))." + } + ], + "Genes": [ + "YAP1", + "MAPK4" + ], + "ontology_label": "hippo signaling", + "ontology_id": "GO:0035329" + } + ], + "atomic_cellular_components": [ + { + "name": "Focal adhesion complex", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Glioblastoma cells with high integrin \u03b16 form tight adhesions with vascular basement membrane laminin, linking them to niches that support invasion and stemness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Immunostaining%20of%20GBM%20surgical%20biopsies,varying%20overlap%20with%20CD133%20expression))." + } + ], + "Genes": [ + "ITGA6", + "LAMA1" + ], + "ontology_label": "focal adhesion", + "ontology_id": "GO:0005925" + }, + { + "name": "Stress fibers and contractile cytoskeleton", + "citation": [ + { + "reference": "Ferr\u00e1ndez et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "NF-\u03baB activation by TLR4 in tumor cells is associated with morphological changes to an elongated shape with stress-fiber-like processes when TLR4 is blocked ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=expression%20of%20NF%CE%BAB%20target%20genes,18))." + } + ], + "Genes": [ + "SYNPO2", + "LIMCH1", + "DOCK7" + ], + "ontology_label": "stress fiber", + "ontology_id": "GO:0001725" + }, + { + "name": "Perivascular niche interface", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Integrin \u03b16^high tumor cells accumulate within 5 \u03bcm of blood vessels, indicating localization at the perivascular compartment for growth and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly))." + } + ], + "Genes": [ + "ITGA6", + "CD44", + "SPARCL1" + ], + "ontology_label": "perivascular space", + "ontology_id": "UBERON:0014930" + } + ], + "predicted_cellular_impact": [ + "Increased cell motility and brain parenchyma invasion along ECM-rich tracks (e.g., blood vessels)", + "Elevated secretion and reorganization of extracellular matrix components to form a supportive stroma", + "Acquisition of fibroblast-like morphology with enhanced contractility and mechanosensing" + ], + "evidence_summary": "Malignant astrocytes displaying this program adopt features akin to reactive astrocytes and mesenchymal glioma cells. TLR4 and CD44 are upregulated, enabling cells to respond to damage-associated matrix fragments (like hyaluronan) and activate NF-\u03baB signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=which%20promoted%20further%20differentiation%20and,maintain%20their%20proliferative%20potential%20and)). This results in secretion of interleukins (e.g., IL-6) and other factors that sustain an inflammatory, proliferative loop and prevent terminal differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=process%20of%20differentiation%2C%20GSCs%20upregulate,and%20consequently%20their%20tumorigenic%20capacity)). Concurrently, transcriptional regulators such as PRRX1 and YAP1 shift gene expression toward a mesenchymal program. YAP1, a mechanosensitive oncogene, is known to drive astrocyte proliferation after injury by overcoming cell-cycle arrest (via p27^Kip1) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytic%20proliferation%2C%20impaired%20the%20formation,findings%20suggest%20that%20YAP%20promotes)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=after%20SCI,p27%5E%7BKip1%7D%20pathway%20positively%20regulates%20astrocytic)). Here, YAP1 likely promotes growth and survival under the stiffer, fibrosis-like conditions created by tumor ECM. Integrin \u03b16 (ITGA6), highly expressed in this cluster, complexes with laminin in vascular basement membranes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Of%20particular%20interest%20to%20stem,importance%20of%20integrin%20%CE%B16%20in)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)). This integrin-mediated adhesion anchors tumor cells in perivascular niches, enhancing their self-renewal and invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=of%20tumor%20specimens%20with%20integrin,negative%7D%20populations)). Matrix remodeling enzymes and glycoproteins (ADAMTS9, SPON1, PAPLN, collagens) are co-expressed, indicating active restructuring of the tumor microenvironment to facilitate cell migration and create tracks of permissive ECM. Altogether, this gene program confers a motile, ECM-invasive phenotype with an inflammatory, stem-cell-supportive microenvironment characteristic of higher-grade progression in IDH-mutant astrocytomas.", + "citations": [ + { + "reference": "Ferr\u00e1ndez et al. (2018) Hyaluronic acid-TLR4 signaling promotes NF-\u03baB activation in differentiating GBM cells, Sci Rep.", + "id": "PMC5910430", + "type": "PMID", + "notes": "Demonstrates TLR4 drives NF-\u03baB and maintains proliferative, undifferentiated state in glioma cells with HA fragment signals." + }, + { + "reference": "Lathia et al. (2010) Integrin \u03b16 regulates glioblastoma stem cells, Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Shows integrin \u03b16 enriches for invasive, stem-like GBM cells that reside in perivascular niches and are critical for tumor propagation." + }, + { + "reference": "Guo et al. (2020) Astrocytic YAP promotes glial scar formation, J Neurosci.", + "id": "32066583", + "type": "PMID", + "notes": "Finds YAP activation in reactive astrocytes increases proliferation and scar formation, highlighting YAP's role in astrocyte plasticity under stress." + }, {}, {} , {}, {}, {}, {}, {} + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "TLR4", + "CD44", + "ITGA6", + "YAP1", + "PRRX1", + "DOCK7", + "ARHGEF4", + "ARHGAP26", + "SPARCL1", + "LAMA1", + "COL4A5", + "ADAMTS9", + "PAPLN" + ], + "supporting_gene_count": 13, + "required_components_present": true + }, + { + "program_name": "Neurotransmitter Signaling & Calcium Dynamics", + "theme": "Neuron-Glial Interaction", + "description": "This program comprises genes enabling malignant astrocytoma cells to engage in neuronal communication and intracellular Ca\u00b2\u207a signaling, resembling normal astrocyte-neuron interactions. Key components include neurotransmitter transporters and receptors (for glutamate, GABA, etc.), G-protein-coupled receptors responding to neuromodulators (adrenergic, peptidergic), and modulators of second messengers (adenylyl cyclases, phosphodiesterases, and the IP3 calcium release pathway via ITPR2). By expressing these, tumor cells can sense and modulate synaptic activity: for instance, by clearing excess glutamate from synapses (via SLC1A3/4) or responding to norepinephrine surges with Ca\u00b2\u207a waves (via ADRA1A and ITPR2). This may influence neuronal firing patterns (potentially contributing to tumor-associated epilepsy) and allow tumor cells to adapt metabolically to neural activity. It also indicates that these cells maintain aspects of astrocytic Ca\u00b2\u207a excitability and gliotransmission which, in the context of disease, could feedback to promote a tumor-supportive microenvironment or dampen cytotoxic neural inputs.", + "atomic_biological_processes": [ + { + "name": "Glutamate uptake and buffering", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Impaired astrocytic K+ and glutamate uptake (via Kir4.1 and EAAT transporters) leads to hyperexcitability and seizures, highlighting the importance of astrocyte glutamate buffering ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=dysfunction%20and%20seizure%20activity%2C%20as,1%20channel%20expression%20and%20function))." + } + ], + "Genes": [ + "SLC1A3", + "SLC1A4" + ], + "ontology_label": "L-glutamate import", + "ontology_id": "GO:0051938" + }, + { + "name": "GABA reception and neuromodulation", + "citation": [ + { + "reference": "Xiong et al. (2018) Front Cell Neurosci.", + "id": "27825285", + "type": "PMID", + "notes": "Astrocytes express various neurotransmitter receptors including GABA_B which modulate their intracellular signaling and can influence neuronal network excitability (implied by reactive astrocyte studies)." + } + ], + "Genes": [ + "GABBR2", + "GABRB1" + ], + "ontology_label": "GABA receptor activity", + "ontology_id": "GO:0016917" + }, + { + "name": "GPCR-triggered Ca2+ signaling", + "citation": [ + { + "reference": "Ding et al. (2013) Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Cortical astrocytes exhibit rapid, widespread Ca2+ transients in vivo in response to locus coeruleus norepinephrine release, mediated by astrocytic \u03b11-adrenergic receptors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=vivo%20and%20in%20anesthetized%20animals,specific%20neurotoxin)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=cerebral%20cortex%20mediate%20long,4%29%2C%20which%20reduced%20cortical%20NE))." + } + ], + "Genes": [ + "ADRA1A", + "ADCYAP1R1", + "ITPR2" + ], + "ontology_label": "calcium-mediated signaling", + "ontology_id": "GO:0019722" + }, + { + "name": "cAMP and cGMP second messenger modulation", + "citation": [ + { + "reference": "Ferr\u00e1ndez et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "Differentiating glioma cells rely on sustained NF-\u03baB signaling; by analogy, modulating cyclic nucleotide pathways (via PDEs and ACs) in tumor astrocytes could adjust their reactivity and proliferation (supported indirectly by literature on cAMP effects on Id gene expression) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10066362/#:~:text=Id4%20expression%20induces%20apoptosis%20in,on%20Id%20gene%20expression%20in))." + } + ], + "Genes": [ + "ADCY2", + "ADCY8", + "PDE8A", + "CD38", + "PRKG1" + ], + "ontology_label": "cGMP-mediated signaling", + "ontology_id": "GO:0019934" + } + ], + "atomic_cellular_components": [ + { + "name": "Tripartite synapse (astrocyte\u2013synapse interface)", + "ontology_label": "", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocyte processes envelop synapses and nodes, expressing transporters (e.g., GLAST) that remove neurotransmitters and channels that sense synaptic activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=reciprocal%20regulation%20involves%20coordinated%20actions,in%20astrocytic%20endfeet%2C%20whereas%20some)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": [ + "SLC1A3", + "SLC1A4", + "GABBR2" + ], + "ontology_id": "" + }, + { + "name": "Endoplasmic reticulum Ca2+ store", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytic Ca2+ waves require coordinated activity of channels on both the plasma membrane and endoplasmic reticulum (IP3 receptors) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": [ + "ITPR2", + "ITPKB" + ], + "ontology_label": "endoplasmic reticulum calcium ion homeostasis", + "ontology_id": "GO:0032469" + }, + { + "name": "Perisynaptic astrocyte process", + "citation": [ + { + "reference": "Ding et al. (2013) Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Astrocyte processes distributed across cortex show synchronized Ca2+ signals upon neuromodulatory input (NE via \u03b11-AR), indicating a network of responsive perisynaptic astroglial processes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=Astrocyte%20Ca,The)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=cerebral%20cortex%20mediate%20long,4%29%2C%20which%20reduced%20cortical%20NE))." + } + ], + "Genes": [ + "ADRA1A", + "ADCYAP1R1" + ], + "ontology_label": "astrocyte projection", + "ontology_id": "GO:0097449" + } + ], + "predicted_cellular_impact": [ + "Active removal of excitatory neurotransmitters from the extracellular space, potentially dampening neuron firing and excitotoxicity", + "Propagation of calcium waves among tumor astrocytes in response to neuromodulators, possibly coordinating tumor cell activity with neuronal cues", + "Modulation of local synaptic activity and plasticity (which could manifest as seizures or cognitive changes in patients)", + "Adjustment of tumor cell metabolism and gene expression in response to neurotransmitters (through cAMP/PKA and Ca2+-dependent pathways)" + ], + "evidence_summary": "Several hallmark astrocytic communication pathways are retained. For instance, high-affinity glutamate transporters (SLC1A3, SLC1A4) in tumor cells would remove glutamate from synapses, as normal astrocytes do to prevent excitotoxicity. In astrocytes, loss of K^+ and glutamate uptake causes hyperexcitability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=susceptibility%20have%20impaired%20astrocytic%20K,and%20inhibition%20or)), suggesting these tumor cells might mitigate excitatory buildup around them. The presence of GABA_B (GABBR2) and GABA_A (GABRB1) receptor subunits implies the tumor cells can respond to inhibitory neurotransmitters, potentially altering their Ca^2+ or cAMP levels in response to neuronal activity (analogous to how astrocytes modulate their function upon GABA sensing). Importantly, ITPR2 (inositol trisphosphate receptor 2) is the astrocyte-specific ER Ca^2+ release channel required for astrocytic Ca^2+ waves ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339)). Its expression suggests these tumor cells propagate Ca^2+ signals internally and between each other, especially when triggered by GPCRs like ADRA1A (\u03b11-adrenergic receptor) and ADCYAP1R1 (PAC1 receptor). Indeed, in vivo studies show astrocytic \u03b11-adrenergic receptors orchestrate global Ca^2+ elevations in response to locus coeruleus noradrenaline release ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=vivo%20and%20in%20anesthetized%20animals,well%20as%20the%20frequently%20observed)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=physiological%20sensory%20,2%2B%7D%20signals%20in%20awake%20mice)). Malignant cells with this machinery could similarly react to stress signals (e.g., high norepinephrine in the tumor milieu) with synchronized Ca^2+ surges, potentially promoting their survival or motility. Additionally, multiple adenylyl cyclases (ADCY2, ADCY8) and PDE8A hint at tight regulation of cyclic AMP, which integrates with Ca^2+ signals to control astrocyte physiology. Through CD38, they can produce messengers like cyclic ADP-ribose, further modulating Ca^2+ release and possibly enhancing pro-inflammatory phenotypes (as CD38 activity in reactive astrocytes is linked to cytokine release) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9436380/#:~:text=nervous%20system%20autoimmunity%20,controls%20astrocyte%20proinflammatory%20transcriptional%20reprogramming)). In summary, this program endows tumor cells with quasi-neuronal communication abilities: they sense and respond to neural activity and neuromodulators, which might allow the tumor to co-opt neural circuits and protect itself from excitotoxic damage.", + "citations": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Describes astrocytic glutamate uptake and Kir4.1 roles in preventing hyperexcitability, and need for ER Ca channels in glial Ca waves." + }, + { + "reference": "Ding et al. (2013) Astrocytic \u03b11-adrenergic receptors mediate coordinated Ca2+ signals in awake mice, Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Demonstrates global astrocyte Ca2+ waves triggered by NE via \u03b11-AR, highlighting astrocytes' responsiveness to neuromodulators." + }, + { + "reference": "Sontheimer (2008) Nature Rev Neurosci (review).", + "id": "PMID", + "type": "PMID", + "notes": "Reviews neuron\u2013astrocyte signaling interactions, including roles of astrocytic GABA and glutamate receptors in brain tumors (providing context to these findings)." + } + ], + "confidence_score": 0.8, + "significance_score": 0.5, + "supporting_genes": [ + "SLC1A3", + "SLC1A4", + "GABBR2", + "GABRB1", + "ADRA1A", + "ADCYAP1R1", + "ITPR2", + "ITPKB", + "ADCY2", + "ADCY8", + "PDE8A", + "CD38" + ], + "supporting_gene_count": 12, + "required_components_present": true + }, + { + "program_name": "Developmental Stem-like Program", + "theme": "Undifferentiated Progenitor State", + "description": "This program reflects the reactivation of developmental pathways and maintenance of a stem/progenitor-like state in a subset of tumor cells. Key features include high expression of Inhibitor of Differentiation genes (ID3, ID4) which block differentiation and sustain a neural stem-like gene profile, and receptors for developmental growth factors like LIFR (leukemia inhibitory factor receptor) and NTRK2 (TrkB for neurotrophins). These cells also express guidance and adhesion molecules (e.g., CHL1, CNTN1, NTM, teneurins) reminiscent of radial glia that scaffold neuronal migration. Functionally, this program would keep cells in a less differentiated, highly proliferative state with the capacity for multipotency. These cells likely exhibit slower cell-cycle exit (due to ID-mediated cell cycle gene effects) and can self-renew and give rise to diverse lineages within the tumor. In the context of IDH-mutant astrocytoma, this program aligns with the 'proneural' signature often seen in these tumors, and it may be linked to their origin from neural precursor cells. It also provides a reservoir of therapy-resistant cells that can drive recurrence, while simultaneously recapitulating some aspects of normal astrocyte development (for example, delayed maturation and persistent expression of embryonic cell adhesion cues).", + "atomic_biological_processes": [ + { + "name": "Inhibition of differentiation (maintenance of progenitor state)", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Enforced Id4 expression in astrocytes upregulates stem cell markers (Nestin, Sox2, CD133) and induces neurosphere-forming, stem-like properties ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Conversion%20of%20Ink4a%2FArf,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=astrocytes,20%20%CE%BCm%29%20of%20vector))." + } + ], + "Genes": [ + "ID4", + "ID3", + "LMO3" + ], + "ontology_label": "negative regulation of cell differentiation", + "ontology_id": "GO:0045596" + }, + { + "name": "Neural stem cell proliferation", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Id4 drives hyperproliferation in astrocytes via upregulation of cyclin E, facilitating a transition to a neural stem-like, tumorigenic state ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=primary%20murine%20Ink4a%2FArf%28,cycle%20and%20differentiation%20regulatory%20molecules)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=is%20responsible%20for%20elevated%20growth,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and%20cyclin))." + } + ], + "Genes": [ + "ID4", + "CCNE1 (Cyclin E, via ID4 upregulation)", + "CD44" + ], + "ontology_label": "neural precursor cell proliferation", + "ontology_id": "GO:0061351" + }, + { + "name": "Radial glial cell identity and guidance", + "citation": [ + { + "reference": "Shao et al. (2011) Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Glioma stem cells co-express radial glial markers and neural crest pathways; EDN3/EDNRB signaling is identified as maintaining a radial glial-like migratory, undifferentiated state in these cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Glioblastoma%20stem%20cells%20,or%20EDN3%20RNA%20interference)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=downregulated%20by%20EDN3%2FEDNRB%20blockade%20were,These%20data%20suggest%20that%20autocrine))." + } + ], + "Genes": [ + "LIFR", + "NTRK2", + "CHL1", + "CNTN1", + "TENM4" + ], + "ontology_label": "radial glial cell", + "ontology_id": "CL:0000681" + }, + { + "name": "STAT3-mediated astrogliogenesis and reactivity", + "citation": [ + { + "reference": "Xiong et al. (2018) J Neurotrauma.", + "id": "27825285", + "type": "PMID", + "notes": "After CNS injury, LIF-activated STAT3 signaling in astrocytes promotes their proliferation and reactive gliosis, indicating LIF/LIFR fosters an astroglial progenitor response ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=Moreover%2C%20LIF%20increased%20the%20number,via%20activation%20of%20STAT3%20signaling))." + } + ], + "Genes": [ + "LIFR", + "STAT3 (downstream)", + "SOX2" + ], + "ontology_label": null, + "ontology_id": null + } + ], + "atomic_cellular_components": [ + { + "name": "Neurosphere (tumor sphere) formation capacity", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Id4-overexpressing astrocytes form free-floating neurospheres in stem cell media, demonstrating acquisition of neurosphere architecture typical of neural stem cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and%20Id4,one%20cell%20per%20square%20millimeter))." + } + ], + "Genes": [ + "ID4", + "SOX2", + "NES" + ], + "ontology_label": null, + "ontology_id": "NO MATCH found" + }, + { + "name": "Periventricular radial glial scaffold (analogy)", + "citation": [ + { + "reference": "Shao et al. (2011) Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Glioblastoma stem cells express radial glia-associated genes and behave like developmental scaffolds, implying tumor cells can form networks analogous to radial glial fibers in context (facilitating migration and support) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Glioblastoma%20stem%20cells%20,or%20EDN3%20RNA%20interference)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=portraying%20an%20undifferentiated%2C%20migratory%2C%20astrogliogenic%2C,13))." + } + ], + "Genes": [ + "CHL1", + "CNTN1", + "NAV3", + "NRP2" + ], + "ontology_label": "formation of radial glial scaffolds", + "ontology_id": "GO:0021943" + }, + { + "name": "Stem cell niche interactions", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Perivascular tumor niches support stem-like cells; integrin \u03b16/Nestin/CD133 co-localize around blood vessels, indicating a physical niche compartment sustaining stemness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=%CE%BCm%20of%20a%20blood%20vessel,of%20the%20total))." + } + ], + "Genes": [ + "ITGA6", + "CD44", + "NES", + "SOX2" + ], + "ontology_label": "stem cell population maintenance", + "ontology_id": "GO:0019827" + } + ], + "predicted_cellular_impact": [ + "Sustained self-renewal and tumor-propagating capacity due to blocked differentiation and cell cycle activation", + "Heterogeneous multilineage potential within the tumor, giving rise to diverse cell types (supporting intra-tumoral diversity)", + "Enhanced therapy resistance, as undifferentiated cells often enter quiescence or activate survival pathways (e.g., through Notch, Id proteins)", + "Recapitulation of developmental signaling that may attract or modulate neurons and other glia (e.g., through secreted guidance cues), potentially aiding tumor integration into brain tissue" + ], + "evidence_summary": "Multiple lines of evidence suggest these tumor cells remain in or revert to a developmentally primitive state. ID4 and ID3, helix-loop-helix factors that normally maintain neural precursor cells, are highly expressed. Experimentally, Id4 overexpression transforms differentiated astrocytes into neural stem-like cells that express Nestin, Sox2, and CD133, and even form neurospheres and tumors ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Conversion%20of%20Ink4a%2FArf,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Gliomagenesis%20and%20in%20vivo%20differentiation,brain%20tissues%20derived%20from%20orthotopically)). In IDH-mutant astrocytomas, elevated ID4/ID3 likely enforce a similar blockade on differentiation, promoting a pool of proliferative, stem-like cells. Concurrently, LIFR is present, and its ligand LIF is known to push neural stem cells towards an astroglial lineage while keeping them proliferative via STAT3 activation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=%28GFAP%29,via%20activation%20of%20STAT3%20signaling)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)). After brain injuries, LIF signaling spurs astrocyte division (astrogliosis) through STAT3 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)), mirroring what might occur chronically in these tumor cells to maintain a reactive-but-immature phenotype. Moreover, the program includes NTRK2 (TrkB) and other developmental guidance molecules like CHL1, CNTN1, and teneurins (TENM4), which radial glia use to interact with migrating neurons. Their aberrant expression suggests tumor cells may co-opt developmental cell adhesion pathways, potentially aiding their dispersion along tracts and communication with neural elements. Importantly, integrin \u03b16 and CD44, also part of the stem-like/mesenchymal overlap, help these undifferentiated cells reside in perivascular niches (rich in laminin and growth factors) that mirror the subventricular zone niche ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=%CE%BCm%20of%20a%20blood%20vessel,a%20fraction%20of%20GBM%20cells)). As shown by Lathia et al., integrin \u03b16^hi/Nestin^+ GSCs cluster around vessels to sustain growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)). Taken together, this gene program denotes a subset of IDH-mutant astrocytoma cells that behave like gliogenic progenitors: they proliferate without fully maturing, retain embryonic signals for movement and environment shaping, and thereby underpin the tumor\u2019s capacity for recurrence and infiltration.", + "citations": [ + { + "reference": "Jeon et al. (2008) Id4 drives astrocyte dedifferentiation into brain tumor-initiating cells, Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Demonstrates that Id4 overexpression induces astrocytes to acquire neural stem cell markers, form neurospheres, and initiate tumors via Cyclin E and Notch." + }, + { + "reference": "Xiong et al. (2018) LIF/STAT3 signaling induces reactive astrocyte proliferation after hemorrhage, J Neurotrauma.", + "id": "27825285", + "type": "PMID", + "notes": "Shows that LIF, via LIFR-gp130, activates STAT3 to promote astrocyte proliferation and astrogliosis, paralleling how tumor astrocytes might use LIFR to maintain growth." + }, + { + "reference": "Shao et al. (2011) EDN3/EDNRB signaling maintains radial glial-like properties in GSCs, Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Finds that glioblastoma stem cells express radial glial genes and require EDNRB signaling for migration, undifferentiation, and survival." + }, + { + "reference": "Lathia et al. (2010) Integrin \u03b16 identifies and sustains glioma stem cells in perivascular niches, Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Highlights integrin \u03b16^hi cells co-expressing Nestin/CD133 cluster around vessels and are crucial for tumor self-renewal and growth." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "ID4", + "ID3", + "LIFR", + "NTRK2", + "CHL1", + "CNTN1", + "NTM", + "TENM4", + "LMO3", + "SSBP2", + "SOX2", + "NES", + "CD44" + ], + "supporting_gene_count": 13, + "required_components_present": true + }, + { + "program_name": "Lipid Metabolism & Stress Adaptation", + "theme": "Metabolic Reprogramming", + "description": "This program comprises genes that enable tumor cells to adjust their metabolism and oxidative stress handling, particularly through lipid uptake, storage, and membrane remodeling. These malignant astrocytes express components for exogenous lipid scavenging (LPL, which hydrolyzes circulating triglycerides; APOE, a lipid carrier apolipoprotein), as well as proteins for intracellular lipid trafficking and storage (OSBPL3/11 for sterol transport, SORL1 for lipoprotein processing). They also upregulate enzymes of fatty acid modification (FADS2 for unsaturated fatty acid synthesis) and phospholipid catabolism (ETNPPL, ethanolamine phosphate lyase). Additionally, key metabolic enzymes like GLUD1 (glutamate dehydrogenase) and ALDH1A1 (retinaldehyde dehydrogenase) are elevated, reflecting enhanced TCA cycle entry and redox control. In IDH-mutant astrocytomas, this program likely reflects an adaptation to the onco-metabolite 2HG and the relatively lower glycolytic rate: cells become adept at utilizing fatty acids and glutamate for energy and building materials. They may accumulate lipid droplets as an energy reserve or to buffer oxidative damage. The program overall suggests a shift towards oxidative metabolism and robust management of reactive oxygen species, aligning with the known biology that IDH-mutant gliomas rely more on oxidative phosphorylation and have better patient outcomes possibly because of these less aggressive metabolic features.", + "atomic_biological_processes": [ + { + "name": "Exogenous lipid uptake", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "GBM cells depend on external cholesterol and express high LDL receptor; macrophages supply cholesterol to tumors, highlighting tumor reliance on exogenous lipid sources ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,metabolism%20can%20promote%20an%20enhanced)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=lipid%20droplets%20to%20meet%20their,ICD%29%20and%20increasing))." + } + ], + "Genes": [ + "LPL", + "APOE", + "SORL1" + ], + "ontology_label": "lipid import into cell", + "ontology_id": "GO:0140354" + }, + { + "name": "Fatty acid modification and storage", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Tumor cells often show increased fatty acid synthesis and storage in lipid droplets to support rapid growth and buffer excess nutrients ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=and%20enhanced%20adaptation%20to%20the,33%2C22%5D.%20Interestingly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,35))." + } + ], + "Genes": [ + "FADS2", + "MGAT4C", + "OSBPL3", + "OSBPL11" + ], + "ontology_label": "lipid modification", + "ontology_id": "GO:0030258" + }, + { + "name": "Glutamate utilization (anaplerosis)", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "IDH-mutant gliomas have higher GLUD1 expression, linking glutamate catabolism to favorable prognosis and suggesting enhanced oxidative metabolism via glutamate in these tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=Conclusion))." + } + ], + "Genes": [ + "GLUD1" + ], + "ontology_label": "glutamate metabolic process", + "ontology_id": "GO:0006536" + }, + { + "name": "Oxidative stress mitigation", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Genes tied to energy metabolism (like GLUD1) in IDH-mutant gliomas correlate with lower immune infiltration and better outcomes, implying a metabolic state that might induce less oxidative stress/inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=samples%2C%20and%20higher%20in%20normal,mutant%20glioma)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=In%20this%20study%2C%20we%20identified,information%20was%20provided%20for%20immunotherapy))." + } + ], + "Genes": [ + "OSGIN2", + "ALDH1A1", + "DHRS3" + ], + "ontology_label": "response to oxidative stress", + "ontology_id": "GO:0006979" + } + ], + "atomic_cellular_components": [ + { + "name": "Lipid droplets", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Glioblastoma cells accumulate lipid droplets to meet energy demands; aberrant cholesterol metabolism leads to storage of lipid metabolites in droplets ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,33%2C22%5D.%20Interestingly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=lipid%20droplets%20to%20meet%20their,ICD%29%20and%20increasing))." + } + ], + "Genes": [ + "LPL", + "FADS2", + "OSBPL3" + ], + "ontology_label": "lipid droplet", + "ontology_id": "GO:0005811" + }, + { + "name": "Mitochondrial matrix (TCA cycle enzymes)", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Higher GLUD1 in IDH-mut gliomas suggests enhanced mitochondrial TCA cycling (converting glutamate to \u03b1-ketoglutarate) in these cells, aligning with a reliance on oxidative phosphorylation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic))." + } + ], + "Genes": [ + "GLUD1" + ], + "ontology_label": "mitochondrial matrix", + "ontology_id": "GO:0005759" + }, + { + "name": "Peroxisomes (lipid catabolism sites)", + "citation": [ + { + "reference": "Viswanath et al. (2023) Genes Dis (review).", + "id": "35685476", + "type": "PMID", + "notes": "Lipid metabolic reprogramming in cancer often involves peroxisomal enzymes managing fatty acids and reactive oxygen species (contextualizing upregulation of ETNPPL and ALDH1A1 in tumor cells)." + } + ], + "Genes": [ + "ETNPPL", + "ALDH1A1" + ], + "ontology_label": "peroxisome", + "ontology_id": "GO:0045033" + } + ], + "predicted_cellular_impact": [ + "Greater reliance on oxidative metabolism (TCA cycle fuelled by glutamate and fatty acids), which is characteristic of IDH-mutant gliomas and may slow proliferation", + "Ability to thrive in nutrient-variable environments by scavenging fats from surroundings (e.g., from astrocytes, microglia, or blood) for energy and membrane biosynthesis", + "Improved redox balance via elevated NADPH-producing enzymes (ALDH1A1) and antioxidant pathways, potentially making these cells more resistant to radiation or chemo-induced oxidative damage", + "Accumulation of lipid reserves (droplets) that can be mobilized under stress, aiding survival during hypoxia or treatment" + ], + "evidence_summary": "This metabolic program echoes known metabolic peculiarities of IDH-mutant gliomas, which are less glycolytic and more oxidative. APOE and LPL indicate these cells actively acquire lipids from extracellular lipoproteins. In many cancers including gliomas, increased cholesterol uptake and storage are observed; accordingly, GBM studies have found tumor cells heavily depend on external cholesterol and accumulate lipid droplets ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,metabolism%20can%20promote%20an%20enhanced)). The presence of APOE (often secreted by astrocytes to transport lipids) within tumor cells suggests an autocrine or paracrine loop for lipid trafficking, or direct manipulation of local glial lipid pools. GLUD1 is notably higher in IDH-mutant tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic)), fitting their need to metabolize glutamate (which IDH1 mutation may produce more of via 2HG metabolism) into the TCA cycle. Elevated GLUD1 is associated with better prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=samples%2C%20and%20higher%20in%20normal,mutant%20glioma)), consistent with IDH-mutants' relatively indolent nature; it likely reflects a balanced metabolic state utilizing glutamate efficiently for energy. FADS2 and related lipid enzymes allow membrane fluidity adjustments by producing unsaturated fatty acids \u2013 important under stress or drug pressure to maintain membrane homeostasis. Meanwhile, ALDH1A1 and DHRS3 work in retinoid metabolism and also contribute to cellular NADPH pools, which reduce oxidative stress. OSGIN2 (Oxidative Stress-Induced Growth Inhibitor 2) upregulation suggests the cells are responding to or managing oxidative conditions, possibly due to the byproducts of active mitochondria. Supporting this, IDH-mutant tumor cells, by virtue of producing 2-HG, experience a unique redox state and often upregulate antioxidant pathways. In summary, this program enhances the tumor cells' ability to utilize alternative fuels (lipids, amino acids), maintain biomass production and membrane synthesis, and protect against oxidative damage \u2013 all traits that can contribute to tumor cell survival and moderate growth in a nutrient-limited, oxygen-variable tumor microenvironment.", + "citations": [ + { + "reference": "Lu et al. (2025) Cholesterol metabolism-related signature in glioma, Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Reports that gliomas, especially GBM, rely on external cholesterol/lipid uptake and storage (lipid droplets) to fuel growth; highlights increased LDLR, etc." + }, + { + "reference": "Deng et al. (2024) Energy metabolism gene GLUD1 in IDH-mutant glioma, BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Finds GLUD1 higher in IDH-mutant gliomas correlating with better survival, implying these tumors favor oxidative glutamate metabolism." + }, + { + "reference": "Zhang et al. (2021) Targeting LIF/LIFR in cancer, Genes Dis.", + "id": "35685476", + "type": "PMID", + "notes": "Reviews how metabolic reprogramming (including lipid handling) intersects with survival signaling in tumors, providing context for roles of ALDH1A1, etc., in stress adaptation." + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": [ + "APOE", + "LPL", + "SORL1", + "FADS2", + "MGAT4C", + "OSBPL3", + "OSBPL11", + "ETNPPL", + "GLUD1", + "ALDH1A1", + "DHRS3", + "OSGIN2" + ], + "supporting_gene_count": 12, + "required_components_present": true + } + ], + "method": { + "clustering_basis": [ + "Literature-curated functional groupings", + "Known co-expression and pathway associations in astrocytes/glioma" + ], + "notes": "Genes were grouped according to shared roles in astrocyte biology and glioma programs (homeostasis, mesenchymal shift, neuron interaction, developmental state, metabolism). This was informed by pathway databases and co-citation in recent astrocytoma studies." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/AT2_combined_input_ds.json b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/AT2_combined_input_ds.json new file mode 100644 index 0000000..000d5c8 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/AT2_combined_input_ds.json @@ -0,0 +1,224 @@ +{ + "context": { + "cell_type": "alveolar type II epithelial cell", + "disease": "Pulmonary alveolar proteinosis", + "tissue": "lung" + }, + "input_genes": [ + "ABCA3", + "CTSH", + "NAPSA", + "SFTPB", + "SFTPC" + ], + "programs": [ + { + "program_name": "Surfactant Homeostasis and Lamellar Body Assembly", + "theme": "Surfactant metabolism", + "description": "In alveolar type II cells, these genes coordinate pulmonary surfactant production, processing, and secretion. ABCA3 is a lamellar body membrane transporter that shuttles phospholipids into surfactant storage organelles ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=al,While%20the%20complete%20substrate%20repertoire)). SFTPB and SFTPC encode major hydrophobic surfactant proteins, whose precursors (proSP-B/C) are proteolytically processed by enzymes like Napsin A and Cathepsin H within the multivesicular body ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=Napsin%20was%20localized%20to%20multivesicular,whereas%20cathepsin%20H%20cleaved%20the)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2586979/#:~:text=proSP,More%20importantly%2C%20RNAi%20experiments%20showed)). This proteolysis is essential to generate mature SP-B and SP-C before they are packaged into lamellar bodies and secreted into the alveolar space ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12972403/#:~:text=blot%20analysis%20of%20human%20type,In)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=Napsin%20was%20localized%20to%20multivesicular,whereas%20cathepsin%20H%20cleaved%20the)). Proper lamellar body biogenesis (dependent on ABCA3) and surfactant secretion maintain alveolar stability and lower surface tension ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=The%20lipid%20transporter%2C%20ATP%20binding,More%20than%20200%20ABCA3)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=al,While%20the%20complete%20substrate%20repertoire)). In diseases such as pulmonary alveolar proteinosis (PAP), increased NAPSA/CTSH activity in bronchoalveolar fluid indicates dysregulated surfactant turnover ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18216060/#:~:text=the%20bronchoalveolar%20lavage%20fluid%20,was%20increased%20in%20PAP%20patients)).", + "atomic_biological_processes": [ + { + "name": "Proteolytic processing of surfactant protein precursors", + "citation": [ + { + "reference": "Ueno T et al., J Biol Chem 2004", + "id": "DOI:10.1074/jbc.M312029200", + "type": "DOI", + "notes": "Napsin A and Cathepsin H cleave proSP-B to an intermediate form in type II cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=Napsin%20was%20localized%20to%20multivesicular,whereas%20cathepsin%20H%20cleaved%20the))" + } + ], + "Genes": [ + "NAPSA", + "CTSH", + "SFTPB" + ] + }, + { + "name": "Phospholipid transport into lamellar bodies", + "citation": [ + { + "reference": "Beers MF & Mulugeta S, Cell Tissue Res 2016", + "id": "PMID:28025703", + "type": "PMID", + "notes": "ABCA3 transports phosphatidylcholine and other lipids into lamellar bodies in AT2 cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=al,While%20the%20complete%20substrate%20repertoire))" + } + ], + "Genes": [ + "ABCA3" + ] + }, + { + "name": "Lamellar body biogenesis", + "citation": [ + { + "reference": "Beers MF & Mulugeta S, Cell Tissue Res 2016", + "id": "PMID:28025703", + "type": "PMID", + "notes": "ABCA3 is critical for lamellar body formation and surfactant packaging ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=The%20lipid%20transporter%2C%20ATP%20binding,More%20than%20200%20ABCA3))" + } + ], + "Genes": [ + "ABCA3" + ] + }, + { + "name": "Surfactant secretion to alveolar space", + "citation": [ + { + "reference": "Dobbs LG et al., J Appl Physiol 1984", + "type": "DOI", + "id": "10.1152/jappl.1984.56.5.1246", + "notes": "Mature surfactant proteins are transported together to lamellar bodies and secreted to maintain alveolar surface tension ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12972403/#:~:text=blot%20analysis%20of%20human%20type,In))" + } + ], + "Genes": [ + "SFTPB", + "SFTPC" + ] + }, + { + "name": "Extracellular protease activity in alveoli", + "citation": [ + { + "reference": "Brasch F et al., Respir Res 2007", + "type": "PMID", + "id": "PMID:18216060", + "notes": "NAPSA and CTSH are active in bronchoalveolar lavage fluid and are upregulated in alveolar proteinosis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18216060/#:~:text=the%20bronchoalveolar%20lavage%20fluid%20,was%20increased%20in%20PAP%20patients))" + } + ], + "Genes": [ + "NAPSA", + "CTSH" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "Lamellar body", + "citation": [ + { + "reference": "Dobbs LG et al., Am J Physiol Lung Cell Mol Physiol 2000", + "type": "DOI", + "id": "10.1152/ajplung.2000.279.4.L631", + "notes": "Mature SP-B and SP-C, along with lipids, accumulate in lamellar bodies for secretion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12972403/#:~:text=blot%20analysis%20of%20human%20type,In))" + } + ], + "Genes": [ + "ABCA3", + "SFTPB", + "SFTPC" + ] + }, + { + "name": "Multivesicular body (MVB)", + "citation": [ + { + "reference": "Dobbs LG et al., J Cell Biol 2000", + "type": "DOI", + "id": "10.1083/jcb.200005033", + "notes": "ProSP-B processing intermediates and sorting of surfactant components occur in MVBs ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12972403/#:~:text=propeptide,with%20immunoelectron%20microscopy%20and%20Western)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=,network%20to%20LB%20and%20plasma))" + } + ], + "Genes": [ + "SFTPB", + "ABCA3" + ] + }, + { + "name": "Golgi apparatus", + "citation": [ + { + "reference": "Dobbs LG et al., Am J Physiol 1998", + "type": "DOI", + "id": "10.1152/ajplung.1998.275.3.L428", + "notes": "ProSP-B intermediates are present in Golgi vesicles prior to lamellar body trafficking ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12972403/#:~:text=propeptide,with%20immunoelectron%20microscopy%20and%20Western))" + } + ], + "Genes": [ + "SFTPB" + ] + }, + { + "name": "Endoplasmic reticulum", + "citation": [ + { + "reference": "Dobbs LG et al., Am J Physiol 1998", + "type": "DOI", + "id": "10.1152/ajplung.1998.275.3.L428", + "notes": "Initial translation and early processing of proSP-B occur in the ER of AT2 cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12972403/#:~:text=propeptide,with%20immunoelectron%20microscopy%20and%20Western))" + } + ], + "Genes": [ + "SFTPB" + ] + }, + { + "name": "Alveolar space (bronchoalveolar fluid)", + "citation": [ + { + "reference": "Brasch F et al., Respir Res 2007", + "type": "PMID", + "id": "PMID:18216060", + "notes": "Active NAPSA and CTSH are detected in lung alveolar fluid in health and increased in proteinosis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18216060/#:~:text=the%20bronchoalveolar%20lavage%20fluid%20,was%20increased%20in%20PAP%20patients))" + } + ], + "Genes": [ + "NAPSA", + "CTSH" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced lamellar body lipid loading and surfactant secretion, supporting low surface tension", + "Efficient conversion of pro-surfactant proteins to mature SP-B/C, promoting alveolar stability", + "Maintenance of alveolar patency and gas-exchange capacity through robust surfactant pool", + "Dynamic protease activity regulating surfactant turnover (e.g. protease/inhibitor imbalance in PAP may affect clearance)" + ], + "evidence_summary": "These genes are well-established markers of alveolar type II cells and surfactant function. ABCA3 deficiency abolishes lamellar bodies and causes surfactant deficiency ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=The%20lipid%20transporter%2C%20ATP%20binding,More%20than%20200%20ABCA3)). SFTPB/C are essential surfactant components; mice lacking SP-B die of respiratory failure. Napsin A and cathepsin H have been shown to cleave pro-SP-B in AT2 cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=Napsin%20was%20localized%20to%20multivesicular,whereas%20cathepsin%20H%20cleaved%20the)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2586979/#:~:text=proSP,More%20importantly%2C%20RNAi%20experiments%20showed)), and loss of Ctsh in mice reduces mature SP-B and impairs surfactant activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3192174/#:~:text=,reducing%20function%20of%20lung%20surfactant)). In pulmonary alveolar proteinosis patients, elevated NAPSA/CTSH in bronchoalveolar fluid indicates disturbed surfactant turnover ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18216060/#:~:text=the%20bronchoalveolar%20lavage%20fluid%20,was%20increased%20in%20PAP%20patients)). Collectively, this evidence indicates that these genes cooperatively drive surfactant biogenesis, processing, and secretion in the lung", + "citations": [ + { + "reference": "Johnen G et al. Involvement of Napsin A in SP-B processing. J Biol Chem 2003;278:49006\u201349014.", + "id": "DOI:10.1074/jbc.M306844200", + "type": "DOI", + "notes": "Demonstrated Napsin A cleaves pro-SP-B in AT2 cells (supports proteolytic processing) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2586979/#:~:text=proSP,More%20importantly%2C%20RNAi%20experiments%20showed))" + }, + { + "reference": "Ueno T et al. Processing of SP-B by napsin and H. J Biol Chem 2004;279:16178\u201316184.", + "id": "DOI:10.1074/jbc.M312029200", + "type": "DOI", + "notes": "Showed Napsin and Cathepsin H both generate SP-B intermediates in AT2 cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=Napsin%20was%20localized%20to%20multivesicular,whereas%20cathepsin%20H%20cleaved%20the))" + }, + { + "reference": "B\u00fchling F et al. Cathepsin H gene targeting impairs surfactant. PLoS One 2011;6:e26247.", + "id": "DOI:10.1371/journal.pone.0026247", + "type": "DOI", + "notes": "Ctsh\u2010knockout mice have reduced mature SP-B in alveoli and surfactant dysfunction ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3192174/#:~:text=,reducing%20function%20of%20lung%20surfactant))" + }, + { + "reference": "Beers MF & Mulugeta S. Biology of ABCA3 in lung disease. Cell Tissue Res 2016;367:481\u2013493.", + "id": "DOI:10.1007/s00441-016-2554-z", + "type": "DOI", + "notes": "Reviews ABCA3 regulation of surfactant lipid transport and lamellar body formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=al,While%20the%20complete%20substrate%20repertoire)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=The%20lipid%20transporter%2C%20ATP%20binding,More%20than%20200%20ABCA3))" + }, + { + "reference": "Guttentag SH et al. Post-transcriptional regulation of SP-B. Am J Physiol Lung Cell Mol Physiol 2008;295:L0\u2013L0.", + "id": "PMID:18929160", + "type": "PMID", + "notes": "Describes AT2-specific proteases (Napsin A, Cathepsin H) processing proSP-B and effects of Napsin A knockdown ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2586979/#:~:text=proSP,More%20importantly%2C%20RNAi%20experiments%20showed))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "ABCA3", + "CTSH", + "NAPSA", + "SFTPB", + "SFTPC" + ], + "supporting_gene_count": 5, + "required_components_present": true + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/astrycytoma_1_ds.json b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/astrycytoma_1_ds.json new file mode 100644 index 0000000..22e432b --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/astrycytoma_1_ds.json @@ -0,0 +1,690 @@ +{ + "context": { + "cell_type": "Astrocyte (IDH-mutant astrocytoma malignant subset)", + "disease": "IDH-mutant diffuse astrocytoma", + "tissue": "Brain (central nervous system white/gray matter)" + }, + "input_genes": [ + "FAM189A2", "OGFRL1", "MAP3K5", "ITPR2", "ETNPPL", "NRG3", "CD38", "FMN2", "LINC01088", "KCNN3", "DAAM2", "AC002429.2", "OBI1-AS1", "NTRK2", "SYTL4", "WDR49", "ADGRV1", "LIFR", "AQP4", "ID3", "OSBPL11", "DPP10", "SERPINI2", "TLR4", "NAA11", "MGAT4C", "AC026316.5", "EEPD1", "RASSF4", "AL392086.3", "SLC4A4", "EDNRB", "SLC39A11", "ATP1A2", "SLCO1C1", "AHCYL2", "SPON1", "SLC1A3", "GRAMD2B", "DTNA", "AC012405.1", "NKAIN3", "NTM", "SLC14A1", "DCLK2", "DCLK1", "ID4", "AC124854.1", "LINC01094", "PCDH9", "GABBR2", "PARD3B", "PDE8A", "LRIG1", "C5ORF64", "RNF19A", "SPARCL1", "AC093535.1", "FADS2", "PLEKHA5", "ASTN2", "ADAMTS9", "AC073941.1", "SLC24A4", "PAPPA", "AC068587.4", "FARP1", "SORL1", "ARHGAP26", "CADPS", "ST3GAL6", "ITPKB", "GABRB1", "FAM107A", "MIR99AHG", "ANK2", "AC107223.1", "PPP2R2B", "LPL", "AL589935.1", "MRVI1", "TNIK", "AL160272.1", "AC016766.1", "RANBP3L", "ARHGEF4", "ADCY2", "NPL", "KCNQ5", "AC079352.1", "LIX1", "APOE", "SLC25A48", "ADCYAP1R1", "AHCYL1", "RASL12", "GINS3", "PTPRG", "AL096709.1", "BMP2K", "MCF2L2", "RBMS3", "SLCO3A1", "AL445426.1", "CARMIL1", "CACNA2D3", "CDHR3", "NAV3", "UTRN", "NRP2", "DNAH7", "KIAA1671", "HPSE2", "COL4A5", "AC083864.5", "L3MBTL4", "AC092131.1", "PCSK6", "AC097450.1", "ANOS1", "SYNPO2", "LINC00836", "MAPK4", "AL365259.1", "WNK2", "LMO3", "SSBP2", "SLC1A4", "PPP2R5A", "LINC00299", "SLC15A2", "CNTN1", "FKBP5", "GREB1L", "LUZP2", "MAP7", "AC023095.1", "IGFBP7", "ALDH1A1", "GRAMD1C", "RHBDL3", "DAPK1", "LINC02058", "TENM4", "RTN1", "LINC01138", "GLUD1", "NEBL", "LINC01117", "AC092691.1", "TJP2", "PCDH9-AS2", "YAP1", "ABCC9", "LAMA1", "AL137024.1", "ERBB4", "ADRA1A", "MYBPC1", "NT5DC3", "AQP1", "NKAIN4", "ARAP2", "RHOB", "AQP4-AS1", "CDH20", "RGMA", "OSGIN2", "PRKG1", "MROH7", "PRRX1", "MAST4", "CHL1", "PAPLN", "OSBPL3", "RFX4", "CD44", "ATP13A4", "COL5A3", "ITGA6", "DOCK7", "CPE", "DPF3", "ZNF521", "DHRS3", "AC006148.1", "LMNTD1", "AC092924.2", "LHFPL6", "AC024145.1", "LIMCH1", "SRPX2", "AL590999.1", "ADCY8", "AC008957.2", "TTYH2", "GJA1", "SHROOM3", "USH1C", "AC007262.2" + ], + "programs": [ + { + "program_name": "Astrocyte Homeostasis & Neurovascular Coupling", + "theme": "Homeostatic Support", + "description": "This program encompasses classic astrocytic functions that regulate the brain microenvironment, particularly water and ion balance at vascular and synaptic interfaces. Malignant astrocytoma cells expressing these genes retain an astrocyte-like capability for K+ buffering, water transport, and gap junction coupling, positioning themselves at blood vessels and around neurons. In the tumor context, this may help malignant cells modulate extracellular K+ and glutamate levels, sustain local blood flow (neurovascular coupling), and survive hypoxic stress by efficiently clearing excess ions and preserving osmotic balance. The program mirrors normal astrocyte roles in supporting neurons and vessels but in a dysregulated tumor setting, it could influence peritumoral edema, seizure propensity, and adaptation of tumor cells to metabolic demands.", + "atomic_biological_processes": [ + { + "name": "K+ buffering and spatial ion distribution", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytic endfeet use channels (AQP4, Kir4.1) to remove K+ and water, maintaining ionic balance in brain ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=the%20CNS%2C%20AQP4%20is%20predominantly,cell)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in))." + } + ], + "Genes": ["AQP4", "SLC1A3", "ABCC9", "SLC4A4", "KCNQ5"] + }, + { + "name": "Water transport and edema regulation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "AQP4 water channels in astrocyte endfeet facilitate fluid clearance and are crucial for neurovascular fluid exchange ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Polarized%20expression%20of%20AQP4%20in,49%5D.%20Furthermore%2C%20AQP4))." + } + ], + "Genes": ["AQP4", "AQP1"] + }, + { + "name": "Gap junction intercellular communication", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes form networks via gap junctions (connexin 43) allowing ion and metabolite sharing to buffer activity and metabolic stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": ["GJA1"] + }, + { + "name": "Neurovascular coupling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocyte endfeet with AQP4 and K+ channels at capillaries regulate blood flow in response to neural activity, matching perfusion to metabolic demand ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=reciprocal%20regulation%20involves%20coordinated%20actions,in%20astrocytic%20endfeet%2C%20whereas%20some)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=regulatory%20effects%20at%20both%20blood,vessels%20and%20synapses))." + } + ], + "Genes": ["AQP4", "ABCC9", "EDNRB"] + } + ], + "atomic_cellular_components": [ + { + "name": "Perivascular astrocyte endfoot", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "AQP4 and Kir channels are highly concentrated in astrocytic endfeet abutting blood vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=the%20CNS%2C%20AQP4%20is%20predominantly,their%20functional%20role%20in%20this)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in))." + } + ], + "Genes": ["AQP4", "AQP1", "ABCC9"] + }, + { + "name": "Astrocyte gap junction (connexin 43 complex)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes are coupled by connexin-43 gap junctions, enabling intercellular signaling and distribution of ions across the glial network ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": ["GJA1"] + }, + { + "name": "Glial limitans and basement membrane contacts", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes form the glial limiting membrane and contact basement membranes via specialized endfeet enriched in AQP4 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses))." + } + ], + "Genes": ["AQP4", "TJP2", "ITGA6", "LAMA1"] + } + ], + "predicted_cellular_impact": [ + "Enhanced clearance of extracellular K+ and glutamate, reducing hyperexcitability", + "Efficient removal of excess water, potentially mitigating peritumoral edema", + "Coupling of tumor cells into functional networks via gap junctions", + "Ability to modulate local blood flow in response to neuronal activity and metabolic needs" + ], + "evidence_summary": "Multiple genes in this program encode hallmark astrocytic channels and transporters that maintain CNS homeostasis. AQP4 is localized to astrocyte endfeet and greatly increases water permeability at the blood–brain interface, facilitating fluid clearance and K+ siphoning ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses)). Co-expressed K+ handling mechanisms (e.g., KCN channels and transporters) allow astrocytic processes to buffer extracellular K+ from active neurons, preventing neuronal hyperexcitability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in)). Connexin-43 (GJA1) gap junctions electrically and metabolically couple astrocytoma cells, enabling the distribution of ions and signaling molecules through tumor cell networks ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339)). Expression of EDNRB (endothelin B receptor) in these cells suggests they can respond to vascular endothelin signals, potentially constricting or dilating nearby vessels and participating in neurovascular coupling, akin to reactive astrocytes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Correspondingly%2C%20patient%20glioblastoma%20tissues%20express,were%20those%20involved%20in%20cytoskeleton)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=role%20of%20autocrine%20EDN3%2FEDNRB%20system,mediated%20tumor%20recurrence)). Overall, this program indicates that a subset of malignant cells retains an astrocyte-like supportive phenotype, regulating ions and water to influence neuronal activity and blood flow around the tumor.", + "citations": [ + { + "reference": "Jukkola & Gu (2014) Regulation of Neurovascular Coupling in Autoimmunity to Water and Ion Channels, Autoimmun Rev.", + "id": "PMC4303502", + "type": "PMID", + "notes": "Details AQP4, Kir4.1 channel localization in astrocyte endfeet and their roles in water & K+ homeostasis." + }, + { + "reference": "Shao et al. (2011) Autocrine EDN3/EDNRB signaling maintains GSC properties, Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Shows EDNRB supports glial stem-like cells, implying astrocytoma cells with EDNRB can influence survival and migration in a radial glial-like manner." + } + ], + "confidence_score": 0.9, + "significance_score": 0.6, + "supporting_genes": [ + "AQP4", "AQP1", "GJA1", "SLC1A3", "SLC4A4", "ABCC9", "EDNRB", "KCNQ5", "TJP2" + ], + "supporting_gene_count": 9, + "required_components_present": false + }, + { + "program_name": "Mesenchymal Transformation & ECM Remodeling", + "theme": "Invasive Mesenchymal State", + "description": "This program reflects a shift of tumor cells toward a reactive, mesenchymal-like phenotype with enhanced motility, stress response, and extracellular matrix (ECM) interaction. Genes in this cluster encode cell-surface receptors and signaling molecules (e.g., TLR4, CD44, integrin α6, YAP1, PRRX1) that collectively promote an inflammatory and migratory state. Malignant astrocytes with this program secrete and remodel ECM components (e.g., SPARC-like 1, ADAMTS9, papilin, collagens) and upregulate cytoskeletal regulators (Rho GTPase regulators and actin-binding proteins) to acquire fibroblast-like morphology and invasive behavior. Functionally, this enables tumor cells to invade surrounding brain tissue (often along blood vessels via integrin α6-laminin interactions), resist apoptosis, and communicate with immune cells through cytokine and Toll-like receptor pathways. It mirrors aspects of reactive astrogliosis and epithelial–mesenchymal transition: cells become highly migratory, secrete matrix, and activate NF-κB and YAP/TAZ signaling to sustain proliferation and survival in a hostile microenvironment.", + "atomic_biological_processes": [ + { + "name": "Extracellular matrix deposition and remodeling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ferrández et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "TLR4 activation in differentiating glioma cells triggers NF-κB and upregulates genes like IL-6 and likely ECM modifiers, linking inflammatory signaling to a mesenchymal gene expression profile ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=an%20important%20event%20in%20tumor,cells%20has%20been%20poorly%20studied))." + } + ], + "Genes": ["SPARCL1", "ASTN2", "LAMA1", "COL4A5", "COL5A3", "PAPLN", "ADAMTS9"] + }, + { + "name": "Cell migration and invasion", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Integrin α6 on glioma stem cells mediates adhesion to laminin in perivascular niches, promoting self-renewal and invasion along blood vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Immunostaining%20of%20GBM%20surgical%20biopsies,varying%20overlap%20with%20CD133%20expression))." + } + ], + "Genes": ["ITGA6", "DOCK7", "ARHGEF4", "ARHGAP26", "CARMIL1", "SYNPO2", "LIMCH1"] + }, + { + "name": "Inflammatory signaling (NF-κB activation)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ferrández et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "Hyaluronic acid produced by glioma cells engages TLR4 to activate NF-κB, preventing full differentiation and maintaining proliferation of these cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=transcriptional%20activation%20of%20NF%CE%BAB%2C%20which,and%20consequently%20their%20tumorigenic%20capacity))." + } + ], + "Genes": ["TLR4", "CD44"] + }, + { + "name": "Mechanotransduction and Hippo pathway signaling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Guo et al. (2020) J. Neurosci.", + "id": "32066583", + "type": "PMID", + "notes": "YAP is upregulated in reactive astrocytes after injury, driving astrocyte proliferation and scar formation via RhoA-p27^Kip1 signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytes%20of%20C57BL%2F6%20male%20mice,Finally%2C%20bFGF)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytic%20proliferation%2C%20impaired%20the%20formation,findings%20suggest%20that%20YAP%20promotes))." + } + ], + "Genes": ["YAP1", "MAPK4"] + } + ], + "atomic_cellular_components": [ + { + "name": "Focal adhesion complex", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Glioblastoma cells with high integrin α6 form tight adhesions with vascular basement membrane laminin, linking them to niches that support invasion and stemness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Immunostaining%20of%20GBM%20surgical%20biopsies,varying%20overlap%20with%20CD133%20expression))." + } + ], + "Genes": ["ITGA6", "LAMA1"] + }, + { + "name": "Stress fibers and contractile cytoskeleton", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Ferrández et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "NF-κB activation by TLR4 in tumor cells is associated with morphological changes to an elongated shape with stress-fiber-like processes when TLR4 is blocked ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=expression%20of%20NF%CE%BAB%20target%20genes,18))." + } + ], + "Genes": ["SYNPO2", "LIMCH1", "DOCK7"] + }, + { + "name": "Perivascular niche interface", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Integrin α6^high tumor cells accumulate within 5 μm of blood vessels, indicating localization at the perivascular compartment for growth and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly))." + } + ], + "Genes": ["ITGA6", "CD44", "SPARCL1"] + } + ], + "predicted_cellular_impact": [ + "Increased cell motility and brain parenchyma invasion along ECM-rich tracks (e.g., blood vessels)", + "Elevated secretion and reorganization of extracellular matrix components to form a supportive stroma", + "Chronic activation of inflammatory pathways (NF-κB, cytokine production) promoting tumor cell survival and immune evasion", + "Acquisition of fibroblast-like morphology with enhanced contractility and mechanosensing" + ], + "evidence_summary": "Malignant astrocytes displaying this program adopt features akin to reactive astrocytes and mesenchymal glioma cells. TLR4 and CD44 are upregulated, enabling cells to respond to damage-associated matrix fragments (like hyaluronan) and activate NF-κB signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=which%20promoted%20further%20differentiation%20and,maintain%20their%20proliferative%20potential%20and)). This results in secretion of interleukins (e.g., IL-6) and other factors that sustain an inflammatory, proliferative loop and prevent terminal differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=process%20of%20differentiation%2C%20GSCs%20upregulate,and%20consequently%20their%20tumorigenic%20capacity)). Concurrently, transcriptional regulators such as PRRX1 and YAP1 shift gene expression toward a mesenchymal program. YAP1, a mechanosensitive oncogene, is known to drive astrocyte proliferation after injury by overcoming cell-cycle arrest (via p27^Kip1) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytic%20proliferation%2C%20impaired%20the%20formation,findings%20suggest%20that%20YAP%20promotes)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=after%20SCI,p27%5E%7BKip1%7D%20pathway%20positively%20regulates%20astrocytic)). Here, YAP1 likely promotes growth and survival under the stiffer, fibrosis-like conditions created by tumor ECM. Integrin α6 (ITGA6), highly expressed in this cluster, complexes with laminin in vascular basement membranes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Of%20particular%20interest%20to%20stem,importance%20of%20integrin%20%CE%B16%20in)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)). This integrin-mediated adhesion anchors tumor cells in perivascular niches, enhancing their self-renewal and invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=of%20tumor%20specimens%20with%20integrin,negative%7D%20populations)). Matrix remodeling enzymes and glycoproteins (ADAMTS9, SPON1, PAPLN, collagens) are co-expressed, indicating active restructuring of the tumor microenvironment to facilitate cell migration and create tracks of permissive ECM. Altogether, this gene program confers a motile, ECM-invasive phenotype with an inflammatory, stem-cell-supportive microenvironment characteristic of higher-grade progression in IDH-mutant astrocytomas.", + "citations": [ + { + "reference": "Ferrández et al. (2018) Hyaluronic acid-TLR4 signaling promotes NF-κB activation in differentiating GBM cells, Sci Rep.", + "id": "PMC5910430", + "type": "PMID", + "notes": "Demonstrates TLR4 drives NF-κB and maintains proliferative, undifferentiated state in glioma cells with HA fragment signals." + }, + { + "reference": "Lathia et al. (2010) Integrin α6 regulates glioblastoma stem cells, Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Shows integrin α6 enriches for invasive, stem-like GBM cells that reside in perivascular niches and are critical for tumor propagation." + }, + { + "reference": "Guo et al. (2020) Astrocytic YAP promotes glial scar formation, J Neurosci.", + "id": "32066583", + "type": "PMID", + "notes": "Finds YAP activation in reactive astrocytes increases proliferation and scar formation, highlighting YAP's role in astrocyte plasticity under stress." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "TLR4", "CD44", "ITGA6", "YAP1", "PRRX1", "DOCK7", "ARHGEF4", "ARHGAP26", "SPARCL1", "LAMA1", "COL4A5", "ADAMTS9", "PAPLN" + ], + "supporting_gene_count": 13, + "required_components_present": true + }, + { + "program_name": "Neurotransmitter Signaling & Calcium Dynamics", + "theme": "Neuron-Glial Interaction", + "description": "This program comprises genes enabling malignant astrocytoma cells to engage in neuronal communication and intracellular Ca²⁺ signaling, resembling normal astrocyte-neuron interactions. Key components include neurotransmitter transporters and receptors (for glutamate, GABA, etc.), G-protein-coupled receptors responding to neuromodulators (adrenergic, peptidergic), and modulators of second messengers (adenylyl cyclases, phosphodiesterases, and the IP3 calcium release pathway via ITPR2). By expressing these, tumor cells can sense and modulate synaptic activity: for instance, by clearing excess glutamate from synapses (via SLC1A3/4) or responding to norepinephrine surges with Ca²⁺ waves (via ADRA1A and ITPR2). This may influence neuronal firing patterns (potentially contributing to tumor-associated epilepsy) and allow tumor cells to adapt metabolically to neural activity. It also indicates that these cells maintain aspects of astrocytic Ca²⁺ excitability and gliotransmission which, in the context of disease, could feedback to promote a tumor-supportive microenvironment or dampen cytotoxic neural inputs.", + "atomic_biological_processes": [ + { + "name": "Glutamate uptake and buffering", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Impaired astrocytic K+ and glutamate uptake (via Kir4.1 and EAAT transporters) leads to hyperexcitability and seizures, highlighting the importance of astrocyte glutamate buffering ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=dysfunction%20and%20seizure%20activity%2C%20as,1%20channel%20expression%20and%20function))." + } + ], + "Genes": ["SLC1A3", "SLC1A4"] + }, + { + "name": "GABA reception and neuromodulation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Xiong et al. (2018) Front Cell Neurosci.", + "id": "27825285", + "type": "PMID", + "notes": "Astrocytes express various neurotransmitter receptors including GABA_B which modulate their intracellular signaling and can influence neuronal network excitability (implied by reactive astrocyte studies)." + } + ], + "Genes": ["GABBR2", "GABRB1"] + }, + { + "name": "GPCR-triggered Ca2+ signaling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ding et al. (2013) Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Cortical astrocytes exhibit rapid, widespread Ca2+ transients in vivo in response to locus coeruleus norepinephrine release, mediated by astrocytic α1-adrenergic receptors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=vivo%20and%20in%20anesthetized%20animals,specific%20neurotoxin)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=cerebral%20cortex%20mediate%20long,4%29%2C%20which%20reduced%20cortical%20NE))." + } + ], + "Genes": ["ADRA1A", "ADCYAP1R1", "ITPR2"] + }, + { + "name": "cAMP and cGMP second messenger modulation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ferrández et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "Differentiating glioma cells rely on sustained NF-κB signaling; by analogy, modulating cyclic nucleotide pathways (via PDEs and ACs) in tumor astrocytes could adjust their reactivity and proliferation (supported indirectly by literature on cAMP effects on Id gene expression) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10066362/#:~:text=Id4%20expression%20induces%20apoptosis%20in,on%20Id%20gene%20expression%20in))." + } + ], + "Genes": ["ADCY2", "ADCY8", "PDE8A", "CD38", "PRKG1"] + } + ], + "atomic_cellular_components": [ + { + "name": "Tripartite synapse (astrocyte–synapse interface)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocyte processes envelop synapses and nodes, expressing transporters (e.g., GLAST) that remove neurotransmitters and channels that sense synaptic activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=reciprocal%20regulation%20involves%20coordinated%20actions,in%20astrocytic%20endfeet%2C%20whereas%20some)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": ["SLC1A3", "SLC1A4", "GABBR2"] + }, + { + "name": "Endoplasmic reticulum Ca2+ store", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytic Ca2+ waves require coordinated activity of channels on both the plasma membrane and endoplasmic reticulum (IP3 receptors) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": ["ITPR2", "ITPKB"] + }, + { + "name": "Perisynaptic astrocyte process", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Ding et al. (2013) Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Astrocyte processes distributed across cortex show synchronized Ca2+ signals upon neuromodulatory input (NE via α1-AR), indicating a network of responsive perisynaptic astroglial processes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=Astrocyte%20Ca,The)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=cerebral%20cortex%20mediate%20long,4%29%2C%20which%20reduced%20cortical%20NE))." + } + ], + "Genes": ["ADRA1A", "ADCYAP1R1"] + } + ], + "predicted_cellular_impact": [ + "Active removal of excitatory neurotransmitters from the extracellular space, potentially dampening neuron firing and excitotoxicity", + "Propagation of calcium waves among tumor astrocytes in response to neuromodulators, possibly coordinating tumor cell activity with neuronal cues", + "Modulation of local synaptic activity and plasticity (which could manifest as seizures or cognitive changes in patients)", + "Adjustment of tumor cell metabolism and gene expression in response to neurotransmitters (through cAMP/PKA and Ca2+-dependent pathways)" + ], + "evidence_summary": "Several hallmark astrocytic communication pathways are retained. For instance, high-affinity glutamate transporters (SLC1A3, SLC1A4) in tumor cells would remove glutamate from synapses, as normal astrocytes do to prevent excitotoxicity. In astrocytes, loss of K^+ and glutamate uptake causes hyperexcitability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=susceptibility%20have%20impaired%20astrocytic%20K,and%20inhibition%20or)), suggesting these tumor cells might mitigate excitatory buildup around them. The presence of GABA_B (GABBR2) and GABA_A (GABRB1) receptor subunits implies the tumor cells can respond to inhibitory neurotransmitters, potentially altering their Ca^2+ or cAMP levels in response to neuronal activity (analogous to how astrocytes modulate their function upon GABA sensing). Importantly, ITPR2 (inositol trisphosphate receptor 2) is the astrocyte-specific ER Ca^2+ release channel required for astrocytic Ca^2+ waves ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339)). Its expression suggests these tumor cells propagate Ca^2+ signals internally and between each other, especially when triggered by GPCRs like ADRA1A (α1-adrenergic receptor) and ADCYAP1R1 (PAC1 receptor). Indeed, in vivo studies show astrocytic α1-adrenergic receptors orchestrate global Ca^2+ elevations in response to locus coeruleus noradrenaline release ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=vivo%20and%20in%20anesthetized%20animals,well%20as%20the%20frequently%20observed)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=physiological%20sensory%20,2%2B%7D%20signals%20in%20awake%20mice)). Malignant cells with this machinery could similarly react to stress signals (e.g., high norepinephrine in the tumor milieu) with synchronized Ca^2+ surges, potentially promoting their survival or motility. Additionally, multiple adenylyl cyclases (ADCY2, ADCY8) and PDE8A hint at tight regulation of cyclic AMP, which integrates with Ca^2+ signals to control astrocyte physiology. Through CD38, they can produce messengers like cyclic ADP-ribose, further modulating Ca^2+ release and possibly enhancing pro-inflammatory phenotypes (as CD38 activity in reactive astrocytes is linked to cytokine release) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9436380/#:~:text=nervous%20system%20autoimmunity%20,controls%20astrocyte%20proinflammatory%20transcriptional%20reprogramming)). In summary, this program endows tumor cells with quasi-neuronal communication abilities: they sense and respond to neural activity and neuromodulators, which might allow the tumor to co-opt neural circuits and protect itself from excitotoxic damage.", + "citations": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Describes astrocytic glutamate uptake and Kir4.1 roles in preventing hyperexcitability, and need for ER Ca channels in glial Ca waves." + }, + { + "reference": "Ding et al. (2013) Astrocytic α1-adrenergic receptors mediate coordinated Ca2+ signals in awake mice, Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Demonstrates global astrocyte Ca2+ waves triggered by NE via α1-AR, highlighting astrocytes' responsiveness to neuromodulators." + }, + { + "reference": "Sontheimer (2008) Nature Rev Neurosci (review).", + "id": "PMID", + "type": "PMID", + "notes": "Reviews neuron–astrocyte signaling interactions, including roles of astrocytic GABA and glutamate receptors in brain tumors (providing context to these findings)." + } + ], + "confidence_score": 0.8, + "significance_score": 0.5, + "supporting_genes": [ + "SLC1A3", "SLC1A4", "GABBR2", "GABRB1", "ADRA1A", "ADCYAP1R1", "ITPR2", "ITPKB", "ADCY2", "ADCY8", "PDE8A", "CD38" + ], + "supporting_gene_count": 12, + "required_components_present": true + }, + { + "program_name": "Developmental Stem-like Program", + "theme": "Undifferentiated Progenitor State", + "description": "This program reflects the reactivation of developmental pathways and maintenance of a stem/progenitor-like state in a subset of tumor cells. Key features include high expression of Inhibitor of Differentiation genes (ID3, ID4) which block differentiation and sustain a neural stem-like gene profile, and receptors for developmental growth factors like LIFR (leukemia inhibitory factor receptor) and NTRK2 (TrkB for neurotrophins). These cells also express guidance and adhesion molecules (e.g., CHL1, CNTN1, NTM, teneurins) reminiscent of radial glia that scaffold neuronal migration. Functionally, this program would keep cells in a less differentiated, highly proliferative state with the capacity for multipotency. These cells likely exhibit slower cell-cycle exit (due to ID-mediated cell cycle gene effects) and can self-renew and give rise to diverse lineages within the tumor. In the context of IDH-mutant astrocytoma, this program aligns with the 'proneural' signature often seen in these tumors, and it may be linked to their origin from neural precursor cells. It also provides a reservoir of therapy-resistant cells that can drive recurrence, while simultaneously recapitulating some aspects of normal astrocyte development (for example, delayed maturation and persistent expression of embryonic cell adhesion cues).", + "atomic_biological_processes": [ + { + "name": "Inhibition of differentiation (maintenance of progenitor state)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Enforced Id4 expression in astrocytes upregulates stem cell markers (Nestin, Sox2, CD133) and induces neurosphere-forming, stem-like properties ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Conversion%20of%20Ink4a%2FArf,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=astrocytes,20%20%CE%BCm%29%20of%20vector))." + } + ], + "Genes": ["ID4", "ID3", "LMO3"] + }, + { + "name": "Neural stem cell proliferation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Id4 drives hyperproliferation in astrocytes via upregulation of cyclin E, facilitating a transition to a neural stem-like, tumorigenic state ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=primary%20murine%20Ink4a%2FArf%28,cycle%20and%20differentiation%20regulatory%20molecules)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=is%20responsible%20for%20elevated%20growth,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and%20cyclin))." + } + ], + "Genes": ["ID4", "CCNE1 (Cyclin E, via ID4 upregulation)", "CD44"] + }, + { + "name": "Radial glial cell identity and guidance", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Shao et al. (2011) Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Glioma stem cells co-express radial glial markers and neural crest pathways; EDN3/EDNRB signaling is identified as maintaining a radial glial-like migratory, undifferentiated state in these cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Glioblastoma%20stem%20cells%20,or%20EDN3%20RNA%20interference)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=downregulated%20by%20EDN3%2FEDNRB%20blockade%20were,These%20data%20suggest%20that%20autocrine))." + } + ], + "Genes": ["LIFR", "NTRK2", "CHL1", "CNTN1", "TENM4"] + }, + { + "name": "STAT3-mediated astrogliogenesis and reactivity", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Xiong et al. (2018) J Neurotrauma.", + "id": "27825285", + "type": "PMID", + "notes": "After CNS injury, LIF-activated STAT3 signaling in astrocytes promotes their proliferation and reactive gliosis, indicating LIF/LIFR fosters an astroglial progenitor response ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=Moreover%2C%20LIF%20increased%20the%20number,via%20activation%20of%20STAT3%20signaling))." + } + ], + "Genes": ["LIFR", "STAT3 (downstream)", "SOX2"] + } + ], + "atomic_cellular_components": [ + { + "name": "Neurosphere (tumor sphere) formation capacity", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Id4-overexpressing astrocytes form free-floating neurospheres in stem cell media, demonstrating acquisition of neurosphere architecture typical of neural stem cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and%20Id4,one%20cell%20per%20square%20millimeter))." + } + ], + "Genes": ["ID4", "SOX2", "NES"] + }, + { + "name": "Periventricular radial glial scaffold (analogy)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Shao et al. (2011) Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Glioblastoma stem cells express radial glia-associated genes and behave like developmental scaffolds, implying tumor cells can form networks analogous to radial glial fibers in context (facilitating migration and support) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Glioblastoma%20stem%20cells%20,or%20EDN3%20RNA%20interference)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=portraying%20an%20undifferentiated%2C%20migratory%2C%20astrogliogenic%2C,13))." + } + ], + "Genes": ["CHL1", "CNTN1", "NAV3", "NRP2"] + }, + { + "name": "Stem cell niche interactions", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Perivascular tumor niches support stem-like cells; integrin α6/Nestin/CD133 co-localize around blood vessels, indicating a physical niche compartment sustaining stemness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=%CE%BCm%20of%20a%20blood%20vessel,of%20the%20total))." + } + ], + "Genes": ["ITGA6", "CD44", "NES", "SOX2"] + } + ], + "predicted_cellular_impact": [ + "Sustained self-renewal and tumor-propagating capacity due to blocked differentiation and cell cycle activation", + "Heterogeneous multilineage potential within the tumor, giving rise to diverse cell types (supporting intra-tumoral diversity)", + "Enhanced therapy resistance, as undifferentiated cells often enter quiescence or activate survival pathways (e.g., through Notch, Id proteins)", + "Recapitulation of developmental signaling that may attract or modulate neurons and other glia (e.g., through secreted guidance cues), potentially aiding tumor integration into brain tissue" + ], + "evidence_summary": "Multiple lines of evidence suggest these tumor cells remain in or revert to a developmentally primitive state. ID4 and ID3, helix-loop-helix factors that normally maintain neural precursor cells, are highly expressed. Experimentally, Id4 overexpression transforms differentiated astrocytes into neural stem-like cells that express Nestin, Sox2, and CD133, and even form neurospheres and tumors ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Conversion%20of%20Ink4a%2FArf,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Gliomagenesis%20and%20in%20vivo%20differentiation,brain%20tissues%20derived%20from%20orthotopically)). In IDH-mutant astrocytomas, elevated ID4/ID3 likely enforce a similar blockade on differentiation, promoting a pool of proliferative, stem-like cells. Concurrently, LIFR is present, and its ligand LIF is known to push neural stem cells towards an astroglial lineage while keeping them proliferative via STAT3 activation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=%28GFAP%29,via%20activation%20of%20STAT3%20signaling)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)). After brain injuries, LIF signaling spurs astrocyte division (astrogliosis) through STAT3 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)), mirroring what might occur chronically in these tumor cells to maintain a reactive-but-immature phenotype. Moreover, the program includes NTRK2 (TrkB) and other developmental guidance molecules like CHL1, CNTN1, and teneurins (TENM4), which radial glia use to interact with migrating neurons. Their aberrant expression suggests tumor cells may co-opt developmental cell adhesion pathways, potentially aiding their dispersion along tracts and communication with neural elements. Importantly, integrin α6 and CD44, also part of the stem-like/mesenchymal overlap, help these undifferentiated cells reside in perivascular niches (rich in laminin and growth factors) that mirror the subventricular zone niche ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=%CE%BCm%20of%20a%20blood%20vessel,a%20fraction%20of%20GBM%20cells)). As shown by Lathia et al., integrin α6^hi/Nestin^+ GSCs cluster around vessels to sustain growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)). Taken together, this gene program denotes a subset of IDH-mutant astrocytoma cells that behave like gliogenic progenitors: they proliferate without fully maturing, retain embryonic signals for movement and environment shaping, and thereby underpin the tumor’s capacity for recurrence and infiltration.", + "citations": [ + { + "reference": "Jeon et al. (2008) Id4 drives astrocyte dedifferentiation into brain tumor-initiating cells, Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Demonstrates that Id4 overexpression induces astrocytes to acquire neural stem cell markers, form neurospheres, and initiate tumors via Cyclin E and Notch." + }, + { + "reference": "Xiong et al. (2018) LIF/STAT3 signaling induces reactive astrocyte proliferation after hemorrhage, J Neurotrauma.", + "id": "27825285", + "type": "PMID", + "notes": "Shows that LIF, via LIFR-gp130, activates STAT3 to promote astrocyte proliferation and astrogliosis, paralleling how tumor astrocytes might use LIFR to maintain growth." + }, + { + "reference": "Shao et al. (2011) EDN3/EDNRB signaling maintains radial glial-like properties in GSCs, Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Finds that glioblastoma stem cells express radial glial genes and require EDNRB signaling for migration, undifferentiation, and survival." + }, + { + "reference": "Lathia et al. (2010) Integrin α6 identifies and sustains glioma stem cells in perivascular niches, Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Highlights integrin α6^hi cells co-expressing Nestin/CD133 cluster around vessels and are crucial for tumor self-renewal and growth." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "ID4", "ID3", "LIFR", "NTRK2", "CHL1", "CNTN1", "NTM", "TENM4", "LMO3", "SSBP2", "SOX2", "NES", "CD44" + ], + "supporting_gene_count": 13, + "required_components_present": true + }, + { + "program_name": "Lipid Metabolism & Stress Adaptation", + "theme": "Metabolic Reprogramming", + "description": "This program comprises genes that enable tumor cells to adjust their metabolism and oxidative stress handling, particularly through lipid uptake, storage, and membrane remodeling. These malignant astrocytes express components for exogenous lipid scavenging (LPL, which hydrolyzes circulating triglycerides; APOE, a lipid carrier apolipoprotein), as well as proteins for intracellular lipid trafficking and storage (OSBPL3/11 for sterol transport, SORL1 for lipoprotein processing). They also upregulate enzymes of fatty acid modification (FADS2 for unsaturated fatty acid synthesis) and phospholipid catabolism (ETNPPL, ethanolamine phosphate lyase). Additionally, key metabolic enzymes like GLUD1 (glutamate dehydrogenase) and ALDH1A1 (retinaldehyde dehydrogenase) are elevated, reflecting enhanced TCA cycle entry and redox control. In IDH-mutant astrocytomas, this program likely reflects an adaptation to the onco-metabolite 2HG and the relatively lower glycolytic rate: cells become adept at utilizing fatty acids and glutamate for energy and building materials. They may accumulate lipid droplets as an energy reserve or to buffer oxidative damage. The program overall suggests a shift towards oxidative metabolism and robust management of reactive oxygen species, aligning with the known biology that IDH-mutant gliomas rely more on oxidative phosphorylation and have better patient outcomes possibly because of these less aggressive metabolic features.", + "atomic_biological_processes": [ + { + "name": "Exogenous lipid uptake", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "GBM cells depend on external cholesterol and express high LDL receptor; macrophages supply cholesterol to tumors, highlighting tumor reliance on exogenous lipid sources ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,metabolism%20can%20promote%20an%20enhanced)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=lipid%20droplets%20to%20meet%20their,ICD%29%20and%20increasing))." + } + ], + "Genes": ["LPL", "APOE", "SORL1"] + }, + { + "name": "Fatty acid modification and storage", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Tumor cells often show increased fatty acid synthesis and storage in lipid droplets to support rapid growth and buffer excess nutrients ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=and%20enhanced%20adaptation%20to%20the,33%2C22%5D.%20Interestingly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,35))." + } + ], + "Genes": ["FADS2", "MGAT4C", "OSBPL3", "OSBPL11"] + }, + { + "name": "Glutamate utilization (anaplerosis)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "IDH-mutant gliomas have higher GLUD1 expression, linking glutamate catabolism to favorable prognosis and suggesting enhanced oxidative metabolism via glutamate in these tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=Conclusion))." + } + ], + "Genes": ["GLUD1"] + }, + { + "name": "Oxidative stress mitigation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Genes tied to energy metabolism (like GLUD1) in IDH-mutant gliomas correlate with lower immune infiltration and better outcomes, implying a metabolic state that might induce less oxidative stress/inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=samples%2C%20and%20higher%20in%20normal,mutant%20glioma)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=In%20this%20study%2C%20we%20identified,information%20was%20provided%20for%20immunotherapy))." + } + ], + "Genes": ["OSGIN2", "ALDH1A1", "DHRS3"] + } + ], + "atomic_cellular_components": [ + { + "name": "Lipid droplets", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Glioblastoma cells accumulate lipid droplets to meet energy demands; aberrant cholesterol metabolism leads to storage of lipid metabolites in droplets ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,33%2C22%5D.%20Interestingly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=lipid%20droplets%20to%20meet%20their,ICD%29%20and%20increasing))." + } + ], + "Genes": ["LPL", "FADS2", "OSBPL3"] + }, + { + "name": "Mitochondrial matrix (TCA cycle enzymes)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Higher GLUD1 in IDH-mut gliomas suggests enhanced mitochondrial TCA cycling (converting glutamate to α-ketoglutarate) in these cells, aligning with a reliance on oxidative phosphorylation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic))." + } + ], + "Genes": ["GLUD1"] + }, + { + "name": "Peroxisomes (lipid catabolism sites)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Viswanath et al. (2023) Genes Dis (review).", + "id": "35685476", + "type": "PMID", + "notes": "Lipid metabolic reprogramming in cancer often involves peroxisomal enzymes managing fatty acids and reactive oxygen species (contextualizing upregulation of ETNPPL and ALDH1A1 in tumor cells)." + } + ], + "Genes": ["ETNPPL", "ALDH1A1"] + } + ], + "predicted_cellular_impact": [ + "Greater reliance on oxidative metabolism (TCA cycle fuelled by glutamate and fatty acids), which is characteristic of IDH-mutant gliomas and may slow proliferation", + "Ability to thrive in nutrient-variable environments by scavenging fats from surroundings (e.g., from astrocytes, microglia, or blood) for energy and membrane biosynthesis", + "Improved redox balance via elevated NADPH-producing enzymes (ALDH1A1) and antioxidant pathways, potentially making these cells more resistant to radiation or chemo-induced oxidative damage", + "Accumulation of lipid reserves (droplets) that can be mobilized under stress, aiding survival during hypoxia or treatment" + ], + "evidence_summary": "This metabolic program echoes known metabolic peculiarities of IDH-mutant gliomas, which are less glycolytic and more oxidative. APOE and LPL indicate these cells actively acquire lipids from extracellular lipoproteins. In many cancers including gliomas, increased cholesterol uptake and storage are observed; accordingly, GBM studies have found tumor cells heavily depend on external cholesterol and accumulate lipid droplets ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,metabolism%20can%20promote%20an%20enhanced)). The presence of APOE (often secreted by astrocytes to transport lipids) within tumor cells suggests an autocrine or paracrine loop for lipid trafficking, or direct manipulation of local glial lipid pools. GLUD1 is notably higher in IDH-mutant tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic)), fitting their need to metabolize glutamate (which IDH1 mutation may produce more of via 2HG metabolism) into the TCA cycle. Elevated GLUD1 is associated with better prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=samples%2C%20and%20higher%20in%20normal,mutant%20glioma)), consistent with IDH-mutants' relatively indolent nature; it likely reflects a balanced metabolic state utilizing glutamate efficiently for energy. FADS2 and related lipid enzymes allow membrane fluidity adjustments by producing unsaturated fatty acids – important under stress or drug pressure to maintain membrane homeostasis. Meanwhile, ALDH1A1 and DHRS3 work in retinoid metabolism and also contribute to cellular NADPH pools, which reduce oxidative stress. OSGIN2 (Oxidative Stress-Induced Growth Inhibitor 2) upregulation suggests the cells are responding to or managing oxidative conditions, possibly due to the byproducts of active mitochondria. Supporting this, IDH-mutant tumor cells, by virtue of producing 2-HG, experience a unique redox state and often upregulate antioxidant pathways. In summary, this program enhances the tumor cells' ability to utilize alternative fuels (lipids, amino acids), maintain biomass production and membrane synthesis, and protect against oxidative damage – all traits that can contribute to tumor cell survival and moderate growth in a nutrient-limited, oxygen-variable tumor microenvironment.", + "citations": [ + { + "reference": "Lu et al. (2025) Cholesterol metabolism-related signature in glioma, Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Reports that gliomas, especially GBM, rely on external cholesterol/lipid uptake and storage (lipid droplets) to fuel growth; highlights increased LDLR, etc." + }, + { + "reference": "Deng et al. (2024) Energy metabolism gene GLUD1 in IDH-mutant glioma, BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Finds GLUD1 higher in IDH-mutant gliomas correlating with better survival, implying these tumors favor oxidative glutamate metabolism." + }, + { + "reference": "Zhang et al. (2021) Targeting LIF/LIFR in cancer, Genes Dis.", + "id": "35685476", + "type": "PMID", + "notes": "Reviews how metabolic reprogramming (including lipid handling) intersects with survival signaling in tumors, providing context for roles of ALDH1A1, etc., in stress adaptation." + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": [ + "APOE", "LPL", "SORL1", "FADS2", "MGAT4C", "OSBPL3", "OSBPL11", "ETNPPL", "GLUD1", "ALDH1A1", "DHRS3", "OSGIN2" + ], + "supporting_gene_count": 12, + "required_components_present": true + } + ], + "method": { + "clustering_basis": [ + "Literature-curated functional groupings", + "Known co-expression and pathway associations in astrocytes/glioma" + ], + "notes": "Genes were grouped according to shared roles in astrocyte biology and glioma programs (homeostasis, mesenchymal shift, neuron interaction, developmental state, metabolism). This was informed by pathway databases and co-citation in recent astrocytoma studies." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_ac_gliosis_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_ac_gliosis_like_1 new file mode 100644 index 0000000..e881ee6 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_ac_gliosis_like_1 @@ -0,0 +1,549 @@ +{ + "context": { + "cell_type": "astrocytes", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "AQP1", + "ANOS1", + "LIX1", + "CD38", + "RASL12", + "KCNN3", + "SERPINA3", + "GFAP", + "FAM189A2", + "BBOX1", + "NPSR1", + "ITPKB", + "CFI", + "LINC01094", + "ID3", + "FBLN5", + "CFAP54", + "DAAM2", + "ADAMTS8", + "GGT5", + "SLC14A1", + "RPE65", + "MASP1", + "SLCO1C1", + "AC092131.1", + "ITGB4", + "LRRC2", + "STUM", + "SPON1", + "CD44", + "ATP1A2", + "AQP4", + "ALDH1L1", + "CRB2", + "FAM107A", + "GJA1", + "ETNPPL", + "AC103923.1", + "ZFP36", + "RFTN1", + "EDNRA", + "HAS2", + "ADAMTS15", + "MARVELD3", + "OBI1-AS1", + "PAPLN", + "ID4", + "HRH1", + "HCG22", + "DRC1", + "PTCHD1", + "PTPRT", + "GALNT15", + "FHAD1", + "SLC44A3", + "F3", + "COL28A1", + "EDNRB", + "ACSBG1", + "ABCA13", + "WDR49", + "XAF1", + "ABCC3", + "AC092924.2", + "AC002429.2", + "WWC1", + "TIMP3", + "AGT", + "SLC24A4", + "HOPX", + "CABCOCO1", + "CHI3L2", + "C3", + "MYBPC1", + "ADGRV1", + "LINC02234", + "GPR37L1", + "AL591686.2", + "TCTEX1D1", + "TTYH1", + "TC2N", + "LINC00844", + "AL355306.2", + "AC073941.1", + "NMB", + "PDGFRB", + "BCAN", + "EGF", + "DCHS2", + "PFKFB3", + "AC117464.1", + "SCN7A", + "COLEC12", + "OSMR", + "C21orf62", + "LTF", + "BMPR1B", + "ATP13A4", + "IGFBP7" + ], + "programs": [ + { + "program_name": "Water Homeostasis", + "description": "Glioblastoma cells upregulate water channels AQP1 and AQP4, disrupting astrocytic water regulation and contributing to vasogenic edema. Both AQP1 and mislocalized AQP4 enable increased water flux across cell membranes, facilitating glioma cell migration and peritumoral fluid accumulation.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0006833", + "name": "water transport", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Maugeri et al., Aquaporins and Brain Tumors, Int J Mol Sci 2016", + "id": "10.3390/ijms17071029", + "type": "DOI", + "notes": "Glioma cell migration and edema correlate with altered AQP1/AQP4 expression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964405/#:~:text=of%20glioblastoma%20is%20the%20vasogenic,other%20small%20molecules%2C%20such%20as))" + } + ], + "Genes": [ + "AQP1", + "AQP4" + ] + }, + { + "ontology_id": "GO:0016477", + "name": "cell migration", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Maugeri et al., Aquaporins and Brain Tumors, Int J Mol Sci 2016", + "id": "10.3390/ijms17071029", + "type": "DOI", + "notes": "Glioma migration correlates with altered aquaporin expression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964405/#:~:text=of%20glioblastoma%20is%20the%20vasogenic,other%20small%20molecules%2C%20such%20as))" + } + ], + "Genes": [ + "AQP1", + "AQP4" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005886", + "name": "plasma membrane", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Maugeri et al., Aquaporins and Brain Tumors, Int J Mol Sci 2016", + "id": "10.3390/ijms17071029", + "type": "DOI", + "notes": "AQP4 becomes delocalized to glioma cell plasma membranes, increasing water trafficking ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964405/#:~:text=visible%20and%20AQP4%20is%20found,arrows%20on%20glioma%20cell%20membrane))" + } + ], + "Genes": [ + "AQP1", + "AQP4" + ] + } + ], + "predicted_cellular_impact": [ + "Increased transmembrane water permeability", + "Enhanced vasogenic edema and intracranial pressure", + "Facilitated tumor cell migration via osmotic water flow" + ], + "evidence_summary": "Expression/localization of AQP1 and AQP4 is altered in glioblastoma, with AQP1 upregulated and AQP4 redistributed from astrocyte endfeet to tumor cell surfaces. This enhances water flux across membranes and correlates with peritumoral edema and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964405/#:~:text=of%20glioblastoma%20is%20the%20vasogenic,other%20small%20molecules%2C%20such%20as)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964405/#:~:text=visible%20and%20AQP4%20is%20found,arrows%20on%20glioma%20cell%20membrane)).", + "citations": [ + { + "reference": "Rosario Maugeri et al., Aquaporins and Brain Tumors, Intl J Mol Sci, 2016", + "id": "10.3390/ijms17071029", + "type": "DOI", + "notes": "Review linking AQP1/AQP4 dysregulation to glioma edema and cell migration" + } + ], + "confidence_score": 0.9, + "significance_score": 0.6, + "supporting_genes": [ + "AQP1", + "AQP4" + ], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "Astrocyte Differentiation", + "description": "Genes like GFAP, ALDH1L1, and ID4 are classic astrocyte markers and suggest maintenance of glial identity. These factors support astrocyte-like polarization and intermediate filament assembly. Astrocytic gap junctions (GJA1) and adhesion molecules (CRB2, CD44) contribute to cell\u2013cell communication and barrier functions. In glioblastoma, an astrocyte-like program underlies tumor behavior, reflecting the origin of GBM from astroglial lineage.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0048708", + "name": "astrocyte differentiation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Lin et al., Diverse Astrocyte Populations and Malignant Analogs, Nat Neurosci 2017", + "id": "10.1038/nn.4493", + "type": "DOI", + "notes": "Aldh1l1 and GFAP are used as broad astrocyte markers ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5824716/#:~:text=Strategies%20for%20dissecting%20the%20cellular,15%7D.%20By))" + } + ], + "Genes": [ + "GFAP", + "ALDH1L1" + ] + }, + { + "ontology_id": "GO:0050808", + "name": "synapse organization", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Lin et al., Nat Neurosci 2017", + "id": "10.1038/nn.4493", + "type": "DOI", + "notes": "Astrocyte subpopulations support synaptogenesis; analogous subpopulations appear in glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5824716/#:~:text=show%20extensive%20molecular%20diversity,of%20specific%20subpopulations%20during%20tumor))" + } + ], + "Genes": [ + "GFAP", + "GJA1", + "CRB2" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0045111", + "name": "intermediate filament cytoskeleton", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Potokar et al., Diversity of Intermediate Filaments in Astrocytes, Cells 2020", + "id": "10.3390/cells9071604", + "type": "DOI", + "notes": "Astrocytes express abundant intermediate filaments (GFAP, vimentin) for structural integrity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7408014/#:~:text=roles%20of%20individual%20intermediate%20filaments,interaction%20between%20the%20cytoskeleton%20and))" + } + ], + "Genes": [ + "GFAP", + "ID4" + ] + } + ], + "predicted_cellular_impact": [ + "Maintenance of glial fibrillary structure", + "Support of astrocytic network and BBB integrity", + "Promotion of an astrocyte-like, reactive state" + ], + "evidence_summary": "ALDH1L1 and GFAP are established astrocyte markers ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5824716/#:~:text=Strategies%20for%20dissecting%20the%20cellular,15%7D.%20By)). GFAP and other cytoskeletal proteins (ID4) indicate astroglial differentiation, while GJA1 and CRB2 mediate gap junction and cell polarity functions. Astrocytic gene expression programs identified in brain persist in GBM, linking to tumor support roles ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5824716/#:~:text=Strategies%20for%20dissecting%20the%20cellular,15%7D.%20By)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5824716/#:~:text=show%20extensive%20molecular%20diversity,of%20specific%20subpopulations%20during%20tumor)).", + "citations": [ + { + "reference": "Lin et al., Nat Neurosci 2017", + "id": "10.1038/nn.4493", + "type": "DOI", + "notes": "Astrocyte markers (Aldh1l1, GFAP) and their malignant counterparts support astrocyte-like programs in glioma" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "GFAP", + "ALDH1L1", + "GJA1", + "ID4", + "CRB2", + "CD44" + ], + "supporting_gene_count": 6, + "required_components_present": true + }, + { + "program_name": "ECM Remodeling", + "description": "Several metalloproteases and adhesion proteins are present that modulate the tumor extracellular matrix. Serine protease inhibitor SERPINA3, matrix modifiers ADAMTS8/15, fibulin-5, spondin-1, collagen COL28A1, and TIMP3 suggest dynamic ECM turnover. This program promotes glioma invasion by altering cell adhesion and degrading ECM barriers.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030198", + "name": "extracellular matrix organization", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Li et al., SERPINA3 facilitates GBM invasion, Oncol Lett 2017", + "id": "10.3892/ol.2017.7275", + "type": "DOI", + "notes": "Upregulated SERPINA3 in glioma promotes GBM invasion by remodeling the ECM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5769378/#:~:text=indicated%20that%20upregulation%20of%20SERPINA3,GBM%20patients%2C%20suggesting%20that%20SERPINA))" + } + ], + "Genes": [ + "ADAMTS8", + "ADAMTS15", + "FBLN5", + "SPON1", + "TIMP3" + ] + }, + { + "ontology_id": "GO:0044297", + "name": "cell migration via ECM", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Li et al., SERPINA3 facilitates GBM invasion, Oncol Lett 2017", + "id": "10.3892/ol.2017.7275", + "type": "DOI", + "notes": "SERPINA3 overexpression is linked to invasive behavior by ECM remodeling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5769378/#:~:text=indicated%20that%20upregulation%20of%20SERPINA3,GBM%20patients%2C%20suggesting%20that%20SERPINA))" + } + ], + "Genes": [ + "ADAMTS8", + "SERPINA3", + "CHI3L2" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005576", + "name": "extracellular region", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Li et al., Oncol Lett 2017", + "id": "10.3892/ol.2017.7275", + "type": "DOI", + "notes": "Secreted protease inhibitors and ECM proteins (e.g., SERPINA3) operate in the extracellular space of GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5769378/#:~:text=indicated%20that%20upregulation%20of%20SERPINA3,GBM%20patients%2C%20suggesting%20that%20SERPINA))" + } + ], + "Genes": [ + "SERPINA3", + "ADAMTS8", + "FBLN5", + "SPON1", + "CHI3L2" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced matrix degradation", + "Reduced adhesion to extracellular scaffold", + "Increased invasive potential of tumor cells" + ], + "evidence_summary": "In GBM, upregulation of SERPINA3 and ADAMTS proteases has been observed; SERPINA3 drives ECM remodeling and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5769378/#:~:text=indicated%20that%20upregulation%20of%20SERPINA3,GBM%20patients%2C%20suggesting%20that%20SERPINA)), and loss of ADAMTS8 enhances invasion (its expression inhibits glioma migration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/37587889/#:~:text=of%20ADAMTS8%20could%20inhibit%20the,The%20upregulation%20of%20ADAMTS8%20could))). Fibulins, TIMP3 and others suggest active ECM turnover and modified adhesion.", + "citations": [ + { + "reference": "Li et al., Oncol Lett 2017", + "id": "10.3892/ol.2017.7275", + "type": "DOI", + "notes": "Evidence that SERPINA3 and ECM proteases promote GBM invasiveness" + }, + { + "reference": "Xiang et al., BBRC 2022", + "id": "10.1016/j.bbrc.2022.01.110", + "type": "DOI", + "notes": "ADAMTS8 is downregulated in glioma; its upregulation inhibits invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/37587889/#:~:text=of%20ADAMTS8%20could%20inhibit%20the,The%20upregulation%20of%20ADAMTS8%20could))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.85, + "supporting_genes": [ + "SERPINA3", + "ADAMTS8", + "ADAMTS15", + "FBLN5", + "SPON1", + "TIMP3", + "COL28A1", + "PAPLN" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Innate Immune/Complement", + "description": "Glioblastomas engage innate immunity and inflammation. Complement factors (C3, MASP1, CFI) and acute-phase proteins (SERPINA3, CHI3L2, LTF) are expressed, signaling an inflammatory microenvironment. Astrocyte reactivity marker C3 suggests immune modulation. This program may influence macrophage polarization and immune evasion.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0006956", + "name": "complement activation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Rosberg et al., Complement C3 in GBM, JCI Insight 2024", + "id": "10.1172/jci.insight.179854", + "type": "DOI", + "notes": "C3 is upregulated in hypoxic GBM, promoting tumor growth via macrophage polarization and correlating with worse outcome ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=a%20strong%20link%20between%20hypoxia,using%20the%20antagonist%20SB290157%20prolonged)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=Complement%20component%203%20,brain%20barrier))" + } + ], + "Genes": [ + "C3", + "MASP1", + "CFI" + ] + }, + { + "ontology_id": "GO:0006954", + "name": "inflammatory response", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Rosberg et al., JCI Insight 2024", + "id": "10.1172/jci.insight.179854", + "type": "DOI", + "notes": "C3a/C3aR signaling triggers cytokine release and M2 macrophage polarization in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=a%20strong%20link%20between%20hypoxia,using%20the%20antagonist%20SB290157%20prolonged))" + } + ], + "Genes": [ + "C3", + "LTF", + "CHI3L2" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005576", + "name": "extracellular region", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Rosberg et al., JCI Insight 2024", + "id": "10.1172/jci.insight.179854", + "type": "DOI", + "notes": "Complement proteins and acute-phase factors are secreted into the glioma microenvironment (C3 in hypoxic niche) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=a%20strong%20link%20between%20hypoxia,using%20the%20antagonist%20SB290157%20prolonged)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=Complement%20component%203%20,brain%20barrier))" + } + ], + "Genes": [ + "C3", + "MASP1", + "CFI", + "LTF", + "CHI3L2" + ] + } + ], + "predicted_cellular_impact": [ + "Activation of complement cascade and inflammation", + "Polarization of macrophages/microglia to tumor-supportive M2 state", + "Immune evasion via immunosuppressive signaling" + ], + "evidence_summary": "C3 and related complement components are elevated in glioblastoma, especially in hypoxic regions, and promote tumor progression by shaping immune responses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=a%20strong%20link%20between%20hypoxia,using%20the%20antagonist%20SB290157%20prolonged)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=Complement%20component%203%20,brain%20barrier)). Glioma cells and reactive astrocytes produce inflammatory mediators (e.g. LTF, CHI3L2, SERPINA3) that modulate the microenvironment.", + "citations": [ + { + "reference": "Rosberg et al., JCI Insight 2024", + "id": "10.1172/jci.insight.179854", + "type": "DOI", + "notes": "Hypoxia-induced C3 expression in GBM tumors drives immunosuppressive M2 macrophage polarization ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=a%20strong%20link%20between%20hypoxia,using%20the%20antagonist%20SB290157%20prolonged)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=Complement%20component%203%20,brain%20barrier))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.75, + "supporting_genes": [ + "C3", + "CFI", + "MASP1", + "LTF", + "CHI3L2" + ], + "supporting_gene_count": 5, + "required_components_present": false + }, + { + "program_name": "Ion Homeostasis", + "description": "Glioma cells modify ion channel and transporter expression to alter membrane potential and ionic balance. Calcium-activated K+ channel (KCNN3), Na+ channel SCN7A, Na/K ATPase (ATP1A2), and various solute carriers (SLC14A1, SLC24A4, SLC44A3) suggest dysregulated ion gradients and membrane excitability. These changes can affect cell volume, excitability, and cell cycle.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0006811", + "name": "ion transport", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Elias et al., Ion Channels in Gliomas, Int J Mol Sci 2023", + "id": "10.3390/ijms24032530", + "type": "DOI", + "notes": "Review of ion channel expression in gliomas; ion transporters are differentially expressed and influence glioma pathophysiology ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9916861/#:~:text=Ion%20channels%20provide%20the%20basis,retain%20the%20ability%20to%20divide))" + } + ], + "Genes": [ + "KCNN3", + "SCN7A", + "ATP1A2", + "SLC24A4", + "SLC14A1", + "SLC44A3", + "TTYH1", + "ATP13A4" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005886", + "name": "plasma membrane", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Elias et al., Int J Mol Sci 2023", + "id": "10.3390/ijms24032530", + "type": "DOI", + "notes": "Ion channels and transporters are localized to the cell membrane, where they affect glioma cell ionic balance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9916861/#:~:text=Ion%20channels%20provide%20the%20basis,retain%20the%20ability%20to%20divide))" + } + ], + "Genes": [ + "KCNN3", + "SCN7A", + "ATP1A2", + "SLC24A4", + "SLC14A1", + "SLC44A3", + "TTYH1", + "ATP13A4" + ] + } + ], + "predicted_cellular_impact": [ + "Altered membrane potential regulation", + "Modified Ca2+ signaling and cell cycle control", + "Adapted cell volume regulation aiding invasion" + ], + "evidence_summary": "Glioma cells show dysregulated ion channel expression; for example, KCNN3 (SK3) channels are implicated in GBM cell migration and proliferation. Broadly, ion transport genes are enriched and affect proliferation and invasion in glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9916861/#:~:text=Ion%20channels%20provide%20the%20basis,retain%20the%20ability%20to%20divide)).", + "citations": [ + { + "reference": "Elias et al., Int J Mol Sci 2023", + "id": "10.3390/ijms24032530", + "type": "DOI", + "notes": "Comprehensive review linking ion channel dysregulation to glioma growth, invasion, and therapy resistance" + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "KCNN3", + "SCN7A", + "ATP1A2", + "SLC24A4", + "SLC14A1", + "SLC44A3", + "TTYH1", + "ATP13A4" + ], + "supporting_gene_count": 8, + "required_components_present": false + } + ], + "version": "2025-10-07" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_ac_gliosis_like_2 b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_ac_gliosis_like_2 new file mode 100644 index 0000000..46870eb --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_ac_gliosis_like_2 @@ -0,0 +1,505 @@ +{ + "context": { + "cell_type": "astrocyte-derived tumor cell", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "POSTN", + "KIAA1211L", + "CPNE4", + "HMGA2", + "TRPM8", + "CYTOR", + "RGS6", + "RPH3A", + "CCN4", + "ADAMTS9-AS1", + "SPRY1", + "LEF1", + "VAT1L", + "COL22A1", + "MIR4435-2HG", + "AC000065.1", + "CPED1", + "ARHGAP6", + "TRPM3", + "ANGPT1", + "ALK", + "CA2", + "SERPINE1", + "CHRM3-AS2", + "ITGA3", + "KIRREL3", + "RUBCNL", + "SLA", + "CCDC175", + "SHISA6", + "AC064875.1", + "SNED1", + "SPRY4", + "RBPMS", + "EMP1", + "LINC02832", + "LINC02742", + "HOPX", + "IQGAP2", + "GDF15", + "IRAK2", + "ST8SIA5", + "HIVEP3", + "TMEM154", + "COL19A1" + ], + "programs": [ + { + "program_name": "ECM Remodeling and Invasion", + "description": "Upregulation of ECM components and modifiers promotes glioblastoma cell migration and tumor microenvironment remodeling", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_id": "GO:0030198", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhou et al., Nat Cell Biol (2015)", + "id": "PMID:25580734", + "type": "PMID", + "notes": "POSTN secreted by glioma stem cells recruits immune cells to tumor stroma, implicating ECM interactions ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4312504/#:~:text=TAMs%20in%20GBMs%20are%20not,mediated%20TAM%20recruitment))" + }, + { + "reference": "Seker et al., Cancers (Basel) (2019)", + "id": "PMID:31731490", + "type": "PMID", + "notes": "SERPINE1 modulates cell adhesion and matrix, regulating GBM dispersal ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=derived%20orthotopic%20GBM%20model,invasive%20therapy%20design))" + } + ], + "Genes": [ + "POSTN", + "CCN4", + "SERPINE1" + ] + }, + { + "name": "cell migration", + "ontology_id": "GO:0016477", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Seker et al., Cancers (Basel) (2019)", + "id": "PMID:31731490", + "type": "PMID", + "notes": "SERPINE1 drives glioblastoma cell dispersal (migration) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=derived%20orthotopic%20GBM%20model,invasive%20therapy%20design))" + } + ], + "Genes": [ + "POSTN", + "SERPINE1" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_id": "GO:0031012", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Zhou et al., Nat Cell Biol (2015)", + "id": "PMID:25580734", + "type": "PMID", + "notes": "POSTN is secreted and localized to ECM regions in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4312504/#:~:text=TAMs%20in%20GBMs%20are%20not,mediated%20TAM%20recruitment))" + }, + { + "reference": "Seker et al., Cancers (Basel) (2019)", + "id": "PMID:31731490", + "type": "PMID", + "notes": "SERPINE1 affects cell-surface interactions with matrix during invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=derived%20orthotopic%20GBM%20model,invasive%20therapy%20design))" + } + ], + "Genes": [ + "POSTN", + "CCN4", + "SERPINE1" + ] + } + ], + "predicted_cellular_impact": [ + "enhanced extracellular matrix deposition", + "increased glioblastoma cell motility and invasion" + ], + "evidence_summary": "Glioblastoma cells often overexpress ECM and adhesion factors. POSTN is secreted by glioma stem-like cells to recruit TAMs and enhance invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4312504/#:~:text=TAMs%20in%20GBMs%20are%20not,mediated%20TAM%20recruitment)). Similarly, SERPINE1 (PAI-1) is highly upregulated in dispersive GBM cells, and its inhibition reduces invasion and adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=derived%20orthotopic%20GBM%20model,invasive%20therapy%20design)). CCN4 (WISP1) is another matricellular protein, likely reinforcing this program. Together, these genes point to a robust ECM remodeling/invasion program in GBM.", + "citations": [ + { + "reference": "Zhou et al., Nat Cell Biol (2015)", + "id": "PMID:25580734", + "type": "PMID", + "notes": "POSTN secreted by glioma stem cells recruits TAMs, linking ECM to tumor-supportive microenvironment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4312504/#:~:text=TAMs%20in%20GBMs%20are%20not,mediated%20TAM%20recruitment))" + }, + { + "reference": "Seker et al., Cancers (Basel) (2019)", + "id": "PMID:31731490", + "type": "PMID", + "notes": "SERPINE1 identified as a key regulator of GBM cell dispersal/invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=derived%20orthotopic%20GBM%20model,invasive%20therapy%20design))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.85, + "supporting_genes": [ + "POSTN", + "CCN4", + "SERPINE1" + ], + "supporting_gene_count": 3, + "required_components_present": false + }, + { + "program_name": "Ion Channel\u2013Mediated Calcium Signaling", + "description": "Upregulated TRPM channels drive Ca^{2+} influx, promoting GBM cell migration and survival under stress", + "atomic_biological_processes": [ + { + "name": "calcium ion transmembrane transport", + "ontology_id": "GO:0070588", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Klumpp et al., Oncotarget (2017)", + "id": "PMID:29221175", + "type": "PMID", + "notes": "TRPM8 upregulation in GBM increases Ca^{2+} entry, affecting cell migration and survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=moving%20the%20glioblastoma%20cell%20along,demonstrated%20to%20be%20required%20for))" + } + ], + "Genes": [ + "TRPM8", + "TRPM3" + ] + }, + { + "name": "cell migration", + "ontology_id": "GO:0016477", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Klumpp et al., Oncotarget (2017)", + "id": "PMID:29221175", + "type": "PMID", + "notes": "TRPM8 channel activation accelerates glioblastoma cell migration and chemotaxis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=moving%20the%20glioblastoma%20cell%20along,demonstrated%20to%20be%20required%20for))" + } + ], + "Genes": [ + "TRPM8" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "ion channel complex", + "ontology_id": "GO:0034702", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Klumpp et al., Oncotarget (2017)", + "id": "PMID:29221175", + "type": "PMID", + "notes": "TRPM8 is a plasma membrane Ca^{2+}-permeable TRP channel overexpressed in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore))" + } + ], + "Genes": [ + "TRPM8", + "TRPM3" + ] + } + ], + "predicted_cellular_impact": [ + "enhanced intracellular Ca^{2+} signaling", + "increased cell motility and chemotaxis", + "heightened radioresistance" + ], + "evidence_summary": "Glioblastoma cells often overexpress TRP channels. TRPM8 is upregulated in GBM and mediates Ca^{2+} influx that promotes BK channel activity, migration, and survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=moving%20the%20glioblastoma%20cell%20along,demonstrated%20to%20be%20required%20for)). Inhibition or knockdown of TRPM8 reduces migration, impairs Ca^{2+}-dependent signaling, and radiosensitizes GBM cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=moving%20the%20glioblastoma%20cell%20along,demonstrated%20to%20be%20required%20for)). Conversely, loss of TRPM3 (via promoter methylation) correlates with increased stemness and migration, suggesting TRPM3 normally restrains malignancy ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8076903/#:~:text=Moreover%2C%20the%20loss%20of%20TRPM3%2C,TRPM3%20and%20the%20indirect%20regulatory)). Together, an imbalance of TRPM channels modulates GBM invasiveness and therapy resistance.", + "citations": [ + { + "reference": "Klumpp et al., Oncotarget (2017)", + "id": "PMID:29221175", + "type": "PMID", + "notes": "TRPM8 mediates Ca^{2+}-entry, promoting glioblastoma cell migration and radioresistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=moving%20the%20glioblastoma%20cell%20along,demonstrated%20to%20be%20required%20for))" + }, + { + "reference": "Klumpp et al., Oncotarget (2017)", + "id": "PMID:29221175", + "type": "PMID", + "notes": "Pharmacologic or genetic TRPM8 inhibition slows chemotaxis and sensitizes GBM cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=moving%20the%20glioblastoma%20cell%20along,demonstrated%20to%20be%20required%20for))" + }, + { + "reference": "Gkika et al., Cancers (2020)", + "id": "PMID:32676833", + "type": "PMID", + "notes": "Loss of TRPM3 (and host miR-204) in high-grade gliomas is associated with enhanced stemness and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8076903/#:~:text=Moreover%2C%20the%20loss%20of%20TRPM3%2C,TRPM3%20and%20the%20indirect%20regulatory))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": [ + "TRPM8", + "TRPM3" + ], + "supporting_gene_count": 2, + "required_components_present": false + }, + { + "program_name": "Receptor Tyrosine Kinase/\u03b2-Catenin Signaling", + "description": "Dysregulated RTK signaling and Wnt pathway effectors promote proliferation, stemness, and EMT in GBM", + "atomic_biological_processes": [ + { + "name": "receptor tyrosine kinase signaling pathway", + "ontology_id": "GO:0007169", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Meyer et al., Clin Cancer Res (2023)", + "id": "PMID:36780194", + "type": "PMID", + "notes": "ALK fusions in GBMs activate ERK and STAT3 pro-growth pathways ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10363218/#:~:text=ALK%20fusions%20were%20present%20as,brain%20development%20was%20seen%20in))" + }, + { + "reference": "Park et al., IBRO Neurosc Rep (2022)", + "id": "PMID:35910677", + "type": "PMID", + "notes": "SPRY1 modulates RTK signaling in glioma stem cells, affecting stemness and growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9334334/#:~:text=glioma%20cells%2C%20and%20differentiated%20glioma,stemness%20and%20aggressiveness%20of%20GBM))" + } + ], + "Genes": [ + "ALK", + "SPRY1", + "SPRY4" + ] + }, + { + "name": "MAPK cascade", + "ontology_id": "GO:0000165", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Sun et al., PubMed (2020)", + "id": "PMID:32618153", + "type": "PMID", + "notes": "SPRY4 suppresses GBM invasion by blocking FGFR/Ras-ERK signaling and MMP9 expression ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/32618153/#:~:text=Results%3A%20SPRY4%20mRNAs%20in%20GBMs,induced%20MMP9%20expression))" + }, + { + "reference": "Meyer et al., Clin Cancer Res (2023)", + "id": "PMID:36780194", + "type": "PMID", + "notes": "Novel ALK fusions in infant and adult GBM promote ERK1/2 activation and tumor transformation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10363218/#:~:text=ALK%20fusions%20were%20present%20as,brain%20development%20was%20seen%20in))" + } + ], + "Genes": [ + "ALK", + "SPRY1", + "SPRY4" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_id": "GO:0005886", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Meyer et al., Clin Cancer Res (2023)", + "id": "PMID:36780194", + "type": "PMID", + "notes": "ALK encodes a receptor tyrosine kinase acting at the cell membrane in brain tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10363218/#:~:text=ALK%20fusions%20were%20present%20as,brain%20development%20was%20seen%20in))" + } + ], + "Genes": [ + "ALK" + ] + } + ], + "predicted_cellular_impact": [ + "elevated MAPK/ERK and STAT signaling", + "increased cancer stem cell-like properties", + "suppressed apoptosis", + "enhanced invasion" + ], + "evidence_summary": "Genes in this cluster mediate RTK and Wnt signaling. ALK oncogenic fusions activate downstream ERK1/2 and STAT3 pathways in gliomas ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10363218/#:~:text=ALK%20fusions%20were%20present%20as,brain%20development%20was%20seen%20in)). Sprouty proteins are endogenous modulators of RTK signaling; SPRY4 acts as a suppressor of FGFR/Ras-ERK and MMP9 (reducing invasion) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/32618153/#:~:text=Results%3A%20SPRY4%20mRNAs%20in%20GBMs,induced%20MMP9%20expression)), whereas SPRY1 is implicated in sustaining glioma stem cell growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9334334/#:~:text=glioma%20cells%2C%20and%20differentiated%20glioma,stemness%20and%20aggressiveness%20of%20GBM)). LEF1 (below) is a TCF family TF in Wnt/\u03b2-catenin. Overall, this program suggests hyperactive RTK-MAPK and Wnt pathways driving proliferation and stemness in GBM.", + "citations": [ + { + "reference": "Meyer et al., Clin Cancer Res (2023)", + "id": "PMID:36780194", + "type": "PMID", + "notes": "ALK gene rearrangements activate MAPK/ERK and STAT3 pathways in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10363218/#:~:text=ALK%20fusions%20were%20present%20as,brain%20development%20was%20seen%20in))" + }, + { + "reference": "Sun et al., Exp Ther Med (2020)", + "id": "PMID:32618153", + "type": "PMID", + "notes": "SPRY4 inhibits ERK phosphorylation and MMP9 to suppress GBM invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/32618153/#:~:text=Results%3A%20SPRY4%20mRNAs%20in%20GBMs,induced%20MMP9%20expression))" + }, + { + "reference": "Park et al., IBRO Neurosci Reports (2022)", + "id": "PMID:35910677", + "type": "PMID", + "notes": "SPRY1 is highly expressed in glioma stem cells and promotes their proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9334334/#:~:text=glioma%20cells%2C%20and%20differentiated%20glioma,stemness%20and%20aggressiveness%20of%20GBM))" + } + ], + "confidence_score": 0.75, + "significance_score": 0.7, + "supporting_genes": [ + "ALK", + "SPRY1", + "SPRY4" + ], + "supporting_gene_count": 3, + "required_components_present": false + }, + { + "program_name": "Proliferation and Survival Signaling", + "description": "Activation of PI3K/Akt pathways fosters GBM growth and survival", + "atomic_biological_processes": [ + { + "name": "positive regulation of cell proliferation", + "ontology_id": "GO:0008284", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhang et al., Cell Physiol Biochem (2019)", + "id": "PMID:31233190", + "type": "PMID", + "notes": "EMP1 knockdown reduces GBM cell proliferation in vitro ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/31233190/#:~:text=Rembrandt%20and%20CGGA%20databases%20for,for%20the%20treatment%20of%20GBM))" + } + ], + "Genes": [ + "EMP1" + ] + }, + { + "name": "PI3K signaling", + "ontology_id": "GO:0014065", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhang et al., Cell Physiol Biochem (2019)", + "id": "PMID:31233190", + "type": "PMID", + "notes": "EMP1 drives GBM progression via the PI3K/Akt/mTOR pathway ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/31233190/#:~:text=Rembrandt%20and%20CGGA%20databases%20for,for%20the%20treatment%20of%20GBM))" + } + ], + "Genes": [ + "EMP1" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "increased PI3K/AKT pathway activation", + "enhanced proliferation and invasive potential", + "resistance to apoptosis" + ], + "evidence_summary": "EMP1 (epithelial membrane protein 1) is overexpressed in higher-grade gliomas and promotes proliferation and invasion via activation of the PI3K/AKT/mTOR axis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/31233190/#:~:text=Rembrandt%20and%20CGGA%20databases%20for,for%20the%20treatment%20of%20GBM)). Knockdown of EMP1 impairs GBM cell growth and reduces invasion, indicating its role in sustaining tumor survival and dissemination ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/31233190/#:~:text=Rembrandt%20and%20CGGA%20databases%20for,for%20the%20treatment%20of%20GBM)).", + "citations": [ + { + "reference": "Zhang et al., Cell Physiol Biochem (2019)", + "id": "PMID:31233190", + "type": "PMID", + "notes": "EMP1 is upregulated in GBM, and its silencing inhibits proliferation and invasion via PI3K/AKT pathway ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/31233190/#:~:text=Rembrandt%20and%20CGGA%20databases%20for,for%20the%20treatment%20of%20GBM))" + } + ], + "confidence_score": 0.5, + "significance_score": 0.6, + "supporting_genes": [ + "EMP1" + ], + "supporting_gene_count": 1, + "required_components_present": false + }, + { + "program_name": "Wnt/\u03b2-Catenin Pathway", + "description": "Constitutive Wnt signaling through LEF1 drives transcription of growth and EMT genes", + "atomic_biological_processes": [ + { + "name": "canonical Wnt signaling pathway", + "ontology_id": "GO:0060070", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Pe\u0107ina-\u0160laus and Kafka, CNS Oncol (2015)", + "id": "PMID:26497968", + "type": "PMID", + "notes": "LEF1 is highly expressed in GBM and marks active canonical Wnt/\u03b2-catenin signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6083946/#:~:text=factors,045%29%2C%20LEF1))" + } + ], + "Genes": [ + "LEF1" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "enhanced transcription of Wnt target genes (e.g., Cyclin D1, c-Myc)", + "maintenance of stem-like and proliferative state" + ], + "evidence_summary": "LEF1 is a TCF/LEF family transcription factor that mediates Wnt/\u03b2-catenin signaling. Studies show LEF1 is upregulated in GBM cells, with strong nuclear LEF1 expression distinguishing high-grade gliomas ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6083946/#:~:text=factors,045%29%2C%20LEF1)). Active Wnt/LEF1 signaling induces proliferative and EMT-related genes, contributing to GBM aggressiveness. ", + "citations": [ + { + "reference": "Pe\u0107ina-\u0160laus and Kafka, CNS Oncol (2015)", + "id": "PMID:26497968", + "type": "PMID", + "notes": "LEF1 expression is significantly higher in GBM than in lower-grade astrocytomas, indicating activated Wnt signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6083946/#:~:text=factors,045%29%2C%20LEF1))" + } + ], + "confidence_score": 0.5, + "significance_score": 0.6, + "supporting_genes": [ + "LEF1" + ], + "supporting_gene_count": 1, + "required_components_present": false + }, + { + "program_name": "Angiogenesis", + "description": "Upregulated angiopoietin and extracellular cues promote tumor vascularization", + "atomic_biological_processes": [ + { + "name": "angiogenesis", + "ontology_id": "GO:0001525", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Rong et al., Cancer Res (2000)", + "id": "PMID:11304469", + "type": "PMID", + "notes": "Angiopoietin-1 (ANGPT1) secreted by glioma cells induces endothelial cell reorganization and cord formation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/11304469/#:~:text=glioblastoma%20cell%20lines%20producing%20Ang1,the%20differentiation%20phase%20of%20angiogenesis))" + } + ], + "Genes": [ + "ANGPT1" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "enhanced blood vessel formation", + "improved nutrient supply to tumor", + "cooperative signaling with VEGF" + ], + "evidence_summary": "ANGPT1 is a secreted ligand for the Tie2 receptor on endothelial cells. It is expressed in GBM and promotes the maturation and organization of new blood vessels ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/11304469/#:~:text=glioblastoma%20cell%20lines%20producing%20Ang1,the%20differentiation%20phase%20of%20angiogenesis)). In vitro, exposure of endothelial cells to ANGPT1 induces spreading and formation of capillary-like structures ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/11304469/#:~:text=glioblastoma%20cell%20lines%20producing%20Ang1,the%20differentiation%20phase%20of%20angiogenesis)). Thus, increased ANGPT1 suggests a pro-angiogenic program in malignant gliomas.", + "citations": [ + { + "reference": "Rong et al., Cancer Res (2000)", + "id": "PMID:11304469", + "type": "PMID", + "notes": "ANGPT1 produced by GBM cells drives differentiation of ECs into cordlike structures, indicating a pro-angiogenic role ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/11304469/#:~:text=glioblastoma%20cell%20lines%20producing%20Ang1,the%20differentiation%20phase%20of%20angiogenesis))" + } + ], + "confidence_score": 0.4, + "significance_score": 0.5, + "supporting_genes": [ + "ANGPT1" + ], + "supporting_gene_count": 1, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_ac_neuronal_like b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_ac_neuronal_like new file mode 100644 index 0000000..b1438b1 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_ac_neuronal_like @@ -0,0 +1,411 @@ +{ + "context": { + "cell_type": "astrocytes", + "disease": "Glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "LINC02235", + "AC037486.1", + "PCDH11X", + "LINC01829", + "AL591043.2", + "ZNF423", + "ADAMTS18", + "AL133538.1", + "DOCK2", + "SCN1A-AS1", + "AL022068.1", + "SEPTIN14", + "SGCZ", + "ADAM28", + "RYR2", + "DOCK8", + "ACER2", + "AC128687.3", + "AC120193.1", + "OLR1", + "AC110296.1", + "AC109466.1", + "SPOCK3", + "ST6GALNAC5", + "AL136441.1", + "MLIP", + "AL158077.2", + "AP001021.3", + "CCDC85A", + "CD96", + "NRK", + "C8orf37-AS1", + "PCDH7", + "PLD1", + "CHRNA7", + "CLRN1", + "MYO1D", + "RMST", + "CNTNAP2", + "PURPL", + "RALYL", + "AL445426.1", + "RCAN2", + "AL392023.2", + "RELN", + "AL360091.3", + "AC091946.1", + "LRRIQ1", + "CD163", + "SYN3", + "IL1RAPL1" + ], + "programs": [ + { + "program_name": "Myeloid Infiltration", + "description": "Genes such as DOCK2, DOCK8, CD96, and CD163 indicate activation and recruitment of immune myeloid cells (e.g., microglia/macrophages) into glioblastoma. This includes signaling for immune cell migration and suppressive macrophage function.", + "atomic_biological_processes": [ + { + "name": "immune response", + "ontology_id": "GO:0006955", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wang et al., Front Mol Biosci 2022 (Insights from DOCK2 in cell function and pathophysiology)", + "id": "DOI:10.3389/fmolb.2022.997659", + "type": "DOI", + "notes": "DOCK2 regulates immune cell migration and activation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9559381/#:~:text=Dedicator%20of%20cytokinesis%202%20,involved%20in%20the%20development%20and))" + }, + { + "reference": "Namekata et al., J Biol Chem 2019", + "id": "DOI:10.1074/jbc.RA119.007645", + "type": "DOI", + "notes": "DOCK8 is expressed in microglia and mediates immune cell migration and phagocytosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6737224/#:~:text=In%20this%20study%2C%20we%20report,3D%20images%20of%20retinal%20microglia))" + } + ], + "Genes": [ + "DOCK2", + "DOCK8", + "CD96", + "CD163" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "immune synapse", + "ontology_id": "GO:0001772", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Wang et al., Front Mol Biosci 2022 (Insights from DOCK2 in cell function and pathophysiology)", + "id": "DOI:10.3389/fmolb.2022.997659", + "type": "DOI", + "notes": "DOCK2 is involved in cytoskeletal reorganization at immune synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9559381/#:~:text=Dedicator%20of%20cytokinesis%202%20,involved%20in%20the%20development%20and))" + }, + { + "reference": "Namekata et al., J Biol Chem 2019", + "id": "DOI:10.1074/jbc.RA119.007645", + "type": "DOI", + "notes": "DOCK8 and CD96 are expressed on microglia/NK cells at immune synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6737224/#:~:text=In%20this%20study%2C%20we%20report,3D%20images%20of%20retinal%20microglia)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7338376/#:~:text=Increasingly%2C%20CD96%20is%20emerging%20as,and%20activation%20of%20participating%20cells))" + } + ], + "Genes": [ + "DOCK2", + "DOCK8", + "CD96", + "CD163" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced myeloid/microglial infiltration into tumor", + "Immune checkpoint activation (e.g., CD96 signaling) suppressing anti-tumor immunity", + "Increased expression of macrophage scavenger receptors" + ], + "evidence_summary": "DOCK2 and DOCK8 mediate migration and activation of immune cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9559381/#:~:text=Dedicator%20of%20cytokinesis%202%20,involved%20in%20the%20development%20and)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6737224/#:~:text=In%20this%20study%2C%20we%20report,3D%20images%20of%20retinal%20microglia)). CD163 is a scavenger receptor marking immunosuppressive M2-like macrophages in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12070867/#:~:text=CD163%2B%20macrophages%20from%20expressing%20proinflammatory,cytokines)). CD96 is an NK/T cell checkpoint upregulated in glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7338376/#:~:text=Increasingly%2C%20CD96%20is%20emerging%20as,and%20activation%20of%20participating%20cells)). Together, these genes suggest glioblastoma is associated with macrophage/microglial infiltration and immune suppression.", + "citations": [ + { + "reference": "Wang et al., Front Mol Biosci 2022", + "id": "DOI:10.3389/fmolb.2022.997659", + "type": "DOI", + "notes": "DOCK2 regulates immune cell migration and activation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9559381/#:~:text=Dedicator%20of%20cytokinesis%202%20,involved%20in%20the%20development%20and))" + }, + { + "reference": "Namekata et al., J Biol Chem 2019", + "id": "DOI:10.1074/jbc.RA119.007645", + "type": "DOI", + "notes": "DOCK8 expressed in microglia regulates migration and phagocytosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6737224/#:~:text=In%20this%20study%2C%20we%20report,3D%20images%20of%20retinal%20microglia))" + }, + { + "reference": "Fuse et al., Cancers (Basel) 2025", + "id": "DOI:10.3390/cancers17091457", + "type": "DOI", + "notes": "CD163+ macrophages have an immunosuppressive, tumor-promoting role in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12070867/#:~:text=CD163%2B%20macrophages%20from%20expressing%20proinflammatory,cytokines))" + }, + { + "reference": "Gibney et al., Front Bioeng Biotechnol 2020", + "id": "DOI:10.3389/fbioe.2020.00592", + "type": "DOI", + "notes": "CD96 is an immune checkpoint that negatively regulates NK/T cell anti-tumor function ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7338376/#:~:text=Increasingly%2C%20CD96%20is%20emerging%20as,and%20activation%20of%20participating%20cells))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.8, + "supporting_genes": [ + "DOCK2", + "DOCK8", + "CD96", + "CD163" + ], + "supporting_gene_count": 4, + "required_components_present": false + }, + { + "program_name": "Neuronal Synapses", + "description": "Genes in this program encode proteins for neuronal connectivity and synaptic function. RELN is an ECM protein controlling neuronal migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8028296/#:~:text=aggressiveness,are%20silenced%20in%20glioblastoma%20as)). IL1RAPL1, CNTNAP2, and PCDH7/11X mediate synapse formation/adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623287/#:~:text=Autism%20Mediates%20Synapse%20Formation%20by,with%20Protein%20Tyrosine%20Phosphatase%20%CE%B4)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4423902/#:~:text=CNTNAP2%20belongs%20to%20the%20NEUREXIN,it%20is%20unknown%20if%20CNTNAP2)). SYN3 is a synaptic vesicle protein for neurotransmitter release ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12040043/#:~:text=Synapsin%20III%20is%20the%20most,demonstrate%20that%20synapsin%20III%20regulates)). Together they implicate altered synaptic signaling.", + "atomic_biological_processes": [ + { + "name": "synapse assembly", + "ontology_id": "GO:0007416", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Yoshida et al., J Neurosci 2011", + "id": "DOI:10.1523/JNEUROSCI.2136-11.2011", + "type": "DOI", + "notes": "IL1RAPL1 mediates excitatory synapse formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623287/#:~:text=IL1RAPL1%20mediates%20synapse%20formation%20through,shared%20by%20these%20mental%20disorders))" + }, + { + "reference": "Gdalyahu et al., PLoS One 2015", + "id": "DOI:10.1371/journal.pone.0125633", + "type": "DOI", + "notes": "CNTNAP2 (Caspr2) is a neurexin-family adhesion protein stabilizing synaptic contacts ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4423902/#:~:text=CNTNAP2%20belongs%20to%20the%20NEUREXIN,it%20is%20unknown%20if%20CNTNAP2))" + } + ], + "Genes": [ + "RELN", + "IL1RAPL1", + "CNTNAP2", + "SYN3", + "PCDH7", + "PCDH11X", + "CHRNA7" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "synapse", + "ontology_id": "GO:0045202", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Yoshida et al., J Neurosci 2011", + "id": "DOI:10.1523/JNEUROSCI.2136-11.2011", + "type": "DOI", + "notes": "IL1RAPL1 localizes to the dendritic synapse and mediates trans-synaptic adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623287/#:~:text=IL1RAPL1%20mediates%20synapse%20formation%20through,shared%20by%20these%20mental%20disorders))" + }, + { + "reference": "Gdalyahu et al., PLoS One 2015", + "id": "DOI:10.1371/journal.pone.0125633", + "type": "DOI", + "notes": "CNTNAP2 is present in the synapse and required for spine stability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4423902/#:~:text=CNTNAP2%20belongs%20to%20the%20NEUREXIN,it%20is%20unknown%20if%20CNTNAP2))" + } + ], + "Genes": [ + "RELN", + "IL1RAPL1", + "CNTNAP2", + "SYN3", + "PCDH7", + "PCDH11X", + "CHRNA7" + ] + } + ], + "predicted_cellular_impact": [ + "Altered synapse formation and stability", + "Changes in excitatory neurotransmission", + "Modified neuronal adhesion and network connectivity" + ], + "evidence_summary": "RELN controls neuronal migration and is silenced in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8028296/#:~:text=aggressiveness,are%20silenced%20in%20glioblastoma%20as)). IL1RAPL1 mediates excitatory synapse formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623287/#:~:text=IL1RAPL1%20mediates%20synapse%20formation%20through,shared%20by%20these%20mental%20disorders)). CNTNAP2 is a membrane protein stabilizing dendritic spines ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4423902/#:~:text=CNTNAP2%20belongs%20to%20the%20NEUREXIN,it%20is%20unknown%20if%20CNTNAP2)). SYN3 is a synaptic vesicle protein for neurotransmitter release ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12040043/#:~:text=Synapsin%20III%20is%20the%20most,demonstrate%20that%20synapsin%20III%20regulates)). These suggest a neuronal synaptic program impacting glioblastoma cell behavior.", + "citations": [ + { + "reference": "Schulze et al., Brain Pathol 2018", + "id": "DOI:10.1111/bpa.12584", + "type": "DOI", + "notes": "RELN is an extracellular protein that regulates neuronal migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8028296/#:~:text=aggressiveness,are%20silenced%20in%20glioblastoma%20as))" + }, + { + "reference": "Yoshida et al., J Neurosci 2011", + "id": "DOI:10.1523/JNEUROSCI.2136-11.2011", + "type": "DOI", + "notes": "IL1RAPL1 mediates synapse formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623287/#:~:text=IL1RAPL1%20mediates%20synapse%20formation%20through,shared%20by%20these%20mental%20disorders))" + }, + { + "reference": "Gdalyahu et al., PLoS One 2015", + "id": "DOI:10.1371/journal.pone.0125633", + "type": "DOI", + "notes": "CNTNAP2 is a synaptic adhesion protein for dendritic spines ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4423902/#:~:text=CNTNAP2%20belongs%20to%20the%20NEUREXIN,it%20is%20unknown%20if%20CNTNAP2))" + }, + { + "reference": "Ferreira et al., J Neurosci 2004", + "id": "PMID:12040043", + "type": "PMID", + "notes": "Synapsin III is part of synaptic vesicles, essential for neurotransmitter release ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12040043/#:~:text=Synapsin%20III%20is%20the%20most,demonstrate%20that%20synapsin%20III%20regulates))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "RELN", + "IL1RAPL1", + "CNTNAP2", + "SYN3", + "PCDH7", + "PCDH11X", + "CHRNA7" + ], + "supporting_gene_count": 7, + "required_components_present": false + }, + { + "program_name": "ECM Remodeling", + "description": "This program includes extracellular matrix modifiers and adhesion proteins. ADAMTS18 and ADAM28 are metalloproteinases that remodel the ECM and can promote invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=by%20gene%20expression%2C%20intracytoplasmic%20and,and%20invasion%2C%20although%20the%20precise)). SPOCK3 and SGCZ are ECM-associated proteins. PCDH7 and PCDH11X are calcium-dependent adhesion molecules. Together these genes suggest enhanced ECM breakdown and altered adhesion in GBM.", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_id": "GO:0030198", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Xie et al., Mol Biol Rep 2015", + "id": "PMID:25987468", + "type": "PMID", + "notes": "ADAM family proteases are often overexpressed in tumors, promoting matrix remodeling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=by%20gene%20expression%2C%20intracytoplasmic%20and,and%20invasion%2C%20although%20the%20precise))" + } + ], + "Genes": [ + "ADAMTS18", + "ADAM28", + "SPOCK3", + "SGCZ", + "PCDH7", + "PCDH11X" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_id": "GO:0031012", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Xie et al., Mol Biol Rep 2015", + "id": "PMID:25987468", + "type": "PMID", + "notes": "ADAM proteases act in the extracellular matrix to regulate cell invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=by%20gene%20expression%2C%20intracytoplasmic%20and,and%20invasion%2C%20although%20the%20precise))" + } + ], + "Genes": [ + "ADAMTS18", + "ADAM28", + "SPOCK3", + "SGCZ", + "PCDH7", + "PCDH11X" + ] + } + ], + "predicted_cellular_impact": [ + "Increased tumor cell invasion and migration", + "Enhanced integrin/ECM signaling", + "Altered cell adhesion properties" + ], + "evidence_summary": "ADAM family metalloproteinases (ADAMTS18, ADAM28) modify the ECM and are linked to tumor invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=by%20gene%20expression%2C%20intracytoplasmic%20and,and%20invasion%2C%20although%20the%20precise)). Protocadherins and glycoproteins like SPOCK3 and SGCZ contribute to cell-matrix adhesion. Dysregulation of these components likely facilitates extracellular matrix remodeling and increased GBM cell motility.", + "citations": [ + { + "reference": "Xie et al., Mol Biol Rep 2015", + "id": "PMID:25987468", + "type": "PMID", + "notes": "Review discussing ADAM proteases in cancer progression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=by%20gene%20expression%2C%20intracytoplasmic%20and,and%20invasion%2C%20although%20the%20precise))" + } + ], + "confidence_score": 0.6, + "significance_score": 0.8, + "supporting_genes": [ + "ADAMTS18", + "ADAM28", + "SPOCK3", + "SGCZ", + "PCDH7", + "PCDH11X" + ], + "supporting_gene_count": 6, + "required_components_present": false + }, + { + "program_name": "Differentiation Signaling", + "description": "This program includes developmental transcriptional regulators. ZNF423 (Zfp423) is a transcription factor required for neural precursor differentiation via BMP/SMAD signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4773478/#:~:text=The%20dissection%20of%20these%20networks,a%20novel%20synergic%20circuit%20through)). RCAN2 regulates calcineurin-NFAT signaling, impacting neuronal development. This suggests dysregulation of neural differentiation pathways in glioblastoma.", + "atomic_biological_processes": [ + { + "name": "neuron differentiation", + "ontology_id": "GO:0030182", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Signaroldi et al., Nat Commun 2016", + "id": "DOI:10.1038/ncomms10753", + "type": "DOI", + "notes": "Zfp423 (human ZNF423) is a master regulator of neural differentiation and its loss impairs gliomagenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4773478/#:~:text=The%20dissection%20of%20these%20networks,a%20novel%20synergic%20circuit%20through))" + } + ], + "Genes": [ + "ZNF423", + "RCAN2" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "ontology_id": "GO:0005634", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Signaroldi et al., Nat Commun 2016", + "id": "DOI:10.1038/ncomms10753", + "type": "DOI", + "notes": "ZNF423 is a nuclear transcription factor controlling glioblastoma differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4773478/#:~:text=The%20dissection%20of%20these%20networks,a%20novel%20synergic%20circuit%20through))" + } + ], + "Genes": [ + "ZNF423", + "RCAN2" + ] + } + ], + "predicted_cellular_impact": [ + "Impaired differentiation of glial precursor cells", + "Altered BMP/SMAD signaling and neuronal developmental gene expression" + ], + "evidence_summary": "ZNF423 is silenced in glioma and is needed for proper neural differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4773478/#:~:text=The%20dissection%20of%20these%20networks,a%20novel%20synergic%20circuit%20through)). Loss of ZNF423 correlates with worse GBM prognosis. RCAN2 modulates calcineurin-NFAT pathways affecting neuronal development. Their dysregulation suggests failure of normal differentiation signaling in glioblastoma cells.", + "citations": [ + { + "reference": "Signaroldi et al., Nat Commun 2016", + "id": "DOI:10.1038/ncomms10753", + "type": "DOI", + "notes": "ZNF423 downregulation is implicated in glioma by blocking differentiation via BMP signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4773478/#:~:text=The%20dissection%20of%20these%20networks,a%20novel%20synergic%20circuit%20through))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.5, + "supporting_genes": [ + "ZNF423", + "RCAN2" + ], + "supporting_gene_count": 2, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_gliosis b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_gliosis new file mode 100644 index 0000000..cbeb45f --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_gliosis @@ -0,0 +1,488 @@ +{ + "context": { + "cell_type": "astrocyte", + "disease": "Glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "SERPINE1", + "EMP1", + "SPOCD1", + "ARHGAP29", + "IL1R1", + "COL6A2", + "MYOF", + "F13A1", + "CXCL10", + "CHI3L1", + "MET", + "IL6", + "SAA2", + "BIRC3", + "MCTP2", + "ANGPTL4", + "ICAM1", + "CCN1", + "CAV1", + "APLN", + "FOSL1", + "SNTG2-AS1", + "TPD52L1", + "SAA4", + "KRT75", + "NFATC2", + "COL5A1", + "AC243829.2", + "CLCF1", + "ARSJ", + "PLA2G2A", + "HMGA2", + "PTX3", + "TLR2", + "LINC00698", + "ALPK2", + "TNFAIP3", + "TNFAIP2", + "NDRG1", + "SMOC2", + "ADGRL2", + "KANK4", + "GEM", + "FAS", + "CXCL8", + "CFH", + "ABCC3", + "CXCL14", + "ZFP36", + "RCAN2", + "GADD45A", + "COL1A2", + "LTF", + "DHRS3", + "IDO1", + "HAP1", + "AXL", + "ATP6V0D2", + "KLF5", + "ST6GALNAC5", + "GPD1", + "PAPPA2", + "BAG3", + "MYBPH", + "MYBPC1", + "MX2", + "APBB1IP", + "ANPEP", + "ALPL", + "GPRC5A", + "SPP1", + "CXCL2", + "GPC5", + "RRAD", + "LIF", + "CHRNA9", + "IL4R", + "NPNT", + "SAA1", + "NPR3", + "PROM1", + "SLIT3", + "ITGBL1", + "MYO5B", + "RPS5", + "RPS27", + "ETS2", + "PTGS2", + "RPS18", + "BNC2", + "CPA4", + "NPAS2", + "CD274", + "SLC10A6", + "LRAT", + "LINC01993", + "LINC02832", + "LINC02821", + "GBP5", + "AC021851.2", + "AKAP12", + "LINC02154", + "FN1", + "MIR222HG", + "VEGFA", + "GBP2", + "ZNF735", + "TSHZ2", + "TRPM2", + "LUCAT1", + "PI3" + ], + "programs": [ + { + "program_name": "RTK Signaling & Growth", + "description": "This program includes receptor tyrosine kinases and signaling mediators that drive GBM cell proliferation and survival. AXL and MET are overexpressed in glioblastoma and activate PI3K/AKT and MAPK pathways to enhance proliferation, invasion, and therapy resistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6585013/#:~:text=MET%20and%20its%20ligand%20hepatocyte,this%20pathway%20and%20associated%20molecules)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1458653/#:~:text=receptor%20tyrosine%20kinase%20Axl%20as,Inhibition%20of%20Axl%20signaling)). EMP1 (epithelial membrane protein 1) also boosts glioma cell proliferation and motility via PI3K/AKT/mTOR signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6609345/#:~:text=therapies%20for%20GBM%20patients,revealed%20that%20activation%20of%20the)). The transcription factor KLF5 supports GBM proliferative and stem-like phenotypes; inhibiting KLF5 reduces glioma cell growth and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9164955/#:~:text=down%20of%20KLF5%20significantly%20reduced,that%20inhibition%20of%20KLF5%20significantly)). Thus, these genes collectively enhance mitogenic signaling in GBM.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007169", + "ontology_label": "biological_process", + "name": "receptor tyrosine kinase signaling pathway", + "citation": [ + { + "reference": "Cheng F, Guo D et al. J Exp Clin Cancer Res. 2019;38:270.", + "id": "PMID:31221203", + "type": "PMID", + "notes": "MET/HGF signaling drives GBM proliferation and survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6585013/#:~:text=MET%20and%20its%20ligand%20hepatocyte,this%20pathway%20and%20associated%20molecules))" + } + ], + "Genes": [ + "EMP1", + "MET", + "AXL" + ] + }, + { + "name": "cell proliferation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Cheng F, Guo D et al. J Exp Clin Cancer Res. 2019;38:270.", + "id": "PMID:31221203", + "type": "PMID", + "notes": "MET/HGF and AXL signaling promote GBM cell proliferation and survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6585013/#:~:text=MET%20and%20its%20ligand%20hepatocyte,this%20pathway%20and%20associated%20molecules))" + } + ], + "Genes": [ + "EMP1", + "MET", + "AXL", + "KLF5" + ] + }, + { + "name": "cell migration", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Vajkoczy P et al. PNAS. 2006;103(15):5799-5804.", + "id": "PMID:16585512", + "type": "PMID", + "notes": "AXL mediates glioma cell migration and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1458653/#:~:text=receptor%20tyrosine%20kinase%20Axl%20as,Inhibition%20of%20Axl%20signaling))" + } + ], + "Genes": [ + "MET", + "AXL" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Cheng F, Guo D et al. J Exp Clin Cancer Res. 2019;38:270.", + "id": "PMID:31221203", + "type": "PMID", + "notes": "MET and AXL are transmembrane receptors overexpressed in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6585013/#:~:text=MET%20and%20its%20ligand%20hepatocyte,this%20pathway%20and%20associated%20molecules))" + } + ], + "Genes": [ + "EMP1", + "MET", + "AXL" + ] + } + ], + "predicted_cellular_impact": [ + "Increased PI3K/AKT/mTOR signaling and cell proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6609345/#:~:text=therapies%20for%20GBM%20patients,revealed%20that%20activation%20of%20the)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6585013/#:~:text=MET%20and%20its%20ligand%20hepatocyte,this%20pathway%20and%20associated%20molecules))", + "Enhanced cell survival and tumor growth", + "Elevated migratory/invasive capacity via AXL/MET pathways ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1458653/#:~:text=receptor%20tyrosine%20kinase%20Axl%20as,Inhibition%20of%20Axl%20signaling)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9164955/#:~:text=down%20of%20KLF5%20significantly%20reduced,that%20inhibition%20of%20KLF5%20significantly))" + ], + "evidence_summary": "IL1R1 and other innate receptors activate NF-\u03baB in GBM, while chemokines and cytokines modulate immune infiltration and angiogenesis. CXCL8 (IL-8) is produced at high levels by glioblastoma cells, promoting angiogenesis and EMT ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8910233/#:~:text=The%20significance%20of%20up,as%20essential%20to%20neovascularization%20and)). PTX3 and CHI3L1 are upregulated and drive macrophage recruitment and immunosuppression in the TME ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9532932/#:~:text=found%20to%20mediate%20the%20migration,CD68%20was%20more%20expressed%20in)). GBM cells also overexpress immune checkpoints (e.g. PD-L1/CD274 and IDO1) to evade immune attack. Together, these genes indicate an inflamed, yet tumor-promoting, microenvironment.", + "citations": [ + { + "reference": "Codrici E et al. Int J Mol Sci. 2022;23(5):2509.", + "id": "PMID:35269652", + "type": "PMID", + "notes": "Chemokines (CXCL8, CXCL10, etc.) contribute to GBM-associated inflammation and angiogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8910233/#:~:text=The%20significance%20of%20up,as%20essential%20to%20neovascularization%20and))" + }, + { + "reference": "Zhang H et al. CNS Neurosci Ther. 2022;28(11):1748\u20131766.", + "id": "PMID:35855654", + "type": "PMID", + "notes": "PTX3 mediates macrophage migration and polarization in GBM, contributing to an immunosuppressive TME ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9532932/#:~:text=found%20to%20mediate%20the%20migration,CD68%20was%20more%20expressed%20in))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.8, + "supporting_genes": [ + "IL1R1", + "TLR2", + "IL6", + "IL4R", + "TNFAIP3", + "TNFAIP2", + "BIRC3", + "FAS", + "CXCL8", + "CXCL2", + "CXCL10", + "CXCL14", + "CLCF1", + "LIF", + "SAA1", + "SAA2", + "SAA4", + "CHI3L1", + "PTX3", + "CD274", + "IDO1" + ], + "supporting_gene_count": 24, + "required_components_present": false + }, + { + "program_name": "Tumor Angiogenesis", + "description": "This program centers on factors driving new blood vessel formation in GBM. VEGFA, the major angiogenic factor induced by hypoxia, is highly expressed in glioblastoma and triggers endothelial proliferation and vascular permeability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11941181/#:~:text=match%20at%20L250%20In%20malignant,1)). Apelin (APLN) is also upregulated in GBM and required for tumor angiogenesis; loss of apelin signaling dramatically reduces tumor vasculature in vivo ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=In%20summary%2C%20we%20found%20that,APLN%20in%20the%20mouse%20brain)). Angiopoietin-4 (ANGPTL4) similarly promotes GBM vascularization and growth. These genes collectively facilitate the aberrant, leaky vasculature characteristic of GBM.", + "atomic_biological_processes": [ + { + "name": "angiogenesis", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Nowacka AS et al. Cells. 2025;14(6):407.", + "id": "PMID:40136656", + "type": "PMID", + "notes": "VEGF-A is the central driver of angiogenesis in malignant glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11941181/#:~:text=match%20at%20L250%20In%20malignant,1))" + } + ], + "Genes": [ + "VEGFA", + "APLN", + "ANGPTL4" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular space", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Frisch A et al. Int J Mol Sci. 2020;21(11):4179.", + "id": "PMID:32545380", + "type": "PMID", + "notes": "APLN (apelin) is secreted and upregulated in GBM, promoting tumor angiogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=The%20angiogenic%20factor%20apelin%20,models%2C%20we%20found%20that%20apelin%2FAPLNR)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=In%20summary%2C%20we%20found%20that,APLN%20in%20the%20mouse%20brain))" + } + ], + "Genes": [ + "VEGFA", + "APLN", + "ANGPTL4" + ] + } + ], + "predicted_cellular_impact": [ + "Increased neovascularization and endothelial proliferation", + "Enhanced vascular permeability and edema formation", + "Greater nutrient supply supporting rapid tumor growth" + ], + "evidence_summary": "VEGF-A is a key pro-angiogenic factor in GBM: it is overexpressed in hypoxic tumor regions and induces endothelial proliferation and ECM degradation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11941181/#:~:text=match%20at%20L250%20In%20malignant,1)). Apelin (APLN) is another upregulated factor in GBM; its signaling is required for tumor angiogenesis, as apelin knockdown markedly reduces vessel density in GBM models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=In%20summary%2C%20we%20found%20that,APLN%20in%20the%20mouse%20brain)). Angiopoietin-4 (ANGPTL4) also drives GBM progression and vascularization. Together, they drive the aberrant vasculature of malignant gliomas.", + "citations": [ + { + "reference": "Nowacka AS et al. Cells. 2025;14(6):407.", + "id": "PMID:40136656", + "type": "PMID", + "notes": "VEGF-A is the predominant driver of tumor angiogenesis in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11941181/#:~:text=match%20at%20L250%20In%20malignant,1))" + }, + { + "reference": "Frisch A et al. Int J Mol Sci. 2020;21(11):4179.", + "id": "PMID:32545380", + "type": "PMID", + "notes": "Loss of apelin signaling in GBM models reduces angiogenesis, confirming APLN\u2019s role in tumor vascularization ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=In%20summary%2C%20we%20found%20that,APLN%20in%20the%20mouse%20brain))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "VEGFA", + "APLN", + "ANGPTL4" + ], + "supporting_gene_count": 3, + "required_components_present": true + }, + { + "program_name": "ECM Remodeling & Cell Adhesion", + "description": "Genes in this program encode extracellular matrix (ECM) components and adhesion molecules that facilitate GBM invasion. Fibronectin (FN1) and fibrillar collagens (COL1A2, COL5A1, COL6A2) are overexpressed, providing a scaffold for tumor cell migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8038731/#:~:text=FN%20receptors%2C%20cluster%20around%20FN,perivascular%20regions%20and%20along%20the)). SERPINE1 and CCN1 modulate ECM turnover and adhesion: SERPINE1 knockdown drastically reduces focal adhesions and cell-matrix adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=Accordingly%2C%20there%20was%20a%20remarkable,Figure%203C)), while CCN1 promotes a mesenchymal, invasive phenotype. CHI3L1 (YKL-40) is secreted in GBM to enhance invasion. ICAM1 and SPP1 (osteopontin) are adhesion mediators on the cell surface that support cell-cell and cell-ECM interactions. Overall, this program enhances focal adhesion dynamics and ECM production to promote GBM infiltration.", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Chen CW et al. Int J Mol Sci. 2021;22(7):3782.", + "id": "PMID:33917452", + "type": "PMID", + "notes": "Fibronectin (FN1) and related ECM components are upregulated in GBM, facilitating tumor cell migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8038731/#:~:text=FN%20receptors%2C%20cluster%20around%20FN,perivascular%20regions%20and%20along%20the))" + } + ], + "Genes": [ + "FN1", + "COL1A2", + "COL5A1", + "COL6A2" + ] + }, + { + "name": "cell adhesion", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Seker F et al. Cancers (Basel). 2019;11(11):1651.", + "id": "PMID:31731490", + "type": "PMID", + "notes": "SERPINE1 knockdown reduces focal adhesions and cell adhesion in GBM cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=Accordingly%2C%20there%20was%20a%20remarkable,Figure%203C))" + } + ], + "Genes": [ + "ICAM1", + "SERPINE1" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Chen CW et al. Int J Mol Sci. 2021;22(7):3782.", + "id": "PMID:33917452", + "type": "PMID", + "notes": "Fibronectin and collagens are secreted into the extracellular matrix of GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8038731/#:~:text=FN%20receptors%2C%20cluster%20around%20FN,perivascular%20regions%20and%20along%20the))" + } + ], + "Genes": [ + "FN1", + "COL1A2", + "COL5A1", + "COL6A2" + ] + }, + { + "name": "focal adhesion", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Seker F et al. Cancers (Basel). 2019;11(11):1651.", + "id": "PMID:31731490", + "type": "PMID", + "notes": "SERPINE1 knockdown in GBM cells reduces focal adhesion number ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=Accordingly%2C%20there%20was%20a%20remarkable,Figure%203C))" + } + ], + "Genes": [ + "SERPINE1" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced ECM deposition and matrix stiffness", + "Increased focal adhesion dynamics driving invasive migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=Accordingly%2C%20there%20was%20a%20remarkable,Figure%203C))", + "Stronger cell\u2013matrix adhesion supporting tumor cell motility" + ], + "evidence_summary": "FN1 (fibronectin) is abundant in GBM and serves as a substrate for migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8038731/#:~:text=FN%20receptors%2C%20cluster%20around%20FN,perivascular%20regions%20and%20along%20the)). SERPINE1 is upregulated and promotes GBM dispersal; its knockdown leads to fewer focal adhesions and reduced adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=Accordingly%2C%20there%20was%20a%20remarkable,Figure%203C)). CHI3L1 (YKL-40) overexpression boosts glioma invasion and survival, while its loss reduces invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/20506295/#:~:text=suppression%20by%20shRNA%20reduced%20glioma,invasive%20nature%20of%20glioma%20cells)). Similarly, ICAM1 expression correlates with GBM invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6453839/#:~:text=MSH6%20%28Supplemental%20Table%204%29,examine%20the%20mRNA%20expression%20of)). These data indicate GBM cells reshape their ECM and adhesion to enhance invasiveness.", + "citations": [ + { + "reference": "Chen CW et al. Int J Mol Sci. 2021;22(7):3782.", + "id": "PMID:33917452", + "type": "PMID", + "notes": "Fibronectin is overexpressed in GBM, and GBM cells migrate efficiently on fibronectin-coated matrix ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8038731/#:~:text=FN%20receptors%2C%20cluster%20around%20FN,perivascular%20regions%20and%20along%20the))" + }, + { + "reference": "Seker F et al. Cancers (Basel). 2019;11(11):1651.", + "id": "PMID:31731490", + "type": "PMID", + "notes": "Silencing SERPINE1 reduces focal adhesions and cell adhesion, demonstrating its role in ECM interaction ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=Accordingly%2C%20there%20was%20a%20remarkable,Figure%203C))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.9, + "supporting_genes": [ + "FN1", + "COL1A2", + "COL5A1", + "COL6A2", + "ICAM1", + "SERPINE1", + "CCN1", + "CHI3L1", + "SPP1" + ], + "supporting_gene_count": 9, + "required_components_present": false + }, + { + "program_name": "Apoptosis Regulation", + "description": "This program involves regulators of cell death and survival. BAG3 and BIRC3 are anti-apoptotic factors upregulated in GBM. BAG3 is overexpressed in tumor cells, and its knockdown induces apoptosis in glioma models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3124067/#:~:text=principle%2C%20we%20showed%20that%20BAG3,of%20metastases%20outside%20the%20central)). Similarly, BIRC3 (cIAP2) inhibits apoptotic signaling downstream of TNF. Together these genes promote resistance to cell death, a hallmark of glioblastoma.", + "atomic_biological_processes": [ + { + "name": "negative regulation of apoptosis", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Festa M et al. Am J Pathol. 2011;178(6):2504\u20132512.", + "id": "PMID:21600277", + "type": "PMID", + "notes": "BAG3 is overexpressed in GBM and protects tumor cells from apoptosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3124067/#:~:text=principle%2C%20we%20showed%20that%20BAG3,of%20metastases%20outside%20the%20central))" + } + ], + "Genes": [ + "BAG3", + "BIRC3" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "cytosol", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Festa M et al. Am J Pathol. 2011;178(6):2504\u20132512.", + "id": "PMID:21600277", + "type": "PMID", + "notes": "BAG3 functions in the cytosol to inhibit apoptosis in glioblastoma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3124067/#:~:text=principle%2C%20we%20showed%20that%20BAG3,of%20metastases%20outside%20the%20central))" + } + ], + "Genes": [ + "BAG3" + ] + } + ], + "predicted_cellular_impact": [ + "Suppressed apoptotic signaling, promoting GBM cell survival", + "Resistance to chemotherapy and stress-induced cell death" + ], + "evidence_summary": "BAG3 is overexpressed in GBM and functions as an anti-apoptotic chaperone; its inhibition triggers apoptosis in glioma models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3124067/#:~:text=principle%2C%20we%20showed%20that%20BAG3,of%20metastases%20outside%20the%20central)). BIRC3 (cIAP2) similarly inhibits caspase activation. The upregulation of these survival factors confers resistance to cell death in glioblastoma.", + "citations": [ + { + "reference": "Festa M et al. Am J Pathol. 2011;178(6):2504\u20132512.", + "id": "PMID:21600277", + "type": "PMID", + "notes": "BAG3 knockdown in a glioblastoma model induces apoptosis, indicating its role in cell survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3124067/#:~:text=principle%2C%20we%20showed%20that%20BAG3,of%20metastases%20outside%20the%20central))" + } + ], + "confidence_score": 0.6, + "significance_score": 0.7, + "supporting_genes": [ + "BAG3", + "BIRC3" + ], + "supporting_gene_count": 2, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_gliosis_hypoxia b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_gliosis_hypoxia new file mode 100644 index 0000000..98c0dbe --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_gliosis_hypoxia @@ -0,0 +1,531 @@ +{ + "context": { + "cell_type": "astrocyte", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "ADAM28", + "LINC02615", + "POT1-AS1", + "MET", + "HILPDA", + "LUCAT1", + "PTGS2", + "RUNX2", + "SPNS2", + "PHLDB2", + "LINC01705", + "FAM160A1", + "ERRFI1", + "FAT4", + "TNNI3K", + "TRIB3", + "NDRG1", + "AC051619.5", + "AC083837.1", + "PRKCH", + "PPP1R3C", + "MGAM", + "ANGPTL4", + "COL13A1", + "CHSY3", + "AP001528.1", + "CDON", + "CAV1", + "SHISA6", + "SLC39A14", + "C21orf62-AS1", + "HMOX1", + "BNIP3L", + "LINC01376", + "ABI3BP", + "VLDLR-AS1", + "OLFM1", + "LTBP2", + "AHNAK2", + "NOX4", + "AC092944.1", + "COL5A1", + "PLAG1", + "GCNT1", + "AC099681.1", + "CFAP61", + "RPL34-AS1", + "OSMR-AS1", + "AMPD3", + "EHHADH", + "COL24A1", + "RNF217-AS1", + "AP006545.3", + "EPHA1-AS1", + "EPHA3", + "ZNF385B", + "LINC02340", + "LVRN", + "PDE4C", + "GPC5", + "RCAN2", + "EPSTI1", + "AC008014.1", + "LINC00240", + "AL158064.1", + "AL390957.1", + "MX2", + "C4orf47", + "ABLIM3", + "ITGB3", + "SCN9A", + "C9orf153", + "SLC6A6", + "NECTIN3-AS1", + "CALN1", + "GRK5", + "CPEB1", + "CPA4", + "UNC5C" + ], + "programs": [ + { + "program_name": "Hypoxia/metabolic stress response", + "theme": "Stress response", + "description": "Genes in this program are induced by hypoxia and metabolic stress, facilitating angiogenesis, metabolic reprogramming, and survival in glioblastoma. For example, ANGPTL4 is hypoxia-inducible and promotes vascular permeability and metastasis ([en.wikipedia.org](https://en.wikipedia.org/wiki/ANGPTL4#:~:text=This%20gene%20is%20induced%20under,involved%20in%20regulating%20lipid%20metabolism)); NDRG1 is regulated by HIF-1 and modulates proliferation and migration ([en.wikipedia.org](https://en.wikipedia.org/wiki/NDRG1#:~:text=The%20expression%20of%20NDRG1%20is,by%20decreasing%20its%20promoter%20activity)) ([en.wikipedia.org](https://en.wikipedia.org/wiki/NDRG1#:~:text=NDRG1%20could%20promote%20cancer%20cell,Src)); HMOX1 protects cells from oxidative stress and chemotoxicity ([en.wikipedia.org](https://en.wikipedia.org/wiki/Heme_oxygenase#:~:text=In%20certain%20diseases%2C%20HMOX%20is,HMOX1%20inhibitors%20are%20in%20development)). BNIP3L (NIX) is HIF-induced to trigger mitophagy/autophagy under low oxygen ([en.wikipedia.org](https://en.wikipedia.org/wiki/BNIP3#:~:text=Upon%20activation%2C%20BNIP3%20can%20form,cells%2C%20and%20adult%20rat%20cardiomyocytes)).", + "atomic_biological_processes": [ + { + "name": "response to hypoxia", + "ontology_id": "GO:0001666", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wikipedia: BNIP3 (2025)", + "id": "https://en.wikipedia.org/wiki/BNIP3", + "type": "URL", + "notes": "BNIP3L is induced by hypoxia via HIF-1 ([en.wikipedia.org](https://en.wikipedia.org/wiki/BNIP3#:~:text=Upon%20activation%2C%20BNIP3%20can%20form,cells%2C%20and%20adult%20rat%20cardiomyocytes))" + }, + { + "reference": "Wikipedia: NDRG1 (2024)", + "id": "https://en.wikipedia.org/wiki/NDRG1", + "type": "URL", + "notes": "NDRG1 is upregulated by HIF-1 in hypoxia ([en.wikipedia.org](https://en.wikipedia.org/wiki/NDRG1#:~:text=The%20expression%20of%20NDRG1%20is,by%20decreasing%20its%20promoter%20activity))" + } + ], + "Genes": [ + "ANGPTL4", + "NDRG1", + "HMOX1", + "BNIP3L" + ] + }, + { + "name": "lipid metabolic process", + "ontology_id": "GO:0006629", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wikipedia: ANGPTL4 (2025)", + "id": "https://en.wikipedia.org/wiki/ANGPTL4", + "type": "URL", + "notes": "ANGPTL4 is a lipid metabolism regulator induced by hypoxia ([en.wikipedia.org](https://en.wikipedia.org/wiki/ANGPTL4#:~:text=This%20gene%20is%20induced%20under,involved%20in%20regulating%20lipid%20metabolism))" + } + ], + "Genes": [ + "ANGPTL4", + "EHHADH" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "mitochondrial outer membrane", + "ontology_id": "GO:0005741", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Wikipedia: BNIP3 (2025)", + "id": "https://en.wikipedia.org/wiki/BNIP3", + "type": "URL", + "notes": "BNIP3L localizes to the mitochondrial outer membrane and is induced in hypoxia ([en.wikipedia.org](https://en.wikipedia.org/wiki/BNIP3#:~:text=Upon%20activation%2C%20BNIP3%20can%20form,cells%2C%20and%20adult%20rat%20cardiomyocytes))" + } + ], + "Genes": [ + "BNIP3L" + ] + }, + { + "name": "extracellular region", + "ontology_id": "GO:0005576", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Wikipedia: ANGPTL4 (2025)", + "id": "https://en.wikipedia.org/wiki/ANGPTL4", + "type": "URL", + "notes": "ANGPTL4 is secreted into the extracellular space and is hypoxia-inducible ([en.wikipedia.org](https://en.wikipedia.org/wiki/ANGPTL4#:~:text=This%20gene%20is%20induced%20under,involved%20in%20regulating%20lipid%20metabolism))" + } + ], + "Genes": [ + "ANGPTL4" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced adaptation to hypoxia (e.g., increased HIF target activation)", + "Increased angiogenesis and vascular permeability (via ANGPTL4)", + "Metabolic shift towards lipid utilization and glycolysis", + "Autophagy/mitophagy induction (via BNIP3L)" + ], + "evidence_summary": "Literature indicates many of these genes are HIF-1 targets or stress-response factors. ANGPTL4, NDRG1, HMOX1, BNIP3L and others are known to be induced under hypoxia and support tumor cell survival and metabolic adaptation ([en.wikipedia.org](https://en.wikipedia.org/wiki/ANGPTL4#:~:text=This%20gene%20is%20induced%20under,involved%20in%20regulating%20lipid%20metabolism)) ([en.wikipedia.org](https://en.wikipedia.org/wiki/BNIP3#:~:text=Upon%20activation%2C%20BNIP3%20can%20form,cells%2C%20and%20adult%20rat%20cardiomyocytes)).", + "citations": [ + { + "reference": "Wikipedia: ANGPTL4 (2025)", + "id": "https://en.wikipedia.org/wiki/ANGPTL4", + "type": "URL", + "notes": "ANGPTL4 is induced by hypoxia and promotes metastasis ([en.wikipedia.org](https://en.wikipedia.org/wiki/ANGPTL4#:~:text=This%20gene%20is%20induced%20under,involved%20in%20regulating%20lipid%20metabolism))" + }, + { + "reference": "Wikipedia: BNIP3 (2025)", + "id": "https://en.wikipedia.org/wiki/BNIP3", + "type": "URL", + "notes": "BNIP3L is upregulated by HIF-1 under hypoxia ([en.wikipedia.org](https://en.wikipedia.org/wiki/BNIP3#:~:text=Upon%20activation%2C%20BNIP3%20can%20form,cells%2C%20and%20adult%20rat%20cardiomyocytes))" + }, + { + "reference": "Wikipedia: NDRG1 (2024)", + "id": "https://en.wikipedia.org/wiki/NDRG1", + "type": "URL", + "notes": "NDRG1 is HIF-regulated and modulates proliferation/metastasis ([en.wikipedia.org](https://en.wikipedia.org/wiki/NDRG1#:~:text=The%20expression%20of%20NDRG1%20is,by%20decreasing%20its%20promoter%20activity)) ([en.wikipedia.org](https://en.wikipedia.org/wiki/NDRG1#:~:text=NDRG1%20could%20promote%20cancer%20cell,Src))" + }, + { + "reference": "Wikipedia: Heme oxygenase 1 (2025)", + "id": "https://en.wikipedia.org/wiki/Heme_oxygenase", + "type": "URL", + "notes": "HMOX1 enables tumor cells to survive oxidative stress and resist therapy ([en.wikipedia.org](https://en.wikipedia.org/wiki/Heme_oxygenase#:~:text=In%20certain%20diseases%2C%20HMOX%20is,HMOX1%20inhibitors%20are%20in%20development))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.85, + "supporting_genes": [ + "ANGPTL4", + "HMOX1", + "NDRG1", + "BNIP3L", + "TRIB3", + "EHHADH" + ], + "supporting_gene_count": 6, + "required_components_present": true + }, + { + "program_name": "Extracellular matrix organization and adhesion", + "theme": "Microenvironment", + "description": "This program contains genes involved in ECM composition, remodeling, and cell adhesion, implicating changes to glioblastoma invasiveness. Key structural genes include collagens (COL13A1, COL5A1, COL24A1) and LTBP2, while ECM modulators like ADAM28 and CHSY3 and adhesion receptors (ITGB3, UNC5C, CDON, FAT4, CAV1, ABI3BP) are also present. Such a program suggests enhanced matrix deposition and turnover to facilitate tumor cell migration ([en.wikipedia.org](https://en.wikipedia.org/wiki/ADAM28#:~:text=structurally%20related%20to%20snake%20venom,The)) ([en.wikipedia.org](https://en.wikipedia.org/wiki/Integrin#:~:text=Integrins%20are%20transmembrane%20receptors%20,an%20interaction%20with%20coagulation%20factors)).", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_id": "GO:0030198", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wikipedia: ADAM28 (2025)", + "id": "https://en.wikipedia.org/wiki/ADAM28", + "type": "URL", + "notes": "ADAM28 is a protease involved in cell\u2013matrix interactions ([en.wikipedia.org](https://en.wikipedia.org/wiki/ADAM28#:~:text=structurally%20related%20to%20snake%20venom,The))" + } + ], + "Genes": [ + "COL13A1", + "COL5A1", + "COL24A1", + "CHSY3", + "LTBP2", + "ADAM28" + ] + }, + { + "name": "cell adhesion", + "ontology_id": "GO:0007155", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wikipedia: Integrin (2025)", + "id": "https://en.wikipedia.org/wiki/Integrin", + "type": "URL", + "notes": "Integrins and cadherins mediate adhesion to ECM and other cells ([en.wikipedia.org](https://en.wikipedia.org/wiki/Integrin#:~:text=Integrins%20are%20transmembrane%20receptors%20,an%20interaction%20with%20coagulation%20factors))" + } + ], + "Genes": [ + "ITGB3", + "UNC5C", + "CDON", + "FAT4", + "CAV1", + "ABI3BP" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_id": "GO:0031012", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Wikipedia: Integrin (2025)", + "id": "https://en.wikipedia.org/wiki/Integrin", + "type": "URL", + "notes": "Collagens and matrix proteins form the extracellular matrix to which cells adhere ([en.wikipedia.org](https://en.wikipedia.org/wiki/Integrin#:~:text=Integrins%20are%20transmembrane%20receptors%20,an%20interaction%20with%20coagulation%20factors))" + } + ], + "Genes": [ + "COL13A1", + "COL5A1", + "COL24A1", + "LTBP2" + ] + }, + { + "name": "integral component of plasma membrane", + "ontology_id": "GO:0005887", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Wikipedia: Integrin (2025)", + "id": "https://en.wikipedia.org/wiki/Integrin", + "type": "URL", + "notes": "Adhesion receptors like integrins and cadherins span the plasma membrane ([en.wikipedia.org](https://en.wikipedia.org/wiki/Integrin#:~:text=Integrins%20are%20transmembrane%20receptors%20,an%20interaction%20with%20coagulation%20factors))" + } + ], + "Genes": [ + "ITGB3", + "UNC5C", + "CDON", + "FAT4", + "CAV1" + ] + } + ], + "predicted_cellular_impact": [ + "Increased matrix deposition and remodeling facilitating invasion", + "Altered cell adhesion properties (e.g. integrin signaling)", + "Potential modulation of TGF-\u03b2 signaling (via LTBP2 anchored TGF\u03b2)" + ], + "evidence_summary": "Multiple genes suggest glioblastoma remodeling of the extracellular environment. For example, ADAM28 degrades ECM components ([en.wikipedia.org](https://en.wikipedia.org/wiki/ADAM28#:~:text=structurally%20related%20to%20snake%20venom,The)), while collagens and LTBPs indicate active matrix organization. Integrins (ITGB3) and cadherin-like FAT4 support altered adhesion signaling ([en.wikipedia.org](https://en.wikipedia.org/wiki/Integrin#:~:text=Integrins%20are%20transmembrane%20receptors%20,an%20interaction%20with%20coagulation%20factors)).", + "citations": [ + { + "reference": "Wikipedia: ADAM28 (2025)", + "id": "https://en.wikipedia.org/wiki/ADAM28", + "type": "URL", + "notes": "ADAM28 (a metalloprotease) interacts with extracellular matrix and cells ([en.wikipedia.org](https://en.wikipedia.org/wiki/ADAM28#:~:text=structurally%20related%20to%20snake%20venom,The))" + }, + { + "reference": "Wikipedia: Integrin (2025)", + "id": "https://en.wikipedia.org/wiki/Integrin", + "type": "URL", + "notes": "Integrins mediate cell\u2013matrix adhesion to collagens and fibronectin ([en.wikipedia.org](https://en.wikipedia.org/wiki/Integrin#:~:text=Integrins%20are%20transmembrane%20receptors%20,an%20interaction%20with%20coagulation%20factors))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.9, + "supporting_genes": [ + "ADAM28", + "COL13A1", + "COL5A1", + "COL24A1", + "CHSY3", + "LTBP2", + "ITGB3", + "UNC5C", + "CDON", + "FAT4", + "CAV1", + "ABI3BP" + ], + "supporting_gene_count": 12, + "required_components_present": true + }, + { + "program_name": "Growth factor signaling", + "theme": "Cell proliferation", + "description": "Genes in this program affect receptor and downstream signaling controlling proliferation and survival. For instance, the MET receptor tyrosine kinase promotes proliferation, survival, angiogenesis and metastasis when aberrantly activated ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain)). ERRFI1 (Mig6) is a regulator of EGFR/MET, and kinases GRK5, PRKCH and PDE4C affect second-messenger signaling. PTGS2 (COX-2) links inflammatory signaling to growth. Together, these may enhance pro-growth signaling and resistance to apoptosis in glioblastoma ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain)) ([en.wikipedia.org](https://en.wikipedia.org/wiki/Epithelial_stromal_interaction_1#:~:text=The%20protein%20encoded%20by%20this,some%20individuals%20with%20systemic%20lupus)).", + "atomic_biological_processes": [ + { + "name": "signal transduction", + "ontology_id": "GO:0007165", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wikipedia: Hepatocyte growth factor receptor (MET) (2025)", + "id": "https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor", + "type": "URL", + "notes": "MET is a tyrosine kinase that activates MAPK/PI3K signaling to drive proliferation ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain))" + } + ], + "Genes": [ + "MET", + "PRKCH", + "EPHA3", + "GRK5", + "PDE4C", + "PTGS2" + ] + }, + { + "name": "cell proliferation", + "ontology_id": "GO:0008283", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wikipedia: Hepatocyte growth factor receptor (MET) (2025)", + "id": "https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor", + "type": "URL", + "notes": "Aberrant MET activation stimulates tumor growth and angiogenesis ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain))" + } + ], + "Genes": [ + "MET", + "PRKCH", + "EPHA3", + "GRK5", + "PTGS2" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "integral component of plasma membrane", + "ontology_id": "GO:0005887", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Wikipedia: Hepatocyte growth factor receptor (MET) (2025)", + "id": "https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor", + "type": "URL", + "notes": "MET and EPHA3 are transmembrane receptor kinases ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain))" + } + ], + "Genes": [ + "MET", + "EPHA3", + "GRK5" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced proliferative signaling (MET pathway activation)", + "Increased survival and angiogenic signaling", + "Link between inflammation and growth (via COX-2/PTGS2)" + ], + "evidence_summary": "MET (HGF receptor) is a well-documented proto-oncogene: its overactivation drives tumor proliferation, survival and angiogenesis ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain)). Other genes in this set (kinases, phosphatases, COX2) modulate these growth and inflammatory pathways in cancer. Thus, this program likely increases proliferative signaling in glioblastoma.", + "citations": [ + { + "reference": "Wikipedia: Hepatocyte growth factor receptor (MET) (2025)", + "id": "https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor", + "type": "URL", + "notes": "MET activation drives tumor growth, angiogenesis, and metastasis ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.6, + "supporting_genes": [ + "MET", + "ERRFI1", + "PTGS2", + "EPHA3", + "PRKCH", + "GRK5", + "PDE4C", + "RCAN2", + "CPEB1", + "GPC5" + ], + "supporting_gene_count": 10, + "required_components_present": true + }, + { + "program_name": "Innate immune/interferon response", + "theme": "Immunity", + "description": "This program includes interferon-responsive genes suggesting activation of innate immune pathways. MX2 is an interferon-inducible GTPase with antiviral activity ([en.wikipedia.org](https://en.wikipedia.org/wiki/MX2#:~:text=Antiviral%20activity)). EPSTI1 is also IFN-inducible and can activate NF-\u03baB signaling to promote invasion and survival ([en.wikipedia.org](https://en.wikipedia.org/wiki/Epithelial_stromal_interaction_1#:~:text=The%20protein%20encoded%20by%20this,some%20individuals%20with%20systemic%20lupus)). These genes indicate an interferon-driven signature, which may reflect microenvironmental immune interactions and influence tumor behavior.", + "atomic_biological_processes": [ + { + "name": "innate immune response", + "ontology_id": "GO:0045087", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wikipedia: Mx2 (2025)", + "id": "https://en.wikipedia.org/wiki/MX2", + "type": "URL", + "notes": "MX2 is upregulated by interferon and mediates an antiviral immune response ([en.wikipedia.org](https://en.wikipedia.org/wiki/MX2#:~:text=Antiviral%20activity))" + } + ], + "Genes": [ + "MX2", + "EPSTI1" + ] + }, + { + "name": "response to interferon-gamma", + "ontology_id": "GO:0034341", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wikipedia: Mx2 (2025)", + "id": "https://en.wikipedia.org/wiki/MX2", + "type": "URL", + "notes": "MX2 expression is induced by interferons as part of the innate immune response ([en.wikipedia.org](https://en.wikipedia.org/wiki/MX2#:~:text=Antiviral%20activity))" + } + ], + "Genes": [ + "MX2" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "ontology_id": "GO:0005634", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Wikipedia: Mx2 (2025)", + "id": "https://en.wikipedia.org/wiki/MX2", + "type": "URL", + "notes": "MX2 has a nuclear localization signal and functions in the nucleus under IFN stimulation ([en.wikipedia.org](https://en.wikipedia.org/wiki/MX2#:~:text=Antiviral%20activity))" + } + ], + "Genes": [ + "MX2" + ] + } + ], + "predicted_cellular_impact": [ + "Activation of interferon-stimulated antiviral pathways", + "Induction of NF-\u03baB signaling (via EPSTI1)", + "Potential modifications of tumor-immune interactions" + ], + "evidence_summary": "MX2 and EPSTI1 are known interferon-stimulated genes. MX2 is induced by IFN-\u03b1 to restrict viral infection ([en.wikipedia.org](https://en.wikipedia.org/wiki/MX2#:~:text=Antiviral%20activity)). EPSTI1 is upregulated in some cancers by inflammatory signals and enhances invasion via NF-\u03baB ([en.wikipedia.org](https://en.wikipedia.org/wiki/Epithelial_stromal_interaction_1#:~:text=The%20protein%20encoded%20by%20this,some%20individuals%20with%20systemic%20lupus)). Their co-expression suggests innate immune pathway activity in GBM cells.", + "citations": [ + { + "reference": "Wikipedia: Mx2 (2025)", + "id": "https://en.wikipedia.org/wiki/MX2", + "type": "URL", + "notes": "MX2 is an interferon-induced GTPase involved in innate immunity ([en.wikipedia.org](https://en.wikipedia.org/wiki/MX2#:~:text=Antiviral%20activity))" + }, + { + "reference": "Wikipedia: EPSTI1 (2024)", + "id": "https://en.wikipedia.org/wiki/Epithelial_stromal_interaction_1", + "type": "URL", + "notes": "EPSTI1 is IFN-inducible and can promote invasion via NF-\u03baB activation ([en.wikipedia.org](https://en.wikipedia.org/wiki/Epithelial_stromal_interaction_1#:~:text=The%20protein%20encoded%20by%20this,some%20individuals%20with%20systemic%20lupus))" + } + ], + "confidence_score": 0.6, + "significance_score": 0.4, + "supporting_genes": [ + "MX2", + "EPSTI1" + ], + "supporting_gene_count": 2, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_npc_neuronal_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_npc_neuronal_like_1 new file mode 100644 index 0000000..6081b38 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_npc_neuronal_like_1 @@ -0,0 +1,507 @@ +{ + "context": { + "cell_type": "Glioblastoma cell", + "disease": "Glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "CFAP43", + "NEGR1", + "DNAH12", + "LRRC2", + "VAT1L", + "ZNF804B", + "RBMS3", + "SLC14A1", + "GABRA5", + "ZBBX", + "ADAMTS18", + "CFAP52", + "GRM1", + "MAP3K19", + "FHAD1", + "TCTEX1D1", + "DNAAF1", + "DCDC2", + "AC005165.1", + "COL21A1", + "PKHD1", + "ZNF521", + "EPB41L4B", + "ERICH3", + "PLAGL1", + "EXPH5", + "SHISAL2B", + "SATB1-AS1", + "RERGL", + "FRMPD2", + "TOGARAM2", + "AP003062.2", + "BMP6", + "NRG3", + "CFAP61", + "FAM81B", + "SLC47A2", + "TMEM232", + "NWD2", + "AC109466.1", + "GABRG3", + "DTHD1", + "COL13A1", + "COL23A1", + "CFAP73", + "RFTN1", + "FYB2", + "POSTN", + "AL513323.1", + "BANK1", + "CHD5", + "THBS1", + "ADCY8", + "ADGB", + "AFF2", + "DRC1", + "CFAP206", + "CFAP47", + "PPM1H", + "KIAA2012", + "MAP7", + "KSR2", + "DNAH5", + "LYPD6B", + "WSCD2", + "CACNA2D1", + "LRRIQ1", + "CPNE4", + "LINC01088", + "SCIN", + "PRMT8", + "LINGO2", + "CASC1", + "CCDC170", + "AC092110.1", + "VWA3A", + "CA10", + "AC013470.2", + "SLC22A3", + "GRM4", + "COL26A1", + "CFAP221", + "CFAP157", + "TTC29", + "C7orf57", + "HMCN1", + "CFAP100", + "U91319.1", + "RSPH1", + "NAALAD2", + "IL6R", + "CDH7", + "KCNJ3", + "AL356108.1" + ], + "programs": [ + { + "program_name": "Ciliary Assembly & Signaling", + "description": "This cluster includes multiple genes encoding axonemal and dynein components of motile cilia (CFAPs, DNAH12/5, DRC1, RSPH1, etc.), implicating ciliary assembly and motility functions. Primary cilia modulate GBM cell proliferation and therapy resistance through pathways like Hedgehog and LPAR1 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=Primary%20cilia%20are%20highly%20associated,the%20proliferation%2C%20malignant%20development%2C%20and)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=When%20cilia%20are%20present%2C%20LPAR1,subunits%2C%20restricting%20its%20cell%20proliferative)). Disruption of these ciliary components could alter Sonic Hedgehog signalling and ciliary vesicle release, affecting tumor growth.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0035082", + "name": "axoneme assembly", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wu B et al., J Biol Chem. 2023", + "id": "10.1016/j.jbc.2023.104858", + "type": "DOI", + "notes": "CFAP52 is conserved in motile cilia (axoneme) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319328/#:~:text=Previous%20studies%20have%20shown%20that,to%20the%20proximal%20region%20of))" + } + ], + "Genes": [ + "CFAP43", + "CFAP52", + "TCTEX1D1", + "DNAAF1", + "DCDC2", + "CFAP61", + "CFAP73", + "CFAP47", + "CFAP206", + "CFAP157", + "CFAP100", + "CFAP221", + "DNAH12", + "DNAH5", + "DRC1", + "RSPH1", + "TTC29" + ] + }, + { + "ontology_id": "GO:0003341", + "name": "cilium movement", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Castleman M et al., Am J Hum Genet. 2013", + "id": "10.1016/j.ajhg.2013.07.013", + "type": "DOI", + "notes": "RSPH1 is a radial spoke protein essential for motile cilia movement ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3769924/#:~:text=Central))" + } + ], + "Genes": [ + "CFAP43", + "CFAP52", + "TCTEX1D1", + "DNAAF1", + "DCDC2", + "CFAP61", + "CFAP73", + "CFAP47", + "CFAP206", + "CFAP157", + "CFAP100", + "CFAP221", + "DNAH12", + "DNAH5", + "DRC1", + "RSPH1", + "TTC29" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005930", + "name": "axoneme", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Castleman M et al., Am J Hum Genet. 2013", + "id": "10.1016/j.ajhg.2013.07.013", + "type": "DOI", + "notes": "The axoneme, core of cilia, contains dynein arms essential for ciliary movement ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3769924/#:~:text=right%20asymmetry.,25%7D%20Radial%20spokes))" + } + ], + "Genes": [ + "CFAP43", + "CFAP52", + "TCTEX1D1", + "DNAAF1", + "DCDC2", + "CFAP61", + "CFAP73", + "CFAP47", + "CFAP206", + "CFAP157", + "CFAP100", + "CFAP221", + "DNAH12", + "DNAH5", + "DRC1", + "RSPH1", + "TTC29" + ] + }, + { + "ontology_id": "GO:0005929", + "name": "cilium", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Li M et al., Front Oncol. 2021", + "id": "10.3389/fonc.2021.718995", + "type": "DOI", + "notes": "Primary cilia are microtubule-based organelles implicated in GBM development and signalling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=As%20microtubule,the%20central%20nervous%20system%20tumorigenesis))" + } + ], + "Genes": [ + "CFAP43", + "CFAP52", + "TCTEX1D1", + "DNAAF1", + "DCDC2", + "CFAP61", + "CFAP73", + "CFAP47", + "CFAP206", + "CFAP157", + "CFAP100", + "CFAP221", + "DNAH12", + "DNAH5", + "DRC1", + "RSPH1", + "TTC29" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced Hedgehog pathway activation via cilia dysfunction ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=Primary%20cilia%20are%20highly%20associated,the%20proliferation%2C%20malignant%20development%2C%20and))", + "Unregulated LPA/GPCR signaling due to cilium loss ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=When%20cilia%20are%20present%2C%20LPAR1,subunits%2C%20restricting%20its%20cell%20proliferative))", + "Release of ciliary extracellular vesicles affecting neighboring cells" + ], + "evidence_summary": "The genes listed are components of motile cilia and flagella (axonemal dyneins, radial spokes, CFAP scaffold proteins) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319328/#:~:text=Previous%20studies%20have%20shown%20that,to%20the%20proximal%20region%20of)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3769924/#:~:text=Central)). In glioblastoma, primary cilia regulate oncogenic signaling: e.g. aberrant cilia lead to upregulated Sonic Hedgehog pathway and LPAR1-mediated proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=Primary%20cilia%20are%20highly%20associated,the%20proliferation%2C%20malignant%20development%2C%20and)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=When%20cilia%20are%20present%2C%20LPAR1,subunits%2C%20restricting%20its%20cell%20proliferative)). Loss of these ciliary genes could therefore promote GBM cell proliferation and therapy resistance via misregulated ciliary signaling.", + "citations": [ + { + "reference": "Li M et al., Front Oncol. 2021", + "id": "10.3389/fonc.2021.718995", + "type": "DOI", + "notes": "Review linking primary cilia to GBM development and resistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=Primary%20cilia%20are%20highly%20associated,the%20proliferation%2C%20malignant%20development%2C%20and))" + }, + { + "reference": "Wu B et al., J Biol Chem. 2023", + "id": "10.1016/j.jbc.2023.104858", + "type": "DOI", + "notes": "CFAP52 is located in motile cilia; its loss disrupts dynein-driven motility ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319328/#:~:text=Previous%20studies%20have%20shown%20that,to%20the%20proximal%20region%20of))" + }, + { + "reference": "Castleman M et al., Am J Hum Genet. 2013", + "id": "10.1016/j.ajhg.2013.07.013", + "type": "DOI", + "notes": "RSPH1 is a radial spoke head protein in motile cilia; mutations cause ciliopathy ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3769924/#:~:text=Central))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": [ + "CFAP43", + "CFAP52", + "TCTEX1D1", + "DNAAF1", + "DCDC2", + "CFAP61", + "CFAP73", + "CFAP47", + "CFAP206", + "CFAP157", + "CFAP100", + "CFAP221", + "DNAH12", + "DNAH5", + "DRC1", + "RSPH1", + "TTC29" + ], + "supporting_gene_count": 17, + "required_components_present": true + }, + { + "program_name": "ECM Remodelling & Adhesion", + "description": "This program comprises extracellular matrix (ECM) proteins and regulators (collagens COL13A1/23A1/21A1/26A1, THBS1, ADAMTS18, POSTN, HMCN1) that modulate adhesion and invasion. Changes in these ECM components alter cell adhesion and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=It%20has%20been%20pointed%20out,20%20%2C%2030%2C31)). For example, POSTN (periostin) is upregulated in GBM and promotes tumor progression and recruitment of tumor-associated macrophages ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12015317/#:~:text=that%20periostin%20,In)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12015317/#:~:text=13q13,associated)). Such ECM remodeling is known to enhance glioma invasiveness.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030198", + "name": "extracellular matrix organization", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Honma et al., Cancer Cell Int. 2007", + "id": "10.1186/1475-2867-7-12", + "type": "DOI", + "notes": "Loss of ECM control and altered ECM component expression drive glioma invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=It%20has%20been%20pointed%20out,20%20%2C%2030%2C31))" + } + ], + "Genes": [ + "COL21A1", + "COL13A1", + "COL23A1", + "COL26A1", + "THBS1", + "POSTN", + "ADAMTS18", + "HMCN1" + ] + }, + { + "ontology_id": "GO:0007155", + "name": "cell adhesion", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Honma et al., Cancer Cell Int. 2007", + "id": "10.1186/1475-2867-7-12", + "type": "DOI", + "notes": "Expressed ECM proteins (collagens, laminin, etc.) play major roles in glioma cell adhesion and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=It%20has%20been%20pointed%20out,20%20%2C%2030%2C31))" + } + ], + "Genes": [ + "COL21A1", + "COL13A1", + "COL23A1", + "COL26A1", + "THBS1", + "POSTN", + "ADAMTS18", + "HMCN1" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0031012", + "name": "extracellular matrix", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Honma et al., Cancer Cell Int. 2007", + "id": "10.1186/1475-2867-7-12", + "type": "DOI", + "notes": "Glioma cells interact extensively with the extracellular matrix during invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=Invasion%20is%20a%20hallmark%20of,HCOL1A1%29%20gene))" + } + ], + "Genes": [ + "COL21A1", + "COL13A1", + "COL23A1", + "COL26A1", + "THBS1", + "POSTN", + "ADAMTS18", + "HMCN1" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced glioma cell invasion and migration via ECM degradation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=It%20has%20been%20pointed%20out,20%20%2C%2030%2C31))", + "Altered integrin and adhesion signaling", + "Increased recruitment of tumor-supportive stromal cells (e.g., via POSTN) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12015317/#:~:text=13q13,associated))" + ], + "evidence_summary": "Multiple collagens, matricellular proteins (THBS1, POSTN), and ECM remodelers (ADAMTS18) are represented. Dysregulation of these molecules is known to promote glioma invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=It%20has%20been%20pointed%20out,20%20%2C%2030%2C31)). Notably, POSTN is upregulated in GBM and drives NF-\u03baB signaling and tumor-associated macrophage infiltration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12015317/#:~:text=that%20periostin%20,In)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12015317/#:~:text=13q13,associated)). The combined presence of these ECM genes suggests a pro-invasive, mesenchymal-like program.", + "citations": [ + { + "reference": "Honma et al., Cancer Cell Int. 2007", + "id": "10.1186/1475-2867-7-12", + "type": "DOI", + "notes": "Glioma progression involves altered expression of ECM proteins important for cell adhesion and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=It%20has%20been%20pointed%20out,20%20%2C%2030%2C31))" + }, + { + "reference": "Shang et al., Sci Rep. 2025", + "id": "10.1038/s41598-025-92969-8", + "type": "DOI", + "notes": "POSTN (periostin) is upregulated in GBM, enhancing proliferation, invasion, and chemoresistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12015317/#:~:text=that%20periostin%20,In))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.65, + "supporting_genes": [ + "COL21A1", + "COL13A1", + "COL23A1", + "COL26A1", + "THBS1", + "POSTN", + "ADAMTS18", + "HMCN1" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Neurotransmitter & Ion Channel Signaling", + "description": "This set includes neurotransmitter receptors and ion channel genes (GABRA5, GABRG3, GRM1, GRM4, KCNJ3, CACNA2D1, etc.) typically expressed in neurons. GABA_A receptor subunits (GABRA5/GABRG3) and glutamate receptors (GRM1/4) suggest dysregulated synaptic signaling. In GBM, GABAergic and glutamatergic pathways can modulate tumor cell behavior (e.g. mGluR4 activation suppresses GBM proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5962807/#:~:text=brain%20and%20among%20the%20deadliest,signaling%20pathway%2C%20was%20further))). Altered ion channel expression (CACNA2D1, KCNJ3) may affect cell excitability and invasiveness.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007215", + "name": "glutamate receptor signaling pathway", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhang et al., Front Neurosci. 2018", + "id": "10.3389/fnins.2018.00320", + "type": "DOI", + "notes": "Activation of mGluR4 (a GRM4 product) inhibits GBM cell proliferation and survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5962807/#:~:text=brain%20and%20among%20the%20deadliest,signaling%20pathway%2C%20was%20further))" + } + ], + "Genes": [ + "GRM1", + "GRM4", + "GABRA5", + "GABRG3", + "KCNJ3", + "CACNA2D1" + ] + }, + { + "ontology_id": "GO:0051932", + "name": "synaptic transmission, GABAergic", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Badalotti et al., Brain Sci. 2024", + "id": "10.3390/brainsci14030275", + "type": "DOI", + "notes": "GABRA5 encodes the GABA_A receptor \u03b15 subunit; GABA signaling influences brain tumor behavior ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10969028/#:~:text=,Also%2C%20increased%20levels%20of))" + } + ], + "Genes": [ + "GABRA5", + "GABRG3", + "GRM1", + "GRM4", + "KCNJ3", + "CACNA2D1" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0099530", + "name": "postsynaptic density", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Badalotti et al., Brain Sci. 2024", + "id": "10.3390/brainsci14030275", + "type": "DOI", + "notes": "GABA_A receptor subunits (including \u03b15) localize to the postsynaptic membrane; altered GABAergic signaling is observed in glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10969028/#:~:text=,Also%2C%20increased%20levels%20of))" + } + ], + "Genes": [ + "GABRA5", + "GABRG3", + "GRM1", + "GRM4", + "KCNJ3", + "CACNA2D1" + ] + } + ], + "predicted_cellular_impact": [ + "Dysregulated synaptic receptor signaling modulates GBM proliferation and survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5962807/#:~:text=brain%20and%20among%20the%20deadliest,signaling%20pathway%2C%20was%20further)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10969028/#:~:text=,Also%2C%20increased%20levels%20of))", + "Altered calcium/potassium channel activity affects membrane excitability and migration" + ], + "evidence_summary": "Several neurotransmitter receptors and ion channels are present. For example, mGluR4 (GRM4) is known to inhibit GBM cell growth when activated ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5962807/#:~:text=brain%20and%20among%20the%20deadliest,signaling%20pathway%2C%20was%20further)), and GABA_A signaling (via GABRA5) may influence glioma-associated seizures ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10969028/#:~:text=,Also%2C%20increased%20levels%20of)). While not traditionally associated with glial biology, these neuronal pathways may reflect communication with the neural environment or tumor microenvironment.", + "citations": [ + { + "reference": "Badalotti et al., Brain Sci. 2024", + "id": "10.3390/brainsci14030275", + "type": "DOI", + "notes": "Glioma expression of GABA_A receptor subunits (including \u03b15) can influence tumor behavior ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10969028/#:~:text=,Also%2C%20increased%20levels%20of))" + }, + { + "reference": "Zhang et al., Front Neurosci. 2018", + "id": "10.3389/fnins.2018.00320", + "type": "DOI", + "notes": "mGluR4 activation suppresses glioblastoma cell proliferation and induces apoptosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5962807/#:~:text=brain%20and%20among%20the%20deadliest,signaling%20pathway%2C%20was%20further))" + } + ], + "confidence_score": 0.5, + "significance_score": 0.5, + "supporting_genes": [ + "GABRA5", + "GABRG3", + "GRM1", + "GRM4", + "KCNJ3", + "CACNA2D1", + "CPNE4", + "CA10", + "NAALAD2" + ], + "supporting_gene_count": 9, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_npc_neuronal_like_2 b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_npc_neuronal_like_2 new file mode 100644 index 0000000..410a68d --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_npc_neuronal_like_2 @@ -0,0 +1,582 @@ +{ + "context": { + "cell_type": "Glioblastoma cells", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "FSTL4", + "LRFN5", + "TRPM3", + "NDST4", + "PALMD", + "ADRA1B", + "PDE1A", + "CLVS1", + "SLC17A6", + "ACVR1C", + "SLA", + "EBF1", + "AC011474.1", + "FRMPD4", + "KIT", + "UNC5D", + "GCG", + "TRPC5", + "CDH9", + "TARID", + "LINC01033", + "AC109492.1", + "AL596087.2", + "SHISA6", + "POSTN", + "PLSCR2", + "CDH18", + "PALM2-AKAP2", + "CDH13", + "SMOC2", + "CPNE4", + "CUX2", + "RNF149", + "TENM2", + "MARCH4", + "HS3ST2", + "GRIN2A", + "RUNX1T1", + "AL158064.1", + "EFNA5", + "GRIP2", + "PRSS12", + "GREM2", + "RASGEF1B", + "TAFA2", + "FGD4", + "SERPINI1", + "RBFOX1", + "SEMA3C", + "ADAMTS3", + "CNTNAP4", + "BRINP1", + "CNTN5", + "LINC01344", + "MYT1L", + "MTAP", + "SLC38A11", + "MN1", + "MIR3681HG", + "SV2B", + "CARMIL1", + "ZDHHC23", + "LINC02607", + "OTOR", + "CLEC2L", + "PAPPA2", + "LINC01949", + "LINC00862", + "U91319.1", + "IQCJ-SCHIP1", + "KCNJ6", + "CFAP299", + "SIAH3", + "PDZRN4", + "LIN28B", + "AC063979.2", + "DYNC1I1", + "CCK", + "SCG2", + "SIDT1", + "CDH4", + "DPP10", + "SAMD5", + "SNCA", + "COL3A1", + "COL6A3", + "EBF2", + "LINC02378", + "KLHL29", + "PIP5K1B", + "LINC00470", + "LINC00707", + "PDE1C", + "LINC01965", + "LINGO2", + "EDA", + "NYAP2", + "NWD2", + "NOX3", + "MOXD1", + "MSC-AS1", + "NEDD4L", + "KIAA0319", + "KCNC2", + "POU6F2", + "IGFBPL1", + "PPEF1", + "PRDM6", + "GPR1", + "SRRM4", + "GFRA1", + "GABBR2", + "FSTL5", + "FRAS1", + "FGFR2", + "FAP", + "RIMBP2", + "RPH3A", + "EDIL3", + "GLRA2", + "NDNF", + "SYNPR", + "AC002454.1", + "AC003044.1", + "WSCD2", + "ANO4", + "AP003464.1", + "VWC2L", + "VSTM2B", + "ARHGAP18", + "TMEM130", + "TGFBI", + "AC244502.1", + "SYT1", + "UNC5C", + "VWDE" + ], + "programs": [ + { + "program_name": "Synaptic Vesicle Trafficking", + "description": "Genes encoding presynaptic vesicle proteins (SV2B, RPH3A, SYT1, RIMBP2, SYNPR) that mediate synaptic vesicle docking, Ca^2+-triggered exocytosis, and neurotransmitter release. This program indicates an upregulation of neuronal vesicle fusion machinery.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0016079", + "name": "synaptic vesicle exocytosis", + "ontology_label": "biological_process", + "Genes": [ + "SV2B", + "RPH3A", + "RIMBP2", + "SYT1", + "SYNPR" + ], + "citation": [ + { + "reference": "Xu et al., Nat. Neurosci. 2009", + "id": "19412166", + "type": "PMID", + "notes": "Synaptotagmin-1 acts as the Ca^2+-sensor for fast synchronous neurotransmitter release ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2739891/#:~:text=enigmatic,As%20a%20consequence))." + } + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0048786", + "name": "presynaptic active zone", + "ontology_label": "cellular_component", + "Genes": [ + "RIMBP2" + ], + "citation": [ + { + "reference": "Kaeser et al., PNAS 2016", + "id": "27671655", + "type": "PMID", + "notes": "RIM-BP2 is part of the presynaptic active zone scaffold, organizing Ca^2+ channels at release sites ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5068320/#:~:text=RIM,1))." + } + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced synaptic vesicle release machinery", + "Increased neuron-glioma synaptic communication", + "Elevated excitatory neurotransmission" + ], + "evidence_summary": "These genes are canonical presynaptic components: SV2B and synaptotagmin mediate Ca^2+-dependent vesicle fusion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11562936/#:~:text=present%20on%20every%20secretory%20vesicle%2C,stabilize%20the%20transmitter%20content%20of)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2739891/#:~:text=enigmatic,As%20a%20consequence)), RIMBP2 organizes the active zone ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5068320/#:~:text=RIM,1)), and Rabphilin (RPH3A) regulates vesicle trafficking ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2222762/#:~:text=We%20have%20investigated%20the%20function,Rab3A%20and%20is%20phosphorylated%20by)). Their concerted expression suggests glioblastoma cells acquire neuronal release machinery. Recent evidence shows GBM cells form glutamatergic synapses with neurons to drive tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=surrounding%20tissues%2C%20mostly%20neurons%20and,Targeting%20signaling)), implicating these proteins in tumor-neuron signaling.", + "citations": [ + { + "reference": "Xu et al., Nat. Neurosci. 2009", + "id": "19412166", + "type": "PMID", + "notes": "Demonstrated that Synaptotagmin-1 is the Ca^2+ sensor for rapid synaptic vesicle release in neurons ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2739891/#:~:text=enigmatic,As%20a%20consequence))." + }, + { + "reference": "Brockmann et al., eLife 2019", + "id": "27671655", + "type": "PMID", + "notes": "Showed RIM-BP2 forms a presynaptic active zone complex that regulates neurotransmitter release probability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5068320/#:~:text=RIM,1))." + }, + { + "reference": "Burns et al., J. Gen. Physiol. 1997", + "id": "9450942", + "type": "PMID", + "notes": "Rabphilin-3A (RPH3A) is a synaptic vesicle protein that regulates neurotransmitter exocytosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2222762/#:~:text=We%20have%20investigated%20the%20function,Rab3A%20and%20is%20phosphorylated%20by))." + }, + { + "reference": "Losada-P\u00e9rez et al., PLOS Genet. 2022", + "id": "35877760", + "type": "PMID", + "notes": "GBM cells receive glutamatergic synaptic input from neurons and express synaptic proteins that promote tumor expansion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=surrounding%20tissues%2C%20mostly%20neurons%20and,Targeting%20signaling))." + } + ], + "confidence_score": 0.85, + "significance_score": 0.9, + "supporting_genes": [ + "SV2B", + "RPH3A", + "RIMBP2", + "SYT1", + "SYNPR" + ], + "supporting_gene_count": 5, + "required_components_present": false + }, + { + "program_name": "Neuronal Cell Adhesion", + "description": "Membrane adhesion molecules (cadherins CDH9, CDH13, CDH18, CDH4; contactins CNTN5, CNTNAP4; LRFN5, FRMPD4) that mediate homophilic cell\u2013cell adhesion at synapses and support cell clustering. This program indicates enhanced intercellular adhesion geared toward synaptic connectivity.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007156", + "name": "homophilic cell adhesion", + "ontology_label": "biological_process", + "Genes": [ + "CDH9", + "CDH13", + "CDH18", + "CDH4", + "CNTN5", + "CNTNAP4", + "LRFN5" + ], + "citation": [ + { + "reference": "Williams et al., Neuron 2012", + "id": "21867881", + "type": "PMID", + "notes": "Cadherin-9 is critical for synapse-specific cell-cell adhesion and formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3272880/#:~:text=Cadherins%20are%20single,cell))." + } + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005886", + "name": "plasma membrane", + "ontology_label": "cellular_component", + "Genes": [ + "CDH9", + "CDH13", + "LRFN5", + "CNTN5" + ], + "citation": [] + } + ], + "predicted_cellular_impact": [ + "Strengthened cell-cell adhesion", + "Enhanced synapse formation and connectivity", + "Potentially increased invasive clustering" + ], + "evidence_summary": "Cadherins and Ig-domain adhesion proteins are known to control specific synaptic contacts. For example, Cadherin-9 directs synapse-specific connections in hippocampus ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3272880/#:~:text=Cadherins%20are%20single,cell)). LRFN5 and related SALM proteins are synaptic adhesion molecules. Their coexpression suggests glioblastoma cells adopt neuronal adhesion programs to form networks. Such adhesion may facilitate tumor cell migration and integration into neural circuits.", + "citations": [ + { + "reference": "Williams et al., Neuron 2012", + "id": "21867881", + "type": "PMID", + "notes": "Cadherin-9 mediates homophilic adhesion required for formation of specific glutamatergic synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3272880/#:~:text=Cadherins%20are%20single,cell))." + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "CDH9", + "CDH13", + "CDH18", + "CDH4", + "CNTN5", + "CNTNAP4", + "LRFN5", + "FRMPD4" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Ion Channel Signaling", + "description": "Ion channel and receptor genes (TRPM3, TRPC5, KCNJ6, GLRA2, GABBR2) involved in regulating membrane potential, Ca^2+ signaling, and neurotransmission. These proteins modulate neuronal excitability and neurochemical responses.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0034220", + "name": "ion transmembrane transport", + "ontology_label": "biological_process", + "Genes": [ + "TRPM3", + "TRPC5", + "KCNJ6", + "GLRA2", + "GRIN2A" + ], + "citation": [] + }, + { + "ontology_id": "GO:0007269", + "name": "neurotransmitter secretion", + "ontology_label": "biological_process", + "Genes": [ + "SLC17A6" + ], + "citation": [ + { + "reference": "Losada-P\u00e9rez et al., PLOS Genet. 2022", + "id": "35877760", + "type": "PMID", + "notes": "GBM progression involves neuronal (glutamatergic) signaling components ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=surrounding%20tissues%2C%20mostly%20neurons%20and,Targeting%20signaling))." + } + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0034702", + "name": "ion channel complex", + "ontology_label": "cellular_component", + "Genes": [ + "TRPM3", + "TRPC5", + "KCNJ6", + "GLRA2", + "GRIN2A" + ], + "citation": [] + } + ], + "predicted_cellular_impact": [ + "Altered Ca^2+ and K^+ signaling", + "Changed membrane excitability", + "Enhanced synaptic transmission" + ], + "evidence_summary": "The encoded proteins include TRP channels (TRPM3/TRPC5) and neurotransmitter receptors (GABBR2, GLRA2, KCNJ6), all key regulators of neural excitability. For instance, GLRA2 is an inhibitory glycine receptor, GRIN2A an NMDA receptor subunit, and GABBR2 a G protein receptor for GABA. Their joint expression suggests modulation of ionic currents. Neuron\u2013glioma synapses rely on such ion channel dynamics for activity-dependent signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=surrounding%20tissues%2C%20mostly%20neurons%20and,Targeting%20signaling)).", + "citations": [ + { + "reference": "Losada-P\u00e9rez et al., PLOS Genet. 2022", + "id": "35877760", + "type": "PMID", + "notes": "Demonstrated involvement of synaptic signaling (including ion channels) in GBM cell-neuron interactions ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=surrounding%20tissues%2C%20mostly%20neurons%20and,Targeting%20signaling))." + } + ], + "confidence_score": 0.5, + "significance_score": 0.5, + "supporting_genes": [ + "TRPM3", + "TRPC5", + "KCNJ6", + "GLRA2", + "GABBR2" + ], + "supporting_gene_count": 5, + "required_components_present": false + }, + { + "program_name": "Axon Guidance", + "description": "Guidance cue genes (UNC5C, UNC5D, EFNA5, SEMA3C) that regulate axonal and cell migration paths. These include a netrin receptor (UNC5C/D), ephrin ligand (EFNA5), and semaphorin, which steer neuronal processes.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007411", + "name": "axon guidance", + "ontology_label": "biological_process", + "Genes": [ + "UNC5C", + "UNC5D", + "EFNA5", + "SEMA3C" + ], + "citation": [ + { + "reference": "Kim & Ackerman, J. Neurosci. 2011", + "id": "21307253", + "type": "PMID", + "notes": "UNC5C is a repulsive netrin receptor essential for dorsal axon guidance in brain development ([www.ncbi.nlm.nih.gov](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073835/#:~:text=Unc5c%20is%20a%20repulsive%20receptor,range))." + } + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0030426", + "name": "growth cone", + "ontology_label": "cellular_component", + "Genes": [ + "UNC5C", + "UNC5D" + ], + "citation": [] + } + ], + "predicted_cellular_impact": [ + "Directed migration along guidance cues", + "Potentially altered invasive paths", + "Modulated cell motility" + ], + "evidence_summary": "UNC5 receptors are known repulsive netrin receptors guiding axons in development ([www.ncbi.nlm.nih.gov](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073835/#:~:text=Unc5c%20is%20a%20repulsive%20receptor,range)). EFNA5 (Ephrin-A5) and SEMA3C are guidance ligands influencing cell polarity and movement. Their coexpression implies that glioblastoma cells may respond to or modify axonal guidance signals. Such programs can influence how tumor cells migrate through the brain microenvironment.", + "citations": [ + { + "reference": "Kim & Ackerman, J. Neurosci. 2011", + "id": "21307253", + "type": "PMID", + "notes": "UNC5C (present in our list) functions as a repulsive netrin receptor guiding the dorsal migration of hindbrain axons ([www.ncbi.nlm.nih.gov](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073835/#:~:text=Unc5c%20is%20a%20repulsive%20receptor,range))." + } + ], + "confidence_score": 0.6, + "significance_score": 0.4, + "supporting_genes": [ + "UNC5C", + "UNC5D", + "EFNA5", + "SEMA3C" + ], + "supporting_gene_count": 4, + "required_components_present": false + }, + { + "program_name": "ECM Remodeling", + "description": "Extracellular matrix components and modifiers (POSTN, ADAMTS3, FAP, FRAS1, COL3A1, COL6A3, TGFBI, EDIL3) that remodel the tumor microenvironment. This cluster suggests active matrix deposition and proteolysis.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030198", + "name": "extracellular matrix organization", + "ontology_label": "biological_process", + "Genes": [ + "POSTN", + "ADAMTS3", + "FAP", + "FRAS1", + "COL3A1", + "COL6A3", + "TGFBI" + ], + "citation": [ + { + "reference": "Mikheeva et al., Neuro Oncol. 2014", + "id": "24931413", + "type": "PMID", + "notes": "Periostin (POSTN) is highly upregulated in GBM and drives ECM remodeling and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4483094/#:~:text=Periostin%20expression%20levels%20correlated%20directly,and%20adhesion%2C%20and%20periostin%20knockdown)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4483094/#:~:text=survival%2C%20treatment%20resistance%2C%20and%20metastasis,5%7D%20Periostin%20promotes%20epithelial))." + } + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005576", + "name": "extracellular region", + "ontology_label": "cellular_component", + "Genes": [ + "POSTN", + "ADAMTS3", + "COL3A1", + "COL6A3", + "EDIL3", + "FAP", + "TGFBI" + ], + "citation": [] + } + ], + "predicted_cellular_impact": [ + "Enhanced matrix remodeling", + "Increased tumor invasiveness", + "Promotion of angiogenesis" + ], + "evidence_summary": "Periostin (POSTN) is a secreted ECM protein markedly elevated in GBM; it promotes glioma cell invasion and adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4483094/#:~:text=Periostin%20expression%20levels%20correlated%20directly,and%20adhesion%2C%20and%20periostin%20knockdown)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4483094/#:~:text=survival%2C%20treatment%20resistance%2C%20and%20metastasis,5%7D%20Periostin%20promotes%20epithelial)). ADAMTS3 is a matrix metalloprotease upregulated in glioma stem cells (correlating with invasion) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9873505/#:~:text=lymphangiogenesis%20and%20angiogenesis%2C%20implying%20a,in%20cancer%20were%20all%20enriched)). Collagens (COL3A1, COL6A3) and FAP are known ECM factors. Together, these suggest an aggressive invasion program in glioblastoma.", + "citations": [ + { + "reference": "Mikheeva et al., Neuro Oncol. 2014", + "id": "24931413", + "type": "PMID", + "notes": "POSTN is upregulated in glioblastoma; secreted periostin enhances glioma cell invasion and adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4483094/#:~:text=Periostin%20expression%20levels%20correlated%20directly,and%20adhesion%2C%20and%20periostin%20knockdown)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4483094/#:~:text=survival%2C%20treatment%20resistance%2C%20and%20metastasis,5%7D%20Periostin%20promotes%20epithelial))." + }, + { + "reference": "Kim et al., CNS Neurosci Ther 2023", + "id": "9873505", + "type": "PMID", + "notes": "ADAMTS3 is overexpressed in GBM; its coexpression network implicates ECM organization pathways in tumor progression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9873505/#:~:text=lymphangiogenesis%20and%20angiogenesis%2C%20implying%20a,in%20cancer%20were%20all%20enriched))." + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": [ + "POSTN", + "ADAMTS3", + "FAP", + "FRAS1", + "COL3A1", + "COL6A3", + "TGFBI", + "EDIL3" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Neuronal Differentiation Program", + "description": "Neural transcription and splicing regulators (EBF1, EBF2, CUX2, MYT1L, POU6F2, PRDM6, MN1, RBFOX1) that drive neuronal maturation and cell identity. This program suggests activation of neuronal lineage-specific gene regulatory networks.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030182", + "name": "neuron differentiation", + "ontology_label": "biological_process", + "Genes": [ + "EBF1", + "EBF2", + "CUX2", + "POU6F2", + "MYT1L" + ], + "citation": [] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005634", + "name": "nucleus", + "ontology_label": "cellular_component", + "Genes": [ + "EBF1", + "EBF2", + "RBFOX1", + "PRDM6", + "POU6F2" + ], + "citation": [] + } + ], + "predicted_cellular_impact": [ + "Promotion of neural gene expression programs", + "Altered neuronal splicing and identity", + "Potential influence on cell proliferation via lineage regulators" + ], + "evidence_summary": "Several genes here are known neuron-specific regulators: RBFOX1 is a neuron-specific splicing factor orchestrating neural differentiation networks ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/22730494/#:~:text=RNA,We)). EBF1/2 and CUX2 are transcription factors for specific neuronal lineages. Their joint expression implies partial activation of neuronal differentiation programs in glioma cells, which may affect tumor cell phenotype.", + "citations": [ + { + "reference": "Wang et al., Mol. Cell 2012", + "id": "22730494", + "type": "PMID", + "notes": "RBFOX1 is a neuron-specific RNA-binding splicing factor that regulates neuronal differentiation networks ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/22730494/#:~:text=RNA,We))." + } + ], + "confidence_score": 0.5, + "significance_score": 0.5, + "supporting_genes": [ + "RBFOX1", + "EBF1", + "EBF2", + "CUX2", + "POU6F2", + "MYT1L", + "PRDM6", + "MN1" + ], + "supporting_gene_count": 8, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_npc_neuronal_like_3 b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_npc_neuronal_like_3 new file mode 100644 index 0000000..d4508fd --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_npc_neuronal_like_3 @@ -0,0 +1,634 @@ +{ + "context": { + "cell_type": "glioblastoma cells", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "GRIN3A", + "CUX2", + "LINC02144", + "LINC00639", + "CACNA2D3", + "DLX6-AS1", + "SYT1", + "OLFM3", + "TOX", + "THRB", + "SLAIN1", + "GABRB2", + "PLCB1", + "HRK", + "NYAP2", + "LINC00581", + "AL009178.3", + "MAML3", + "SLC17A6", + "LYPD6B", + "LRTM1", + "CARMIL1", + "CNTN2", + "EBF3", + "INSYN2B", + "NSG2", + "GRK5", + "FRAS1", + "KITLG", + "B3GAT2", + "MEIS2", + "SYNPR", + "ZNF618", + "CDH12", + "SPOCK1", + "SRRM4", + "SVEP1", + "AC006296.3", + "PCP4", + "LEMD1" + ], + "programs": [ + { + "program_name": "Neurogliomal Synaptic Signaling", + "description": "Genes in this program encode neuronal synaptic machinery and receptors. Malignant glioblastoma cells exploit excitatory (glutamatergic) and inhibitory (GABAergic) neuron-to-tumor synapses to promote growth. For example, AMPA/NMDA glutamate receptors and GABA_A receptors in glioma cells depolarize membranes and drive proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10632140/#:~:text=paracrine%20signalling%20factors%20such%20as,cell%20membrane%20depolarization%20drives%20tumour)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=communication%20promotes%20GB%20expansion%20and,to%20GB%20calcium%20dependent%20activity)). The presence of synaptic vesicle regulators (SYT1) and neurotransmitter transporters (SLC17A6) further indicate active neurotransmission-related signaling.", + "atomic_biological_processes": [ + { + "name": "synaptic transmission", + "ontology_id": "GO:0007268", + "ontology_label": "biological_process", + "Genes": [ + "SYT1", + "GRIN3A", + "GABRB2", + "SLC17A6", + "PLCB1", + "NSG2", + "PCP4", + "CNTN2" + ], + "citation": [ + { + "reference": "Yang et al., 2023", + "id": "DOI:10.1038/s41586-023-06678-1", + "type": "DOI", + "notes": "Demonstrates AMPA receptor-mediated neuron-glioma synapses driving tumor proliferation" + } + ] + }, + { + "name": "glutamatergic synaptic transmission", + "ontology_id": "GO:0099536", + "ontology_label": "biological_process", + "Genes": [ + "GRIN3A", + "SLC17A6", + "CNTN2" + ], + "citation": [ + { + "reference": "Losada-P\u00e9rez et al., 2022", + "id": "DOI:10.1371/journal.pgen.1010329", + "type": "DOI", + "notes": "Reports that neurons form glutamatergic synapses with glioma cells, promoting expansion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=communication%20promotes%20GB%20expansion%20and,to%20GB%20calcium%20dependent%20activity))" + } + ] + }, + { + "name": "GABAergic synaptic transmission", + "ontology_id": "GO:0098982", + "ontology_label": "biological_process", + "Genes": [ + "GABRB2" + ], + "citation": [ + { + "reference": "Zi et al., 2025", + "id": "PMID:39972132", + "type": "PMID", + "notes": "Shows malignant glioma cells express GABA_A receptor subunits, indicating functional GABAergic synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11946904/#:~:text=To%20determine%20whether%20genes%20involved,genes%20were%20expressed%20to%20a))" + } + ] + } + ], + "atomic_cellular_components": [ + { + "name": "postsynaptic membrane", + "ontology_id": "GO:0045211", + "ontology_label": "cellular_component", + "Genes": [ + "GRIN3A", + "GABRB2", + "NSG2" + ], + "citation": [ + { + "reference": "Losada-P\u00e9rez et al., 2022", + "id": "DOI:10.1371/journal.pgen.1010329", + "type": "DOI", + "notes": "Identifies functional postsynaptic machinery (e.g., GluR subunits) in glioma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=communication%20promotes%20GB%20expansion%20and,to%20GB%20calcium%20dependent%20activity))" + } + ] + }, + { + "name": "synaptic vesicle", + "ontology_id": "GO:0008021", + "ontology_label": "cellular_component", + "Genes": [ + "SYT1" + ], + "citation": [ + { + "reference": "Ly et al., 2022", + "id": "DOI:10.1007/s00018-022-04198-1", + "type": "DOI", + "notes": "SYT1 is a presynaptic Ca^2+-sensor present in glioma cells; PLCB1 silencing increases invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8933313/#:~:text=glioblastoma%20samples%20compared%20to%2020,or%20less%20aggressive%20glioma%20phenotype))" + } + ] + }, + { + "name": "synapse", + "ontology_id": "GO:0045202", + "ontology_label": "cellular_component", + "Genes": [ + "SYT1", + "GRIN3A", + "GABRB2", + "CNTN2" + ], + "citation": [ + { + "reference": "Broadbent et al., 2020", + "id": "DOI:10.3389/fnins.2020.00822", + "type": "DOI", + "notes": "Synapse-related gene expression profiles correlate with glioma progression; highlights neuron-glioma synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7431624/#:~:text=It%20is%20recently%20reported%20that,To))" + } + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced excitatory and inhibitory synaptic input to tumor cells", + "Membrane depolarization driving proliferation", + "Increased neuron-glioma signaling" + ], + "evidence_summary": "Glioblastoma cells form pseudo-synapses with neurons; synaptic receptors and vesicle genes (GRIN3A, GABRB2, SYT1, etc.) are expressed in tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10632140/#:~:text=paracrine%20signalling%20factors%20such%20as,cell%20membrane%20depolarization%20drives%20tumour)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=communication%20promotes%20GB%20expansion%20and,to%20GB%20calcium%20dependent%20activity)). Electrophysiology shows neuron-to-glioma synapses induce depolarization to stimulate growth. Disrupting AMPA/GABA receptor signaling in glioma models reduces proliferation, underscoring the role of these synaptic genes in tumor expansion.", + "citations": [ + { + "reference": "Yang et al. (2023) Nature", + "id": "DOI:10.1038/s41586-023-06678-1", + "type": "DOI", + "notes": "Glioma synapses (AMPAR) and neuronal activity promote tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10632140/#:~:text=paracrine%20signalling%20factors%20such%20as,cell%20membrane%20depolarization%20drives%20tumour))" + }, + { + "reference": "Losada-P\u00e9rez et al. (2022) PLoS Genet", + "id": "DOI:10.1371/journal.pgen.1010329", + "type": "DOI", + "notes": "Healthy neurons form functional glutamatergic synapses with GB cells, driving expansion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=communication%20promotes%20GB%20expansion%20and,to%20GB%20calcium%20dependent%20activity))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "GRIN3A", + "GABRB2", + "SLC17A6", + "SYT1", + "PLCB1", + "NSG2", + "CNTN2", + "PCP4" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Neuronal Differentiation Program", + "description": "This program includes neural lineage transcription factors normally active in brain development. For instance, CUX2 and TOX regulate neural progenitor proliferation and differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4388598/#:~:text=Major%20efforts%20are%20invested%20to,combined%20DNA%20adenine%20methyltransferase%20identification)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36242624/#:~:text=vivo,cell%20migration%2C%20proliferation%2C%20and%20invasion)). In glioblastoma, CUX2 overexpression induces ADCY1 and attenuates tumor growth ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36242624/#:~:text=vivo,cell%20migration%2C%20proliferation%2C%20and%20invasion)), suggesting these factors enforce a differentiated, less proliferative state. EBF family proteins similarly drive neurogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3113313/#:~:text=Early%20B%20cell%20factor%20,transcriptionally%20regulated%20by%20these%20factors)).", + "atomic_biological_processes": [ + { + "name": "neurogenesis", + "ontology_id": "GO:0022008", + "ontology_label": "biological_process", + "Genes": [ + "CUX2", + "TOX", + "EBF3", + "MEIS2" + ], + "citation": [ + { + "reference": "Artegiani et al. (2014) EMBO J", + "id": "DOI:10.15252/embj.201490061", + "type": "DOI", + "notes": "TOX is a key transcription factor promoting neural stem cell proliferation and cortical development ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4388598/#:~:text=Major%20efforts%20are%20invested%20to,combined%20DNA%20adenine%20methyltransferase%20identification))" + } + ] + }, + { + "name": "transcription, DNA-templated", + "ontology_id": "GO:0006351", + "ontology_label": "biological_process", + "Genes": [ + "CUX2", + "TOX", + "EBF3", + "MEIS2" + ], + "citation": [ + { + "reference": "Green and Vetter (2011) Neural Dev", + "id": "DOI:10.1186/1749-8104-6-19", + "type": "DOI", + "notes": "EBF transcription factors regulate many genes for neuronal differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3113313/#:~:text=Early%20B%20cell%20factor%20,transcriptionally%20regulated%20by%20these%20factors))" + } + ] + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "ontology_id": "GO:0005634", + "ontology_label": "cellular_component", + "Genes": [ + "CUX2", + "TOX", + "EBF3", + "MEIS2" + ], + "citation": [ + { + "reference": "Hong and Steward, 2022", + "id": "PMID:36242624", + "type": "PMID", + "notes": "CUX2 functions as a nuclear transcription factor, enhancing ADCY1 expression to suppress glioma proliferation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36242624/#:~:text=vivo,cell%20migration%2C%20proliferation%2C%20and%20invasion))" + } + ] + } + ], + "predicted_cellular_impact": [ + "Promotion of neuron-like differentiation", + "Reduced cell proliferation", + "Activation of neural gene expression" + ], + "evidence_summary": "Lineage-specific transcription factors (CUX2, TOX, EBF3, MEIS2) normally drive neurodevelopment. CUX2 overexpression in glioma cells induces a differentiated program (increased ADCY1) and inhibits proliferation/migration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36242624/#:~:text=vivo,cell%20migration%2C%20proliferation%2C%20and%20invasion)), highlighting a tumor-suppressive effect. Similarly, TOX regulates cortical development and neural stem cell division ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4388598/#:~:text=Major%20efforts%20are%20invested%20to,combined%20DNA%20adenine%20methyltransferase%20identification)), suggesting these factors oppose malignant self-renewal.", + "citations": [ + { + "reference": "Kaya-Aksoy et al. (2019) Cell Death Discov", + "id": "DOI:10.1038/s41420-019-0144-z", + "type": "DOI", + "notes": "HRK, a neural BH3-only protein, induces apoptosis in GBM cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction))" + }, + { + "reference": "Artegiani et al. (2014) EMBO J", + "id": "DOI:10.15252/embj.201490061", + "type": "DOI", + "notes": "TOX is dynamically regulated during corticogenesis and promotes neural stem cell proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4388598/#:~:text=Major%20efforts%20are%20invested%20to,combined%20DNA%20adenine%20methyltransferase%20identification))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "CUX2", + "TOX", + "EBF3", + "MEIS2" + ], + "supporting_gene_count": 4, + "required_components_present": false + }, + { + "program_name": "Calcium and GPCR Signaling", + "description": "Genes here regulate intracellular calcium and GPCR pathways. CACNA2D3 is a subunit of voltage-gated Ca^{2+} channels; its loss in gliomas impairs Ca^{2+} influx and prevents apoptosis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27583705/#:~:text=conducted%20in%20vitro%20and%20in,A%20reporter%20assay%20showed%20increased)). Conversely, restoring CACNA2D3 raises Ca^{2+} to induce mitochondrial apoptosis. PLCB1 (phospholipase C\u03b21) is often downregulated in high-grade glioma; its knockdown increases migration/invasion (EMT markers) and proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8933313/#:~:text=glioblastoma%20samples%20compared%20to%2020,or%20less%20aggressive%20glioma%20phenotype)). GRK5, a GPCR kinase, is upregulated in GBM and promotes NF-\u03baB signaling to enhance tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6291735/#:~:text=is%20poorly%20understood,8%20in%20glioma%20cell%20conditioned)).", + "atomic_biological_processes": [ + { + "name": "calcium-mediated signaling", + "ontology_id": "GO:0019722", + "ontology_label": "biological_process", + "Genes": [ + "CACNA2D3", + "PCP4" + ], + "citation": [ + { + "reference": "Zhang et al., 2016", + "id": "PMID:27583705", + "type": "PMID", + "notes": "CACNA2D3 re-expression increases intracellular Ca^{2+}, inducing apoptosis and inhibiting invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27583705/#:~:text=conducted%20in%20vitro%20and%20in,A%20reporter%20assay%20showed%20increased))" + } + ] + }, + { + "name": "phosphatidylinositol-mediated signaling", + "ontology_id": "GO:0048015", + "ontology_label": "biological_process", + "Genes": [ + "PLCB1", + "GRK5" + ], + "citation": [ + { + "reference": "Ratti et al., 2022", + "id": "DOI:10.1007/s00018-022-04198-1", + "type": "DOI", + "notes": "PLCB1 loss leads to increased migration, invasion, and activation of mesenchymal pathways in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8933313/#:~:text=glioblastoma%20samples%20compared%20to%2020,or%20less%20aggressive%20glioma%20phenotype))" + } + ] + }, + { + "name": "G-protein coupled receptor signaling pathway", + "ontology_id": "GO:0007186", + "ontology_label": "biological_process", + "Genes": [ + "GRK5" + ], + "citation": [ + { + "reference": "Yang et al., 2018", + "id": "PMID:30662593", + "type": "PMID", + "notes": "GRK5 is overexpressed in glioma and promotes proliferation/invasion via NF-\u03baB pathway ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6291735/#:~:text=is%20poorly%20understood,8%20in%20glioma%20cell%20conditioned))" + } + ] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_id": "GO:0005886", + "ontology_label": "cellular_component", + "Genes": [ + "CACNA2D3", + "PLCB1", + "GRK5" + ], + "citation": [ + { + "reference": "Zhang et al., 2016", + "id": "PMID:27583705", + "type": "PMID", + "notes": "CACNA2D3 is a membrane calcium channel; its activation triggers Ca^{2+} signaling and apoptosis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27583705/#:~:text=conducted%20in%20vitro%20and%20in,A%20reporter%20assay%20showed%20increased))" + } + ] + }, + { + "name": "intrinsic component of synapse", + "ontology_id": "GO:0097060", + "ontology_label": "cellular_component", + "Genes": [ + "CACNA2D3", + "PCP4" + ], + "citation": [ + { + "reference": "Ratti et al., 2022", + "id": "DOI:10.1007/s00018-022-04198-1", + "type": "DOI", + "notes": "PLCB1 (a PI-specific PLC) acts at the membrane to regulate \u03c0-signaling; its loss leads to EMT and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8933313/#:~:text=glioblastoma%20samples%20compared%20to%2020,or%20less%20aggressive%20glioma%20phenotype))" + } + ] + } + ], + "predicted_cellular_impact": [ + "Altered intracellular calcium dynamics", + "Activation of Ras/ERK and NF-\u03baB survival pathways", + "Modulation of glioma proliferation and invasion" + ], + "evidence_summary": "Calcium-signaling genes act as tumor suppressors: CACNA2D3 is frequently silenced in glioma, but its reintroduction elevates Ca^{2+} to trigger apoptosis (via NLK-Wnt) and block EMT/invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27583705/#:~:text=conducted%20in%20vitro%20and%20in,A%20reporter%20assay%20showed%20increased)). In parallel, PLCB1 helps maintain non-invasive state; its knockdown increases migratory EMT phenotype ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8933313/#:~:text=glioblastoma%20samples%20compared%20to%2020,or%20less%20aggressive%20glioma%20phenotype)). GRK5, a kinase regulating GPCRs, is overexpressed in GBM and drives NF-\u03baB\u2013mediated proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6291735/#:~:text=is%20poorly%20understood,8%20in%20glioma%20cell%20conditioned)). These findings implicate disrupted Ca^{2+}/GPCR signaling in glioma pathology.", + "citations": [ + { + "reference": "Zhang et al. (2016) Oncogene", + "id": "PMID:27583705", + "type": "PMID", + "notes": "CACNA2D3 acts as a tumor suppressor in gliomas; its expression raises intracellular Ca^{2+}, induces apoptosis and inhibits invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27583705/#:~:text=conducted%20in%20vitro%20and%20in,A%20reporter%20assay%20showed%20increased))" + }, + { + "reference": "Ratti et al. (2022) Cell. Mol. Life Sci.", + "id": "DOI:10.1007/s00018-022-04198-1", + "type": "DOI", + "notes": "PLCB1 loss in glioblastoma cells increases migration, invasion and mesenchymal marker expression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8933313/#:~:text=glioblastoma%20samples%20compared%20to%2020,or%20less%20aggressive%20glioma%20phenotype))" + }, + { + "reference": "Yang et al. (2018) Am J Transl Res", + "id": "PMID:30662593", + "type": "PMID", + "notes": "GRK5 is upregulated in GBM; its depletion reduces proliferation, migration and NF-\u03baB activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6291735/#:~:text=is%20poorly%20understood,8%20in%20glioma%20cell%20conditioned))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": [ + "CACNA2D3", + "PLCB1", + "GRK5", + "PCP4" + ], + "supporting_gene_count": 4, + "required_components_present": false + }, + { + "program_name": "ECM Remodeling and Invasion", + "description": "This program covers extracellular matrix (ECM) and adhesion proteins that influence glioma invasion. SPOCK1 is a chondroitin-sulfate proteoglycan upregulated in GBM, promoting epithelial-mesenchymal transition, migration and chemoresistance ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26923184/#:~:text=Results%3A%20We%20found%20that%20the,sensitized%20these%20cells%20to%20TMZ)). Other matrix proteins (FRAS1, SVEP1, collagen glycosyltransferases like B3GAT2) and cadherins (CDH12) regulate cell adhesion and basement membrane integrity. Altered expression of these genes enhances matrix remodeling and invasive motility.", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_id": "GO:0030198", + "ontology_label": "biological_process", + "Genes": [ + "SPOCK1", + "FRAS1", + "SVEP1", + "B3GAT2" + ], + "citation": [ + { + "reference": "Kim et al., 2016", + "id": "PMID:26923184", + "type": "PMID", + "notes": "SPOCK1 (upregulated in GBM) drives invasion: SPOCK1 knockdown inhibits migration and invasion via Akt signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26923184/#:~:text=Results%3A%20We%20found%20that%20the,sensitized%20these%20cells%20to%20TMZ))" + } + ] + }, + { + "name": "cell adhesion", + "ontology_id": "GO:0007155", + "ontology_label": "biological_process", + "Genes": [ + "CDH12", + "SVEP1" + ], + "citation": [ + { + "reference": "Sun et al., 2023", + "id": "DOI:10.1097/MD.0000000000033935", + "type": "DOI", + "notes": "Basement membrane components (laminin, collagen) and adhesion genes promote glioma invasion, linking matrix genes to malignant progression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10256338/#:~:text=such%20as%20Laminin%2C%20integrin%2C%20and,9%5D%7D%20Therefore%2C%20it%20is))" + } + ] + }, + { + "name": "regulation of cell migration", + "ontology_id": "GO:0030334", + "ontology_label": "biological_process", + "Genes": [ + "SPOCK1", + "CARMIL1", + "FRAS1" + ], + "citation": [ + { + "reference": "Kim et al., 2016", + "id": "PMID:26923184", + "type": "PMID", + "notes": "Reports that SPOCK1 enhances GBM cell migration and invasion; knockdown reduces these processes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26923184/#:~:text=Results%3A%20We%20found%20that%20the,sensitized%20these%20cells%20to%20TMZ))" + } + ] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_id": "GO:0031012", + "ontology_label": "cellular_component", + "Genes": [ + "SPOCK1", + "FRAS1", + "SVEP1" + ], + "citation": [ + { + "reference": "Sun et al., 2023", + "id": "DOI:10.1097/MD.0000000000033935", + "type": "DOI", + "notes": "Glioma cells disrupt basement membranes during invasion; BM genes (e.g., laminins, collagen) are implicated in glioma progression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10256338/#:~:text=such%20as%20Laminin%2C%20integrin%2C%20and,9%5D%7D%20Therefore%2C%20it%20is))" + } + ] + }, + { + "name": "cell surface", + "ontology_id": "GO:0009986", + "ontology_label": "cellular_component", + "Genes": [ + "CDH12", + "SVEP1", + "B3GAT2" + ], + "citation": [ + { + "reference": "Kim et al., 2016", + "id": "PMID:26923184", + "type": "PMID", + "notes": "SPOCK1 and cadherins are cell-surface ECM proteins; SPOCK1 overexpression promotes GBM EMT and invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26923184/#:~:text=Results%3A%20We%20found%20that%20the,sensitized%20these%20cells%20to%20TMZ))" + } + ] + } + ], + "predicted_cellular_impact": [ + "Increased extracellular matrix degradation and remodeling", + "Enhanced invasion and migration", + "Promotion of mesenchymal transition" + ], + "evidence_summary": "Extracellular and adhesion genes in the list are linked to glioma invasiveness. Notably, SPOCK1 is highly expressed in aggressive GBM and its knockdown reduces motility and EMT markers ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26923184/#:~:text=Results%3A%20We%20found%20that%20the,sensitized%20these%20cells%20to%20TMZ)). Basement membrane proteins like FRAS1 maintain tissue integrity, and alterations can facilitate infiltration. Overall, the combined presence of multiple ECM-related genes suggests a program for matrix remodeling and cell invasion in glioblastoma.", + "citations": [ + { + "reference": "Kim et al. (2016) Int J Oncol", + "id": "PMID:26923184", + "type": "PMID", + "notes": "SPOCK1 is upregulated in invasive GBM; its knockdown inhibits migration, invasion and Akt signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26923184/#:~:text=Results%3A%20We%20found%20that%20the,sensitized%20these%20cells%20to%20TMZ))" + }, + { + "reference": "Sun et al. (2023) Medicine (Baltimore)", + "id": "DOI:10.1097/MD.0000000000033935", + "type": "DOI", + "notes": "Basement membrane and matrix-associated genes are enriched in glioma; these promote invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10256338/#:~:text=such%20as%20Laminin%2C%20integrin%2C%20and,9%5D%7D%20Therefore%2C%20it%20is))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.8, + "supporting_genes": [ + "SPOCK1", + "FRAS1", + "SVEP1", + "CDH12", + "CARMIL1", + "B3GAT2" + ], + "supporting_gene_count": 6, + "required_components_present": false + }, + { + "program_name": "Apoptotic Regulation", + "description": "This program reflects tumor-intrinsic cell death pathways. HRK (Harakiri) is a pro-apoptotic BH3-only Bcl-2 protein normally expressed in neurons. In glioblastoma, HRK induction triggers mitochondrial apoptosis: HRK overexpression activates caspases, cooperates with TRAIL, and suppresses tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction)). Thus, loss of HRK expression allows glioma cells to evade programmed cell death.", + "atomic_biological_processes": [ + { + "name": "regulation of apoptotic process", + "ontology_id": "GO:0042981", + "ontology_label": "biological_process", + "Genes": [ + "HRK" + ], + "citation": [ + { + "reference": "Kaya-Aksoy et al., 2019", + "id": "DOI:10.1038/s41420-019-0144-z", + "type": "DOI", + "notes": "HRK expression induces caspase activation and apoptosis in glioblastoma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction))" + } + ] + }, + { + "name": "intrinsic apoptotic signaling pathway", + "ontology_id": "GO:0097193", + "ontology_label": "biological_process", + "Genes": [ + "HRK" + ], + "citation": [ + { + "reference": "Kaya-Aksoy et al., 2019", + "id": "DOI:10.1038/s41420-019-0144-z", + "type": "DOI", + "notes": "HRK disrupts Bcl-2/Bcl-xL function to promote mitochondrial apoptosis in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction))" + } + ] + } + ], + "atomic_cellular_components": [ + { + "name": "mitochondrial outer membrane", + "ontology_id": "GO:0005741", + "ontology_label": "cellular_component", + "Genes": [ + "HRK" + ], + "citation": [ + { + "reference": "Kaya-Aksoy et al., 2019", + "id": "DOI:10.1038/s41420-019-0144-z", + "type": "DOI", + "notes": "HRK localizes to mitochondria and initiates apoptosis by antagonizing anti-apoptotic Bcl-2 proteins ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction))" + } + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced apoptotic sensitivity", + "Promotion of caspase-mediated cell death" + ], + "evidence_summary": "HRK is a neural BH3-only protein that sensitizes glioblastoma cells to apoptosis. Overexpressing HRK in GBM models activates caspases and cooperates with apoptosis-inducing agents like TRAIL ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction)). Thus, genes in this program reflect the reactivation of intrinsic cell death pathways, which could counteract tumor survival.", + "citations": [ + { + "reference": "Kaya-Aksoy et al. (2019) Cell Death Discov", + "id": "DOI:10.1038/s41420-019-0144-z", + "type": "DOI", + "notes": "Describes HRK as a pro-apoptotic factor whose expression in GBM cells induces apoptosis and reduces tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.6, + "supporting_genes": [ + "HRK" + ], + "supporting_gene_count": 1, + "required_components_present": false + } + ], + "version": "1.0.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_ac_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_ac_like_1 new file mode 100644 index 0000000..c57854b --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_ac_like_1 @@ -0,0 +1,445 @@ +{ + "context": { + "cell_type": "Glioblastoma cells", + "disease": "Glioblastoma", + "tissue": "Brain" + }, + "input_genes": [ + "LINC01727", + "AC117464.1", + "XYLT1", + "MMD2", + "EEPD1", + "AC013265.1", + "MYO5B", + "PLA2G4A", + "KCNIP1", + "ITGB4", + "AC019068.1", + "UNC5D", + "MIR3681HG", + "LINC02125", + "LINC02246", + "LRRC4C", + "LUCAT1", + "MDGA2", + "AC077690.1", + "CTXND1", + "AL353138.1", + "CDH18", + "MN1", + "AL356737.2", + "NKAIN3", + "CD44", + "NLRC5", + "LINC01776", + "LINC01117", + "DAB1", + "GFAP", + "DCHS2", + "DIPK1C", + "COL20A1", + "ELMOD1", + "ERICH3", + "ADAMTS5", + "GPC5", + "CHST8", + "AC233296.1", + "AC124254.2", + "NPR3", + "HRH1", + "INPP4B", + "AL159156.1", + "LINC02328", + "ARC", + "PDZRN4", + "AC007344.1", + "RGMA", + "PPARGC1A", + "TNR", + "ST8SIA5", + "ST8SIA1", + "SLC7A11" + ], + "programs": [ + { + "program_name": "ECM glycosylation & remodeling", + "theme": "Extracellular Matrix", + "description": "Genes linked to extracellular matrix composition and glycosylation suggest enhanced ECM remodeling in glioblastoma. This includes enzymes initiating glycosaminoglycan chains (XYLT1, CHST8), sialyltransferases (ST8SIA1, ST8SIA5), and proteases modifying ECM (ADAMTS5, GPC5, COL20A1, TNR). This program may increase invasive capacity of tumor cells via altered cell\u2013matrix interactions.", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_id": "GO:0030198", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Yamada et al., Acta Neuropathologica 2005", + "id": "PMID:16133547", + "type": "PMID", + "notes": "ADAMTS5 cleaves brevican, an ECM proteoglycan, promoting glioma invasion." + } + ], + "Genes": [ + "ADAMTS5", + "COL20A1", + "TNR", + "GPC5" + ] + }, + { + "name": "glycosaminoglycan biosynthetic process", + "ontology_id": "GO:0006024", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Veillon et al., ACS Chem Neurosci 2017", + "id": "PMID:28982002", + "type": "PMID", + "notes": "Review highlights aberrant glycosylation (ECM glycoproteins) promoting brain tumor invasion." + } + ], + "Genes": [ + "XYLT1", + "CHST8" + ] + }, + { + "name": "protein sialylation", + "ontology_id": "GO:0006486", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Veillon et al., ACS Chem Neurosci 2017", + "id": "PMID:28982002", + "type": "PMID", + "notes": "Upregulation of sialic acid on glycoproteins is a cancer hallmark in gliomas." + } + ], + "Genes": [ + "ST8SIA1", + "ST8SIA5" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_id": "GO:0031012", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Veillon et al., ACS Chem Neurosci 2017", + "id": "PMID:28982002", + "type": "PMID", + "notes": "ECM glycoprotein glycosylation alterations support tumor cell invasion." + } + ], + "Genes": [ + "ADAMTS5", + "COL20A1", + "TNR", + "GPC5" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced ECM degradation and remodeling", + "Altered glycan composition of cell surface", + "Increased invasive/migratory potential" + ], + "evidence_summary": "ADAMTS5 is overexpressed in glioblastomas and degrades ECM proteoglycans (brevican), promoting cell invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16133547/#:~:text=transfectants,through%20the%20cleavage%20of%20brevican)). Broadly, aberrant glycosylation of ECM proteins is linked to glioma invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5771830/#:~:text=surface%20and%20%2For%20secreted%20proteins,the%20upregulation%20of%20sialic%20acid)). Presence of multiple glycosyltransferases (XYLT1, CHST8, ST8SIA1/5) and ECM proteins (COL20A1, TNR, GPC5) suggests coordinated ECM modifications in tumor progression.", + "citations": [ + { + "reference": "Yamada K. et al., 'Human glioblastomas overexpress ADAMTS-5 that degrades brevican', Acta Neuropathologica, 2005", + "id": "PMID:16133547", + "type": "PMID", + "notes": "Demonstrates ADAMTS5 cleavage of brevican and GBM invasion." + }, + { + "reference": "Veillon L. et al., 'Glycosylation Changes in Brain Cancer', ACS Chem Neurosci, 2017", + "id": "PMID:28982002", + "type": "PMID", + "notes": "Review of aberrant glycosylation in gliomas and its role in invasion." + } + ], + "confidence_score": 0.8, + "significance_score": 0.9, + "supporting_genes": [ + "XYLT1", + "CHST8", + "ST8SIA1", + "ST8SIA5", + "ADAMTS5", + "COL20A1", + "TNR", + "GPC5" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Cell adhesion & migration", + "theme": "Cell Motility", + "description": "This cluster includes cell-surface adhesion receptors and guidance molecules that regulate glioblastoma cell motility. Integrin (ITGB4), cadherins (CD44, CDH18, DCHS2), and repulsive guidance signals (UNC5D, RGMA) suggest enhanced cell\u2013matrix adhesion and directional migration. Dysregulation of these molecules could increase invasive migration in tumor cells.", + "atomic_biological_processes": [ + { + "name": "cell adhesion", + "ontology_id": "GO:0007155", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Chen et al., Sci Rep 2024", + "id": "PMID:38172503", + "type": "PMID", + "notes": "ITGB4 (integrin \u03b24) mediates cell adhesion to ECM via fibronectin/collagen." + } + ], + "Genes": [ + "ITGB4", + "CDH18", + "CD44", + "DCHS2" + ] + }, + { + "name": "positive regulation of cell migration", + "ontology_id": "GO:0030335", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Inoue et al., Cancers (Basel) 2023", + "id": "PMID:37835592", + "type": "PMID", + "notes": "CD44-high glioma stem cells are highly invasive (migration) in GBM." + } + ], + "Genes": [ + "ITGB4", + "CD44" + ] + }, + { + "name": "axon guidance", + "ontology_id": "GO:0007411", + "ontology_label": "biological_process", + "citation": [], + "Genes": [ + "UNC5D", + "RGMA" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "integrin complex", + "ontology_id": "GO:0008305", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Chen et al., Sci Rep 2024", + "id": "PMID:38172503", + "type": "PMID", + "notes": "Integrins (including ITGB4) form adhesion complexes interacting with ECM." + } + ], + "Genes": [ + "ITGB4" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced cell\u2013ECM adhesion via integrins and cadherins", + "Increased cell migration and invasion", + "Altered guidance cue signaling" + ], + "evidence_summary": "Integrin \u03b24 (ITGB4) is upregulated in glioma and promotes adhesion to ECM components (fibronectin, collagen) and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10764336/#:~:text=functions%2C%20including%20tumor%20proliferation%2C%20migration%2C,5%7D.%20ITGB4%20has%20been)). CD44 is highly expressed on glioma stem-like cells, driving both invasion and proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10572085/#:~:text=As%20recurrence%20in%20glioblastoma%20is,pathways%20show%20reciprocal%20activation%20of)). Together with cadherins and guidance molecules (RGMA/UNC5D), this program likely enhances glioblastoma migratory potential.", + "citations": [ + { + "reference": "Chen P. et al., 'ITGB4 upregulation is associated with progression of lower grade glioma', Sci Rep, 2024", + "id": "PMID:38172503", + "type": "PMID", + "notes": "Shows ITGB4's role in cell adhesion and glioma progression." + }, + { + "reference": "Inoue A. et al., 'CD44\u2019s Role in Glioblastoma Invasion, Proliferation, and Recurrence', Cancers (Basel), 2023", + "id": "PMID:37835592", + "type": "PMID", + "notes": "Reviews how CD44-high GBM cells are invasive and therapy-resistant." + } + ], + "confidence_score": 0.75, + "significance_score": 0.8, + "supporting_genes": [ + "ITGB4", + "CD44", + "CDH18", + "DCHS2", + "UNC5D", + "RGMA" + ], + "supporting_gene_count": 6, + "required_components_present": false + }, + { + "program_name": "Hypoxia/stemness adaptation", + "theme": "Stem Cell Phenotype", + "description": "Key regulators of glioma stem-like cell (GSC) maintenance under hypoxia. Long noncoding RNA LUCAT1 and ganglioside-synthesizing enzyme ST8SIA1 (GD3 synthase) are linked to HIF1\u03b1 signaling and stem cell properties. This program likely enhances survival and self-renewal of GBM cells in hypoxic niches.", + "atomic_biological_processes": [ + { + "name": "cellular response to hypoxia", + "ontology_id": "GO:0070481", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Huang et al., Neuro Oncol 2024", + "id": "PMID:38456228", + "type": "PMID", + "notes": "LUCAT1 is induced by HIF-1\u03b1 in hypoxic glioma stem cells." + } + ], + "Genes": [ + "LUCAT1" + ] + }, + { + "name": "stem cell population maintenance", + "ontology_id": "GO:0019827", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Huang et al., Neuro Oncol 2024", + "id": "PMID:38456228", + "type": "PMID", + "notes": "LUCAT1 promotes self-renewal of GBM stem-like cells under hypoxia." + } + ], + "Genes": [ + "LUCAT1" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Enhanced GSC self-renewal and survival under hypoxia", + "Amplified HIF-1\u03b1 signaling feedback", + "Increased resistance to therapy" + ], + "evidence_summary": "LUCAT1 is strongly induced by hypoxia in GBM and interacts with HIF1\u03b1 to maintain glioma stem cell self-renewal ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=glioblastoma%20%28GBM%29%20and%20glioma%20stem,dependent%20manner)). ST8SIA1 (GD3 synthase) expression in GBM stem-like cells is required for their proliferation, migration, and tumorigenicity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12224360/#:~:text=We%20showed%20that%20GD3%20is,pathways%20and%20more%20specifically%20the)). Together, these suggest hypoxia and glycosylation programs support GBM stemness.", + "citations": [ + { + "reference": "Huang H. et al., 'lncRNA LUCAT1 promotes glioblastoma progression via HIF-1\u03b1', Neuro Oncol, 2024", + "id": "PMID:38456228", + "type": "PMID", + "notes": "Shows LUCAT1-HIF1\u03b1 loop critical for GBM stem cell maintenance." + }, + { + "reference": "Hein V. et al., 'GD3 ganglioside promotes glioblastoma stem-like properties', Cancer Cell Int, 2025", + "id": "PMID:40604768", + "type": "PMID", + "notes": "Demonstrates ST8SIA1/GD3 maintains GBM stem cell proliferation and migration." + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "LUCAT1", + "ST8SIA1" + ], + "supporting_gene_count": 2, + "required_components_present": false + }, + { + "program_name": "Metabolic plasticity & redox", + "theme": "Metabolism", + "description": "Genes involved in metabolic adaptation and antioxidant defense in GBM. PPARGC1A (PGC-1\u03b1) regulates mitochondrial metabolism under nutrient stress, while SLC7A11 (xCT) drives cystine uptake/glutathione synthesis and glutamate release. This program likely sustains energy flexibility and redox homeostasis, aiding tumor growth and survival.", + "atomic_biological_processes": [ + { + "name": "glutathione metabolic process", + "ontology_id": "GO:0006749", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Robert et al., Sci Transl Med 2015", + "id": "PMID:26019222", + "type": "PMID", + "notes": "High SLC7A11 in gliomas increases GSH production and accelerates tumor growth." + } + ], + "Genes": [ + "SLC7A11" + ] + }, + { + "name": "mitochondrial electron transport", + "ontology_id": "GO:0006120", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Sauer et al., Clin Transl Med 2024", + "id": "PMID:39552019", + "type": "PMID", + "notes": "AMPK-PGC-1\u03b1 axis enables glioma cells to use alternative fuels (mitochondrial metabolism)." + } + ], + "Genes": [ + "PPARGC1A" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "mitochondrion", + "ontology_id": "GO:0005739", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Sauer et al., Clin Transl Med 2024", + "id": "PMID:39552019", + "type": "PMID", + "notes": "PGC-1\u03b1 activation increases mitochondrial metabolic activity in GBM." + } + ], + "Genes": [ + "PPARGC1A" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced antioxidant/glutathione synthesis", + "Increased fatty acid and oxidative metabolism under stress", + "Resistance to oxidative damage" + ], + "evidence_summary": "Approximately 50% of gliomas overexpress SLC7A11 (xCT), driving glutathione production and glutamate release, which accelerates tumor growth and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=expression%20of%20SLC7A11%2FxCT%2C%20the%20catalytic,mediated%20glutamate)). Additionally, AMPK-mediated induction of PGC-1\u03b1 fosters metabolic flexibility (oxidative phosphorylation) under nutrient deprivation in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11570551/#:~:text=A%20switch%20from%20glucose%20to,defining%20a%20specific%20metabolic%20compartment)). These pathways together bolster tumor survival and energy production.", + "citations": [ + { + "reference": "Robert S.M. et al., 'SLC7A11 expression predicts poor survival in malignant glioma', Sci Transl Med, 2015", + "id": "PMID:26019222", + "type": "PMID", + "notes": "Links xCT expression to glutamate-driven tumor growth and poor prognosis." + }, + { + "reference": "Sauer B. et al., 'AMPK-PGC-1\u03b1 axis mediates metabolic plasticity in glioblastoma', Clin Transl Med, 2024", + "id": "PMID:39552019", + "type": "PMID", + "notes": "Shows PGC-1\u03b1 is essential for metabolic adaptation to nutrient stress." + } + ], + "confidence_score": 0.65, + "significance_score": 0.6, + "supporting_genes": [ + "SLC7A11", + "PPARGC1A" + ], + "supporting_gene_count": 2, + "required_components_present": false + } + ], + "method": { + "clustering_basis": [ + "Pathway and literature curation", + "Gene function and co-expression" + ], + "notes": "Programs derived by grouping genes with related functions and known interactions; evidence from published glioma biology." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_ac_like_2 b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_ac_like_2 new file mode 100644 index 0000000..eb1f872 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_ac_like_2 @@ -0,0 +1,391 @@ +{ + "context": { + "cell_type": "astrocytes", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "AC007402.1", + "LINC02397", + "DLL3", + "PRR5L", + "MYO5C", + "UNC13C", + "EGFR", + "AL359546.1", + "SLC24A3", + "INKA2", + "AC003991.1", + "ZNF804B", + "LINC01902", + "AC087854.1", + "DUSP10", + "SWAP70", + "LUZP2", + "RAB27B", + "AC117464.1", + "DLL1", + "AC013265.1", + "NKD1", + "KLRC2", + "SLC22A3", + "BX284613.2", + "CREM", + "AC002069.2", + "HES6", + "HIP1", + "GRM5", + "DPF3", + "MIR4300HG", + "CNTN6", + "HRH2", + "COL20A1", + "ANKFN1", + "MCTP1", + "GLYCTK-AS1", + "CHST9", + "CASZ1" + ], + "programs": [ + { + "program_name": "Synaptic Vesicle Exocytosis", + "theme": "Neuronal signaling", + "description": "Genes in this program (UNC13C, RAB27B, HIP1, MYO5C, CNTN6, GRM5, SLC24A3, MCTP1) are involved in synaptic vesicle trafficking and neurotransmission. In GBM cells, Rab27b is upregulated after irradiation and mediates secretion of epiregulin (EREG), activating EGFR signaling and supporting cell survival. UNC13C and MCTP1 regulate synaptic vesicle priming and neurotransmitter release, suggesting enhanced excitatory signaling and neuro-gliomal communication.", + "atomic_biological_processes": [ + { + "name": "synaptic vesicle exocytosis", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Nishioka S et al. Rab27b contributes to radioresistance via EREG secretion in glioblastoma. Neuro Oncol Adv. 2020.", + "id": "DOI:10.1093/noajnl/vdaa091", + "type": "DOI", + "notes": "Rab27b is a secretory GTPase that mediates EREG secretion and EGFR activation in GBM" + } + ], + "Genes": [ + "UNC13C", + "RAB27B", + "HIP1", + "MCTP1" + ] + }, + { + "name": "neurotransmitter secretion", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Gen\u010d O et al. MCTP is an ER-resident Ca2+ sensor that stabilizes synaptic transmission. eLife. 2017.", + "id": "DOI:10.7554/eLife.22904", + "type": "DOI", + "notes": "MCTP1 localizes to presynaptic terminals and is essential for neurotransmitter release" + } + ], + "Genes": [ + "UNC13C", + "RAB27B", + "MCTP1" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "presynaptic active zone", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Gen\u010d O et al. MCTP is an ER-resident Ca2+ sensor that stabilizes synaptic transmission. eLife. 2017.", + "id": "DOI:10.7554/eLife.22904", + "type": "DOI", + "notes": "MCTP1 functions at presynaptic terminals to coordinate neurotransmitter release" + } + ], + "Genes": [ + "UNC13C", + "MCTP1", + "HIP1" + ] + }, + { + "name": "synapse", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Gen\u010d O et al. MCTP is an ER-resident Ca2+ sensor that stabilizes synaptic transmission. eLife. 2017.", + "id": "DOI:10.7554/eLife.22904", + "type": "DOI", + "notes": "MCTP1 is distributed throughout the presynaptic region supporting neurotransmission" + } + ], + "Genes": [ + "UNC13C", + "RAB27B", + "MCTP1", + "HIP1" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced neurotransmitter release", + "Increased synaptic connectivity", + "Elevated autocrine/paracrine growth signaling" + ], + "evidence_summary": "Rab27b (from this gene list) is upregulated in irradiated GBM cells and promotes secretion of EREG, driving EGFR signaling and cell survival. MCTP1 acts as an ER Ca2+ sensor necessary for stable neurotransmission in neurons. Together, these gene functions imply increased synaptic signaling and secretory communication in glioblastoma cells.", + "citations": [ + { + "reference": "Nishioka S et al. Rab27b contributes to radioresistance via EREG secretion in glioblastoma. Neuro Oncol Adv. 2020.", + "id": "DOI:10.1093/noajnl/vdaa091", + "type": "DOI", + "notes": "Rab27b mediates vesicle-mediated release of EREG, which activates EGFR signaling in GBM (supports enhanced secretion)" + } + ], + "confidence_score": 0.85, + "significance_score": 0.9, + "supporting_genes": [ + "UNC13C", + "RAB27B", + "HIP1", + "MYO5C", + "CNTN6", + "GRM5", + "SLC24A3", + "MCTP1" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Notch Signaling", + "theme": "Developmental pathway", + "description": "This program includes Notch pathway genes (DLL1, DLL3, HES6). Notch signaling in GBM supports stem/progenitor identities and regulates differentiation. Altered expression of Notch ligands and targets can affect GBM growth: e.g., modulating DLL1/3 levels influences proliferation and cell fate.", + "atomic_biological_processes": [ + { + "name": "Notch signaling pathway", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Drakulic D et al. Review of dysregulated neurodevelopmental pathways in glioblastoma. Cells. 2022.", + "id": "PMID:36010607", + "type": "PMID", + "notes": "Notch signaling (via DLL ligands and HES genes) maintains glioma stem cells and promotes proliferation" + } + ], + "Genes": [ + "DLL1", + "DLL3", + "HES6" + ] + }, + { + "name": "cell differentiation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Drakulic D et al. Review of dysregulated neurodevelopmental pathways in glioblastoma. Cells. 2022.", + "id": "PMID:36010607", + "type": "PMID", + "notes": "Notch influences neural progenitor differentiation in GBM" + } + ], + "Genes": [ + "DLL1", + "DLL3" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "integral component of membrane", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Drakulic D et al. Review of dysregulated neurodevelopmental pathways in glioblastoma. Cells. 2022.", + "id": "PMID:36010607", + "type": "PMID", + "notes": "DLL1 and DLL3 encode transmembrane Notch ligands" + } + ], + "Genes": [ + "DLL1", + "DLL3" + ] + } + ], + "predicted_cellular_impact": [ + "Maintenance of progenitor-like state", + "Suppressed differentiation", + "Enhanced glioma stemness" + ], + "evidence_summary": "The presence of DLL1/DLL3 and HES6 suggests active Notch signaling. Notch activity can maintain GBM stemness; its inhibition reduces proliferation in glioma models. Therefore, this program likely supports a less differentiated, stem-like state in GBM cells.", + "citations": [ + { + "reference": "Drakulic D et al. Review of dysregulated neurodevelopmental pathways in glioblastoma. Cells. 2022.", + "id": "PMID:36010607", + "type": "PMID", + "notes": "Activation of Notch signaling (ligands DLL1/DLL3 and targets like HES family) promotes self-renewal of GBM stem-like cells and impacts differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9406959/#:~:text=oncogenic%20function%20of%20Notch%20signaling,Activation%20of%20the%20Notch))." + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "DLL1", + "DLL3", + "HES6" + ], + "supporting_gene_count": 3, + "required_components_present": false + }, + { + "program_name": "EGFR Signaling", + "theme": "Growth factor signaling", + "description": "Genes EGFR and RAB27B indicate an RTK signaling program. Rab27b-mediated secretion of the EGFR ligand epiregulin can activate EGFR in a paracrine loop, driving GBM cell proliferation and therapy resistance. EGFR itself is a key oncogene in glioblastoma.", + "atomic_biological_processes": [ + { + "name": "EGFR signaling pathway", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Nishioka S et al. Rab27b contributes to GBM radioresistance via EREG secretion. Neuro Oncol Adv. 2020.", + "id": "PMID:33409495", + "type": "PMID", + "notes": "Rab27b upregulation drives EREG secretion, leading to EGFR activation in GBM" + } + ], + "Genes": [ + "EGFR", + "RAB27B" + ] + }, + { + "name": "MAPK cascade", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Nishioka S et al. Rab27b contributes to GBM radioresistance via EREG secretion. Neuro Oncol Adv. 2020.", + "id": "PMID:33409495", + "type": "PMID", + "notes": "EGFR activation triggers downstream MAPK signaling to enhance GBM cell survival" + } + ], + "Genes": [ + "EGFR" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane receptor complex", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Nishioka S et al. Rab27b contributes to GBM radioresistance via EREG secretion. Neuro Oncol Adv. 2020.", + "id": "PMID:33409495", + "type": "PMID", + "notes": "EGFR is a membrane-bound receptor activated by secreted EGF-like ligands (e.g., EREG)" + } + ], + "Genes": [ + "EGFR" + ] + } + ], + "predicted_cellular_impact": [ + "Increased cell proliferation", + "Enhanced therapeutic resistance", + "Autocrine/paracrine growth signaling" + ], + "evidence_summary": "Rab27b from the gene list is shown to upregulate secretion of EREG, activating EGFR signaling and contributing to radioresistance. EGFR is a known driver of GBM growth. This program likely amplifies MAPK pathway signaling and survival in tumor cells.", + "citations": [ + { + "reference": "Nishioka S et al. Rab27b contributes to GBM radioresistance via EREG secretion. Neuro Oncol Adv. 2020.", + "id": "PMID:33409495", + "type": "PMID", + "notes": "Rab27b-mediated secretion of EREG activates EGFR signaling in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7770522/#:~:text=recipient%20mice.%20Interestingly%2C%20the%20co,mechanism%2C%20activated%20EGF%20receptor%20and)), driving proliferation and survival" + } + ], + "confidence_score": 0.9, + "significance_score": 0.95, + "supporting_genes": [ + "EGFR", + "RAB27B" + ], + "supporting_gene_count": 2, + "required_components_present": false + }, + { + "program_name": "Oncogenic Transcription", + "theme": "Transcriptional regulation", + "description": "This program includes transcriptional regulators (CASZ1, CREM, DPF3). CASZ1 is an oncogenic transcription factor overexpressed in glioma, promoting proliferation via target genes like p75NTR. Altered transcription regulation by these factors can shift GBM cell identity and growth.", + "atomic_biological_processes": [ + { + "name": "regulation of transcription, DNA-templated", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Mao C et al. CASZ1 is an oncogenic transcription factor in glioma. MedComm. 2022.", + "id": "PMID:36276925", + "type": "PMID", + "notes": "CASZ1 drives transcription of target genes (e.g., p75NTR) in glioma cells" + } + ], + "Genes": [ + "CASZ1", + "CREM", + "DPF3" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Mao C et al. CASZ1 is an oncogenic transcription factor in glioma. MedComm. 2022.", + "id": "PMID:36276925", + "type": "PMID", + "notes": "CASZ1 functions in the nucleus to regulate gene expression" + } + ], + "Genes": [ + "CASZ1", + "CREM", + "DPF3" + ] + } + ], + "predicted_cellular_impact": [ + "Upregulated oncogenic gene expression", + "Activation of proliferation programs", + "Altered differentiation gene networks" + ], + "evidence_summary": "CASZ1 is highly expressed in glioma and acts as an oncogene by promoting transcription of growth-related genes; its knockdown reduces proliferation. CREM and DPF3 likely modulate gene expression too. The combined effect is a shift toward oncogenic transcriptional programs in GBM cells.", + "citations": [ + { + "reference": "Mao C et al. CASZ1 is an oncogenic transcription factor in glioma. MedComm. 2022.", + "id": "PMID:36276925", + "type": "PMID", + "notes": "CASZ1 overexpression correlates with poor glioma prognosis and drives proliferation through transcriptional activation of p75NTR" + } + ], + "confidence_score": 0.6, + "significance_score": 0.6, + "supporting_genes": [ + "CASZ1", + "CREM", + "DPF3" + ], + "supporting_gene_count": 3, + "required_components_present": false + } + ], + "method": { + "clustering_basis": [ + "pathway databases", + "literature curation", + "gene co-expression" + ], + "notes": "Genes were grouped based on known pathways and coordinated functions in neural and cancer contexts." + }, + "version": "1.0.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_like_1 new file mode 100644 index 0000000..175b677 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_like_1 @@ -0,0 +1,586 @@ +{ + "context": { + "cell_type": "astrocytes", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "AFAP1L2", + "COL4A3", + "FERMT1", + "VIPR2", + "AL512308.1", + "CALCRL", + "REPS2", + "FGF12", + "CCDC26", + "OTOGL", + "ELMO1", + "PCDH15", + "COL4A4", + "THSD4", + "FA2H", + "LRRC7", + "PLPP4", + "PLA2G4A", + "AR", + "LINC00689", + "TNS3", + "BCAS1", + "DLL3", + "KCNIP3", + "MIR503HG", + "ANO3", + "PLAAT1", + "MEGF11", + "GSG1L", + "UGT8", + "COL20A1", + "ALCAM", + "C2orf27A", + "LHFPL3-AS1", + "CA10", + "SLC5A4", + "ADAMTS17", + "DCT", + "CHST9", + "NRSN1", + "AC110285.1", + "CCND1", + "TRPC4", + "TACR1", + "TNR", + "SOX6", + "PDE4A", + "GPR17", + "ARPP21", + "MYRF" + ], + "programs": [ + { + "program_name": "ECM Remodeling & Adhesion", + "description": "Multiple collagen IV chains (COL4A3, COL4A4), other ECM proteins (THSD4, COL20A1) and ECM regulators (ADAMTS17, CHST9) suggest active extracellular matrix organization. Adhesion molecules (ALCAM, PCDH15, FERMT1, TNS3) and integrin-associated factors indicate enhanced cell adhesion. In malignant glioblastoma, elevated ECM deposition and remodeling drive tumor invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10046791/#:~:text=blockage%20%20,great%20interest%20in%20GBM%20treatment)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3452333/#:~:text=Downregulation%20of%20ALCAM%20expression%20on,ALCAM%20siRNA%E2%80%93transfected%20and%20negative%20control)).", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030198", + "name": "extracellular matrix organization", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Caffo et al. Collagen IV in GBM.", + "id": "", + "type": "", + "notes": "Glioblastoma cells produce type IV collagen, indicating active ECM assembly ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10046791/#:~:text=blockage%20%20,great%20interest%20in%20GBM%20treatment))" + } + ], + "Genes": [ + "COL4A3", + "COL4A4", + "COL20A1", + "THSD4", + "ADAMTS17", + "CHST9" + ] + }, + { + "ontology_id": "GO:0007155", + "name": "cell adhesion", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Kijima et al., Neuro Oncol 2011", + "id": "", + "type": "", + "notes": "ALCAM knockdown increases GBM invasion, implicating ALCAM in cell adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3452333/#:~:text=Downregulation%20of%20ALCAM%20expression%20on,ALCAM%20siRNA%E2%80%93transfected%20and%20negative%20control))" + } + ], + "Genes": [ + "ALCAM", + "PCDH15", + "FERMT1", + "TNS3" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0031012", + "name": "extracellular matrix", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Caffo et al. 2004", + "id": "", + "type": "", + "notes": "Glioblastoma cells produce collagen IV in vitro, contributing to the ECM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10046791/#:~:text=blockage%20%20,great%20interest%20in%20GBM%20treatment))" + } + ], + "Genes": [ + "COL4A3", + "COL4A4", + "COL20A1", + "THSD4" + ] + }, + { + "ontology_id": "GO:0005925", + "name": "focal adhesion", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Fust\u00e9 et al., Sci Rep 2019", + "id": "", + "type": "", + "notes": "Cyclin D1 induces focal adhesion kinase and paxillin, linking adhesion to invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=activates%20the%20invasion%20of%20primary,GBM%20dissemination%20through%20cytoplasmic%20and))" + } + ], + "Genes": [ + "FERMT1", + "TNS3" + ] + } + ], + "predicted_cellular_impact": [ + "increased ECM deposition enabling tumor invasion", + "enhanced focal adhesion signaling" + ], + "evidence_summary": "Glioblastoma cells characteristically overproduce type IV collagens and other matrix proteins, increasing ECM density ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10046791/#:~:text=blockage%20%20,great%20interest%20in%20GBM%20treatment)). Adhesion receptors like ALCAM and integrin regulators (FERMT1, TNS3) are present; ALCAM downregulation enhances invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3452333/#:~:text=Downregulation%20of%20ALCAM%20expression%20on,ALCAM%20siRNA%E2%80%93transfected%20and%20negative%20control)). Together these suggest heightened cell-ECM interactions and motility.", + "citations": [ + { + "reference": "Caffo et al., J Neurooncol 2004", + "id": "", + "type": "", + "notes": "Evidence of collagen IV production by GBM cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10046791/#:~:text=blockage%20%20,great%20interest%20in%20GBM%20treatment))." + }, + { + "reference": "Kijima et al., Neuro Oncol 2011", + "id": "", + "type": "", + "notes": "ALCAM involvement in GBM invasion via cell adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3452333/#:~:text=Downregulation%20of%20ALCAM%20expression%20on,ALCAM%20siRNA%E2%80%93transfected%20and%20negative%20control))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "COL4A3", + "COL4A4", + "COL20A1", + "THSD4", + "ADAMTS17", + "CHST9", + "ALCAM", + "PCDH15", + "FERMT1", + "TNS3", + "PLA2G4A" + ], + "supporting_gene_count": 11, + "required_components_present": true + }, + { + "program_name": "GPCR/Ca2+ Signaling", + "description": "G-protein coupled receptors (VIPR2, CALCRL, TACR1) and ion channels (TRPC4, ANO3, KCNIP3) suggest active GPCR/Ca^{2+}-mediated signaling. VIPR2 and CALCRL activation drives PI3K/Akt and proliferation pathways, while GPR17 (in clustered program) modulates survival ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36237322/#:~:text=MCF,related%20protein%203%2C%20and%20actin)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36618798/#:~:text=CALCRL%20expression%20was%20highest%20in,apoptosis%20rate%20was%20significantly%20increased)). Altered intracellular Ca^{2+} (via TRP channels, ANO3 chloride channel) likely impacts migration. ", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007186", + "name": "G-protein coupled receptor signaling pathway", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Asano et al., Cancers 2022", + "id": "", + "type": "", + "notes": "VIPR2 (GPCR) activation promotes tumor cell migration via PI3K/WAVE2 actin signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36237322/#:~:text=MCF,related%20protein%203%2C%20and%20actin))" + } + ], + "Genes": [ + "VIPR2", + "CALCRL", + "TACR1" + ] + }, + { + "ontology_id": "GO:0019722", + "name": "calcium-mediated signaling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Doan et al., Cancers 2021", + "id": "", + "type": "", + "notes": "GPR17 (a GPCR) triggers MAPK/PI3K pathways and cell cycle arrest in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8345100/#:~:text=mechanism%20of%20action%20of%20the,barrier%20and%20reduces%20tumor%20volume))" + } + ], + "Genes": [ + "TRPC4", + "ANO3", + "KCNIP3" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005886", + "name": "plasma membrane", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Asano et al., Cancers 2022", + "id": "", + "type": "", + "notes": "VIPR2 and other receptors localize to membrane to drive signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36237322/#:~:text=MCF,related%20protein%203%2C%20and%20actin))" + } + ], + "Genes": [ + "VIPR2", + "CALCRL", + "TACR1", + "TRPC4", + "ANO3" + ] + } + ], + "predicted_cellular_impact": [ + "enhanced chemotactic migration via GPCR-PI3K signaling", + "modulated Ca^{2+}-dependent signaling affecting proliferation" + ], + "evidence_summary": "VIPR2 activation in cancer cells promotes migration through PI3K and actin remodeling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36237322/#:~:text=MCF,related%20protein%203%2C%20and%20actin)). In glioma, high CALCRL drives proliferation and survival ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36618798/#:~:text=CALCRL%20expression%20was%20highest%20in,apoptosis%20rate%20was%20significantly%20increased)). Together, multiple GPCRs and Ca^{2+}/Cl^{-} channels suggest dysregulated cAMP/Ca^{2+} signaling influencing GBM growth and motility.", + "citations": [ + { + "reference": "Asano et al., Cancers 2022", + "id": "", + "type": "", + "notes": "VIPR2 induces PI3K-mediated migration in cancer cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36237322/#:~:text=MCF,related%20protein%203%2C%20and%20actin))." + }, + { + "reference": "Gu et al., Ann Transl Med 2021", + "id": "", + "type": "", + "notes": "CALCRL knockdown reduces glioma proliferation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36618798/#:~:text=CALCRL%20expression%20was%20highest%20in,apoptosis%20rate%20was%20significantly%20increased))." + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": [ + "VIPR2", + "CALCRL", + "TACR1", + "TRPC4", + "ANO3", + "KCNIP3" + ], + "supporting_gene_count": 6, + "required_components_present": true + }, + { + "program_name": "Oligodendrocyte Differentiation", + "description": "Genes associated with oligodendrocyte lineage and myelination are enriched. MYRF is a master regulator of myelin gene expression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3742440/#:~:text=induced%20during%20oligodendrocyte%20differentiation,terms%20for%20genes%20proximal%20to)). Lipid enzymes (UGT8, FA2H) and marker BCAS1 indicate myelin synthesis. Extracellular protein TNR (Tenascin-R) promotes oligodendrocyte maturation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6573339/#:~:text=expression%20and%20the%20upregulation%20of,for%20CNS%20myelination%20and%20remyelination)). This program reflects an oligodendrocyte-like differentiation state in GBM cells.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0042552", + "name": "myelination", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Bujalka et al., PLoS Biol 2013", + "id": "", + "type": "", + "notes": "MYRF directly activates myelin genes during oligodendrocyte differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3742440/#:~:text=induced%20during%20oligodendrocyte%20differentiation,terms%20for%20genes%20proximal%20to))" + } + ], + "Genes": [ + "MYRF", + "BCAS1", + "FA2H", + "UGT8" + ] + }, + { + "ontology_id": "GO:0048709", + "name": "oligodendrocyte differentiation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Pesheva et al., J Neurosci 1997", + "id": "", + "type": "", + "notes": "Tenascin-R stimulates oligodendrocyte differentiation in vitro ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6573339/#:~:text=expression%20and%20the%20upregulation%20of,for%20CNS%20myelination%20and%20remyelination))" + } + ], + "Genes": [ + "MYRF", + "BCAS1", + "TNR", + "GPR17", + "SOX6", + "FA2H", + "UGT8" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0043209", + "name": "myelin sheath", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Bujalka et al., PLoS Biol 2013", + "id": "", + "type": "", + "notes": "MYRF upregulates myelin-related genes (e.g. MAG, MBP) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3742440/#:~:text=induced%20during%20oligodendrocyte%20differentiation,terms%20for%20genes%20proximal%20to))" + } + ], + "Genes": [ + "UGT8", + "FA2H" + ] + } + ], + "predicted_cellular_impact": [ + "enhanced myelin-specific gene expression", + "promotion of oligodendrocyte-like differentiation" + ], + "evidence_summary": "Several genes (MYRF, BCAS1, UGT8, FA2H) are canonical oligodendrocyte/myelination markers ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3742440/#:~:text=induced%20during%20oligodendrocyte%20differentiation,terms%20for%20genes%20proximal%20to)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6573339/#:~:text=expression%20and%20the%20upregulation%20of,for%20CNS%20myelination%20and%20remyelination)). Tenascin-R (TNR) is a known autocrine promoter of oligodendrocyte maturation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6573339/#:~:text=expression%20and%20the%20upregulation%20of,for%20CNS%20myelination%20and%20remyelination)). This constellation suggests GBM cells may adopt an oligodendrocyte-like program, potentially altering metabolism (lipid-rich myelin) and growth behavior.", + "citations": [ + { + "reference": "Pesheva et al., J Neurosci 1997", + "id": "", + "type": "", + "notes": "Tenascin-R promotes oligodendrocyte maturation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6573339/#:~:text=expression%20and%20the%20upregulation%20of,for%20CNS%20myelination%20and%20remyelination))." + }, + { + "reference": "Bujalka et al., PLoS Biol 2013", + "id": "", + "type": "", + "notes": "MYRF drives expression of myelin and ensheathment genes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3742440/#:~:text=induced%20during%20oligodendrocyte%20differentiation,terms%20for%20genes%20proximal%20to))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": [ + "MYRF", + "BCAS1", + "TNR", + "GPR17", + "UGT8", + "FA2H", + "SOX6" + ], + "supporting_gene_count": 7, + "required_components_present": true + }, + { + "program_name": "Cell Cycle Progression", + "description": "CCND1 (Cyclin D1) is a key cell-cycle regulator. In GBM, Cyclin D1 overexpression drives proliferation and also unexpectedly promotes invasion via cytoplasmic signaling to RalA/paxillin ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=activates%20the%20invasion%20of%20primary,GBM%20dissemination%20through%20cytoplasmic%20and)). This program indicates highly active G1/S progression and linked motility signaling in tumor cells.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007049", + "name": "cell cycle", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Fust\u00e9 et al., Sci Rep 2019", + "id": "", + "type": "", + "notes": "Cyclin D1/Cdk4 axis is frequently altered in GBM, leading to overproliferation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=to%20overproliferation%20by%20RB1%20deletion,acting%20upstream%20of%20those%20regulators))" + } + ], + "Genes": [ + "CCND1" + ] + }, + { + "ontology_id": "GO:0030334", + "name": "regulation of cell migration", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Fust\u00e9 et al., Sci Rep 2019", + "id": "", + "type": "", + "notes": "Cytoplasmic Cyclin D1 activates RalA and paxillin to enhance GBM cell invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=activates%20the%20invasion%20of%20primary,GBM%20dissemination%20through%20cytoplasmic%20and))" + } + ], + "Genes": [ + "CCND1" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005634", + "name": "nucleus", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Fust\u00e9 et al., Sci Rep 2019", + "id": "", + "type": "", + "notes": "Cyclin D1 functions as a nuclear cell-cycle regulator ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=to%20overproliferation%20by%20RB1%20deletion,acting%20upstream%20of%20those%20regulators))" + } + ], + "Genes": [ + "CCND1" + ] + }, + { + "ontology_id": "GO:0005829", + "name": "cytosol", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Fust\u00e9 et al., Sci Rep 2019", + "id": "", + "type": "", + "notes": "Cyclin D1 can act in the cytoplasm to regulate invasion via RalA ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=activates%20the%20invasion%20of%20primary,GBM%20dissemination%20through%20cytoplasmic%20and))" + } + ], + "Genes": [ + "CCND1" + ] + } + ], + "predicted_cellular_impact": [ + "accelerated proliferation", + "enhanced invasiveness via RalA/paxillin signaling" + ], + "evidence_summary": "Cyclin D1 is overexpressed in GBM and drives the G1/S transition. Elevated CCND1 not only promotes proliferation but also increases cytoplasmic signaling that activates RalA and paxillin, augmenting tumor cell invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=activates%20the%20invasion%20of%20primary,GBM%20dissemination%20through%20cytoplasmic%20and)).", + "citations": [ + { + "reference": "Fust\u00e9 et al., Sci Rep 2019", + "id": "", + "type": "", + "notes": "Cyclin D1/Cdk4 activation leads to GBM overproliferation; Cyclin D1 induces RalA/paxillin to promote invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=to%20overproliferation%20by%20RB1%20deletion,acting%20upstream%20of%20those%20regulators)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=activates%20the%20invasion%20of%20primary,GBM%20dissemination%20through%20cytoplasmic%20and))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": [ + "CCND1" + ], + "supporting_gene_count": 1, + "required_components_present": true + }, + { + "program_name": "Androgen Receptor Signaling", + "description": "Androgen receptor (AR) is highly expressed in GBM and contributes to tumor growth. AR can be activated via EGFR/AKT signaling even without ligand ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8535837/#:~:text=Androgen%20receptor%20,correlation%20between%20AR%20and%20EGFR)). Active AR translocates to the nucleus to drive proliferation and survival gene programs, collaborating with oncogenic kinase pathways.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0043401", + "name": "steroid hormone mediated signaling pathway", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zalcman et al., Int J Mol Sci 2021", + "id": "", + "type": "", + "notes": "AR is overexpressed in most GBMs; EGFR signaling increases AR activation and nuclear translocation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8535837/#:~:text=Androgen%20receptor%20,correlation%20between%20AR%20and%20EGFR))" + } + ], + "Genes": [ + "AR" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005634", + "name": "nucleus", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Zalcman et al., Int J Mol Sci 2021", + "id": "", + "type": "", + "notes": "Activated AR localizes to the nucleus to regulate transcription ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8535837/#:~:text=Androgen%20receptor%20,correlation%20between%20AR%20and%20EGFR))" + } + ], + "Genes": [ + "AR" + ] + } + ], + "predicted_cellular_impact": [ + "enhanced proliferation and survival via cross-talk with RTK pathways" + ], + "evidence_summary": "AR is amplified in glioblastoma and correlates with EGFR levels. EGFR or EGFRvIII overexpression in GBM cells induces AR phosphorylation and nuclear localization, promoting cell growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8535837/#:~:text=Androgen%20receptor%20,correlation%20between%20AR%20and%20EGFR)). Thus androgen receptor signaling supports GBM proliferation independent of androgens.", + "citations": [ + { + "reference": "Zalcman et al., Int J Mol Sci 2021", + "id": "", + "type": "", + "notes": "EGFR signaling activates AR in GBM, suggesting AR-driven transcription aids tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8535837/#:~:text=Androgen%20receptor%20,correlation%20between%20AR%20and%20EGFR))." + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": [ + "AR" + ], + "supporting_gene_count": 1, + "required_components_present": false + }, + { + "program_name": "Notch Signaling Modulation", + "description": "DLL3 is an inhibitory ligand of the Notch pathway. In gliomas, high DLL3 expression is associated with better prognosis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33713320/#:~:text=between%20DLL3%20gene%20expression%20and,targeted%20therapies)), suggesting that DLL3 attenuates Notch signaling. This program may influence cell differentiation and the immune microenvironment in GBM.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007219", + "name": "Notch signaling pathway", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wang et al., J Cancer 2021", + "id": "", + "type": "", + "notes": "DLL3 expression stratifies glioma prognosis; low DLL3 links to shorter survival, implicating DLL3 in Notch pathway inhibition ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33713320/#:~:text=between%20DLL3%20gene%20expression%20and,targeted%20therapies))" + } + ], + "Genes": [ + "DLL3" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0009986", + "name": "cell surface", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Zhang et al., Biochim Biophys Acta 2013", + "id": "", + "type": "", + "notes": "DLL3 is a transmembrane Notch ligand; its surface expression modulates signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33713320/#:~:text=between%20DLL3%20gene%20expression%20and,targeted%20therapies))" + } + ], + "Genes": [ + "DLL3" + ] + } + ], + "predicted_cellular_impact": [ + "modulation of differentiation via Notch inhibition", + "altered immune response" + ], + "evidence_summary": "In malignant glioma, DLL3 acts as a Notch inhibitor and its high expression predicts longer survival ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33713320/#:~:text=between%20DLL3%20gene%20expression%20and,targeted%20therapies)). Lower DLL3 correlates with enhanced immune and inflammatory pathways. Thus DLL3 likely influences tumor cell fate by dampening Notch signaling.", + "citations": [ + { + "reference": "Wang et al., J Cancer 2021", + "id": "", + "type": "", + "notes": "DLL3 stratifies patient survival; lower DLL3 is linked to more aggressive GBM and upregulated immune pathways ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33713320/#:~:text=between%20DLL3%20gene%20expression%20and,targeted%20therapies))." + } + ], + "confidence_score": 0.7, + "significance_score": 0.5, + "supporting_genes": [ + "DLL3" + ], + "supporting_gene_count": 1, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_like_2 b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_like_2 new file mode 100644 index 0000000..d78baf9 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_like_2 @@ -0,0 +1,511 @@ +{ + "context": { + "cell_type": "glioblastoma cells", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "PPP1R16B", + "BCAS1", + "AC008080.4", + "MOG", + "GLRA3", + "ENPP6", + "ADAM33", + "GPC3", + "CLDN11", + "PLD1", + "SEMA4D", + "MYRF", + "MBP", + "GPR17", + "KCNS3", + "TNS3", + "RASGEF1B", + "AC069209.2", + "ADRA1A", + "CD22", + "FA2H", + "CDK18", + "ST18", + "FERMT1", + "NOS1", + "TMEM235", + "AC110285.1", + "ACAN", + "MAG", + "PRICKLE1", + "AL512308.1", + "FAM83D", + "BMP2", + "BMPER", + "COL18A1", + "LINC01447", + "P2RX7", + "ZNF536", + "ATP6V0A4", + "AMPD3" + ], + "programs": [ + { + "program_name": "Oligodendrocyte Myelination", + "description": "This program comprises canonical oligodendrocyte and myelin genes. MOG, MBP, MAG, CLDN11, FA2H, ENPP6 and BCAS1 are all known myelin/oligodendrocyte markers, often co-expressed in oligodendrocyte precursor cell (OPC) differentiation. MYRF and GPR17 are oligodendrocyte lineage regulators (GPR17 as a myelination timer ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2783566/#:~:text=intrinsic%20timer%20of%20myelination%20,intrinsic%20timer%20of)), MYRF a master TF). In normal brain these drive myelin sheath assembly. In GBM, expression suggests a proneural/OPC-like differentiation state ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3100315/#:~:text=match%20at%20L126%20tumors%20closely,genes%20that%20are%20differentially%20expressed)).", + "atomic_biological_processes": [ + { + "name": "myelination", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Chen Y et al. GPR17 is a cell-intrinsic timer of myelination. Nat Neurosci. 2009.", + "id": "19838178", + "type": "PMID", + "notes": "GPR17 is oligodendrocyte-specific and controls timing of CNS myelination ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2783566/#:~:text=intrinsic%20timer%20of%20myelination%20,intrinsic%20timer%20of))" + } + ], + "Genes": [ + "GPR17", + "MOG", + "MBP", + "MAG", + "CLDN11", + "FA2H", + "ENPP6", + "BCAS1" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "myelin sheath", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Fulton D et al. Multiple roles of myelin protein genes in oligodendrocyte development. ASN Neuro. 2010.", + "id": "20017732", + "type": "PMID", + "notes": "MBP and MAG localize to myelin sheaths and are critical for compact myelin structure ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2814326/#:~:text=MBP%20are%20distributed%20within%20the,interactions%20between%20myelin%20and%20axonal))" + } + ], + "Genes": [ + "MOG", + "MBP", + "MAG", + "CLDN11", + "FA2H" + ] + } + ], + "predicted_cellular_impact": [ + "Adoption of oligodendrocyte-like differentiation signature", + "Ectopic myelin protein expression in tumor cells", + "Altered cell-cell/axon interactions via myelin components" + ], + "evidence_summary": "MOG, MBP, MAG, CLDN11, ENPP6, FA2H and BCAS1 are classic oligodendrocyte/myelin proteins highly expressed during myelination. GPR17 is an oligodendrocyte-specific GPCR that times myelination ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2783566/#:~:text=intrinsic%20timer%20of%20myelination%20,intrinsic%20timer%20of)). MYRF is a master regulator of oligodendrocyte differentiation. Together these indicate activation of an oligodendrocyte/myelination program. Such signatures are known in the proneural GBM subtype, reflecting an OPC-like state ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3100315/#:~:text=match%20at%20L126%20tumors%20closely,genes%20that%20are%20differentially%20expressed)). Thus, tumor cells may aberrantly activate myelin gene expression (influencing membrane properties or cell interactions).", + "citations": [ + { + "reference": "Chen Y et al. The oligodendrocyte-specific G-protein coupled receptor GPR17 is a cell-intrinsic timer of myelination. Nat Neurosci. 2009.", + "id": "19838178", + "type": "PMID", + "notes": "Supports GPR17 in oligodendrocyte myelination ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2783566/#:~:text=intrinsic%20timer%20of%20myelination%20,intrinsic%20timer%20of))" + }, + { + "reference": "Fulton D et al. Multiple roles of myelin protein genes in oligodendrocyte development. ASN Neuro. 2010.", + "id": "20017732", + "type": "PMID", + "notes": "Describes MBP, MAG, etc. in myelin sheaths ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2814326/#:~:text=MBP%20are%20distributed%20within%20the,interactions%20between%20myelin%20and%20axonal))" + }, + { + "reference": "Lei L et al. GBM proneural subtype enriched for OPC gene expression. PLoS One. 2011.", + "id": "21532771", + "type": "PMID", + "notes": "Proneural glioblastomas show enrichment of oligodendrocyte/OPC gene signatures ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3100315/#:~:text=match%20at%20L126%20tumors%20closely,genes%20that%20are%20differentially%20expressed))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "GPR17", + "MOG", + "MBP", + "MAG", + "CLDN11", + "FA2H", + "ENPP6", + "BCAS1", + "MYRF" + ], + "supporting_gene_count": 9, + "required_components_present": true + }, + { + "program_name": "ECM Remodeling and Cell Adhesion", + "description": "This cluster involves extracellular matrix (ECM) proteins and proteases. ADAM33 (a disintegrin metalloprotease) and SEMA4D (semaphorin ligand) mediate matrix remodeling and angiogenic signaling. COL18A1 encodes collagen XVIII from which endostatin (an anti-angiogenic fragment) is derived ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1871889/#:~:text=Endostatin%20was%20originally%20reported%20to,The%20receptor%20or)). GPC3 and ACAN are secreted proteoglycans, FERMT1 and TNS3 link integrins/focal adhesions. This program suggests altered matrix composition and cell adhesion properties. In glioblastoma, such changes can promote invasive migration and modulate angiogenesis.", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Mochizuki S, Okada Y. ADAMs in cancer proliferation and progression. Cancer Sci. 2007.", + "id": "17355265", + "type": "PMID", + "notes": "ADAM proteases remodel the ECM and promote cancer cell invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=reports%20suggest%20that%20ADAM8%20is,tumor%20cell%20migration%20and%20invasion))" + } + ], + "Genes": [ + "ADAM33", + "COL18A1", + "GPC3", + "ACAN", + "ACAT*", + "PRICKLE1" + ] + }, + { + "name": "angiogenesis", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Rege TA et al. Endostatin inhibits glioma angiogenesis. Neuro Oncol. 2005.", + "id": "15831230", + "type": "PMID", + "notes": "Endostatin (from COL18A1) is anti-angiogenic in gliomas ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1871889/#:~:text=Endostatin%20was%20originally%20reported%20to,The%20receptor%20or))" + } + ], + "Genes": [ + "COL18A1", + "SEMA4D", + "BMPER" + ] + }, + { + "name": "cell adhesion", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Mochizuki S, Okada Y. ADAMs in cancer proliferation and progression. Cancer Sci. 2007.", + "id": "17355265", + "type": "PMID", + "notes": "ADAM-family metalloproteases interact with integrins contributing to adhesion and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=through%20the%20PKC%20and%20MAPK,regulate%20cell%20proliferation%20signals%20through))" + } + ], + "Genes": [ + "FERMT1", + "TNS3", + "PRICKLE1", + "SEMA4D" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Rege TA et al. Endostatin inhibits glioma angiogenesis. Neuro Oncol. 2005.", + "id": "15831230", + "type": "PMID", + "notes": "Collagen XVIII (COL18A1) is an ECM component providing endostatin ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1871889/#:~:text=Endostatin%20was%20originally%20reported%20to,The%20receptor%20or))" + } + ], + "Genes": [ + "COL18A1", + "GPC3", + "ACAN" + ] + }, + { + "name": "cell surface receptor complex", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Mochizuki S, Okada Y. ADAMs in cancer proliferation and progression. Cancer Sci. 2007.", + "id": "17355265", + "type": "PMID", + "notes": "ADAMs (e.g., ADAM33) can act as cell adhesion molecules via integrins ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=through%20the%20PKC%20and%20MAPK,regulate%20cell%20proliferation%20signals%20through))" + } + ], + "Genes": [ + "ADAM33", + "SEMA4D", + "FERMT1" + ] + } + ], + "predicted_cellular_impact": [ + "Increased ECM restructuring and proteolysis", + "Enhanced tumor cell migration and invasion", + "Modulation of angiogenesis (via endostatin and SEMA4D signaling)" + ], + "evidence_summary": "ADAM33 is a metalloprotease that can digest ECM and help tumor invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=reports%20suggest%20that%20ADAM8%20is,tumor%20cell%20migration%20and%20invasion)). SEMA4D promotes tumor angiogenesis and progression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2442644/#:~:text=Tumor%20angiogenesis%20and%20progression%20are,associated%20macrophages)). COL18A1-derived endostatin is a potent anti-angiogenic factor in gliomas ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1871889/#:~:text=Endostatin%20was%20originally%20reported%20to,The%20receptor%20or)). Integrin adaptor FERMT1 and focal adhesion protein TNS3 suggest altered adhesion signaling. Together these genes point to active matrix remodeling and changing adhesion in GBM, consistent with invasion and angiogenesis roles. ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=reports%20suggest%20that%20ADAM8%20is,tumor%20cell%20migration%20and%20invasion)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1871889/#:~:text=Endostatin%20was%20originally%20reported%20to,The%20receptor%20or)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2442644/#:~:text=Tumor%20angiogenesis%20and%20progression%20are,associated%20macrophages))", + "citations": [ + { + "reference": "Mochizuki S, Okada Y. ADAMs in cancer proliferation and progression. Cancer Sci. 2007.", + "id": "17355265", + "type": "PMID", + "notes": "ADAM proteases promote tumor cell invasion and adhesion changes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=reports%20suggest%20that%20ADAM8%20is,tumor%20cell%20migration%20and%20invasion))" + }, + { + "reference": "Rege TA et al. Endostatin inhibits glioma angiogenesis. Neuro Oncol. 2005.", + "id": "15831230", + "type": "PMID", + "notes": "Collagen XVIII/endostatin modulates glioma angiogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1871889/#:~:text=Endostatin%20was%20originally%20reported%20to,The%20receptor%20or))" + }, + { + "reference": "Xue W et al. BMPER promotes glioma neovascularization. Front Oncol. 2020.", + "id": "32432046", + "type": "PMID", + "notes": "BMPER expression enhances tumor angiogenesis in GBM models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7214627/#:~:text=conclusion%20BMPER%2C%20CXCL10%2C%20and%20HOXA9,expression%20statuses%20of%20these%20genes))" + }, + { + "reference": "Sierra JR et al. Tumor-derived SEMA4D promotes angiogenesis. J Exp Med. 2008.", + "id": "18559453", + "type": "PMID", + "notes": "SEMA4D from macrophages enhances tumor angiogenesis and growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2442644/#:~:text=Tumor%20angiogenesis%20and%20progression%20are,associated%20macrophages))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": [ + "ADAM33", + "COL18A1", + "GPC3", + "ACAN", + "SEMA4D", + "FERMT1", + "TNS3", + "PRICKLE1" + ], + "supporting_gene_count": 8, + "required_components_present": true + }, + { + "program_name": "Neurotransmitter and Ion Channel Signaling", + "description": "This program groups cell surface receptors and channels that modulate glioblastoma signaling. GLRA3 (glycine receptor), ADRA1A (\u03b11-adrenergic GPCR), NOS1 (neuronal nitric oxide synthase) and P2RX7 (ATP-gated cation channel) together suggest heightened neurotransmitter/purinergic signaling in tumor cells. In GBM P2X7 activation drives proliferation and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5818963/#:~:text=4.1.%20Activation%20of%20P2X_,and%20Migration%20of%20Glioma%20Cells)), while NOS1-derived NO and adrenergic signaling modulate tumor and microenvironment responses. GLRA3 may regulate inhibitory tone. Overall this hints at altered neuronal-like signaling and calcium flux in GBM cells.", + "atomic_biological_processes": [ + { + "name": "purinergic receptor signaling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ji Z et al. P2X7R in gliomas proliferation and migration. Biomed Res Int. 2018.", + "id": "29546069", + "type": "PMID", + "notes": "Activation of P2X7 receptor enhances glioma cell proliferation and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5818963/#:~:text=4.1.%20Activation%20of%20P2X_,and%20Migration%20of%20Glioma%20Cells))" + } + ], + "Genes": [ + "P2RX7" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Ji Z et al. P2X7R in gliomas proliferation and migration. Biomed Res Int. 2018.", + "id": "29546069", + "type": "PMID", + "notes": "P2X7 and other receptors are membrane proteins mediating tumor signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5818963/#:~:text=4.1.%20Activation%20of%20P2X_,and%20Migration%20of%20Glioma%20Cells))" + } + ], + "Genes": [ + "P2RX7", + "GLRA3", + "ADRA1A", + "NOS1" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced purinergic and adrenergic signaling", + "Increased intracellular Ca^2+ and NO signaling", + "Promotion of glioma cell proliferation and motility" + ], + "evidence_summary": "P2RX7 is an ATP-gated cation channel; its activation promotes glioma proliferation and migration through ERK signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5818963/#:~:text=4.1.%20Activation%20of%20P2X_,and%20Migration%20of%20Glioma%20Cells)). NOS1 generates nitric oxide, which can promote tumor growth. ADRA1A is implicated in tumor cell signaling via Gq/PLC. These receptors together suggest that glioma cells may exploit neurotransmitter-like signaling pathways. Such purinergic signaling is linked to GBM aggressiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5818963/#:~:text=4.1.%20Activation%20of%20P2X_,and%20Migration%20of%20Glioma%20Cells)).", + "citations": [ + { + "reference": "Ji Z et al. Involvement of P2X7 receptor in proliferation and migration of human glioma cells. Biomed Res Int. 2018.", + "id": "29546069", + "type": "PMID", + "notes": "P2X7R activity drives glioma cell proliferation and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5818963/#:~:text=4.1.%20Activation%20of%20P2X_,and%20Migration%20of%20Glioma%20Cells))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.6, + "supporting_genes": [ + "GLRA3", + "KCNS3", + "ADRA1A", + "NOS1", + "P2RX7" + ], + "supporting_gene_count": 5, + "required_components_present": false + }, + { + "program_name": "BMP Signaling", + "description": "This program highlights BMP pathway regulators. BMP2 is a secreted ligand that induces differentiation of glioma stem cells to a less proliferative state, sensitizing them to therapy ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4022209/#:~:text=Persano%20and%20coworkers%20,TMZ%20delivered%20separately%20did%20not)). BMPER (Vwc2) is a BMP-binding protein that modulates BMP availability and also promotes tumor neovascularization ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7214627/#:~:text=conclusion%20BMPER%2C%20CXCL10%2C%20and%20HOXA9,expression%20statuses%20of%20these%20genes)). Together, BMP2/BMPER suggest active BMP signaling in the microenvironment, affecting tumor differentiation and angiogenesis.", + "atomic_biological_processes": [ + { + "name": "BMP signaling pathway", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Persano L et al. BMP2 sensitizes glioblastoma stem cells to temozolomide. Cell Death Dis. 2012.", + "id": "23076220", + "type": "PMID", + "notes": "BMP2-induced differentiation of GBM stem cells increases chemosensitivity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4022209/#:~:text=Persano%20and%20coworkers%20,TMZ%20delivered%20separately%20did%20not))" + } + ], + "Genes": [ + "BMP2", + "BMPER" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular region", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Persano L et al. BMP2 sensitizes glioblastoma stem cells to temozolomide. Cell Death Dis. 2012.", + "id": "23076220", + "type": "PMID", + "notes": "BMP2 is a secreted growth factor acting in the extracellular milieu" + } + ], + "Genes": [ + "BMP2", + "BMPER" + ] + } + ], + "predicted_cellular_impact": [ + "Increased differentiation of glioma stem cells", + "Altered tumor sensitivity to chemotherapy (via BMP2)", + "Enhanced angiogenic signaling modulation (via BMPER)" + ], + "evidence_summary": "BMP2 expression increases with glioma grade and promotes differentiation of glioma stem cells, leading to reduced HIF-1\u03b1 and MGMT levels, which sensitizes cells to temozolomide ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4022209/#:~:text=Persano%20and%20coworkers%20,TMZ%20delivered%20separately%20did%20not)). BMPER binds BMPs and is upregulated in growing gliomas, enhancing angiogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7214627/#:~:text=conclusion%20BMPER%2C%20CXCL10%2C%20and%20HOXA9,expression%20statuses%20of%20these%20genes)). Thus, BMP pathway activation here may drive tumor cell differentiation and modulate vascular growth in GBM.", + "citations": [ + { + "reference": "Persano L et al. BMP2 induces differentiation and chemosensitivity in GBM stem cells. Cell Death Dis. 2012.", + "id": "23076220", + "type": "PMID", + "notes": "BMP2 drives GBM stem cell differentiation and increases therapy sensitivity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4022209/#:~:text=Persano%20and%20coworkers%20,TMZ%20delivered%20separately%20did%20not))" + }, + { + "reference": "Xue W et al. BMPER promotes glioma neovascularization. Front Oncol. 2020.", + "id": "32432046", + "type": "PMID", + "notes": "BMPER expression enhances angiogenesis in glioblastoma models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7214627/#:~:text=conclusion%20BMPER%2C%20CXCL10%2C%20and%20HOXA9,expression%20statuses%20of%20these%20genes))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": [ + "BMP2", + "BMPER" + ], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "Proliferation and DNA Repair", + "description": "This program includes signaling effectors linked to proliferation and genome maintenance. FAM83D is overexpressed in GBM and activates the AKT/mTOR pathway, driving cell proliferation, invasion and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9136185/#:~:text=match%20at%20L69%20FAM83D%20overexpression,vivo%20experiments%20demonstrated%20that%20silencing)). CDK18 promotes ATR-mediated homologous recombination DNA repair, enabling survival from replication stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6606647/#:~:text=dependent%20kinase%2018%20,established%20that%20targeting%20PARP%20together)). RASGEF1B (a Ras GEF) may also drive Ras-pathway proliferation. Altogether, these suggest enhanced proliferative signaling and DNA repair capacity in tumor cells.", + "atomic_biological_processes": [ + { + "name": "cell proliferation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Li X et al. FAM83D activates AKT/mTOR to promote glioma proliferation. Transl Oncol. 2022.", + "id": "35617811", + "type": "PMID", + "notes": "FAM83D overexpression promotes glioma cell proliferation via AKT/mTOR ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9136185/#:~:text=match%20at%20L69%20FAM83D%20overexpression,vivo%20experiments%20demonstrated%20that%20silencing))" + } + ], + "Genes": [ + "FAM83D", + "RASGEF1B" + ] + }, + { + "name": "homologous recombination", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ning JF et al. CDK18 promotes ATR-mediated HR in glioblastoma. Nat Commun. 2019.", + "id": "31266951", + "type": "PMID", + "notes": "CDK18 enhances homologous recombination DNA repair in GBM cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6606647/#:~:text=dependent%20kinase%2018%20,established%20that%20targeting%20PARP%20together))" + } + ], + "Genes": [ + "CDK18" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Ning JF et al. CDK18 promotes ATR-mediated HR in glioblastoma. Nat Commun. 2019.", + "id": "31266951", + "type": "PMID", + "notes": "CDK18 functions in the nucleus to regulate DNA repair" + } + ], + "Genes": [ + "CDK18", + "FAM83D" + ] + } + ], + "predicted_cellular_impact": [ + "Increased tumor cell proliferation and survival (via AKT/mTOR)", + "Enhanced DNA repair (via ATR/HR pathways)", + "Activated Ras signaling and cell cycle progression" + ], + "evidence_summary": "FAM83D overexpression is observed in GBM and activates the AKT/mTOR pathway to drive cell proliferation, invasion and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9136185/#:~:text=match%20at%20L69%20FAM83D%20overexpression,vivo%20experiments%20demonstrated%20that%20silencing)). CDK18 is implicated in ATR-mediated homologous recombination repair in glioblastoma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6606647/#:~:text=dependent%20kinase%2018%20,established%20that%20targeting%20PARP%20together)), promoting DNA damage tolerance. These functions suggest that this gene set enhances proliferative growth and genome maintenance in malignant glioma cells, consistent with tumor progression.", + "citations": [ + { + "reference": "Li X et al. FAM83D overexpression activates AKT/mTOR in glioma. Transl Oncol. 2022.", + "id": "35617811", + "type": "PMID", + "notes": "FAM83D upregulation promotes glioblastoma proliferation via AKT/mTOR ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9136185/#:~:text=match%20at%20L69%20FAM83D%20overexpression,vivo%20experiments%20demonstrated%20that%20silencing))" + }, + { + "reference": "Ning JF et al. CDK18 drives ATR-mediated DNA repair in GBM. Nat Commun. 2019.", + "id": "31266951", + "type": "PMID", + "notes": "CDK18 promotes homologous recombination repair in glioma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6606647/#:~:text=dependent%20kinase%2018%20,established%20that%20targeting%20PARP%20together))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "FAM83D", + "RASGEF1B", + "CDK18" + ], + "supporting_gene_count": 3, + "required_components_present": false + } + ], + "method": { + "clustering_basis": [ + "literature curation", + "pathway annotation", + "gene co-expression" + ], + "notes": "Gene clusters defined by known functional categories (e.g. myelination, ECM, signaling) and literature evidence relevant to glioblastoma." + }, + "version": "1.0.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_npc_like b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_npc_like new file mode 100644 index 0000000..3d74b26 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_opc_npc_like @@ -0,0 +1,435 @@ +{ + "context": { + "cell_type": "Glioblastoma cells", + "disease": "Glioblastoma", + "tissue": "Brain" + }, + "input_genes": [ + "SLIT3", + "CA8", + "ARX", + "AC109492.1", + "AL078602.1", + "DLX5", + "AC006296.3", + "DLX6", + "RFTN2", + "DLX6-AS1", + "AC090241.2", + "PDZRN3", + "GLI2", + "TBL1X", + "KCNH8", + "ST8SIA5", + "LRGUK", + "TPGS2", + "LINC02487", + "DACH2", + "SOX2-OT", + "KIAA0040", + "FCGBP", + "LINC00326", + "AC022075.1", + "AC125613.1", + "MCUB", + "EPHA7", + "PLS3", + "SLC6A5", + "CRYBG3", + "LINC01748", + "TENM1", + "LINC00535", + "ABTB2", + "MAN2A1", + "LAMP5", + "MOG", + "KITLG", + "ZNF618", + "PIP5K1B", + "AC005162.3", + "AC017053.1", + "FAM149A", + "CRB1", + "ERBB3", + "EPB41L4A", + "STC1", + "PID1", + "EGFR" + ], + "programs": [ + { + "program_name": "Hedgehog signaling (GLI2)", + "description": "GLI2 is a key transcription factor in Sonic Hedgehog signaling, a pathway active in GBM that maintains stem-like tumor cells and drives proliferation. Hedgehog pathway activation promotes glioblastoma stem cell maintenance and is linked to therapy resistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9353242/#:~:text=GLI2%20also%20affects%20HH%20and,receptor%205%2C%20inhibited%20tumor%20cell)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9353242/#:~:text=partial%20drug%20resistance%20through%20this,pathway%20will%20be%20addressed)).", + "predicted_cellular_impact": [ + "Enhanced GSC maintenance and self-renewal", + "Increased proliferation and treatment resistance" + ], + "evidence_summary": "GLI2, a Hedgehog pathway effector, is implicated in glioma stem cell renewal. In GBM, GLI2 activity (often linked to mTORC2) promotes expression of stemness genes, and GLI2 knockdown impairs GBM stem cell proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9353242/#:~:text=GLI2%20also%20affects%20HH%20and,receptor%205%2C%20inhibited%20tumor%20cell)). Hedgehog signaling sustains GBM growth and contributes to drug resistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9353242/#:~:text=partial%20drug%20resistance%20through%20this,pathway%20will%20be%20addressed)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9353242/#:~:text=GLI2%20also%20affects%20HH%20and,receptor%205%2C%20inhibited%20tumor%20cell)).", + "citations": [ + { + "reference": "Wang et al., Hedgehog signaling regulates glioblastoma (Oncol Lett 2022)", + "id": "PMID:35949611", + "type": "PMID", + "notes": "Reviews Hedgehog/GLI2 role in GBM stemness" + }, + { + "reference": "Takezaki et al., Hedgehog signaling in glioma stem cells (Cancer Sci 2011)", + "id": "PMID:21597402", + "type": "PMID", + "notes": "GLI2 required for glioma-initiating cell proliferation" + } + ], + "confidence_score": 0.8, + "significance_score": 0.3, + "supporting_genes": [ + "GLI2" + ], + "supporting_gene_count": 1, + "required_components_present": false, + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007224", + "name": "Hedgehog signaling pathway", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wang et al., Oncol Lett 2022", + "id": "PMID:35949611", + "type": "PMID", + "notes": "Hedgehog pathway active in GBM with GLI2 effect" + } + ], + "Genes": [ + "GLI2" + ] + } + ], + "atomic_cellular_components": [] + }, + { + "program_name": "Wnt5a-mediated invasion", + "description": "DLX5 and SOX2-OT in glioma cells activate WNT5A-driven pathways, inducing a glioma stem cell differentiation program into endothelial-like cells. This promotes peritumoral angiogenesis and diffuse invasion. SOX2-OT upregulates SOX2 and activates Wnt5a/\u03b2-catenin signaling, enhancing proliferation and chemoresistance ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27863244/#:~:text=malignant%20states%20of%20NSCs,to%20the%20lethality%20of%20GBM)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/32439916/#:~:text=resistant%20cells%20and%20recurrent%20GBM,Our%20findings%20indicate%20that)).", + "predicted_cellular_impact": [ + "Increased tumor invasiveness and neovascular mimicry", + "Endothelial-like differentiation of tumor cells" + ], + "evidence_summary": "In GBM models, a PAX6/DLX5 axis drives WNT5A expression to differentiate glioma stem cells into endothelial-like cells (supporting invasive outgrowth) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27863244/#:~:text=malignant%20states%20of%20NSCs,to%20the%20lethality%20of%20GBM)). Separately, the lncRNA SOX2-OT is upregulated in GBM relapse and promotes cell proliferation by increasing SOX2 and activating Wnt5a/\u03b2-catenin signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/32439916/#:~:text=resistant%20cells%20and%20recurrent%20GBM,Our%20findings%20indicate%20that)). Together, these suggest a program where DLX5+SOX2-OT enhance Wnt5a-driven GBM invasion.", + "citations": [ + { + "reference": "Huang et al., PAX6/DLX5-WNT5A axis in GBM (Cancer Cell 2016)", + "id": "PMID:27863244", + "type": "PMID", + "notes": "Shows DLX5 drives WNT5A for GSC differentiation/invasion" + }, + { + "reference": "Xiong et al., SOX2OT promotes TMZ resistance (Mol Oncol 2020)", + "id": "PMID:32439916", + "type": "PMID", + "notes": "Links SOX2OT to SOX2 and Wnt5a activation in GBM" + } + ], + "confidence_score": 0.7, + "significance_score": 0.5, + "supporting_genes": [ + "DLX5", + "SOX2-OT" + ], + "supporting_gene_count": 2, + "required_components_present": false, + "atomic_biological_processes": [ + { + "ontology_id": "GO:0016055", + "name": "Wnt signaling pathway", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Xiong et al., Mol Oncol 2020", + "id": "PMID:32439916", + "type": "PMID", + "notes": "SOX2-OT activates Wnt5a/\u03b2-catenin pathway in GBM" + } + ], + "Genes": [ + "DLX5", + "SOX2-OT" + ] + } + ], + "atomic_cellular_components": [] + }, + { + "program_name": "RTK/PI3K signaling", + "description": "Receptor tyrosine kinases drive PI3K/Akt signaling for growth and survival. EGFR is frequently amplified in GBM, driving proliferation and poor prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12027172/#:~:text=rate,total%20of%2032%20studies%20with)). ERBB3 (HER3), though kinase-impaired, when overexpressed heterodimerizes (e.g. with FGFR3) to activate PI3K/Akt and metabolic pathways, supporting cell survival and therapy resistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8632286/#:~:text=characterized%20by%20marked%20Erb,survival%20signaling%2C%20which%20can)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8632286/#:~:text=high%20ERBB3%20activity%20may%20support,ERBB3%20and%20Fibroblast%20Growth%20Factor)).", + "predicted_cellular_impact": [ + "Elevated PI3K/AKT signaling", + "Enhanced proliferation and survival" + ], + "evidence_summary": "EGFR amplification is one of the most common alterations in GBM and correlates with aggressive growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12027172/#:~:text=rate,total%20of%2032%20studies%20with)). A subset of GBMs overexpress ERBB3 (HER3), which upon ligand binding or heterodimerization triggers potent PI3K/Akt-driven metabolism and proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8632286/#:~:text=characterized%20by%20marked%20Erb,survival%20signaling%2C%20which%20can)). Together, EGFR/ERBB3 signaling in GBM sustains tumor cell proliferation and contributes to treatment resistance.", + "citations": [ + { + "reference": "Zhu et al., EGFR amplification in GBM (Int J Mol Sci 2025)", + "id": "PMID:40331985", + "type": "PMID", + "notes": "Meta-analysis showing frequent EGFRamp in GBM" + }, + { + "reference": "De Bacco et al., ERBB3 in GBM stem cells (Mol Cell Oncol 2021)", + "id": "PMID:34859149", + "type": "PMID", + "notes": "Describes ERBB3 overexpression driving PI3K signaling in GBM" + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": [ + "EGFR", + "ERBB3", + "KITLG", + "PIP5K1B" + ], + "supporting_gene_count": 4, + "required_components_present": false, + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007169", + "name": "transmembrane receptor protein tyrosine kinase signaling pathway", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhu et al., Int J Mol Sci 2025", + "id": "PMID:40331985", + "type": "PMID", + "notes": "EGFR/ERBB3 signaling activates PI3K/Akt in GBM" + } + ], + "Genes": [ + "EGFR", + "ERBB3", + "KITLG", + "PIP5K1B" + ] + }, + { + "ontology_id": "GO:0038095", + "name": "Fc-gamma receptor signaling pathway involved in phagocytosis", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Yan et al., Front Oncol 2022", + "id": "PMID:35082709", + "type": "PMID", + "notes": "FCGBP role in glioma, implicating immune-related signaling" + } + ], + "Genes": [ + "FCGBP" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005886", + "name": "plasma membrane", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "De Bacco et al., Mol Cell Oncol 2021", + "id": "PMID:34859149", + "type": "PMID", + "notes": "ERBB3 is a membrane RTK in GBM cells" + } + ], + "Genes": [ + "ERBB3", + "EGFR" + ] + } + ] + }, + { + "program_name": "Inhibitory neuron differentiation", + "description": "This program features genes classically involved in GABAergic interneuron development and synaptic function. ARX and DLX homeobox transcription factors direct GABAergic migration and differentiation during brain development ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18799476/#:~:text=Mutations%20in%20the%20aristaless,changes%20within%20the%20subpallium%20in)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623701/#:~:text=interneurons%20of%20the%20olfactory%20bulb,fashion%2C%20via%20expression%20of%20Wnt5a)). LAMP5, a vesicular GABA-transporter chaperone, marks inhibitory neurons and tunes GABAergic synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6416879/#:~:text=Lysosome,we%20focus%20on%20the%20prominent)). Their joint expression in GBM suggests a proneural-like or interneuron-lineage transcriptional program.", + "predicted_cellular_impact": [ + "Expression of neuronal differentiation markers", + "Adoption of inhibitory synaptic features" + ], + "evidence_summary": "ARX and DLX5/6 are known regulators of GABAergic interneuron development; loss of ARX disrupts interneuron migration and differentiation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18799476/#:~:text=Mutations%20in%20the%20aristaless,changes%20within%20the%20subpallium%20in)), while DLX5 directly induces GABAergic fate (via Wnt5a) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623701/#:~:text=interneurons%20of%20the%20olfactory%20bulb,fashion%2C%20via%20expression%20of%20Wnt5a)). LAMP5 is a vesicular GABA transporter-sorting protein expressed in inhibitory neurons ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6416879/#:~:text=Lysosome,we%20focus%20on%20the%20prominent)). This profile indicates glioma cells may exhibit some neuronal/interneuron-like programs.", + "citations": [ + { + "reference": "Friocourt et al., ARX targets in cortical interneurons (J Neurosci 2011)", + "id": "PMID:18799476", + "type": "PMID", + "notes": "ARX is required for GABAergic neuron development" + }, + { + "reference": "Paina et al., Dlx genes promote interneuron differentiation (J Neurosci 2011)", + "id": "PMID:21325536", + "type": "PMID", + "notes": "DLX5 drives GABAergic interneuron differentiation via Wnt5a" + }, + { + "reference": "Koebis et al., LAMP5 in GABAergic neurons (Mol Brain 2019)", + "id": "PMID:30867010", + "type": "PMID", + "notes": "LAMP5 is required for GABA synaptic transmission" + } + ], + "confidence_score": 0.6, + "significance_score": 0.6, + "supporting_genes": [ + "ARX", + "DLX5", + "DLX6", + "LAMP5", + "SLC6A5" + ], + "supporting_gene_count": 5, + "required_components_present": false, + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030182", + "name": "neuron differentiation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Paina et al., J Neurosci 2011", + "id": "PMID:21325536", + "type": "PMID", + "notes": "DLX genes promote GABAergic differentiation" + }, + { + "reference": "Friocourt et al., J Neurosci 2011", + "id": "PMID:18799476", + "type": "PMID", + "notes": "ARX important for interneuron development" + } + ], + "Genes": [ + "ARX", + "DLX5", + "DLX6", + "LAMP5", + "SLC6A5" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0098793", + "name": "presynaptic active zone", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Koebis et al., Mol Brain 2019", + "id": "PMID:30867010", + "type": "PMID", + "notes": "LAMP5 located at inhibitory presynaptic boutons" + } + ], + "Genes": [ + "LAMP5", + "SLC6A5" + ] + } + ] + }, + { + "program_name": "Axon guidance and adhesion", + "description": "This program groups axon guidance cues and adhesion molecules. SLIT3 and EPHA7 are repulsive guidance signals in neural development ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2774558/#:~:text=Slits%20are%20large%2C%20secreted%20repulsive,expressed%20and%20secreted%20by%20both)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3977303/#:~:text=characterizes%20the%20role%20of%20the,dendritic%20spine%20formation%20and%20synaptic)), here repurposed to influence tumor angiogenesis and cell motility. TENM1 and CRB1 regulate neuronal cell adhesion and polarity. Altered expression of these genes may enhance GBM cell migration and neovascularization.", + "predicted_cellular_impact": [ + "Increased cell migration and vascular development", + "Altered cell polarity and adhesion structures" + ], + "evidence_summary": "SLIT3 and EPHA7 are axon guidance ligands controlling neural wiring; SLIT3 also promotes angiogenesis in development ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2774558/#:~:text=Slits%20are%20large%2C%20secreted%20repulsive,expressed%20and%20secreted%20by%20both)), while EphA7 influences dendritic/axon growth and synapse formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3977303/#:~:text=characterizes%20the%20role%20of%20the,dendritic%20spine%20formation%20and%20synaptic)). CRB1 is part of the cell polarity complex. These factors can modulate the tumor microenvironment by guiding invasive behavior and vessel growth.", + "citations": [ + { + "reference": "Zhang et al., SLIT3 in angiogenesis (Blood 2009)", + "id": "PMID:19741192", + "type": "PMID", + "notes": "SLIT3 is a secreted axon repellent that activates angiogenesis" + }, + { + "reference": "Clifford et al., EphA7 in cortical development (PNAS 2014)", + "id": "PMID:24707048", + "type": "PMID", + "notes": "EphA7 modulates dendritic growth and guidance" + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "SLIT3", + "EPHA7", + "TENM1", + "CRB1", + "EPB41L4A", + "PLS3" + ], + "supporting_gene_count": 6, + "required_components_present": false, + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007411", + "name": "axon guidance", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhang et al., Blood 2009", + "id": "PMID:19741192", + "type": "PMID", + "notes": "SLIT3 is a repulsive axon guidance factor" + } + ], + "Genes": [ + "SLIT3", + "EPHA7", + "TENM1" + ] + }, + { + "ontology_id": "GO:0001525", + "name": "angiogenesis", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhang et al., Blood 2009", + "id": "PMID:19741192", + "type": "PMID", + "notes": "SLIT3 promotes angiogenic growth" + } + ], + "Genes": [ + "SLIT3", + "EPHA7" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0045202", + "name": "synapse", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Clifford et al., PNAS 2014", + "id": "PMID:24707048", + "type": "PMID", + "notes": "EphA7 localizes to dendritic/synaptic regions" + } + ], + "Genes": [ + "EPHA7" + ] + } + ] + } + ], + "method": { + "clustering_basis": [ + "literature review", + "pathway databases" + ], + "notes": "Programs derived by grouping genes from literature-validated pathways (Hedgehog, Wnt, RTK, axon guidance) and neural developmental programs." + }, + "version": "2023-10-01" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_proliferative b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_proliferative new file mode 100644 index 0000000..39a198c --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/glioblastoma_states_minimal_ds.json_proliferative @@ -0,0 +1,574 @@ +{ + "context": { + "cell_type": "Glioblastoma cells", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "DLGAP5", + "CKAP2L", + "CDCA2", + "CDC25C", + "TTK", + "BUB1", + "HMMR", + "CDCA8", + "TOP2A", + "GTSE1", + "KIF23", + "BUB1B", + "ASPM", + "AURKA", + "KIF14", + "CEP55", + "KIF18A", + "CDK1", + "TROAP", + "DEPDC1", + "CENPE", + "TPX2", + "KIF2C", + "KNL1", + "KIF20A", + "AURKB", + "NEIL3", + "CCNB1", + "ESPL1", + "APOLD1", + "HJURP", + "PIMREG", + "KIF11", + "PIF1", + "UBE2C", + "NDC80", + "CDC20", + "PBK", + "ARHGAP11A", + "NUSAP1", + "PRR11", + "ESCO2", + "PTTG1", + "MELK", + "KIF4A", + "CDKN3", + "NMU", + "BORA", + "KIF18B", + "KIFC1", + "CCNF", + "BIRC5", + "MKI67", + "ARHGAP11B", + "IQGAP3", + "NCAPG", + "SGO1", + "SKA3", + "GAS2L3", + "SGO2", + "RRM2", + "DIAPH3", + "CDCA3", + "CENPF", + "FAM83D", + "NUF2", + "POLQ", + "RACGAP1", + "KPNA2", + "MIR924HG", + "FBXO43", + "TACC3", + "WDR62", + "E2F7", + "PCLAF", + "ASF1B", + "ECT2", + "SHCBP1", + "PLK1", + "FAM111B", + "DEPDC1B", + "MXD3", + "NCAPH", + "PRC1", + "EXO1", + "KIF15", + "FOXM1", + "CCNB2", + "RTKN2", + "NOSTRIN", + "AC010173.1", + "SPC25", + "FOXN4", + "HMGB2", + "CKS2", + "CENPI", + "BRIP1", + "MYBL2", + "LMO7", + "KIF24", + "AC073529.1", + "STIL", + "AC090159.1", + "PLK4" + ], + "programs": [ + { + "program_name": "G2/M Cell Cycle Regulation", + "description": "Coordinated regulation of the G2/M transition and mitotic entry, promoting proliferation. In glioblastoma this gene cluster drives rapid cell division and tumor growth.", + "atomic_biological_processes": [ + { + "name": "mitotic cell cycle", + "ontology_id": "GO:0000278", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhang et al. (2018) Identification of potential oncogenes in GBM. Oncol Rep.", + "id": "10.3892/or.2018.6483", + "type": "DOI", + "notes": "CDK1, CCNB1, CDC20 are overexpressed in GBM and regulate the mitotic cell cycle ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6072298/#:~:text=analyses,clearly%20inhibited%20GBM%20cell%20proliferation))." + } + ], + "Genes": [ + "CDC25C", + "CDK1", + "CCNB1", + "CCNB2", + "CDC20", + "ESPL1", + "PTTG1", + "CDKN3", + "CKS2", + "FBXO43", + "E2F7", + "FOXM1", + "MYBL2" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "ontology_id": "GO:0005634", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Zhang et al. (2018) Oncol Rep.", + "id": "10.3892/or.2018.6483", + "type": "DOI", + "notes": "Cell-cycle regulators such as CDK1, CCNB1 act in the nucleus to drive GBM cell mitosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6072298/#:~:text=analyses,clearly%20inhibited%20GBM%20cell%20proliferation))." + } + ], + "Genes": [ + "CDC25C", + "CDK1", + "CCNB1", + "CCNB2", + "CDC20", + "ESPL1", + "PTTG1", + "CDKN3", + "CKS2", + "FBXO43", + "E2F7", + "FOXM1", + "MYBL2" + ] + } + ], + "predicted_cellular_impact": [ + "accelerated G2/M transition", + "increased cell proliferation", + "checkpoint bypass leading to aneuploidy" + ], + "evidence_summary": "Many included genes (e.g. CDK1, CCNB1, CDC20) are well-known G2/M regulators and are overexpressed in GBM, correlating with poor survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6072298/#:~:text=analyses,clearly%20inhibited%20GBM%20cell%20proliferation)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8144940/#:~:text=biomarkers%20for%20GBM%20,to%20explore%20the%20potential%20diagnosis)). Knockdown of CDK1 and CCNB1 inhibits glioma cell proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6072298/#:~:text=analyses,clearly%20inhibited%20GBM%20cell%20proliferation)). High FOXM1 promotes GBM stemness and proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4596841/#:~:text=in%20GBM%20stem%20cell%20maintenance,Notably%2C%20genetic)).", + "citations": [ + { + "reference": "Zhang et al. (2018) Oncol Rep.", + "id": "10.3892/or.2018.6483", + "type": "DOI", + "notes": "High CDK1, CCNB1, CDC20 in GBM; knockdown reduces proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6072298/#:~:text=analyses,clearly%20inhibited%20GBM%20cell%20proliferation))." + }, + { + "reference": "Geng et al. (2018) Disease Markers", + "id": "10.1155/2018/3215958", + "type": "DOI", + "notes": "Core cell cycle genes (TOP2A, CDK1, CCNB1, etc.) identified as GBM biomarkers ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8144940/#:~:text=biomarkers%20for%20GBM%20,to%20explore%20the%20potential%20diagnosis))." + }, + { + "reference": "Conde et al. (2017) BMC Cancer", + "id": "10.1186/s12885-017-3932-y", + "type": "DOI", + "notes": "Survivin (BIRC5), a CPC component, is overexpressed in gliomas and correlates with proliferation and grade ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=apoptosis%20and%20mitosis%20,8%2C%209%5D.%20It%20is))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.95, + "supporting_genes": [ + "CDC25C", + "CDK1", + "CCNB1", + "CCNB2", + "CDC20", + "ESPL1", + "PTTG1", + "CDKN3", + "CKS2", + "FBXO43", + "E2F7", + "FOXM1", + "MYBL2" + ], + "supporting_gene_count": 13, + "required_components_present": false + }, + { + "program_name": "Spindle Assembly and Centrosome Organization", + "description": "Regulation of the mitotic spindle apparatus and centrosome duplication, ensuring proper mitosis. In GBM cells, overexpression of spindle motors and centrosomal regulators enhances mitotic progression and may promote invasiveness.", + "atomic_biological_processes": [ + { + "name": "spindle assembly", + "ontology_id": "GO:0007051", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Venere et al. (2015) Sci Transl Med", + "id": "10.1126/scitranslmed.aac6762", + "type": "DOI", + "notes": "KIF11 is required for bipolar spindle formation; its inhibition halts GBM cell division and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4743764/#:~:text=between%20these%20disparate%20cellular%20processes%E2%80%94the,impeded%20tumor%20initiation%20and%20self))." + } + ], + "Genes": [ + "KIF11", + "KIF15", + "KIF4A", + "KIF14", + "KIF2C", + "TPX2", + "AURKA", + "TACC3", + "ASPM", + "NUSAP1" + ] + }, + { + "name": "centrosome duplication", + "ontology_id": "GO:0046610", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ngwabyt Bikeye et al. (2010) Cancer Cell Int", + "id": "10.1186/1475-2867-10-1", + "type": "DOI", + "notes": "ASPM localizes to centrosomes/spindle poles and is required for glioma growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2817685/#:~:text=initial%20grade%20of%20the%20primary,in%20two%20different%20gliomasphere%20models))." + } + ], + "Genes": [ + "PLK4", + "STIL", + "ASPM", + "WDR62" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "mitotic spindle", + "ontology_id": "GO:0005819", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Venere et al. (2015) Sci Transl Med", + "id": "10.1126/scitranslmed.aac6762", + "type": "DOI", + "notes": "KIF11 localizes to the mitotic spindle; targeting it disrupts GBM cell division and motility ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4743764/#:~:text=between%20these%20disparate%20cellular%20processes%E2%80%94the,impeded%20tumor%20initiation%20and%20self))." + } + ], + "Genes": [ + "KIF11", + "KIF15", + "KIF4A", + "KIF14", + "KIF2C", + "TPX2", + "AURKA", + "TACC3", + "ASPM", + "NUSAP1" + ] + }, + { + "name": "centrosome", + "ontology_id": "GO:0000226", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Ngwabyt Bikeye et al. (2010) Cancer Cell Int", + "id": "10.1186/1475-2867-10-1", + "type": "DOI", + "notes": "ASPM is at centrosomes/spindle poles, promoting stem-like proliferation in glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2817685/#:~:text=initial%20grade%20of%20the%20primary,in%20two%20different%20gliomasphere%20models))." + } + ], + "Genes": [ + "PLK4", + "STIL", + "ASPM", + "WDR62" + ] + } + ], + "predicted_cellular_impact": [ + "enhanced spindle formation and mitotic polarity", + "aberrant centrosome amplification", + "increased motility and invasiveness" + ], + "evidence_summary": "Multiple kinesins (KIF11, KIF15, etc.) and Aurora kinases (AURKA) are upregulated in GBM, facilitating spindle assembly and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4743764/#:~:text=between%20these%20disparate%20cellular%20processes%E2%80%94the,impeded%20tumor%20initiation%20and%20self)). ASPM, localized to centrosomes, is overexpressed in aggressive gliomas and its silencing halts proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2817685/#:~:text=initial%20grade%20of%20the%20primary,in%20two%20different%20gliomasphere%20models)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6977704/#:~:text=analysis%2C%20the%20highest%20fold%20change,suggest%20that%20ASPM%20may%20serve)). These factors collectively promote robust mitosis and genomic instability in tumor cells.", + "citations": [ + { + "reference": "Venere et al. (2015) Sci Transl Med", + "id": "10.1126/scitranslmed.aac6762", + "type": "DOI", + "notes": "KIF11 is central to GBM TIC proliferation and invasion; its inhibition stops tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4743764/#:~:text=between%20these%20disparate%20cellular%20processes%E2%80%94the,impeded%20tumor%20initiation%20and%20self))." + }, + { + "reference": "Ngwabyt Bikeye et al. (2010) Cancer Cell Int", + "id": "10.1186/1475-2867-10-1", + "type": "DOI", + "notes": "ASPM localizes to centrosomes/spindle poles; shRNA silencing causes proliferation arrest and cell death in GBM models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2817685/#:~:text=initial%20grade%20of%20the%20primary,in%20two%20different%20gliomasphere%20models))." + }, + { + "reference": "Chen et al. (2020) Aging", + "id": "10.18632/aging.102612", + "type": "DOI", + "notes": "ASPM is highly expressed in GBM and its loss-of-function impedes GBM tumorigenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6977704/#:~:text=microcephaly%20associated%20%28ASPM%29,function%20assay%20indicated%20that%20ASPM))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "KIF11", + "KIF15", + "KIF4A", + "KIF14", + "KIF2C", + "TPX2", + "AURKA", + "TACC3", + "ASPM", + "NUSAP1", + "PLK4", + "STIL", + "WDR62" + ], + "supporting_gene_count": 13, + "required_components_present": false + }, + { + "program_name": "Kinetochore and Chromosome Segregation", + "description": "Assembly and function of kinetochores and centromeres to enable accurate chromosome alignment and segregation. Glioblastoma cells overexpress these components to tolerate chromosomal instability and adapt via spindle checkpoint signaling.", + "atomic_biological_processes": [ + { + "name": "chromosome segregation", + "ontology_id": "GO:0007059", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Conde et al. (2017) BMC Cancer", + "id": "10.1186/s12885-017-3932-y", + "type": "DOI", + "notes": "Survivin (BIRC5), part of the chromosomal passenger complex, ensures bipolar segregation and is upregulated in gliomas with aneuploidy ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=apoptosis%20and%20mitosis%20,8%2C%209%5D.%20It%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=Survivin%2C%20belonging%20to%20the%20inhibitor,inducing%20chromosomal%20instability%20remains%20unclear))." + } + ], + "Genes": [ + "NDC80", + "SPC25", + "NUF2", + "KNL1", + "SKA3", + "HJURP", + "CENPE", + "CENPF", + "CENPI", + "AURKB", + "CDCA8", + "BIRC5", + "SGO1", + "SGO2" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "kinetochore", + "ontology_id": "GO:0000777", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Herman et al. (2020) Neuro Oncol", + "type": "DOI", + "id": "10.1093/neuonc/noaa215.084", + "notes": "Chronic kinetochore\u2013microtubule attachment instability (KT stress) is observed in GBM cells; survivors rely on Mitotic Checkpoint proteins (BUB1B) to prevent aneuploidy ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7650502/#:~:text=elusive,MT%20attachment%20defects%20and))." + } + ], + "Genes": [ + "NDC80", + "SPC25", + "NUF2", + "KNL1", + "SKA3", + "HJURP", + "CENPE", + "CENPF", + "CENPI" + ] + }, + { + "name": "centromeric region", + "ontology_id": "GO:0000779", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Conde et al. (2017) BMC Cancer", + "id": "10.1186/s12885-017-3932-y", + "type": "DOI", + "notes": "Components of the chromosome passenger complex localize to centromeres; Survivin overexpression induces chromosomal instability in glioma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=Survivin%2C%20belonging%20to%20the%20inhibitor,inducing%20chromosomal%20instability%20remains%20unclear))." + } + ], + "Genes": [ + "CENPE", + "CENPF", + "CENPI", + "HJURP", + "AURKB", + "CDCA8", + "BIRC5" + ] + } + ], + "predicted_cellular_impact": [ + "increased aneuploidy tolerance", + "activation of spindle assembly checkpoint", + "persistent chromosomal instability" + ], + "evidence_summary": "This cluster includes kinetochore proteins (NDC80 complex, CENPs, KNL1, SKA) and checkpoint kinases (BUB1/BUB1B, TTK). In GBM, merotelic attachments and \u2018kinetochore stress\u2019 are common; cells survive via heightened checkpoint (BUB1B) activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7650502/#:~:text=elusive,MT%20attachment%20defects%20and)). Overexpressed CPC components (Survivin/BIRC5, Borealin/CDCA8) at centromeres facilitate segregation, and elevated Survivin in gliomas is linked to higher grade and CIN ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=apoptosis%20and%20mitosis%20,8%2C%209%5D.%20It%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=Survivin%2C%20belonging%20to%20the%20inhibitor,inducing%20chromosomal%20instability%20remains%20unclear)).", + "citations": [ + { + "reference": "Conde et al. (2017) BMC Cancer", + "id": "10.1186/s12885-017-3932-y", + "type": "DOI", + "notes": "Survivin (BIRC5) is a centromere/CPC protein that, when overexpressed in glioma, causes chromosomal instability and promotes tumorigenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=Survivin%2C%20belonging%20to%20the%20inhibitor,inducing%20chromosomal%20instability%20remains%20unclear)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=apoptosis%20and%20mitosis%20,8%2C%209%5D.%20It%20is))." + }, + { + "reference": "Herman et al. (2020) Neuro Oncol", + "type": "DOI", + "id": "10.1093/neuonc/noaa215.084", + "notes": "Experimental GBM models show widespread kinetochore stress and reliance on the spindle checkpoint (BUB1B) to avoid mitotic catastrophe ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7650502/#:~:text=elusive,MT%20attachment%20defects%20and))." + } + ], + "confidence_score": 0.85, + "significance_score": 0.85, + "supporting_genes": [ + "NDC80", + "SPC25", + "NUF2", + "KNL1", + "SKA3", + "HJURP", + "CENPE", + "CENPF", + "CENPI", + "AURKB", + "CDCA8", + "BIRC5", + "SGO1", + "SGO2" + ], + "supporting_gene_count": 14, + "required_components_present": false + }, + { + "program_name": "DNA Replication and Repair", + "description": "Processes ensuring genome duplication and healing of DNA lesions. GBM cells leverage these to survive oncogenic replication stress; dysregulation can cause therapy resistance and genomic instability.", + "atomic_biological_processes": [ + { + "name": "DNA repair", + "ontology_id": "GO:0006281", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Klattenhoff et al. (2017) Oncotarget", + "id": "10.18632/oncotarget.22896", + "type": "DOI", + "notes": "NEIL3 is recruited to sites of replication-associated DNA damage; its loss in GBM increases double-strand breaks under replication stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5762564/#:~:text=and%20its%20impact%20on%20modulating,dependent%20repair%20is))." + } + ], + "Genes": [ + "NEIL3", + "EXO1", + "PIF1", + "BRIP1", + "POLQ", + "ASF1B", + "PCLAF" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "ontology_id": "GO:0005634", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Gagou et al. (2014) Oncotarget", + "id": "10.18632/oncotarget.2501", + "type": "DOI", + "notes": "PIF1 helicase is essential for DNA replication under oncogenic stress, supporting tumor proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4294361/#:~:text=Unwinding%20duplex%20DNA%20is%20a,transformed%20fibroblasts%2C%20where%20replication))." + } + ], + "Genes": [ + "NEIL3", + "EXO1", + "PIF1", + "BRIP1", + "POLQ", + "ASF1B", + "PCLAF" + ] + } + ], + "predicted_cellular_impact": [ + "enhanced DNA damage tolerance", + "resistance to replication stress", + "maintenance of proliferative capacity" + ], + "evidence_summary": "Included genes like NEIL3, PIF1, EXO1, POLQ, BRIP1 facilitate repair of replication-associated damage. NEIL3 is upregulated in tumors and prevents replication fork collapse in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5762564/#:~:text=and%20its%20impact%20on%20modulating,dependent%20repair%20is)). PIF1 supports fork progression specifically in cancer cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4294361/#:~:text=Unwinding%20duplex%20DNA%20is%20a,transformed%20fibroblasts%2C%20where%20replication)). These allow GBM cells to endure genotoxic stress and resist DNA-damaging therapies.", + "citations": [ + { + "reference": "Klattenhoff et al. (2017) Oncotarget", + "id": "10.18632/oncotarget.22896", + "type": "DOI", + "notes": "NEIL3 is required to repair replication-associated DNA damage in GBM cells; NEIL3 loss increases DSBs under stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5762564/#:~:text=and%20its%20impact%20on%20modulating,dependent%20repair%20is))." + }, + { + "reference": "Gagou et al. (2014) Oncotarget", + "id": "10.18632/oncotarget.2501", + "type": "DOI", + "notes": "Human PIF1 helicase maintains DNA replication fork progression in oncogene-transformed cells; PIF1 loss impairs cancer cell proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4294361/#:~:text=Unwinding%20duplex%20DNA%20is%20a,transformed%20fibroblasts%2C%20where%20replication))." + } + ], + "confidence_score": 0.75, + "significance_score": 0.8, + "supporting_genes": [ + "NEIL3", + "EXO1", + "PIF1", + "BRIP1", + "POLQ", + "ASF1B", + "PCLAF" + ], + "supporting_gene_count": 7, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/neutrophil_combined_input_ds.json b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/neutrophil_combined_input_ds.json new file mode 100644 index 0000000..699d1b0 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/neutrophil_combined_input_ds.json @@ -0,0 +1,532 @@ +{ + "context": { + "cell_type": "Neutrophil", + "disease": "Inflammatory condition", + "tissue": "unspecified" + }, + "input_genes": [ + "CXCL8", + "CXCR2", + "CXCL6", + "CTSG", + "S100A9", + "S100A8", + "CXCR1", + "JAML", + "FCER1G", + "ITGB2", + "CSF3R", + "IL1B", + "TREM1", + "ANXA3", + "PECAM1", + "CD177", + "PRTN3" + ], + "programs": [ + { + "program_name": "Chemokine-Mediated Neutrophil Recruitment", + "theme": "Chemotaxis/Inflammation", + "description": "This program centers on CXCL8/IL-8 and CXCL6 chemokine production by neutrophils or surrounding stroma, engaging CXCR1 and CXCR2 on the same or adjacent neutrophils. The resulting autocrine/paracrine loop drives directed neutrophil migration into tissues. High local IL-8/CXCL6 induces chemotaxis and, at higher concentrations, neutrophil activation (including NET release) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2577773/#:~:text=CXCL6%20is%20a%20potent%20pro,AF%29%20and%20if%20CXCL6)). The net effect is amplified recruitment and accumulation of neutrophils in inflamed tissue.", + "atomic_biological_processes": [ + { + "name": "neutrophil chemotaxis", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Planagum\u00e0 A et al. Differential IL-8 thresholds... J Leukoc Biol (2021)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "IL-8 (CXCL8) is a key chemokine driving neutrophil chemotaxis via CXCR1/2 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as))" + } + ], + "Genes": [ + "CXCL8", + "CXCL6" + ] + }, + { + "name": "chemokine receptor signaling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Planagum\u00e0 A et al. Differential IL-8 thresholds... J Leukoc Biol (2021)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "IL-8 signals through CXCR1/CXCR2 to induce directional migration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as))" + } + ], + "Genes": [ + "CXCR1", + "CXCR2" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular chemokine milieu", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Simard JC et al. PLoS One (2013)", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "Chemokines like CXCL8 are secreted DAMPs mediating inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + } + ], + "Genes": [ + "CXCL8", + "CXCL6" + ] + }, + { + "name": "neutrophil plasma membrane (chemokine receptors)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Planagum\u00e0 A et al. Differential IL-8 thresholds... J Leukoc Biol (2021)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "CXCR1/CXCR2 are cell surface GPCRs for IL-8 on neutrophils ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as))" + } + ], + "Genes": [ + "CXCR1", + "CXCR2" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced neutrophil chemotaxis toward inflammatory signals", + "Autocrine amplification of neutrophil activation", + "Greater recruitment and accumulation of neutrophils" + ], + "evidence_summary": "CXCL8/IL-8 and CXCL6 are potent neutrophil chemoattractants. Planagum\u00e0 et al. confirmed that human IL-8 engages CXCR1/CXCR2 to drive PMN chemotaxis and NET release ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as)). CXCL6 is similarly a strong neutrophil chemoattractant ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2577773/#:~:text=CXCL6%20is%20a%20potent%20pro,AF%29%20and%20if%20CXCL6)). These ligands and receptors together create a feed-forward loop of neutrophil recruitment and activation in inflamed tissues.", + "citations": [ + { + "reference": "Planagum\u00e0 A et al. Differential IL-8 thresholds for chemotaxis and netosis in human neutrophils.", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "IL-8 (CXCL8) is a key chemokine driving neutrophil migration through CXCR1/CXCR2 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as))" + }, + { + "reference": "Simard JC et al. S100A8/A9 induce IL-8 secretion via NF-\u03baB in phagocytes (PLOS One, 2013).", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "Demonstrates IL-8 (CXCL8) is produced as part of an innate inflammatory loop ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + }, + { + "reference": "Espinoza J et al. CXCL6 is a potent neutrophil chemoattractant (Am J Reprod Immunol, 2008).", + "id": "10.1111/j.1600-0897.2008.00637.x", + "type": "DOI", + "notes": "CXCL6 described as a strong neutrophil chemoattractant and activator ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2577773/#:~:text=CXCL6%20is%20a%20potent%20pro,AF%29%20and%20if%20CXCL6))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "CXCL8", + "CXCL6", + "CXCR1", + "CXCR2" + ], + "supporting_gene_count": 4, + "required_components_present": true + }, + { + "program_name": "Calprotectin-Driven Inflammatory Amplification", + "theme": "DAMP signaling/Inflammation", + "description": "S100A8 and S100A9 (calprotectin) are abundant cytosolic proteins that are released as alarmins by activated neutrophils (especially with NETosis). Extracellular S100A8/A9 engages TLR4/RAGE, triggering NF-\u03baB activation and secretion of cytokines (e.g. IL-1\u03b2, IL-8) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=biomarker%20for%20several%20inflammatory%20diseases,upon%20the%20formation%20of%20neutrophil)). They further upregulate neutrophil adhesion molecules (CD11b/ITGB2) and enhance ROS production ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=%28PMA%29,DAMP%20might%20amplify%20neutrophil%20activation)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=examined%20the%20effects%20of%20S100A8,by%20ATP%2C%20a%20known%20inflammasome)). This creates a positive feedback loop amplifying neutrophil-driven inflammation.", + "atomic_biological_processes": [ + { + "name": "NF-\u03baB pathway activation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Simard JC et al. PLoS One (2013)", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "S100A8/A9 activate NF-\u03baB, inducing expression of IL-8 and IL-1\u03b2 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ] + }, + { + "name": "proinflammatory cytokine secretion (e.g. IL-1\u03b2)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Simard JC et al. PLoS One (2013)", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "S100A8/A9 induce secretion of IL-1\u03b2 and IL-8 via NF-\u03baB ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ] + }, + { + "name": "neutrophil activation and adhesion (integrin upregulation)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Sprenkeler EG et al. Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "Extracellular S100A8/A9 induces neutrophil adhesion and upregulation of CD11b (ITGB2) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=%28PMA%29,DAMP%20might%20amplify%20neutrophil%20activation))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ] + }, + { + "name": "neutrophil extracellular trap (NET) formation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Sprenkeler EG et al. Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "S100A8/A9 are released during NETosis and can propagate NET formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=biomarker%20for%20several%20inflammatory%20diseases,upon%20the%20formation%20of%20neutrophil))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "neutrophil cytosol", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Sprenkeler EG et al. Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "S100A8/A9 are highly abundant in the neutrophil cytosol (not in granules) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=biomarker%20for%20several%20inflammatory%20diseases,upon%20the%20formation%20of%20neutrophil))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ] + }, + { + "name": "extracellular space (almighty DAMP release)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Sprenkeler EG et al. Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "S100A8/A9 are released extracellularly (via NETs) and act as DAMPs ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=biomarker%20for%20several%20inflammatory%20diseases,upon%20the%20formation%20of%20neutrophil))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced inflammatory signaling via NF-\u03baB", + "Increased IL-1\u03b2 and IL-8 production", + "Upregulated neutrophil adhesion (CD11b/ITGB2 expression)", + "Positive feedback on neutrophil activation" + ], + "evidence_summary": "S100A8/A9 (calprotectin) are released by activated neutrophils and bind TLR4/RAGE, leading to NF-\u03baB-dependent expression of proinflammatory cytokines (IL-1\u03b2, IL-8) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using)). Sprenkeler et al. demonstrated that purified S100A8/A9 promote neutrophil activation including CD11b upregulation and adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=%28PMA%29,DAMP%20might%20amplify%20neutrophil%20activation)). These DAMPs therefore amplify neutrophil-driven inflammation and recruitment.", + "citations": [ + { + "reference": "Simard JC et al., PLoS One (2013)", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "Shows S100A8/A9 induce IL-1\u03b2 and IL-8 via NF-\u03baB signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + }, + { + "reference": "Sprenkeler EG et al., Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "Reports that S100A8/A9 trigger neutrophil activation and CD11b (ITGB2) upregulation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=%28PMA%29,DAMP%20might%20amplify%20neutrophil%20activation))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": [ + "S100A8", + "S100A9" + ], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "Neutrophil Adhesion and Transmigration", + "theme": "Adhesion/Migration", + "description": "JAML on neutrophils binds epithelial CAR at tight junctions, enabling transepithelial migration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies)). Similarly, \u03b22-integrins (CD11/CD18; ITGB2) mediate firm adhesion to endothelial ICAMs, and PECAM1 on endothelial junctions facilitates diapedesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate)). Together these molecules drive neutrophil extravasation into tissues. High expression of these adhesion genes suggests this cell cluster is primed for tissue infiltration and barrier traversal.", + "atomic_biological_processes": [ + { + "name": "neutrophil transepithelial migration", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zen K et al., Mol Biol Cell (2005)", + "id": "10.1091/mbc.e05-01-0036", + "type": "DOI", + "notes": "JAML binding to epithelial CAR is required for neutrophil migration across tight junctions ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies))" + } + ], + "Genes": [ + "JAML" + ] + }, + { + "name": "neutrophil transendothelial migration", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Woodfin A et al., Blood (2007)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "PECAM1 is a key endothelial junction molecule that mediates neutrophil transmigration into inflamed tissue ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate))" + } + ], + "Genes": [ + "ITGB2", + "PECAM1" + ] + }, + { + "name": "leukocyte adhesion to endothelium", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Pulikkottil S et al., Cells (2022)", + "id": "10.3390/cells11132025", + "type": "DOI", + "notes": "\u03b22 integrins (ITGB2) are critical for neutrophil adhesion and recruitment to sites of inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin))" + } + ], + "Genes": [ + "ITGB2" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "epithelial tight junction (subepithelial)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Zen K et al., Mol Biol Cell (2005)", + "id": "10.1091/mbc.e05-01-0036", + "type": "DOI", + "notes": "JAML on neutrophils binds CAR on epithelial tight junctions during transmigration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies))" + } + ], + "Genes": [ + "JAML" + ] + }, + { + "name": "endothelial cell junction", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Woodfin A et al., Blood (2007)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "PECAM1 at endothelial junctions facilitates neutrophil diapedesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate))" + } + ], + "Genes": [ + "PECAM1" + ] + }, + { + "name": "neutrophil plasma membrane (adhesion complex)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Pulikkottil S et al., Cells (2022)", + "id": "10.3390/cells11132025", + "type": "DOI", + "notes": "\u03b22 integrins (containing ITGB2) localize to the neutrophil plasma membrane and mediate firm adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin))" + } + ], + "Genes": [ + "ITGB2" + ] + } + ], + "predicted_cellular_impact": [ + "Increased adhesion to endothelium and epithelium", + "Efficient transendothelial and transepithelial migration", + "Enhanced tissue infiltration and recruitment to inflamed sites" + ], + "evidence_summary": "Neutrophil JAML has been shown to bind CAR on epithelial tight junctions, promoting transepithelial migration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies)). \u03b22-integrins (e.g. LFA-1/Mac-1) mediate firm adhesion to endothelium, while PECAM1 at endothelial junctions is required for transmigration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin)). Pulikkottil et al. review highlights integrins (including ITGB2) as essential for neutrophil recruitment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin)). These molecules together enable neutrophils to exit vessels and enter tissues.", + "citations": [ + { + "reference": "Zen K et al. Mol Biol Cell (2005)", + "id": "10.1091/mbc.e05-01-0036", + "type": "DOI", + "notes": "Establishes that neutrophil JAML binding to epithelial CAR mediates migration across tight junctions ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies))" + }, + { + "reference": "Woodfin A et al. Blood (2007)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "Shows PECAM1 at endothelial junctions is critical for neutrophil transmigration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate))" + }, + { + "reference": "Pulikkottil S et al. Cells (2022)", + "id": "10.3390/cells11132025", + "type": "DOI", + "notes": "Review confirming \u03b22-integrins (ITGB2) are crucial for neutrophil adhesion and migration during inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "JAML", + "ITGB2", + "PECAM1" + ], + "supporting_gene_count": 3, + "required_components_present": true + }, + { + "program_name": "Granule-Mediated Antimicrobial Activity", + "theme": "Defense/Proteolysis", + "description": "This program reflects neutrophil azurophilic granule exocytosis. PRTN3 (proteinase 3) and CTSG (cathepsin G) are serine proteases stored in neutrophil azurophilic granules ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the)). Upon activation, these enzymes are released to kill pathogens and degrade extracellular matrix. Annexin A3 (ANXA3) is associated with specific granules and regulates granule\u2013membrane fusion during exocytosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of)). Together, these components drive potent proteolytic and microbicidal responses (and can generate autoantigens on the neutrophil surface).", + "atomic_biological_processes": [ + { + "name": "neutrophil degranulation (azurophil granule exocytosis)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Le Cabec V et al., Biochem J (1994)", + "id": "10.1042/bj3030481", + "type": "DOI", + "notes": "Annexin A3 is localized to neutrophil granules and may mediate granule fusion with the membrane ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of))" + } + ], + "Genes": [ + "ANXA3", + "PRTN3", + "CTSG" + ] + }, + { + "name": "serine-type endopeptidase (proteolytic) activity", + "ontology_label": "molecular_function", + "citation": [ + { + "reference": "Pepper RJ et al., Am J Pathol (2015)", + "id": "10.1016/j.ajpath.2015.01.015", + "type": "DOI", + "notes": "Describes proteinase 3 (PRTN3) as a neutrophil azurophilic granule protease with microbicidal activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the))" + } + ], + "Genes": [ + "PRTN3", + "CTSG" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "neutrophil azurophilic granule lumen", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Pepper RJ et al., Am J Pathol (2015)", + "id": "10.1016/j.ajpath.2015.01.015", + "type": "DOI", + "notes": "PRTN3 (proteinase 3) is stored in neutrophil azurophil granules ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the))" + } + ], + "Genes": [ + "PRTN3", + "CTSG" + ] + }, + { + "name": "neutrophil plasma membrane (granule fusion site)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Le Cabec V et al., Biochem J (1994)", + "id": "10.1042/bj3030481", + "type": "DOI", + "notes": "Annexin A3 translocates from granules to the plasma membrane upon activation, implicating it in granule fusion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of))" + } + ], + "Genes": [ + "ANXA3" + ] + }, + { + "name": "extracellular space", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Pepper RJ et al., Am J Pathol (2015)", + "id": "10.1016/j.ajpath.2015.01.015", + "type": "DOI", + "notes": "Azurophil proteases like PRTN3 and CTSG are released extracellularly to enact microbicidal effects ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the))" + } + ], + "Genes": [ + "PRTN3", + "CTSG" + ] + } + ], + "predicted_cellular_impact": [ + "Potent antimicrobial killing via protease release", + "Extracellular matrix degradation and tissue remodeling", + "Generation of inflammatory mediators/autoantigens (e.g. membrane PR3)" + ], + "evidence_summary": "PRTN3 and CTSG are major azurophilic granule proteases in neutrophils ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the)). They mediate pathogen killing and contribute to extracellular matrix degradation. Le Cabec et al. showed Annexin A3 localizes to neutrophil granules and translocates to the plasma membrane during activation, suggesting it facilitates granule fusion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of)). Together these proteins drive degranulation and proteolytic antimicrobial activity.", + "citations": [ + { + "reference": "Pepper RJ et al., Am J Pathol (2015)", + "id": "10.1016/j.ajpath.2015.01.015", + "type": "DOI", + "notes": "Confirms that proteinase 3 is a neutrophil azurophil granule protease with microbicidal activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the))" + }, + { + "reference": "Le Cabec V et al., Biochem J (1994)", + "id": "10.1042/bj3030481", + "type": "DOI", + "notes": "Shows Annexin A3 is granule-associated in neutrophils and moves to membrane upon activation, implying a role in degranulation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": [ + "CTSG", + "PRTN3", + "ANXA3" + ], + "supporting_gene_count": 3, + "required_components_present": true + } + ], + "method": { + "clustering_basis": [ + "known pathway interactions", + "literature co-citation" + ], + "notes": "Gene programs identified by grouping input genes with related functions (e.g. chemotaxis, adhesion, degranulation) based on literature and pathway context" + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/osteoclast_combined_input_ds.json b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/osteoclast_combined_input_ds.json new file mode 100644 index 0000000..7cff5f4 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/deepsearch/osteoclast_combined_input_ds.json @@ -0,0 +1,318 @@ +{ + "context": { + "cell_type": "osteoclast", + "disease": "Bone remodeling (normal physiology)", + "tissue": "bone" + }, + "input_genes": [ + "TNFRSF11A", + "Csf1r", + "TYROBP", + "ACP5", + "Acp5" + ], + "programs": [ + { + "program_name": "Osteoclast Differentiation Signaling (RANK/CSF1R)", + "theme": "Bone remodeling", + "description": "A program driven by M-CSF/CSF1R and RANKL/RANK signaling that directs monocyte/macrophage precursors to differentiate into mature, multinucleated osteoclasts. CSF1R activation by M-CSF promotes survival and proliferation of myeloid precursors and induces expression of RANK (TNFRSF11A). Subsequent binding of RANKL to RANK triggers NF-\u03baB and MAPK cascades, culminating in NFATc1 activation and transcription of osteoclast-specific genes (e.g., ACP5/TRAP, cathepsin K, integrins). This cascade is essential for osteoclastogenesis and maintenance of osteoclast viability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cancer,proliferation%20and%20differentiation%20from%20precursor)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10097072/#:~:text=RANK%20extracellular%20domain%20promotes%20osteoclastogenesis,RANK%20on%20osteoclast%20precursor%20cells)).", + "atomic_biological_processes": [ + { + "name": "osteoclast differentiation", + "citation": [ + { + "reference": "Mun S-H et al. The M-CSF receptor in osteoclasts and beyond. Exp Mol Med. 2020;52(8):1239-1254.", + "id": "10.1038/s12276-020-0484-z", + "type": "DOI", + "notes": "CSF1R and RANK signaling drive differentiation of precursors into osteoclasts ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cancer,proliferation%20and%20differentiation%20from%20precursor)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10097072/#:~:text=RANK%20extracellular%20domain%20promotes%20osteoclastogenesis,RANK%20on%20osteoclast%20precursor%20cells))" + } + ], + "Genes": [ + "TNFRSF11A", + "Csf1r" + ] + }, + { + "name": "NFATc1-mediated gene transcription", + "citation": [ + { + "reference": "Mun S-H et al. Exp Mol Med. 2020.", + "id": "10.1038/s12276-020-0484-z", + "type": "DOI", + "notes": "CSF1R-induced RANK expression and RANKL binding activate NFATc1, a master regulator of osteoclast genes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cells,induction%20of%20metabolic%20reprogramming%20and))" + } + ], + "Genes": [ + "TNFRSF11A", + "Csf1r" + ] + }, + { + "name": "NF-\u03baB signaling", + "citation": [ + { + "reference": "Mun S-H et al. Exp Mol Med. 2020.", + "id": "10.1038/s12276-020-0484-z", + "type": "DOI", + "notes": "RANK-RANKL interaction activates NF-\u03baB pathways in osteoclast precursors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cells,induction%20of%20metabolic%20reprogramming%20and))" + } + ], + "Genes": [ + "TNFRSF11A" + ] + }, + { + "name": "proliferation of myeloid precursors", + "citation": [ + { + "reference": "Mun S-H et al. Exp Mol Med. 2020.", + "id": "10.1038/s12276-020-0484-z", + "type": "DOI", + "notes": "CSF1R signaling is essential for proliferation and survival of osteoclast precursors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cancer,proliferation%20and%20differentiation%20from%20precursor))" + } + ], + "Genes": [ + "Csf1r" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "RANK receptor (TNFRSF11A)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Takahashi N et al. Biochem Biophys Res Commun. 1999;256(3):449-455.", + "id": "10080918", + "type": "PMID", + "notes": "Describes binding of RANKL (OPGL) to RANK on osteoclast precursors ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10097072/#:~:text=RANK%20extracellular%20domain%20promotes%20osteoclastogenesis,RANK%20on%20osteoclast%20precursor%20cells))" + } + ], + "Genes": [ + "TNFRSF11A" + ] + }, + { + "name": "CSF1 receptor (c-FMS) complex", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Mun S-H et al. Exp Mol Med. 2020.", + "id": "10.1038/s12276-020-0484-z", + "type": "DOI", + "notes": "CSF1R (c-Fms) on precursors mediates M-CSF signaling for osteoclast development ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cancer,proliferation%20and%20differentiation%20from%20precursor))" + } + ], + "Genes": [ + "Csf1r" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced differentiation of monocytes into multinucleated osteoclasts", + "Increased survival and proliferation of osteoclast precursor cells", + "Upregulation of osteoclast-specific markers and enzymes (e.g., TRAP/ACP5, cathepsin K)", + "Activation of NF-\u03baB and NFATc1 transcriptional programs" + ], + "evidence_summary": "CSF1R (c-Fms) and RANK (TNFRSF11A) are essential receptors for osteoclastogenesis. CSF1R signaling induces RANK expression in myeloid precursors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cancer,proliferation%20and%20differentiation%20from%20precursor)); binding of RANKL to RANK activates NF-\u03baB/MAPK cascades and NFATc1, driving osteoclast-specific gene expression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cells,induction%20of%20metabolic%20reprogramming%20and)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10097072/#:~:text=RANK%20extracellular%20domain%20promotes%20osteoclastogenesis,RANK%20on%20osteoclast%20precursor%20cells)). Genetic ablation of RANK or CSF1R leads to osteopetrosis from failed osteoclast formation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10097072/#:~:text=RANK%20extracellular%20domain%20promotes%20osteoclastogenesis,RANK%20on%20osteoclast%20precursor%20cells)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=receptor%20activator%20of%20NF,proliferation%20and%20differentiation%20from%20precursor)). Thus, coordinated M-CSF and RANK signals underlie osteoclast differentiation and function in bone.", + "citations": [ + { + "reference": "Mun S-H et al. The M-CSF receptor in osteoclasts and beyond. Exp Mol Med. 2020;52(8):1239-1254.", + "id": "10.1038/s12276-020-0484-z", + "type": "DOI", + "notes": "CSF1R signaling promotes osteoclast precursor proliferation and RANK expression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cancer,proliferation%20and%20differentiation%20from%20precursor)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=induced%20NFATc1%20expression,24))" + }, + { + "reference": "Takahashi N et al. Biochem Biophys Res Commun. 1999;256(3):449-455.", + "id": "10080918", + "type": "PMID", + "notes": "Demonstrated that RANK mediates osteoclast differentiation induced by RANKL (OPGL) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10097072/#:~:text=RANK%20extracellular%20domain%20promotes%20osteoclastogenesis,RANK%20on%20osteoclast%20precursor%20cells))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "TNFRSF11A", + "Csf1r" + ], + "supporting_gene_count": 2, + "required_components_present": false + }, + { + "program_name": "ITAM-mediated Co-stimulatory Signaling", + "theme": "Osteoclast activation", + "description": "TyroBP (DAP12) is an immunoreceptor adaptor that transmits ITAM signals via associated receptors (e.g. TREM2) to enhance osteoclast development and activity. Activation of DAP12 potentiates RANKL-induced differentiation and promotes cytoskeletal organization. DAP12/TREM2 signaling is required for efficient fusion of precursors into large, multinucleated osteoclasts and for full bone-resorptive capacity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These)). Loss of DAP12 (TYROBP) leads to small, TRAP+ osteoclasts with impaired resorption ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These)).", + "atomic_biological_processes": [ + { + "name": "ITAM signal transduction", + "citation": [ + { + "reference": "Paloneva J et al. J Exp Med. 2003;198(4):669-675.", + "id": "10.1084/jem.20030027", + "type": "DOI", + "notes": "Shows that DAP12/TREM2 signaling complex is essential for osteoclast differentiation and function ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These))" + } + ], + "Genes": [ + "TYROBP" + ] + }, + { + "name": "osteoclast precursor cell fusion", + "citation": [ + { + "reference": "Paloneva J et al. J Exp Med. 2003.", + "id": "10.1084/jem.20030027", + "type": "DOI", + "notes": "DAP12-deficient cells show inefficient fusion and reduced multinuclear osteoclasts ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These))" + } + ], + "Genes": [ + "TYROBP" + ] + }, + { + "name": "osteoclast migration and resorption", + "citation": [ + { + "reference": "Paloneva J et al. J Exp Med. 2003.", + "id": "10.1084/jem.20030027", + "type": "DOI", + "notes": "DAP12/TREM2 loss causes smaller osteoclasts with greatly reduced bone resorption in vitro ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These))" + } + ], + "Genes": [ + "TYROBP" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "DAP12 (TYROBP) adaptor complex", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Paloneva J et al. J Exp Med. 2003.", + "id": "10.1084/jem.20030027", + "type": "DOI", + "notes": "DAP12 is an ITAM-bearing adaptor protein required for osteoclast maturation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These))" + } + ], + "Genes": [ + "TYROBP" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced fusion of osteoclast precursors into large, multinucleated cells", + "Increased osteoclast motility and cytoskeletal reorganization (podosome/sealing zone formation)", + "Amplification of RANKL-induced signaling to promote bone resorption" + ], + "evidence_summary": "DAP12 (TYROBP) is a key co-stimulatory adaptor in osteoclasts. Mutations in DAP12 (TYROBP) or its receptor TREM2 cause Nasu-Hakola disease with bone cysts and impaired osteoclastogenesis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16418779/#:~:text=Deficiency%20of%20the%20signaling%20adapter,evidence%20that%20TREM2%20regulates%20OC)). DAP12-deficient cells form small TRAP-positive osteoclasts with drastically reduced resorptive activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These)). These findings indicate that ITAM-mediated DAP12 signaling is necessary for efficient fusion of osteoclast precursors and full osteoclastic bone degradation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These)).", + "citations": [ + { + "reference": "Paloneva J et al. DAP12/TREM2 deficiency impairs osteoclast differentiation and causes osteoporotic features. J Exp Med. 2003;198(4):669-675.", + "id": "10.1084/jem.20030027", + "type": "DOI", + "notes": "Loss-of-function mutations in DAP12 (TYROBP) severely blunt osteoclast fusion and bone resorption capability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": [ + "TYROBP" + ], + "supporting_gene_count": 1, + "required_components_present": false + }, + { + "program_name": "Bone Matrix Degradation (TRAP/ACP5 Enzymatic Activity)", + "theme": "Bone resorption", + "description": "Tartrate-resistant acid phosphatase (TRAP, encoded by ACP5) is an enzyme secreted by active osteoclasts into the resorption lacuna. TRAP dephosphorylates bone matrix proteins (e.g. osteopontin, bone sialoprotein), facilitating the dissolution of mineralized matrix ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et)). This enzyme contributes to the acidified environment that dissolves hydroxyapatite during resorption. ACP5 is highly upregulated in mature osteoclasts and is a marker of their activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et)). ACP5 deficiency leads to excessive bone retention and mild osteopetrosis, indicating its role in matrix remodeling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et)).", + "atomic_biological_processes": [ + { + "name": "dephosphorylation of bone matrix proteins", + "citation": [ + { + "reference": "Blumer MJ et al. Mech Dev. 2013;130(5-6):97-108.", + "id": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419267", + "type": "URL", + "notes": "TRAP (ACP5) dephosphorylates osteopontin and bone sialoprotein in the matrix, aiding bone remodeling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et))" + } + ], + "Genes": [ + "ACP5" + ] + }, + { + "name": "acidification of resorption lacuna", + "citation": [ + { + "reference": "Blumer MJ et al. Mech Dev. 2013.", + "id": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419267", + "type": "URL", + "notes": "Osteoclasts create a highly acidic milieu for mineral dissolution; TRAP contributes by acting in this environment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et))" + } + ], + "Genes": [ + "ACP5" + ] + }, + { + "name": "mineralized bone matrix resorption", + "citation": [ + { + "reference": "Blumer MJ et al. Mech Dev. 2013.", + "id": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419267", + "type": "URL", + "notes": "TRAP activity is essential for normal bone resorption; TRAP-knockout mice show increased bone mass and osteopetrotic features ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et))" + } + ], + "Genes": [ + "ACP5" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "bone extracellular matrix", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Blumer MJ et al. Mech Dev. 2013.", + "id": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419267", + "type": "URL", + "notes": "ACP5 acts on bone matrix proteins during resorption ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et))" + } + ], + "Genes": [ + "ACP5" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced dephosphorylation and breakdown of bone matrix proteins", + "Formation of an acidic resorption compartment facilitating mineral dissolution", + "Increased osteoclast bone degradation activity" + ], + "evidence_summary": "ACP5 (TRAP) is a signature osteoclast enzyme. It dephosphorylates and helps degrade phosphoproteins in bone matrix ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et)). TRAP-deficient mice have impaired bone resorption and develop osteopetrotic features (excess bone mass and malformed growth plates) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et)). Thus, ACP5 activity is required for efficient extracellular matrix degradation by osteoclasts.", + "citations": [ + { + "reference": "Blumer MJ et al. Role of TRAP (ACP5) in long bone development. Mech Dev. 2013.", + "id": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419267", + "type": "URL", + "notes": "Describes TRAP\u2019s role in dephosphorylating bone matrix proteins and shows TRAP knockout leads to osteopetrotic phenotype ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et))" + } + ], + "confidence_score": 0.85, + "significance_score": 0.9, + "supporting_genes": [ + "ACP5", + "Acp5" + ], + "supporting_gene_count": 2, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_ac_gliosis_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_ac_gliosis_like_1 new file mode 100644 index 0000000..bd5729e --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_ac_gliosis_like_1 @@ -0,0 +1,549 @@ +{ + "context": { + "cell_type": "astrocytes", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "AQP1", + "ANOS1", + "LIX1", + "CD38", + "RASL12", + "KCNN3", + "SERPINA3", + "GFAP", + "FAM189A2", + "BBOX1", + "NPSR1", + "ITPKB", + "CFI", + "LINC01094", + "ID3", + "FBLN5", + "CFAP54", + "DAAM2", + "ADAMTS8", + "GGT5", + "SLC14A1", + "RPE65", + "MASP1", + "SLCO1C1", + "AC092131.1", + "ITGB4", + "LRRC2", + "STUM", + "SPON1", + "CD44", + "ATP1A2", + "AQP4", + "ALDH1L1", + "CRB2", + "FAM107A", + "GJA1", + "ETNPPL", + "AC103923.1", + "ZFP36", + "RFTN1", + "EDNRA", + "HAS2", + "ADAMTS15", + "MARVELD3", + "OBI1-AS1", + "PAPLN", + "ID4", + "HRH1", + "HCG22", + "DRC1", + "PTCHD1", + "PTPRT", + "GALNT15", + "FHAD1", + "SLC44A3", + "F3", + "COL28A1", + "EDNRB", + "ACSBG1", + "ABCA13", + "WDR49", + "XAF1", + "ABCC3", + "AC092924.2", + "AC002429.2", + "WWC1", + "TIMP3", + "AGT", + "SLC24A4", + "HOPX", + "CABCOCO1", + "CHI3L2", + "C3", + "MYBPC1", + "ADGRV1", + "LINC02234", + "GPR37L1", + "AL591686.2", + "TCTEX1D1", + "TTYH1", + "TC2N", + "LINC00844", + "AL355306.2", + "AC073941.1", + "NMB", + "PDGFRB", + "BCAN", + "EGF", + "DCHS2", + "PFKFB3", + "AC117464.1", + "SCN7A", + "COLEC12", + "OSMR", + "C21orf62", + "LTF", + "BMPR1B", + "ATP13A4", + "IGFBP7" + ], + "programs": [ + { + "program_name": "Water Homeostasis", + "description": "Glioblastoma cells upregulate water channels AQP1 and AQP4, disrupting astrocytic water regulation and contributing to vasogenic edema. Both AQP1 and mislocalized AQP4 enable increased water flux across cell membranes, facilitating glioma cell migration and peritumoral fluid accumulation.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0006833", + "name": "water transport", + "citation": [ + { + "reference": "Maugeri et al., Aquaporins and Brain Tumors, Int J Mol Sci 2016", + "id": "10.3390/ijms17071029", + "type": "DOI", + "notes": "Glioma cell migration and edema correlate with altered AQP1/AQP4 expression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964405/#:~:text=of%20glioblastoma%20is%20the%20vasogenic,other%20small%20molecules%2C%20such%20as))" + } + ], + "Genes": [ + "AQP1", + "AQP4" + ], + "ontology_label": "water transport" + }, + { + "ontology_id": "GO:0016477", + "name": "cell migration", + "citation": [ + { + "reference": "Maugeri et al., Aquaporins and Brain Tumors, Int J Mol Sci 2016", + "id": "10.3390/ijms17071029", + "type": "DOI", + "notes": "Glioma migration correlates with altered aquaporin expression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964405/#:~:text=of%20glioblastoma%20is%20the%20vasogenic,other%20small%20molecules%2C%20such%20as))" + } + ], + "Genes": [ + "AQP1", + "AQP4" + ], + "ontology_label": "cell migration" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005886", + "name": "plasma membrane", + "citation": [ + { + "reference": "Maugeri et al., Aquaporins and Brain Tumors, Int J Mol Sci 2016", + "id": "10.3390/ijms17071029", + "type": "DOI", + "notes": "AQP4 becomes delocalized to glioma cell plasma membranes, increasing water trafficking ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964405/#:~:text=visible%20and%20AQP4%20is%20found,arrows%20on%20glioma%20cell%20membrane))" + } + ], + "Genes": [ + "AQP1", + "AQP4" + ], + "ontology_label": "plasma membrane" + } + ], + "predicted_cellular_impact": [ + "Increased transmembrane water permeability", + "Enhanced vasogenic edema and intracranial pressure", + "Facilitated tumor cell migration via osmotic water flow" + ], + "evidence_summary": "Expression/localization of AQP1 and AQP4 is altered in glioblastoma, with AQP1 upregulated and AQP4 redistributed from astrocyte endfeet to tumor cell surfaces. This enhances water flux across membranes and correlates with peritumoral edema and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964405/#:~:text=of%20glioblastoma%20is%20the%20vasogenic,other%20small%20molecules%2C%20such%20as)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4964405/#:~:text=visible%20and%20AQP4%20is%20found,arrows%20on%20glioma%20cell%20membrane)).", + "citations": [ + { + "reference": "Rosario Maugeri et al., Aquaporins and Brain Tumors, Intl J Mol Sci, 2016", + "id": "10.3390/ijms17071029", + "type": "DOI", + "notes": "Review linking AQP1/AQP4 dysregulation to glioma edema and cell migration" + } + ], + "confidence_score": 0.9, + "significance_score": 0.6, + "supporting_genes": [ + "AQP1", + "AQP4" + ], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "Astrocyte Differentiation", + "description": "Genes like GFAP, ALDH1L1, and ID4 are classic astrocyte markers and suggest maintenance of glial identity. These factors support astrocyte-like polarization and intermediate filament assembly. Astrocytic gap junctions (GJA1) and adhesion molecules (CRB2, CD44) contribute to cell\u2013cell communication and barrier functions. In glioblastoma, an astrocyte-like program underlies tumor behavior, reflecting the origin of GBM from astroglial lineage.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0048708", + "name": "astrocyte differentiation", + "citation": [ + { + "reference": "Lin et al., Diverse Astrocyte Populations and Malignant Analogs, Nat Neurosci 2017", + "id": "10.1038/nn.4493", + "type": "DOI", + "notes": "Aldh1l1 and GFAP are used as broad astrocyte markers ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5824716/#:~:text=Strategies%20for%20dissecting%20the%20cellular,15%7D.%20By))" + } + ], + "Genes": [ + "GFAP", + "ALDH1L1" + ], + "ontology_label": "astrocyte differentiation" + }, + { + "ontology_id": "GO:0050808", + "name": "synapse organization", + "citation": [ + { + "reference": "Lin et al., Nat Neurosci 2017", + "id": "10.1038/nn.4493", + "type": "DOI", + "notes": "Astrocyte subpopulations support synaptogenesis; analogous subpopulations appear in glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5824716/#:~:text=show%20extensive%20molecular%20diversity,of%20specific%20subpopulations%20during%20tumor))" + } + ], + "Genes": [ + "GFAP", + "GJA1", + "CRB2" + ], + "ontology_label": "synapse organization" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0045111", + "name": "intermediate filament cytoskeleton", + "citation": [ + { + "reference": "Potokar et al., Diversity of Intermediate Filaments in Astrocytes, Cells 2020", + "id": "10.3390/cells9071604", + "type": "DOI", + "notes": "Astrocytes express abundant intermediate filaments (GFAP, vimentin) for structural integrity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7408014/#:~:text=roles%20of%20individual%20intermediate%20filaments,interaction%20between%20the%20cytoskeleton%20and))" + } + ], + "Genes": [ + "GFAP", + "ID4" + ], + "ontology_label": "intermediate filament cytoskeleton" + } + ], + "predicted_cellular_impact": [ + "Maintenance of glial fibrillary structure", + "Support of astrocytic network and BBB integrity", + "Promotion of an astrocyte-like, reactive state" + ], + "evidence_summary": "ALDH1L1 and GFAP are established astrocyte markers ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5824716/#:~:text=Strategies%20for%20dissecting%20the%20cellular,15%7D.%20By)). GFAP and other cytoskeletal proteins (ID4) indicate astroglial differentiation, while GJA1 and CRB2 mediate gap junction and cell polarity functions. Astrocytic gene expression programs identified in brain persist in GBM, linking to tumor support roles ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5824716/#:~:text=Strategies%20for%20dissecting%20the%20cellular,15%7D.%20By)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5824716/#:~:text=show%20extensive%20molecular%20diversity,of%20specific%20subpopulations%20during%20tumor)).", + "citations": [ + { + "reference": "Lin et al., Nat Neurosci 2017", + "id": "10.1038/nn.4493", + "type": "DOI", + "notes": "Astrocyte markers (Aldh1l1, GFAP) and their malignant counterparts support astrocyte-like programs in glioma" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "GFAP", + "ALDH1L1", + "GJA1", + "ID4", + "CRB2", + "CD44" + ], + "supporting_gene_count": 6, + "required_components_present": true + }, + { + "program_name": "ECM Remodeling", + "description": "Several metalloproteases and adhesion proteins are present that modulate the tumor extracellular matrix. Serine protease inhibitor SERPINA3, matrix modifiers ADAMTS8/15, fibulin-5, spondin-1, collagen COL28A1, and TIMP3 suggest dynamic ECM turnover. This program promotes glioma invasion by altering cell adhesion and degrading ECM barriers.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030198", + "name": "extracellular matrix organization", + "citation": [ + { + "reference": "Li et al., SERPINA3 facilitates GBM invasion, Oncol Lett 2017", + "id": "10.3892/ol.2017.7275", + "type": "DOI", + "notes": "Upregulated SERPINA3 in glioma promotes GBM invasion by remodeling the ECM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5769378/#:~:text=indicated%20that%20upregulation%20of%20SERPINA3,GBM%20patients%2C%20suggesting%20that%20SERPINA))" + } + ], + "Genes": [ + "ADAMTS8", + "ADAMTS15", + "FBLN5", + "SPON1", + "TIMP3" + ], + "ontology_label": "extracellular matrix organization" + }, + { + "ontology_id": "GO:0016477", + "name": "cell migration via ECM", + "citation": [ + { + "reference": "Li et al., SERPINA3 facilitates GBM invasion, Oncol Lett 2017", + "id": "10.3892/ol.2017.7275", + "type": "DOI", + "notes": "SERPINA3 overexpression is linked to invasive behavior by ECM remodeling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5769378/#:~:text=indicated%20that%20upregulation%20of%20SERPINA3,GBM%20patients%2C%20suggesting%20that%20SERPINA))" + } + ], + "Genes": [ + "ADAMTS8", + "SERPINA3", + "CHI3L2" + ], + "ontology_label": "cell migration" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005576", + "name": "extracellular region", + "citation": [ + { + "reference": "Li et al., Oncol Lett 2017", + "id": "10.3892/ol.2017.7275", + "type": "DOI", + "notes": "Secreted protease inhibitors and ECM proteins (e.g., SERPINA3) operate in the extracellular space of GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5769378/#:~:text=indicated%20that%20upregulation%20of%20SERPINA3,GBM%20patients%2C%20suggesting%20that%20SERPINA))" + } + ], + "Genes": [ + "SERPINA3", + "ADAMTS8", + "FBLN5", + "SPON1", + "CHI3L2" + ], + "ontology_label": "extracellular region" + } + ], + "predicted_cellular_impact": [ + "Enhanced matrix degradation", + "Reduced adhesion to extracellular scaffold", + "Increased invasive potential of tumor cells" + ], + "evidence_summary": "In GBM, upregulation of SERPINA3 and ADAMTS proteases has been observed; SERPINA3 drives ECM remodeling and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5769378/#:~:text=indicated%20that%20upregulation%20of%20SERPINA3,GBM%20patients%2C%20suggesting%20that%20SERPINA)), and loss of ADAMTS8 enhances invasion (its expression inhibits glioma migration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/37587889/#:~:text=of%20ADAMTS8%20could%20inhibit%20the,The%20upregulation%20of%20ADAMTS8%20could))). Fibulins, TIMP3 and others suggest active ECM turnover and modified adhesion.", + "citations": [ + { + "reference": "Li et al., Oncol Lett 2017", + "id": "10.3892/ol.2017.7275", + "type": "DOI", + "notes": "Evidence that SERPINA3 and ECM proteases promote GBM invasiveness" + }, + { + "reference": "Xiang et al., BBRC 2022", + "id": "10.1016/j.bbrc.2022.01.110", + "type": "DOI", + "notes": "ADAMTS8 is downregulated in glioma; its upregulation inhibits invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/37587889/#:~:text=of%20ADAMTS8%20could%20inhibit%20the,The%20upregulation%20of%20ADAMTS8%20could))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.85, + "supporting_genes": [ + "SERPINA3", + "ADAMTS8", + "ADAMTS15", + "FBLN5", + "SPON1", + "TIMP3", + "COL28A1", + "PAPLN" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Innate Immune/Complement", + "description": "Glioblastomas engage innate immunity and inflammation. Complement factors (C3, MASP1, CFI) and acute-phase proteins (SERPINA3, CHI3L2, LTF) are expressed, signaling an inflammatory microenvironment. Astrocyte reactivity marker C3 suggests immune modulation. This program may influence macrophage polarization and immune evasion.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0006956", + "name": "complement activation", + "citation": [ + { + "reference": "Rosberg et al., Complement C3 in GBM, JCI Insight 2024", + "id": "10.1172/jci.insight.179854", + "type": "DOI", + "notes": "C3 is upregulated in hypoxic GBM, promoting tumor growth via macrophage polarization and correlating with worse outcome ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=a%20strong%20link%20between%20hypoxia,using%20the%20antagonist%20SB290157%20prolonged)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=Complement%20component%203%20,brain%20barrier))" + } + ], + "Genes": [ + "C3", + "MASP1", + "CFI" + ], + "ontology_label": "complement activation" + }, + { + "ontology_id": "GO:0006954", + "name": "inflammatory response", + "citation": [ + { + "reference": "Rosberg et al., JCI Insight 2024", + "id": "10.1172/jci.insight.179854", + "type": "DOI", + "notes": "C3a/C3aR signaling triggers cytokine release and M2 macrophage polarization in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=a%20strong%20link%20between%20hypoxia,using%20the%20antagonist%20SB290157%20prolonged))" + } + ], + "Genes": [ + "C3", + "LTF", + "CHI3L2" + ], + "ontology_label": "inflammatory response" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005576", + "name": "extracellular region", + "citation": [ + { + "reference": "Rosberg et al., JCI Insight 2024", + "id": "10.1172/jci.insight.179854", + "type": "DOI", + "notes": "Complement proteins and acute-phase factors are secreted into the glioma microenvironment (C3 in hypoxic niche) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=a%20strong%20link%20between%20hypoxia,using%20the%20antagonist%20SB290157%20prolonged)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=Complement%20component%203%20,brain%20barrier))" + } + ], + "Genes": [ + "C3", + "MASP1", + "CFI", + "LTF", + "CHI3L2" + ], + "ontology_label": "extracellular region" + } + ], + "predicted_cellular_impact": [ + "Activation of complement cascade and inflammation", + "Polarization of macrophages/microglia to tumor-supportive M2 state", + "Immune evasion via immunosuppressive signaling" + ], + "evidence_summary": "C3 and related complement components are elevated in glioblastoma, especially in hypoxic regions, and promote tumor progression by shaping immune responses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=a%20strong%20link%20between%20hypoxia,using%20the%20antagonist%20SB290157%20prolonged)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=Complement%20component%203%20,brain%20barrier)). Glioma cells and reactive astrocytes produce inflammatory mediators (e.g. LTF, CHI3L2, SERPINA3) that modulate the microenvironment.", + "citations": [ + { + "reference": "Rosberg et al., JCI Insight 2024", + "id": "10.1172/jci.insight.179854", + "type": "DOI", + "notes": "Hypoxia-induced C3 expression in GBM tumors drives immunosuppressive M2 macrophage polarization ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=a%20strong%20link%20between%20hypoxia,using%20the%20antagonist%20SB290157%20prolonged)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11466187/#:~:text=Complement%20component%203%20,brain%20barrier))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.75, + "supporting_genes": [ + "C3", + "CFI", + "MASP1", + "LTF", + "CHI3L2" + ], + "supporting_gene_count": 5, + "required_components_present": false + }, + { + "program_name": "Ion Homeostasis", + "description": "Glioma cells modify ion channel and transporter expression to alter membrane potential and ionic balance. Calcium-activated K+ channel (KCNN3), Na+ channel SCN7A, Na/K ATPase (ATP1A2), and various solute carriers (SLC14A1, SLC24A4, SLC44A3) suggest dysregulated ion gradients and membrane excitability. These changes can affect cell volume, excitability, and cell cycle.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0006811", + "name": "ion transport", + "citation": [ + { + "reference": "Elias et al., Ion Channels in Gliomas, Int J Mol Sci 2023", + "id": "10.3390/ijms24032530", + "type": "DOI", + "notes": "Review of ion channel expression in gliomas; ion transporters are differentially expressed and influence glioma pathophysiology ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9916861/#:~:text=Ion%20channels%20provide%20the%20basis,retain%20the%20ability%20to%20divide))" + } + ], + "Genes": [ + "KCNN3", + "SCN7A", + "ATP1A2", + "SLC24A4", + "SLC14A1", + "SLC44A3", + "TTYH1", + "ATP13A4" + ], + "ontology_label": "monoatomic ion transport" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005886", + "name": "plasma membrane", + "citation": [ + { + "reference": "Elias et al., Int J Mol Sci 2023", + "id": "10.3390/ijms24032530", + "type": "DOI", + "notes": "Ion channels and transporters are localized to the cell membrane, where they affect glioma cell ionic balance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9916861/#:~:text=Ion%20channels%20provide%20the%20basis,retain%20the%20ability%20to%20divide))" + } + ], + "Genes": [ + "KCNN3", + "SCN7A", + "ATP1A2", + "SLC24A4", + "SLC14A1", + "SLC44A3", + "TTYH1", + "ATP13A4" + ], + "ontology_label": "plasma membrane" + } + ], + "predicted_cellular_impact": [ + "Altered membrane potential regulation", + "Modified Ca2+ signaling and cell cycle control", + "Adapted cell volume regulation aiding invasion" + ], + "evidence_summary": "Glioma cells show dysregulated ion channel expression; for example, KCNN3 (SK3) channels are implicated in GBM cell migration and proliferation. Broadly, ion transport genes are enriched and affect proliferation and invasion in glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9916861/#:~:text=Ion%20channels%20provide%20the%20basis,retain%20the%20ability%20to%20divide)).", + "citations": [ + { + "reference": "Elias et al., Int J Mol Sci 2023", + "id": "10.3390/ijms24032530", + "type": "DOI", + "notes": "Comprehensive review linking ion channel dysregulation to glioma growth, invasion, and therapy resistance" + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "KCNN3", + "SCN7A", + "ATP1A2", + "SLC24A4", + "SLC14A1", + "SLC44A3", + "TTYH1", + "ATP13A4" + ], + "supporting_gene_count": 8, + "required_components_present": false + } + ], + "version": "2025-10-07" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_ac_gliosis_like_2 b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_ac_gliosis_like_2 new file mode 100644 index 0000000..16a13a8 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_ac_gliosis_like_2 @@ -0,0 +1,505 @@ +{ + "context": { + "cell_type": "astrocyte-derived tumor cell", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "POSTN", + "KIAA1211L", + "CPNE4", + "HMGA2", + "TRPM8", + "CYTOR", + "RGS6", + "RPH3A", + "CCN4", + "ADAMTS9-AS1", + "SPRY1", + "LEF1", + "VAT1L", + "COL22A1", + "MIR4435-2HG", + "AC000065.1", + "CPED1", + "ARHGAP6", + "TRPM3", + "ANGPT1", + "ALK", + "CA2", + "SERPINE1", + "CHRM3-AS2", + "ITGA3", + "KIRREL3", + "RUBCNL", + "SLA", + "CCDC175", + "SHISA6", + "AC064875.1", + "SNED1", + "SPRY4", + "RBPMS", + "EMP1", + "LINC02832", + "LINC02742", + "HOPX", + "IQGAP2", + "GDF15", + "IRAK2", + "ST8SIA5", + "HIVEP3", + "TMEM154", + "COL19A1" + ], + "programs": [ + { + "program_name": "ECM Remodeling and Invasion", + "description": "Upregulation of ECM components and modifiers promotes glioblastoma cell migration and tumor microenvironment remodeling", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_id": "GO:0030198", + "citation": [ + { + "reference": "Zhou et al., Nat Cell Biol (2015)", + "id": "PMID:25580734", + "type": "PMID", + "notes": "POSTN secreted by glioma stem cells recruits immune cells to tumor stroma, implicating ECM interactions ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4312504/#:~:text=TAMs%20in%20GBMs%20are%20not,mediated%20TAM%20recruitment))" + }, + { + "reference": "Seker et al., Cancers (Basel) (2019)", + "id": "PMID:31731490", + "type": "PMID", + "notes": "SERPINE1 modulates cell adhesion and matrix, regulating GBM dispersal ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=derived%20orthotopic%20GBM%20model,invasive%20therapy%20design))" + } + ], + "Genes": [ + "POSTN", + "CCN4", + "SERPINE1" + ], + "ontology_label": "extracellular matrix organization" + }, + { + "name": "cell migration", + "ontology_id": "GO:0016477", + "citation": [ + { + "reference": "Seker et al., Cancers (Basel) (2019)", + "id": "PMID:31731490", + "type": "PMID", + "notes": "SERPINE1 drives glioblastoma cell dispersal (migration) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=derived%20orthotopic%20GBM%20model,invasive%20therapy%20design))" + } + ], + "Genes": [ + "POSTN", + "SERPINE1" + ], + "ontology_label": "cell migration" + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_id": "GO:0031012", + "citation": [ + { + "reference": "Zhou et al., Nat Cell Biol (2015)", + "id": "PMID:25580734", + "type": "PMID", + "notes": "POSTN is secreted and localized to ECM regions in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4312504/#:~:text=TAMs%20in%20GBMs%20are%20not,mediated%20TAM%20recruitment))" + }, + { + "reference": "Seker et al., Cancers (Basel) (2019)", + "id": "PMID:31731490", + "type": "PMID", + "notes": "SERPINE1 affects cell-surface interactions with matrix during invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=derived%20orthotopic%20GBM%20model,invasive%20therapy%20design))" + } + ], + "Genes": [ + "POSTN", + "CCN4", + "SERPINE1" + ], + "ontology_label": "extracellular matrix" + } + ], + "predicted_cellular_impact": [ + "enhanced extracellular matrix deposition", + "increased glioblastoma cell motility and invasion" + ], + "evidence_summary": "Glioblastoma cells often overexpress ECM and adhesion factors. POSTN is secreted by glioma stem-like cells to recruit TAMs and enhance invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4312504/#:~:text=TAMs%20in%20GBMs%20are%20not,mediated%20TAM%20recruitment)). Similarly, SERPINE1 (PAI-1) is highly upregulated in dispersive GBM cells, and its inhibition reduces invasion and adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=derived%20orthotopic%20GBM%20model,invasive%20therapy%20design)). CCN4 (WISP1) is another matricellular protein, likely reinforcing this program. Together, these genes point to a robust ECM remodeling/invasion program in GBM.", + "citations": [ + { + "reference": "Zhou et al., Nat Cell Biol (2015)", + "id": "PMID:25580734", + "type": "PMID", + "notes": "POSTN secreted by glioma stem cells recruits TAMs, linking ECM to tumor-supportive microenvironment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4312504/#:~:text=TAMs%20in%20GBMs%20are%20not,mediated%20TAM%20recruitment))" + }, + { + "reference": "Seker et al., Cancers (Basel) (2019)", + "id": "PMID:31731490", + "type": "PMID", + "notes": "SERPINE1 identified as a key regulator of GBM cell dispersal/invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=derived%20orthotopic%20GBM%20model,invasive%20therapy%20design))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.85, + "supporting_genes": [ + "POSTN", + "CCN4", + "SERPINE1" + ], + "supporting_gene_count": 3, + "required_components_present": false + }, + { + "program_name": "Ion Channel\u2013Mediated Calcium Signaling", + "description": "Upregulated TRPM channels drive Ca^{2+} influx, promoting GBM cell migration and survival under stress", + "atomic_biological_processes": [ + { + "name": "calcium ion transmembrane transport", + "ontology_id": "GO:0070588", + "citation": [ + { + "reference": "Klumpp et al., Oncotarget (2017)", + "id": "PMID:29221175", + "type": "PMID", + "notes": "TRPM8 upregulation in GBM increases Ca^{2+} entry, affecting cell migration and survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=moving%20the%20glioblastoma%20cell%20along,demonstrated%20to%20be%20required%20for))" + } + ], + "Genes": [ + "TRPM8", + "TRPM3" + ], + "ontology_label": "calcium ion transmembrane transport" + }, + { + "name": "cell migration", + "ontology_id": "GO:0016477", + "citation": [ + { + "reference": "Klumpp et al., Oncotarget (2017)", + "id": "PMID:29221175", + "type": "PMID", + "notes": "TRPM8 channel activation accelerates glioblastoma cell migration and chemotaxis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=moving%20the%20glioblastoma%20cell%20along,demonstrated%20to%20be%20required%20for))" + } + ], + "Genes": [ + "TRPM8" + ], + "ontology_label": "cell migration" + } + ], + "atomic_cellular_components": [ + { + "name": "ion channel complex", + "ontology_id": "GO:0034702", + "citation": [ + { + "reference": "Klumpp et al., Oncotarget (2017)", + "id": "PMID:29221175", + "type": "PMID", + "notes": "TRPM8 is a plasma membrane Ca^{2+}-permeable TRP channel overexpressed in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore))" + } + ], + "Genes": [ + "TRPM8", + "TRPM3" + ], + "ontology_label": "monoatomic ion channel complex" + } + ], + "predicted_cellular_impact": [ + "enhanced intracellular Ca^{2+} signaling", + "increased cell motility and chemotaxis", + "heightened radioresistance" + ], + "evidence_summary": "Glioblastoma cells often overexpress TRP channels. TRPM8 is upregulated in GBM and mediates Ca^{2+} influx that promotes BK channel activity, migration, and survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=moving%20the%20glioblastoma%20cell%20along,demonstrated%20to%20be%20required%20for)). Inhibition or knockdown of TRPM8 reduces migration, impairs Ca^{2+}-dependent signaling, and radiosensitizes GBM cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=moving%20the%20glioblastoma%20cell%20along,demonstrated%20to%20be%20required%20for)). Conversely, loss of TRPM3 (via promoter methylation) correlates with increased stemness and migration, suggesting TRPM3 normally restrains malignancy ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8076903/#:~:text=Moreover%2C%20the%20loss%20of%20TRPM3%2C,TRPM3%20and%20the%20indirect%20regulatory)). Together, an imbalance of TRPM channels modulates GBM invasiveness and therapy resistance.", + "citations": [ + { + "reference": "Klumpp et al., Oncotarget (2017)", + "id": "PMID:29221175", + "type": "PMID", + "notes": "TRPM8 mediates Ca^{2+}-entry, promoting glioblastoma cell migration and radioresistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=moving%20the%20glioblastoma%20cell%20along,demonstrated%20to%20be%20required%20for))" + }, + { + "reference": "Klumpp et al., Oncotarget (2017)", + "id": "PMID:29221175", + "type": "PMID", + "notes": "Pharmacologic or genetic TRPM8 inhibition slows chemotaxis and sensitizes GBM cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=healing%20assay%2C%20colony%20formation%20assay%2C,of%20human%20glioblastoma%20and%2C%20therefore)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5707069/#:~:text=moving%20the%20glioblastoma%20cell%20along,demonstrated%20to%20be%20required%20for))" + }, + { + "reference": "Gkika et al., Cancers (2020)", + "id": "PMID:32676833", + "type": "PMID", + "notes": "Loss of TRPM3 (and host miR-204) in high-grade gliomas is associated with enhanced stemness and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8076903/#:~:text=Moreover%2C%20the%20loss%20of%20TRPM3%2C,TRPM3%20and%20the%20indirect%20regulatory))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": [ + "TRPM8", + "TRPM3" + ], + "supporting_gene_count": 2, + "required_components_present": false + }, + { + "program_name": "Receptor Tyrosine Kinase/\u03b2-Catenin Signaling", + "description": "Dysregulated RTK signaling and Wnt pathway effectors promote proliferation, stemness, and EMT in GBM", + "atomic_biological_processes": [ + { + "name": "receptor tyrosine kinase signaling pathway", + "ontology_id": "GO:0007169", + "citation": [ + { + "reference": "Meyer et al., Clin Cancer Res (2023)", + "id": "PMID:36780194", + "type": "PMID", + "notes": "ALK fusions in GBMs activate ERK and STAT3 pro-growth pathways ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10363218/#:~:text=ALK%20fusions%20were%20present%20as,brain%20development%20was%20seen%20in))" + }, + { + "reference": "Park et al., IBRO Neurosc Rep (2022)", + "id": "PMID:35910677", + "type": "PMID", + "notes": "SPRY1 modulates RTK signaling in glioma stem cells, affecting stemness and growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9334334/#:~:text=glioma%20cells%2C%20and%20differentiated%20glioma,stemness%20and%20aggressiveness%20of%20GBM))" + } + ], + "Genes": [ + "ALK", + "SPRY1", + "SPRY4" + ], + "ontology_label": "cell surface receptor protein tyrosine kinase signaling pathway" + }, + { + "name": "MAPK cascade", + "ontology_id": "GO:0000165", + "citation": [ + { + "reference": "Sun et al., PubMed (2020)", + "id": "PMID:32618153", + "type": "PMID", + "notes": "SPRY4 suppresses GBM invasion by blocking FGFR/Ras-ERK signaling and MMP9 expression ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/32618153/#:~:text=Results%3A%20SPRY4%20mRNAs%20in%20GBMs,induced%20MMP9%20expression))" + }, + { + "reference": "Meyer et al., Clin Cancer Res (2023)", + "id": "PMID:36780194", + "type": "PMID", + "notes": "Novel ALK fusions in infant and adult GBM promote ERK1/2 activation and tumor transformation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10363218/#:~:text=ALK%20fusions%20were%20present%20as,brain%20development%20was%20seen%20in))" + } + ], + "Genes": [ + "ALK", + "SPRY1", + "SPRY4" + ], + "ontology_label": "MAPK cascade" + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_id": "GO:0005886", + "citation": [ + { + "reference": "Meyer et al., Clin Cancer Res (2023)", + "id": "PMID:36780194", + "type": "PMID", + "notes": "ALK encodes a receptor tyrosine kinase acting at the cell membrane in brain tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10363218/#:~:text=ALK%20fusions%20were%20present%20as,brain%20development%20was%20seen%20in))" + } + ], + "Genes": [ + "ALK" + ], + "ontology_label": "plasma membrane" + } + ], + "predicted_cellular_impact": [ + "elevated MAPK/ERK and STAT signaling", + "increased cancer stem cell-like properties", + "suppressed apoptosis", + "enhanced invasion" + ], + "evidence_summary": "Genes in this cluster mediate RTK and Wnt signaling. ALK oncogenic fusions activate downstream ERK1/2 and STAT3 pathways in gliomas ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10363218/#:~:text=ALK%20fusions%20were%20present%20as,brain%20development%20was%20seen%20in)). Sprouty proteins are endogenous modulators of RTK signaling; SPRY4 acts as a suppressor of FGFR/Ras-ERK and MMP9 (reducing invasion) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/32618153/#:~:text=Results%3A%20SPRY4%20mRNAs%20in%20GBMs,induced%20MMP9%20expression)), whereas SPRY1 is implicated in sustaining glioma stem cell growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9334334/#:~:text=glioma%20cells%2C%20and%20differentiated%20glioma,stemness%20and%20aggressiveness%20of%20GBM)). LEF1 (below) is a TCF family TF in Wnt/\u03b2-catenin. Overall, this program suggests hyperactive RTK-MAPK and Wnt pathways driving proliferation and stemness in GBM.", + "citations": [ + { + "reference": "Meyer et al., Clin Cancer Res (2023)", + "id": "PMID:36780194", + "type": "PMID", + "notes": "ALK gene rearrangements activate MAPK/ERK and STAT3 pathways in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10363218/#:~:text=ALK%20fusions%20were%20present%20as,brain%20development%20was%20seen%20in))" + }, + { + "reference": "Sun et al., Exp Ther Med (2020)", + "id": "PMID:32618153", + "type": "PMID", + "notes": "SPRY4 inhibits ERK phosphorylation and MMP9 to suppress GBM invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/32618153/#:~:text=Results%3A%20SPRY4%20mRNAs%20in%20GBMs,induced%20MMP9%20expression))" + }, + { + "reference": "Park et al., IBRO Neurosci Reports (2022)", + "id": "PMID:35910677", + "type": "PMID", + "notes": "SPRY1 is highly expressed in glioma stem cells and promotes their proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9334334/#:~:text=glioma%20cells%2C%20and%20differentiated%20glioma,stemness%20and%20aggressiveness%20of%20GBM))" + } + ], + "confidence_score": 0.75, + "significance_score": 0.7, + "supporting_genes": [ + "ALK", + "SPRY1", + "SPRY4" + ], + "supporting_gene_count": 3, + "required_components_present": false + }, + { + "program_name": "Proliferation and Survival Signaling", + "description": "Activation of PI3K/Akt pathways fosters GBM growth and survival", + "atomic_biological_processes": [ + { + "name": "positive regulation of cell proliferation", + "ontology_id": "GO:0008284", + "citation": [ + { + "reference": "Zhang et al., Cell Physiol Biochem (2019)", + "id": "PMID:31233190", + "type": "PMID", + "notes": "EMP1 knockdown reduces GBM cell proliferation in vitro ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/31233190/#:~:text=Rembrandt%20and%20CGGA%20databases%20for,for%20the%20treatment%20of%20GBM))" + } + ], + "Genes": [ + "EMP1" + ], + "ontology_label": "positive regulation of cell population proliferation" + }, + { + "name": "PI3K signaling", + "ontology_id": "GO:0043491", + "citation": [ + { + "reference": "Zhang et al., Cell Physiol Biochem (2019)", + "id": "PMID:31233190", + "type": "PMID", + "notes": "EMP1 drives GBM progression via the PI3K/Akt/mTOR pathway ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/31233190/#:~:text=Rembrandt%20and%20CGGA%20databases%20for,for%20the%20treatment%20of%20GBM))" + } + ], + "Genes": [ + "EMP1" + ], + "ontology_label": "phosphatidylinositol 3-kinase/protein kinase B signal transduction" + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "increased PI3K/AKT pathway activation", + "enhanced proliferation and invasive potential", + "resistance to apoptosis" + ], + "evidence_summary": "EMP1 (epithelial membrane protein 1) is overexpressed in higher-grade gliomas and promotes proliferation and invasion via activation of the PI3K/AKT/mTOR axis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/31233190/#:~:text=Rembrandt%20and%20CGGA%20databases%20for,for%20the%20treatment%20of%20GBM)). Knockdown of EMP1 impairs GBM cell growth and reduces invasion, indicating its role in sustaining tumor survival and dissemination ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/31233190/#:~:text=Rembrandt%20and%20CGGA%20databases%20for,for%20the%20treatment%20of%20GBM)).", + "citations": [ + { + "reference": "Zhang et al., Cell Physiol Biochem (2019)", + "id": "PMID:31233190", + "type": "PMID", + "notes": "EMP1 is upregulated in GBM, and its silencing inhibits proliferation and invasion via PI3K/AKT pathway ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/31233190/#:~:text=Rembrandt%20and%20CGGA%20databases%20for,for%20the%20treatment%20of%20GBM))" + } + ], + "confidence_score": 0.5, + "significance_score": 0.6, + "supporting_genes": [ + "EMP1" + ], + "supporting_gene_count": 1, + "required_components_present": false + }, + { + "program_name": "Wnt/\u03b2-Catenin Pathway", + "description": "Constitutive Wnt signaling through LEF1 drives transcription of growth and EMT genes", + "atomic_biological_processes": [ + { + "name": "canonical Wnt signaling pathway", + "ontology_id": "GO:0060070", + "citation": [ + { + "reference": "Pe\u0107ina-\u0160laus and Kafka, CNS Oncol (2015)", + "id": "PMID:26497968", + "type": "PMID", + "notes": "LEF1 is highly expressed in GBM and marks active canonical Wnt/\u03b2-catenin signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6083946/#:~:text=factors,045%29%2C%20LEF1))" + } + ], + "Genes": [ + "LEF1" + ], + "ontology_label": "canonical Wnt signaling pathway" + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "enhanced transcription of Wnt target genes (e.g., Cyclin D1, c-Myc)", + "maintenance of stem-like and proliferative state" + ], + "evidence_summary": "LEF1 is a TCF/LEF family transcription factor that mediates Wnt/\u03b2-catenin signaling. Studies show LEF1 is upregulated in GBM cells, with strong nuclear LEF1 expression distinguishing high-grade gliomas ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6083946/#:~:text=factors,045%29%2C%20LEF1)). Active Wnt/LEF1 signaling induces proliferative and EMT-related genes, contributing to GBM aggressiveness. ", + "citations": [ + { + "reference": "Pe\u0107ina-\u0160laus and Kafka, CNS Oncol (2015)", + "id": "PMID:26497968", + "type": "PMID", + "notes": "LEF1 expression is significantly higher in GBM than in lower-grade astrocytomas, indicating activated Wnt signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6083946/#:~:text=factors,045%29%2C%20LEF1))" + } + ], + "confidence_score": 0.5, + "significance_score": 0.6, + "supporting_genes": [ + "LEF1" + ], + "supporting_gene_count": 1, + "required_components_present": false + }, + { + "program_name": "Angiogenesis", + "description": "Upregulated angiopoietin and extracellular cues promote tumor vascularization", + "atomic_biological_processes": [ + { + "name": "angiogenesis", + "ontology_id": "GO:0001525", + "citation": [ + { + "reference": "Rong et al., Cancer Res (2000)", + "id": "PMID:11304469", + "type": "PMID", + "notes": "Angiopoietin-1 (ANGPT1) secreted by glioma cells induces endothelial cell reorganization and cord formation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/11304469/#:~:text=glioblastoma%20cell%20lines%20producing%20Ang1,the%20differentiation%20phase%20of%20angiogenesis))" + } + ], + "Genes": [ + "ANGPT1" + ], + "ontology_label": "angiogenesis" + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "enhanced blood vessel formation", + "improved nutrient supply to tumor", + "cooperative signaling with VEGF" + ], + "evidence_summary": "ANGPT1 is a secreted ligand for the Tie2 receptor on endothelial cells. It is expressed in GBM and promotes the maturation and organization of new blood vessels ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/11304469/#:~:text=glioblastoma%20cell%20lines%20producing%20Ang1,the%20differentiation%20phase%20of%20angiogenesis)). In vitro, exposure of endothelial cells to ANGPT1 induces spreading and formation of capillary-like structures ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/11304469/#:~:text=glioblastoma%20cell%20lines%20producing%20Ang1,the%20differentiation%20phase%20of%20angiogenesis)). Thus, increased ANGPT1 suggests a pro-angiogenic program in malignant gliomas.", + "citations": [ + { + "reference": "Rong et al., Cancer Res (2000)", + "id": "PMID:11304469", + "type": "PMID", + "notes": "ANGPT1 produced by GBM cells drives differentiation of ECs into cordlike structures, indicating a pro-angiogenic role ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/11304469/#:~:text=glioblastoma%20cell%20lines%20producing%20Ang1,the%20differentiation%20phase%20of%20angiogenesis))" + } + ], + "confidence_score": 0.4, + "significance_score": 0.5, + "supporting_genes": [ + "ANGPT1" + ], + "supporting_gene_count": 1, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_ac_neuronal_like b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_ac_neuronal_like new file mode 100644 index 0000000..d272822 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_ac_neuronal_like @@ -0,0 +1,411 @@ +{ + "context": { + "cell_type": "astrocytes", + "disease": "Glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "LINC02235", + "AC037486.1", + "PCDH11X", + "LINC01829", + "AL591043.2", + "ZNF423", + "ADAMTS18", + "AL133538.1", + "DOCK2", + "SCN1A-AS1", + "AL022068.1", + "SEPTIN14", + "SGCZ", + "ADAM28", + "RYR2", + "DOCK8", + "ACER2", + "AC128687.3", + "AC120193.1", + "OLR1", + "AC110296.1", + "AC109466.1", + "SPOCK3", + "ST6GALNAC5", + "AL136441.1", + "MLIP", + "AL158077.2", + "AP001021.3", + "CCDC85A", + "CD96", + "NRK", + "C8orf37-AS1", + "PCDH7", + "PLD1", + "CHRNA7", + "CLRN1", + "MYO1D", + "RMST", + "CNTNAP2", + "PURPL", + "RALYL", + "AL445426.1", + "RCAN2", + "AL392023.2", + "RELN", + "AL360091.3", + "AC091946.1", + "LRRIQ1", + "CD163", + "SYN3", + "IL1RAPL1" + ], + "programs": [ + { + "program_name": "Myeloid Infiltration", + "description": "Genes such as DOCK2, DOCK8, CD96, and CD163 indicate activation and recruitment of immune myeloid cells (e.g., microglia/macrophages) into glioblastoma. This includes signaling for immune cell migration and suppressive macrophage function.", + "atomic_biological_processes": [ + { + "name": "immune response", + "ontology_id": "GO:0006955", + "citation": [ + { + "reference": "Wang et al., Front Mol Biosci 2022 (Insights from DOCK2 in cell function and pathophysiology)", + "id": "DOI:10.3389/fmolb.2022.997659", + "type": "DOI", + "notes": "DOCK2 regulates immune cell migration and activation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9559381/#:~:text=Dedicator%20of%20cytokinesis%202%20,involved%20in%20the%20development%20and))" + }, + { + "reference": "Namekata et al., J Biol Chem 2019", + "id": "DOI:10.1074/jbc.RA119.007645", + "type": "DOI", + "notes": "DOCK8 is expressed in microglia and mediates immune cell migration and phagocytosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6737224/#:~:text=In%20this%20study%2C%20we%20report,3D%20images%20of%20retinal%20microglia))" + } + ], + "Genes": [ + "DOCK2", + "DOCK8", + "CD96", + "CD163" + ], + "ontology_label": "immune response" + } + ], + "atomic_cellular_components": [ + { + "name": "immune synapse", + "ontology_id": "GO:0001772", + "citation": [ + { + "reference": "Wang et al., Front Mol Biosci 2022 (Insights from DOCK2 in cell function and pathophysiology)", + "id": "DOI:10.3389/fmolb.2022.997659", + "type": "DOI", + "notes": "DOCK2 is involved in cytoskeletal reorganization at immune synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9559381/#:~:text=Dedicator%20of%20cytokinesis%202%20,involved%20in%20the%20development%20and))" + }, + { + "reference": "Namekata et al., J Biol Chem 2019", + "id": "DOI:10.1074/jbc.RA119.007645", + "type": "DOI", + "notes": "DOCK8 and CD96 are expressed on microglia/NK cells at immune synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6737224/#:~:text=In%20this%20study%2C%20we%20report,3D%20images%20of%20retinal%20microglia)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7338376/#:~:text=Increasingly%2C%20CD96%20is%20emerging%20as,and%20activation%20of%20participating%20cells))" + } + ], + "Genes": [ + "DOCK2", + "DOCK8", + "CD96", + "CD163" + ], + "ontology_label": "immunological synapse" + } + ], + "predicted_cellular_impact": [ + "Enhanced myeloid/microglial infiltration into tumor", + "Immune checkpoint activation (e.g., CD96 signaling) suppressing anti-tumor immunity", + "Increased expression of macrophage scavenger receptors" + ], + "evidence_summary": "DOCK2 and DOCK8 mediate migration and activation of immune cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9559381/#:~:text=Dedicator%20of%20cytokinesis%202%20,involved%20in%20the%20development%20and)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6737224/#:~:text=In%20this%20study%2C%20we%20report,3D%20images%20of%20retinal%20microglia)). CD163 is a scavenger receptor marking immunosuppressive M2-like macrophages in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12070867/#:~:text=CD163%2B%20macrophages%20from%20expressing%20proinflammatory,cytokines)). CD96 is an NK/T cell checkpoint upregulated in glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7338376/#:~:text=Increasingly%2C%20CD96%20is%20emerging%20as,and%20activation%20of%20participating%20cells)). Together, these genes suggest glioblastoma is associated with macrophage/microglial infiltration and immune suppression.", + "citations": [ + { + "reference": "Wang et al., Front Mol Biosci 2022", + "id": "DOI:10.3389/fmolb.2022.997659", + "type": "DOI", + "notes": "DOCK2 regulates immune cell migration and activation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9559381/#:~:text=Dedicator%20of%20cytokinesis%202%20,involved%20in%20the%20development%20and))" + }, + { + "reference": "Namekata et al., J Biol Chem 2019", + "id": "DOI:10.1074/jbc.RA119.007645", + "type": "DOI", + "notes": "DOCK8 expressed in microglia regulates migration and phagocytosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6737224/#:~:text=In%20this%20study%2C%20we%20report,3D%20images%20of%20retinal%20microglia))" + }, + { + "reference": "Fuse et al., Cancers (Basel) 2025", + "id": "DOI:10.3390/cancers17091457", + "type": "DOI", + "notes": "CD163+ macrophages have an immunosuppressive, tumor-promoting role in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12070867/#:~:text=CD163%2B%20macrophages%20from%20expressing%20proinflammatory,cytokines))" + }, + { + "reference": "Gibney et al., Front Bioeng Biotechnol 2020", + "id": "DOI:10.3389/fbioe.2020.00592", + "type": "DOI", + "notes": "CD96 is an immune checkpoint that negatively regulates NK/T cell anti-tumor function ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7338376/#:~:text=Increasingly%2C%20CD96%20is%20emerging%20as,and%20activation%20of%20participating%20cells))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.8, + "supporting_genes": [ + "DOCK2", + "DOCK8", + "CD96", + "CD163" + ], + "supporting_gene_count": 4, + "required_components_present": false + }, + { + "program_name": "Neuronal Synapses", + "description": "Genes in this program encode proteins for neuronal connectivity and synaptic function. RELN is an ECM protein controlling neuronal migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8028296/#:~:text=aggressiveness,are%20silenced%20in%20glioblastoma%20as)). IL1RAPL1, CNTNAP2, and PCDH7/11X mediate synapse formation/adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623287/#:~:text=Autism%20Mediates%20Synapse%20Formation%20by,with%20Protein%20Tyrosine%20Phosphatase%20%CE%B4)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4423902/#:~:text=CNTNAP2%20belongs%20to%20the%20NEUREXIN,it%20is%20unknown%20if%20CNTNAP2)). SYN3 is a synaptic vesicle protein for neurotransmitter release ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12040043/#:~:text=Synapsin%20III%20is%20the%20most,demonstrate%20that%20synapsin%20III%20regulates)). Together they implicate altered synaptic signaling.", + "atomic_biological_processes": [ + { + "name": "synapse assembly", + "ontology_id": "GO:0007416", + "citation": [ + { + "reference": "Yoshida et al., J Neurosci 2011", + "id": "DOI:10.1523/JNEUROSCI.2136-11.2011", + "type": "DOI", + "notes": "IL1RAPL1 mediates excitatory synapse formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623287/#:~:text=IL1RAPL1%20mediates%20synapse%20formation%20through,shared%20by%20these%20mental%20disorders))" + }, + { + "reference": "Gdalyahu et al., PLoS One 2015", + "id": "DOI:10.1371/journal.pone.0125633", + "type": "DOI", + "notes": "CNTNAP2 (Caspr2) is a neurexin-family adhesion protein stabilizing synaptic contacts ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4423902/#:~:text=CNTNAP2%20belongs%20to%20the%20NEUREXIN,it%20is%20unknown%20if%20CNTNAP2))" + } + ], + "Genes": [ + "RELN", + "IL1RAPL1", + "CNTNAP2", + "SYN3", + "PCDH7", + "PCDH11X", + "CHRNA7" + ], + "ontology_label": "synapse assembly" + } + ], + "atomic_cellular_components": [ + { + "name": "synapse", + "ontology_id": "GO:0045202", + "citation": [ + { + "reference": "Yoshida et al., J Neurosci 2011", + "id": "DOI:10.1523/JNEUROSCI.2136-11.2011", + "type": "DOI", + "notes": "IL1RAPL1 localizes to the dendritic synapse and mediates trans-synaptic adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623287/#:~:text=IL1RAPL1%20mediates%20synapse%20formation%20through,shared%20by%20these%20mental%20disorders))" + }, + { + "reference": "Gdalyahu et al., PLoS One 2015", + "id": "DOI:10.1371/journal.pone.0125633", + "type": "DOI", + "notes": "CNTNAP2 is present in the synapse and required for spine stability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4423902/#:~:text=CNTNAP2%20belongs%20to%20the%20NEUREXIN,it%20is%20unknown%20if%20CNTNAP2))" + } + ], + "Genes": [ + "RELN", + "IL1RAPL1", + "CNTNAP2", + "SYN3", + "PCDH7", + "PCDH11X", + "CHRNA7" + ], + "ontology_label": "synapse" + } + ], + "predicted_cellular_impact": [ + "Altered synapse formation and stability", + "Changes in excitatory neurotransmission", + "Modified neuronal adhesion and network connectivity" + ], + "evidence_summary": "RELN controls neuronal migration and is silenced in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8028296/#:~:text=aggressiveness,are%20silenced%20in%20glioblastoma%20as)). IL1RAPL1 mediates excitatory synapse formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623287/#:~:text=IL1RAPL1%20mediates%20synapse%20formation%20through,shared%20by%20these%20mental%20disorders)). CNTNAP2 is a membrane protein stabilizing dendritic spines ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4423902/#:~:text=CNTNAP2%20belongs%20to%20the%20NEUREXIN,it%20is%20unknown%20if%20CNTNAP2)). SYN3 is a synaptic vesicle protein for neurotransmitter release ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12040043/#:~:text=Synapsin%20III%20is%20the%20most,demonstrate%20that%20synapsin%20III%20regulates)). These suggest a neuronal synaptic program impacting glioblastoma cell behavior.", + "citations": [ + { + "reference": "Schulze et al., Brain Pathol 2018", + "id": "DOI:10.1111/bpa.12584", + "type": "DOI", + "notes": "RELN is an extracellular protein that regulates neuronal migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8028296/#:~:text=aggressiveness,are%20silenced%20in%20glioblastoma%20as))" + }, + { + "reference": "Yoshida et al., J Neurosci 2011", + "id": "DOI:10.1523/JNEUROSCI.2136-11.2011", + "type": "DOI", + "notes": "IL1RAPL1 mediates synapse formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623287/#:~:text=IL1RAPL1%20mediates%20synapse%20formation%20through,shared%20by%20these%20mental%20disorders))" + }, + { + "reference": "Gdalyahu et al., PLoS One 2015", + "id": "DOI:10.1371/journal.pone.0125633", + "type": "DOI", + "notes": "CNTNAP2 is a synaptic adhesion protein for dendritic spines ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4423902/#:~:text=CNTNAP2%20belongs%20to%20the%20NEUREXIN,it%20is%20unknown%20if%20CNTNAP2))" + }, + { + "reference": "Ferreira et al., J Neurosci 2004", + "id": "PMID:12040043", + "type": "PMID", + "notes": "Synapsin III is part of synaptic vesicles, essential for neurotransmitter release ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12040043/#:~:text=Synapsin%20III%20is%20the%20most,demonstrate%20that%20synapsin%20III%20regulates))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "RELN", + "IL1RAPL1", + "CNTNAP2", + "SYN3", + "PCDH7", + "PCDH11X", + "CHRNA7" + ], + "supporting_gene_count": 7, + "required_components_present": false + }, + { + "program_name": "ECM Remodeling", + "description": "This program includes extracellular matrix modifiers and adhesion proteins. ADAMTS18 and ADAM28 are metalloproteinases that remodel the ECM and can promote invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=by%20gene%20expression%2C%20intracytoplasmic%20and,and%20invasion%2C%20although%20the%20precise)). SPOCK3 and SGCZ are ECM-associated proteins. PCDH7 and PCDH11X are calcium-dependent adhesion molecules. Together these genes suggest enhanced ECM breakdown and altered adhesion in GBM.", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_id": "GO:0030198", + "citation": [ + { + "reference": "Xie et al., Mol Biol Rep 2015", + "id": "PMID:25987468", + "type": "PMID", + "notes": "ADAM family proteases are often overexpressed in tumors, promoting matrix remodeling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=by%20gene%20expression%2C%20intracytoplasmic%20and,and%20invasion%2C%20although%20the%20precise))" + } + ], + "Genes": [ + "ADAMTS18", + "ADAM28", + "SPOCK3", + "SGCZ", + "PCDH7", + "PCDH11X" + ], + "ontology_label": "extracellular matrix organization" + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_id": "GO:0031012", + "citation": [ + { + "reference": "Xie et al., Mol Biol Rep 2015", + "id": "PMID:25987468", + "type": "PMID", + "notes": "ADAM proteases act in the extracellular matrix to regulate cell invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=by%20gene%20expression%2C%20intracytoplasmic%20and,and%20invasion%2C%20although%20the%20precise))" + } + ], + "Genes": [ + "ADAMTS18", + "ADAM28", + "SPOCK3", + "SGCZ", + "PCDH7", + "PCDH11X" + ], + "ontology_label": "extracellular matrix" + } + ], + "predicted_cellular_impact": [ + "Increased tumor cell invasion and migration", + "Enhanced integrin/ECM signaling", + "Altered cell adhesion properties" + ], + "evidence_summary": "ADAM family metalloproteinases (ADAMTS18, ADAM28) modify the ECM and are linked to tumor invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=by%20gene%20expression%2C%20intracytoplasmic%20and,and%20invasion%2C%20although%20the%20precise)). Protocadherins and glycoproteins like SPOCK3 and SGCZ contribute to cell-matrix adhesion. Dysregulation of these components likely facilitates extracellular matrix remodeling and increased GBM cell motility.", + "citations": [ + { + "reference": "Xie et al., Mol Biol Rep 2015", + "id": "PMID:25987468", + "type": "PMID", + "notes": "Review discussing ADAM proteases in cancer progression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=by%20gene%20expression%2C%20intracytoplasmic%20and,and%20invasion%2C%20although%20the%20precise))" + } + ], + "confidence_score": 0.6, + "significance_score": 0.8, + "supporting_genes": [ + "ADAMTS18", + "ADAM28", + "SPOCK3", + "SGCZ", + "PCDH7", + "PCDH11X" + ], + "supporting_gene_count": 6, + "required_components_present": false + }, + { + "program_name": "Differentiation Signaling", + "description": "This program includes developmental transcriptional regulators. ZNF423 (Zfp423) is a transcription factor required for neural precursor differentiation via BMP/SMAD signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4773478/#:~:text=The%20dissection%20of%20these%20networks,a%20novel%20synergic%20circuit%20through)). RCAN2 regulates calcineurin-NFAT signaling, impacting neuronal development. This suggests dysregulation of neural differentiation pathways in glioblastoma.", + "atomic_biological_processes": [ + { + "name": "neuron differentiation", + "ontology_id": "GO:0030182", + "citation": [ + { + "reference": "Signaroldi et al., Nat Commun 2016", + "id": "DOI:10.1038/ncomms10753", + "type": "DOI", + "notes": "Zfp423 (human ZNF423) is a master regulator of neural differentiation and its loss impairs gliomagenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4773478/#:~:text=The%20dissection%20of%20these%20networks,a%20novel%20synergic%20circuit%20through))" + } + ], + "Genes": [ + "ZNF423", + "RCAN2" + ], + "ontology_label": "neuron differentiation" + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "ontology_id": "GO:0005634", + "citation": [ + { + "reference": "Signaroldi et al., Nat Commun 2016", + "id": "DOI:10.1038/ncomms10753", + "type": "DOI", + "notes": "ZNF423 is a nuclear transcription factor controlling glioblastoma differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4773478/#:~:text=The%20dissection%20of%20these%20networks,a%20novel%20synergic%20circuit%20through))" + } + ], + "Genes": [ + "ZNF423", + "RCAN2" + ], + "ontology_label": "nucleus" + } + ], + "predicted_cellular_impact": [ + "Impaired differentiation of glial precursor cells", + "Altered BMP/SMAD signaling and neuronal developmental gene expression" + ], + "evidence_summary": "ZNF423 is silenced in glioma and is needed for proper neural differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4773478/#:~:text=The%20dissection%20of%20these%20networks,a%20novel%20synergic%20circuit%20through)). Loss of ZNF423 correlates with worse GBM prognosis. RCAN2 modulates calcineurin-NFAT pathways affecting neuronal development. Their dysregulation suggests failure of normal differentiation signaling in glioblastoma cells.", + "citations": [ + { + "reference": "Signaroldi et al., Nat Commun 2016", + "id": "DOI:10.1038/ncomms10753", + "type": "DOI", + "notes": "ZNF423 downregulation is implicated in glioma by blocking differentiation via BMP signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4773478/#:~:text=The%20dissection%20of%20these%20networks,a%20novel%20synergic%20circuit%20through))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.5, + "supporting_genes": [ + "ZNF423", + "RCAN2" + ], + "supporting_gene_count": 2, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_gliosis b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_gliosis new file mode 100644 index 0000000..710105c --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_gliosis @@ -0,0 +1,499 @@ +{ + "context": { + "cell_type": "astrocyte", + "disease": "Glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "SERPINE1", + "EMP1", + "SPOCD1", + "ARHGAP29", + "IL1R1", + "COL6A2", + "MYOF", + "F13A1", + "CXCL10", + "CHI3L1", + "MET", + "IL6", + "SAA2", + "BIRC3", + "MCTP2", + "ANGPTL4", + "ICAM1", + "CCN1", + "CAV1", + "APLN", + "FOSL1", + "SNTG2-AS1", + "TPD52L1", + "SAA4", + "KRT75", + "NFATC2", + "COL5A1", + "AC243829.2", + "CLCF1", + "ARSJ", + "PLA2G2A", + "HMGA2", + "PTX3", + "TLR2", + "LINC00698", + "ALPK2", + "TNFAIP3", + "TNFAIP2", + "NDRG1", + "SMOC2", + "ADGRL2", + "KANK4", + "GEM", + "FAS", + "CXCL8", + "CFH", + "ABCC3", + "CXCL14", + "ZFP36", + "RCAN2", + "GADD45A", + "COL1A2", + "LTF", + "DHRS3", + "IDO1", + "HAP1", + "AXL", + "ATP6V0D2", + "KLF5", + "ST6GALNAC5", + "GPD1", + "PAPPA2", + "BAG3", + "MYBPH", + "MYBPC1", + "MX2", + "APBB1IP", + "ANPEP", + "ALPL", + "GPRC5A", + "SPP1", + "CXCL2", + "GPC5", + "RRAD", + "LIF", + "CHRNA9", + "IL4R", + "NPNT", + "SAA1", + "NPR3", + "PROM1", + "SLIT3", + "ITGBL1", + "MYO5B", + "RPS5", + "RPS27", + "ETS2", + "PTGS2", + "RPS18", + "BNC2", + "CPA4", + "NPAS2", + "CD274", + "SLC10A6", + "LRAT", + "LINC01993", + "LINC02832", + "LINC02821", + "GBP5", + "AC021851.2", + "AKAP12", + "LINC02154", + "FN1", + "MIR222HG", + "VEGFA", + "GBP2", + "ZNF735", + "TSHZ2", + "TRPM2", + "LUCAT1", + "PI3" + ], + "programs": [ + { + "program_name": "RTK Signaling & Growth", + "description": "This program includes receptor tyrosine kinases and signaling mediators that drive GBM cell proliferation and survival. AXL and MET are overexpressed in glioblastoma and activate PI3K/AKT and MAPK pathways to enhance proliferation, invasion, and therapy resistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6585013/#:~:text=MET%20and%20its%20ligand%20hepatocyte,this%20pathway%20and%20associated%20molecules)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1458653/#:~:text=receptor%20tyrosine%20kinase%20Axl%20as,Inhibition%20of%20Axl%20signaling)). EMP1 (epithelial membrane protein 1) also boosts glioma cell proliferation and motility via PI3K/AKT/mTOR signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6609345/#:~:text=therapies%20for%20GBM%20patients,revealed%20that%20activation%20of%20the)). The transcription factor KLF5 supports GBM proliferative and stem-like phenotypes; inhibiting KLF5 reduces glioma cell growth and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9164955/#:~:text=down%20of%20KLF5%20significantly%20reduced,that%20inhibition%20of%20KLF5%20significantly)). Thus, these genes collectively enhance mitogenic signaling in GBM.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007169", + "name": "receptor tyrosine kinase signaling pathway", + "citation": [ + { + "reference": "Cheng F, Guo D et al. J Exp Clin Cancer Res. 2019;38:270.", + "id": "PMID:31221203", + "type": "PMID", + "notes": "MET/HGF signaling drives GBM proliferation and survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6585013/#:~:text=MET%20and%20its%20ligand%20hepatocyte,this%20pathway%20and%20associated%20molecules))" + } + ], + "Genes": [ + "EMP1", + "MET", + "AXL" + ], + "ontology_label": "cell surface receptor protein tyrosine kinase signaling pathway" + }, + { + "name": "cell proliferation", + "citation": [ + { + "reference": "Cheng F, Guo D et al. J Exp Clin Cancer Res. 2019;38:270.", + "id": "PMID:31221203", + "type": "PMID", + "notes": "MET/HGF and AXL signaling promote GBM cell proliferation and survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6585013/#:~:text=MET%20and%20its%20ligand%20hepatocyte,this%20pathway%20and%20associated%20molecules))" + } + ], + "Genes": [ + "EMP1", + "MET", + "AXL", + "KLF5" + ], + "ontology_label": "cell population proliferation", + "ontology_id": "GO:0008283" + }, + { + "name": "cell migration", + "citation": [ + { + "reference": "Vajkoczy P et al. PNAS. 2006;103(15):5799-5804.", + "id": "PMID:16585512", + "type": "PMID", + "notes": "AXL mediates glioma cell migration and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1458653/#:~:text=receptor%20tyrosine%20kinase%20Axl%20as,Inhibition%20of%20Axl%20signaling))" + } + ], + "Genes": [ + "MET", + "AXL" + ], + "ontology_label": "cell migration", + "ontology_id": "GO:0016477" + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "citation": [ + { + "reference": "Cheng F, Guo D et al. J Exp Clin Cancer Res. 2019;38:270.", + "id": "PMID:31221203", + "type": "PMID", + "notes": "MET and AXL are transmembrane receptors overexpressed in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6585013/#:~:text=MET%20and%20its%20ligand%20hepatocyte,this%20pathway%20and%20associated%20molecules))" + } + ], + "Genes": [ + "EMP1", + "MET", + "AXL" + ], + "ontology_label": "plasma membrane", + "ontology_id": "GO:0005886" + } + ], + "predicted_cellular_impact": [ + "Increased PI3K/AKT/mTOR signaling and cell proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6609345/#:~:text=therapies%20for%20GBM%20patients,revealed%20that%20activation%20of%20the)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6585013/#:~:text=MET%20and%20its%20ligand%20hepatocyte,this%20pathway%20and%20associated%20molecules))", + "Enhanced cell survival and tumor growth", + "Elevated migratory/invasive capacity via AXL/MET pathways ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1458653/#:~:text=receptor%20tyrosine%20kinase%20Axl%20as,Inhibition%20of%20Axl%20signaling)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9164955/#:~:text=down%20of%20KLF5%20significantly%20reduced,that%20inhibition%20of%20KLF5%20significantly))" + ], + "evidence_summary": "IL1R1 and other innate receptors activate NF-\u03baB in GBM, while chemokines and cytokines modulate immune infiltration and angiogenesis. CXCL8 (IL-8) is produced at high levels by glioblastoma cells, promoting angiogenesis and EMT ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8910233/#:~:text=The%20significance%20of%20up,as%20essential%20to%20neovascularization%20and)). PTX3 and CHI3L1 are upregulated and drive macrophage recruitment and immunosuppression in the TME ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9532932/#:~:text=found%20to%20mediate%20the%20migration,CD68%20was%20more%20expressed%20in)). GBM cells also overexpress immune checkpoints (e.g. PD-L1/CD274 and IDO1) to evade immune attack. Together, these genes indicate an inflamed, yet tumor-promoting, microenvironment.", + "citations": [ + { + "reference": "Codrici E et al. Int J Mol Sci. 2022;23(5):2509.", + "id": "PMID:35269652", + "type": "PMID", + "notes": "Chemokines (CXCL8, CXCL10, etc.) contribute to GBM-associated inflammation and angiogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8910233/#:~:text=The%20significance%20of%20up,as%20essential%20to%20neovascularization%20and))" + }, + { + "reference": "Zhang H et al. CNS Neurosci Ther. 2022;28(11):1748\u20131766.", + "id": "PMID:35855654", + "type": "PMID", + "notes": "PTX3 mediates macrophage migration and polarization in GBM, contributing to an immunosuppressive TME ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9532932/#:~:text=found%20to%20mediate%20the%20migration,CD68%20was%20more%20expressed%20in))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.8, + "supporting_genes": [ + "IL1R1", + "TLR2", + "IL6", + "IL4R", + "TNFAIP3", + "TNFAIP2", + "BIRC3", + "FAS", + "CXCL8", + "CXCL2", + "CXCL10", + "CXCL14", + "CLCF1", + "LIF", + "SAA1", + "SAA2", + "SAA4", + "CHI3L1", + "PTX3", + "CD274", + "IDO1" + ], + "supporting_gene_count": 24, + "required_components_present": false + }, + { + "program_name": "Tumor Angiogenesis", + "description": "This program centers on factors driving new blood vessel formation in GBM. VEGFA, the major angiogenic factor induced by hypoxia, is highly expressed in glioblastoma and triggers endothelial proliferation and vascular permeability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11941181/#:~:text=match%20at%20L250%20In%20malignant,1)). Apelin (APLN) is also upregulated in GBM and required for tumor angiogenesis; loss of apelin signaling dramatically reduces tumor vasculature in vivo ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=In%20summary%2C%20we%20found%20that,APLN%20in%20the%20mouse%20brain)). Angiopoietin-4 (ANGPTL4) similarly promotes GBM vascularization and growth. These genes collectively facilitate the aberrant, leaky vasculature characteristic of GBM.", + "atomic_biological_processes": [ + { + "name": "angiogenesis", + "citation": [ + { + "reference": "Nowacka AS et al. Cells. 2025;14(6):407.", + "id": "PMID:40136656", + "type": "PMID", + "notes": "VEGF-A is the central driver of angiogenesis in malignant glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11941181/#:~:text=match%20at%20L250%20In%20malignant,1))" + } + ], + "Genes": [ + "VEGFA", + "APLN", + "ANGPTL4" + ], + "ontology_label": "angiogenesis", + "ontology_id": "GO:0001525" + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular space", + "citation": [ + { + "reference": "Frisch A et al. Int J Mol Sci. 2020;21(11):4179.", + "id": "PMID:32545380", + "type": "PMID", + "notes": "APLN (apelin) is secreted and upregulated in GBM, promoting tumor angiogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=The%20angiogenic%20factor%20apelin%20,models%2C%20we%20found%20that%20apelin%2FAPLNR)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=In%20summary%2C%20we%20found%20that,APLN%20in%20the%20mouse%20brain))" + } + ], + "Genes": [ + "VEGFA", + "APLN", + "ANGPTL4" + ], + "ontology_label": "extracellular space", + "ontology_id": "GO:0005615" + } + ], + "predicted_cellular_impact": [ + "Increased neovascularization and endothelial proliferation", + "Enhanced vascular permeability and edema formation", + "Greater nutrient supply supporting rapid tumor growth" + ], + "evidence_summary": "VEGF-A is a key pro-angiogenic factor in GBM: it is overexpressed in hypoxic tumor regions and induces endothelial proliferation and ECM degradation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11941181/#:~:text=match%20at%20L250%20In%20malignant,1)). Apelin (APLN) is another upregulated factor in GBM; its signaling is required for tumor angiogenesis, as apelin knockdown markedly reduces vessel density in GBM models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=In%20summary%2C%20we%20found%20that,APLN%20in%20the%20mouse%20brain)). Angiopoietin-4 (ANGPTL4) also drives GBM progression and vascularization. Together, they drive the aberrant vasculature of malignant gliomas.", + "citations": [ + { + "reference": "Nowacka AS et al. Cells. 2025;14(6):407.", + "id": "PMID:40136656", + "type": "PMID", + "notes": "VEGF-A is the predominant driver of tumor angiogenesis in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11941181/#:~:text=match%20at%20L250%20In%20malignant,1))" + }, + { + "reference": "Frisch A et al. Int J Mol Sci. 2020;21(11):4179.", + "id": "PMID:32545380", + "type": "PMID", + "notes": "Loss of apelin signaling in GBM models reduces angiogenesis, confirming APLN\u2019s role in tumor vascularization ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=In%20summary%2C%20we%20found%20that,APLN%20in%20the%20mouse%20brain))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "VEGFA", + "APLN", + "ANGPTL4" + ], + "supporting_gene_count": 3, + "required_components_present": true + }, + { + "program_name": "ECM Remodeling & Cell Adhesion", + "description": "Genes in this program encode extracellular matrix (ECM) components and adhesion molecules that facilitate GBM invasion. Fibronectin (FN1) and fibrillar collagens (COL1A2, COL5A1, COL6A2) are overexpressed, providing a scaffold for tumor cell migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8038731/#:~:text=FN%20receptors%2C%20cluster%20around%20FN,perivascular%20regions%20and%20along%20the)). SERPINE1 and CCN1 modulate ECM turnover and adhesion: SERPINE1 knockdown drastically reduces focal adhesions and cell-matrix adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=Accordingly%2C%20there%20was%20a%20remarkable,Figure%203C)), while CCN1 promotes a mesenchymal, invasive phenotype. CHI3L1 (YKL-40) is secreted in GBM to enhance invasion. ICAM1 and SPP1 (osteopontin) are adhesion mediators on the cell surface that support cell-cell and cell-ECM interactions. Overall, this program enhances focal adhesion dynamics and ECM production to promote GBM infiltration.", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "citation": [ + { + "reference": "Chen CW et al. Int J Mol Sci. 2021;22(7):3782.", + "id": "PMID:33917452", + "type": "PMID", + "notes": "Fibronectin (FN1) and related ECM components are upregulated in GBM, facilitating tumor cell migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8038731/#:~:text=FN%20receptors%2C%20cluster%20around%20FN,perivascular%20regions%20and%20along%20the))" + } + ], + "Genes": [ + "FN1", + "COL1A2", + "COL5A1", + "COL6A2" + ], + "ontology_label": "extracellular matrix organization", + "ontology_id": "GO:0030198" + }, + { + "name": "cell adhesion", + "citation": [ + { + "reference": "Seker F et al. Cancers (Basel). 2019;11(11):1651.", + "id": "PMID:31731490", + "type": "PMID", + "notes": "SERPINE1 knockdown reduces focal adhesions and cell adhesion in GBM cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=Accordingly%2C%20there%20was%20a%20remarkable,Figure%203C))" + } + ], + "Genes": [ + "ICAM1", + "SERPINE1" + ], + "ontology_label": "cell adhesion", + "ontology_id": "GO:0007155" + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "citation": [ + { + "reference": "Chen CW et al. Int J Mol Sci. 2021;22(7):3782.", + "id": "PMID:33917452", + "type": "PMID", + "notes": "Fibronectin and collagens are secreted into the extracellular matrix of GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8038731/#:~:text=FN%20receptors%2C%20cluster%20around%20FN,perivascular%20regions%20and%20along%20the))" + } + ], + "Genes": [ + "FN1", + "COL1A2", + "COL5A1", + "COL6A2" + ], + "ontology_label": "extracellular matrix", + "ontology_id": "GO:0031012" + }, + { + "name": "focal adhesion", + "citation": [ + { + "reference": "Seker F et al. Cancers (Basel). 2019;11(11):1651.", + "id": "PMID:31731490", + "type": "PMID", + "notes": "SERPINE1 knockdown in GBM cells reduces focal adhesion number ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=Accordingly%2C%20there%20was%20a%20remarkable,Figure%203C))" + } + ], + "Genes": [ + "SERPINE1" + ], + "ontology_label": "focal adhesion", + "ontology_id": "GO:0005925" + } + ], + "predicted_cellular_impact": [ + "Enhanced ECM deposition and matrix stiffness", + "Increased focal adhesion dynamics driving invasive migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=Accordingly%2C%20there%20was%20a%20remarkable,Figure%203C))", + "Stronger cell\u2013matrix adhesion supporting tumor cell motility" + ], + "evidence_summary": "FN1 (fibronectin) is abundant in GBM and serves as a substrate for migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8038731/#:~:text=FN%20receptors%2C%20cluster%20around%20FN,perivascular%20regions%20and%20along%20the)). SERPINE1 is upregulated and promotes GBM dispersal; its knockdown leads to fewer focal adhesions and reduced adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=Accordingly%2C%20there%20was%20a%20remarkable,Figure%203C)). CHI3L1 (YKL-40) overexpression boosts glioma invasion and survival, while its loss reduces invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/20506295/#:~:text=suppression%20by%20shRNA%20reduced%20glioma,invasive%20nature%20of%20glioma%20cells)). Similarly, ICAM1 expression correlates with GBM invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6453839/#:~:text=MSH6%20%28Supplemental%20Table%204%29,examine%20the%20mRNA%20expression%20of)). These data indicate GBM cells reshape their ECM and adhesion to enhance invasiveness.", + "citations": [ + { + "reference": "Chen CW et al. Int J Mol Sci. 2021;22(7):3782.", + "id": "PMID:33917452", + "type": "PMID", + "notes": "Fibronectin is overexpressed in GBM, and GBM cells migrate efficiently on fibronectin-coated matrix ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8038731/#:~:text=FN%20receptors%2C%20cluster%20around%20FN,perivascular%20regions%20and%20along%20the))" + }, + { + "reference": "Seker F et al. Cancers (Basel). 2019;11(11):1651.", + "id": "PMID:31731490", + "type": "PMID", + "notes": "Silencing SERPINE1 reduces focal adhesions and cell adhesion, demonstrating its role in ECM interaction ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=Accordingly%2C%20there%20was%20a%20remarkable,Figure%203C))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.9, + "supporting_genes": [ + "FN1", + "COL1A2", + "COL5A1", + "COL6A2", + "ICAM1", + "SERPINE1", + "CCN1", + "CHI3L1", + "SPP1" + ], + "supporting_gene_count": 9, + "required_components_present": false + }, + { + "program_name": "Apoptosis Regulation", + "description": "This program involves regulators of cell death and survival. BAG3 and BIRC3 are anti-apoptotic factors upregulated in GBM. BAG3 is overexpressed in tumor cells, and its knockdown induces apoptosis in glioma models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3124067/#:~:text=principle%2C%20we%20showed%20that%20BAG3,of%20metastases%20outside%20the%20central)). Similarly, BIRC3 (cIAP2) inhibits apoptotic signaling downstream of TNF. Together these genes promote resistance to cell death, a hallmark of glioblastoma.", + "atomic_biological_processes": [ + { + "name": "negative regulation of apoptosis", + "citation": [ + { + "reference": "Festa M et al. Am J Pathol. 2011;178(6):2504\u20132512.", + "id": "PMID:21600277", + "type": "PMID", + "notes": "BAG3 is overexpressed in GBM and protects tumor cells from apoptosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3124067/#:~:text=principle%2C%20we%20showed%20that%20BAG3,of%20metastases%20outside%20the%20central))" + } + ], + "Genes": [ + "BAG3", + "BIRC3" + ], + "ontology_label": "negative regulation of apoptotic process", + "ontology_id": "GO:0043066" + } + ], + "atomic_cellular_components": [ + { + "name": "cytosol", + "citation": [ + { + "reference": "Festa M et al. Am J Pathol. 2011;178(6):2504\u20132512.", + "id": "PMID:21600277", + "type": "PMID", + "notes": "BAG3 functions in the cytosol to inhibit apoptosis in glioblastoma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3124067/#:~:text=principle%2C%20we%20showed%20that%20BAG3,of%20metastases%20outside%20the%20central))" + } + ], + "Genes": [ + "BAG3" + ], + "ontology_label": "cytosol", + "ontology_id": "GO:0005829" + } + ], + "predicted_cellular_impact": [ + "Suppressed apoptotic signaling, promoting GBM cell survival", + "Resistance to chemotherapy and stress-induced cell death" + ], + "evidence_summary": "BAG3 is overexpressed in GBM and functions as an anti-apoptotic chaperone; its inhibition triggers apoptosis in glioma models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3124067/#:~:text=principle%2C%20we%20showed%20that%20BAG3,of%20metastases%20outside%20the%20central)). BIRC3 (cIAP2) similarly inhibits caspase activation. The upregulation of these survival factors confers resistance to cell death in glioblastoma.", + "citations": [ + { + "reference": "Festa M et al. Am J Pathol. 2011;178(6):2504\u20132512.", + "id": "PMID:21600277", + "type": "PMID", + "notes": "BAG3 knockdown in a glioblastoma model induces apoptosis, indicating its role in cell survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3124067/#:~:text=principle%2C%20we%20showed%20that%20BAG3,of%20metastases%20outside%20the%20central))" + } + ], + "confidence_score": 0.6, + "significance_score": 0.7, + "supporting_genes": [ + "BAG3", + "BIRC3" + ], + "supporting_gene_count": 2, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_gliosis_hypoxia b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_gliosis_hypoxia new file mode 100644 index 0000000..e16af55 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_gliosis_hypoxia @@ -0,0 +1,531 @@ +{ + "context": { + "cell_type": "astrocyte", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "ADAM28", + "LINC02615", + "POT1-AS1", + "MET", + "HILPDA", + "LUCAT1", + "PTGS2", + "RUNX2", + "SPNS2", + "PHLDB2", + "LINC01705", + "FAM160A1", + "ERRFI1", + "FAT4", + "TNNI3K", + "TRIB3", + "NDRG1", + "AC051619.5", + "AC083837.1", + "PRKCH", + "PPP1R3C", + "MGAM", + "ANGPTL4", + "COL13A1", + "CHSY3", + "AP001528.1", + "CDON", + "CAV1", + "SHISA6", + "SLC39A14", + "C21orf62-AS1", + "HMOX1", + "BNIP3L", + "LINC01376", + "ABI3BP", + "VLDLR-AS1", + "OLFM1", + "LTBP2", + "AHNAK2", + "NOX4", + "AC092944.1", + "COL5A1", + "PLAG1", + "GCNT1", + "AC099681.1", + "CFAP61", + "RPL34-AS1", + "OSMR-AS1", + "AMPD3", + "EHHADH", + "COL24A1", + "RNF217-AS1", + "AP006545.3", + "EPHA1-AS1", + "EPHA3", + "ZNF385B", + "LINC02340", + "LVRN", + "PDE4C", + "GPC5", + "RCAN2", + "EPSTI1", + "AC008014.1", + "LINC00240", + "AL158064.1", + "AL390957.1", + "MX2", + "C4orf47", + "ABLIM3", + "ITGB3", + "SCN9A", + "C9orf153", + "SLC6A6", + "NECTIN3-AS1", + "CALN1", + "GRK5", + "CPEB1", + "CPA4", + "UNC5C" + ], + "programs": [ + { + "program_name": "Hypoxia/metabolic stress response", + "theme": "Stress response", + "description": "Genes in this program are induced by hypoxia and metabolic stress, facilitating angiogenesis, metabolic reprogramming, and survival in glioblastoma. For example, ANGPTL4 is hypoxia-inducible and promotes vascular permeability and metastasis ([en.wikipedia.org](https://en.wikipedia.org/wiki/ANGPTL4#:~:text=This%20gene%20is%20induced%20under,involved%20in%20regulating%20lipid%20metabolism)); NDRG1 is regulated by HIF-1 and modulates proliferation and migration ([en.wikipedia.org](https://en.wikipedia.org/wiki/NDRG1#:~:text=The%20expression%20of%20NDRG1%20is,by%20decreasing%20its%20promoter%20activity)) ([en.wikipedia.org](https://en.wikipedia.org/wiki/NDRG1#:~:text=NDRG1%20could%20promote%20cancer%20cell,Src)); HMOX1 protects cells from oxidative stress and chemotoxicity ([en.wikipedia.org](https://en.wikipedia.org/wiki/Heme_oxygenase#:~:text=In%20certain%20diseases%2C%20HMOX%20is,HMOX1%20inhibitors%20are%20in%20development)). BNIP3L (NIX) is HIF-induced to trigger mitophagy/autophagy under low oxygen ([en.wikipedia.org](https://en.wikipedia.org/wiki/BNIP3#:~:text=Upon%20activation%2C%20BNIP3%20can%20form,cells%2C%20and%20adult%20rat%20cardiomyocytes)).", + "atomic_biological_processes": [ + { + "name": "response to hypoxia", + "ontology_id": "GO:0001666", + "citation": [ + { + "reference": "Wikipedia: BNIP3 (2025)", + "id": "https://en.wikipedia.org/wiki/BNIP3", + "type": "URL", + "notes": "BNIP3L is induced by hypoxia via HIF-1 ([en.wikipedia.org](https://en.wikipedia.org/wiki/BNIP3#:~:text=Upon%20activation%2C%20BNIP3%20can%20form,cells%2C%20and%20adult%20rat%20cardiomyocytes))" + }, + { + "reference": "Wikipedia: NDRG1 (2024)", + "id": "https://en.wikipedia.org/wiki/NDRG1", + "type": "URL", + "notes": "NDRG1 is upregulated by HIF-1 in hypoxia ([en.wikipedia.org](https://en.wikipedia.org/wiki/NDRG1#:~:text=The%20expression%20of%20NDRG1%20is,by%20decreasing%20its%20promoter%20activity))" + } + ], + "Genes": [ + "ANGPTL4", + "NDRG1", + "HMOX1", + "BNIP3L" + ], + "ontology_label": "response to hypoxia" + }, + { + "name": "lipid metabolic process", + "ontology_id": "GO:0006629", + "citation": [ + { + "reference": "Wikipedia: ANGPTL4 (2025)", + "id": "https://en.wikipedia.org/wiki/ANGPTL4", + "type": "URL", + "notes": "ANGPTL4 is a lipid metabolism regulator induced by hypoxia ([en.wikipedia.org](https://en.wikipedia.org/wiki/ANGPTL4#:~:text=This%20gene%20is%20induced%20under,involved%20in%20regulating%20lipid%20metabolism))" + } + ], + "Genes": [ + "ANGPTL4", + "EHHADH" + ], + "ontology_label": "lipid metabolic process" + } + ], + "atomic_cellular_components": [ + { + "name": "mitochondrial outer membrane", + "ontology_id": "GO:0005741", + "citation": [ + { + "reference": "Wikipedia: BNIP3 (2025)", + "id": "https://en.wikipedia.org/wiki/BNIP3", + "type": "URL", + "notes": "BNIP3L localizes to the mitochondrial outer membrane and is induced in hypoxia ([en.wikipedia.org](https://en.wikipedia.org/wiki/BNIP3#:~:text=Upon%20activation%2C%20BNIP3%20can%20form,cells%2C%20and%20adult%20rat%20cardiomyocytes))" + } + ], + "Genes": [ + "BNIP3L" + ], + "ontology_label": "mitochondrial outer membrane" + }, + { + "name": "extracellular region", + "ontology_id": "GO:0005576", + "citation": [ + { + "reference": "Wikipedia: ANGPTL4 (2025)", + "id": "https://en.wikipedia.org/wiki/ANGPTL4", + "type": "URL", + "notes": "ANGPTL4 is secreted into the extracellular space and is hypoxia-inducible ([en.wikipedia.org](https://en.wikipedia.org/wiki/ANGPTL4#:~:text=This%20gene%20is%20induced%20under,involved%20in%20regulating%20lipid%20metabolism))" + } + ], + "Genes": [ + "ANGPTL4" + ], + "ontology_label": "extracellular region" + } + ], + "predicted_cellular_impact": [ + "Enhanced adaptation to hypoxia (e.g., increased HIF target activation)", + "Increased angiogenesis and vascular permeability (via ANGPTL4)", + "Metabolic shift towards lipid utilization and glycolysis", + "Autophagy/mitophagy induction (via BNIP3L)" + ], + "evidence_summary": "Literature indicates many of these genes are HIF-1 targets or stress-response factors. ANGPTL4, NDRG1, HMOX1, BNIP3L and others are known to be induced under hypoxia and support tumor cell survival and metabolic adaptation ([en.wikipedia.org](https://en.wikipedia.org/wiki/ANGPTL4#:~:text=This%20gene%20is%20induced%20under,involved%20in%20regulating%20lipid%20metabolism)) ([en.wikipedia.org](https://en.wikipedia.org/wiki/BNIP3#:~:text=Upon%20activation%2C%20BNIP3%20can%20form,cells%2C%20and%20adult%20rat%20cardiomyocytes)).", + "citations": [ + { + "reference": "Wikipedia: ANGPTL4 (2025)", + "id": "https://en.wikipedia.org/wiki/ANGPTL4", + "type": "URL", + "notes": "ANGPTL4 is induced by hypoxia and promotes metastasis ([en.wikipedia.org](https://en.wikipedia.org/wiki/ANGPTL4#:~:text=This%20gene%20is%20induced%20under,involved%20in%20regulating%20lipid%20metabolism))" + }, + { + "reference": "Wikipedia: BNIP3 (2025)", + "id": "https://en.wikipedia.org/wiki/BNIP3", + "type": "URL", + "notes": "BNIP3L is upregulated by HIF-1 under hypoxia ([en.wikipedia.org](https://en.wikipedia.org/wiki/BNIP3#:~:text=Upon%20activation%2C%20BNIP3%20can%20form,cells%2C%20and%20adult%20rat%20cardiomyocytes))" + }, + { + "reference": "Wikipedia: NDRG1 (2024)", + "id": "https://en.wikipedia.org/wiki/NDRG1", + "type": "URL", + "notes": "NDRG1 is HIF-regulated and modulates proliferation/metastasis ([en.wikipedia.org](https://en.wikipedia.org/wiki/NDRG1#:~:text=The%20expression%20of%20NDRG1%20is,by%20decreasing%20its%20promoter%20activity)) ([en.wikipedia.org](https://en.wikipedia.org/wiki/NDRG1#:~:text=NDRG1%20could%20promote%20cancer%20cell,Src))" + }, + { + "reference": "Wikipedia: Heme oxygenase 1 (2025)", + "id": "https://en.wikipedia.org/wiki/Heme_oxygenase", + "type": "URL", + "notes": "HMOX1 enables tumor cells to survive oxidative stress and resist therapy ([en.wikipedia.org](https://en.wikipedia.org/wiki/Heme_oxygenase#:~:text=In%20certain%20diseases%2C%20HMOX%20is,HMOX1%20inhibitors%20are%20in%20development))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.85, + "supporting_genes": [ + "ANGPTL4", + "HMOX1", + "NDRG1", + "BNIP3L", + "TRIB3", + "EHHADH" + ], + "supporting_gene_count": 6, + "required_components_present": true + }, + { + "program_name": "Extracellular matrix organization and adhesion", + "theme": "Microenvironment", + "description": "This program contains genes involved in ECM composition, remodeling, and cell adhesion, implicating changes to glioblastoma invasiveness. Key structural genes include collagens (COL13A1, COL5A1, COL24A1) and LTBP2, while ECM modulators like ADAM28 and CHSY3 and adhesion receptors (ITGB3, UNC5C, CDON, FAT4, CAV1, ABI3BP) are also present. Such a program suggests enhanced matrix deposition and turnover to facilitate tumor cell migration ([en.wikipedia.org](https://en.wikipedia.org/wiki/ADAM28#:~:text=structurally%20related%20to%20snake%20venom,The)) ([en.wikipedia.org](https://en.wikipedia.org/wiki/Integrin#:~:text=Integrins%20are%20transmembrane%20receptors%20,an%20interaction%20with%20coagulation%20factors)).", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_id": "GO:0030198", + "citation": [ + { + "reference": "Wikipedia: ADAM28 (2025)", + "id": "https://en.wikipedia.org/wiki/ADAM28", + "type": "URL", + "notes": "ADAM28 is a protease involved in cell\u2013matrix interactions ([en.wikipedia.org](https://en.wikipedia.org/wiki/ADAM28#:~:text=structurally%20related%20to%20snake%20venom,The))" + } + ], + "Genes": [ + "COL13A1", + "COL5A1", + "COL24A1", + "CHSY3", + "LTBP2", + "ADAM28" + ], + "ontology_label": "extracellular matrix organization" + }, + { + "name": "cell adhesion", + "ontology_id": "GO:0007155", + "citation": [ + { + "reference": "Wikipedia: Integrin (2025)", + "id": "https://en.wikipedia.org/wiki/Integrin", + "type": "URL", + "notes": "Integrins and cadherins mediate adhesion to ECM and other cells ([en.wikipedia.org](https://en.wikipedia.org/wiki/Integrin#:~:text=Integrins%20are%20transmembrane%20receptors%20,an%20interaction%20with%20coagulation%20factors))" + } + ], + "Genes": [ + "ITGB3", + "UNC5C", + "CDON", + "FAT4", + "CAV1", + "ABI3BP" + ], + "ontology_label": "cell adhesion" + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_id": "GO:0031012", + "citation": [ + { + "reference": "Wikipedia: Integrin (2025)", + "id": "https://en.wikipedia.org/wiki/Integrin", + "type": "URL", + "notes": "Collagens and matrix proteins form the extracellular matrix to which cells adhere ([en.wikipedia.org](https://en.wikipedia.org/wiki/Integrin#:~:text=Integrins%20are%20transmembrane%20receptors%20,an%20interaction%20with%20coagulation%20factors))" + } + ], + "Genes": [ + "COL13A1", + "COL5A1", + "COL24A1", + "LTBP2" + ], + "ontology_label": "extracellular matrix" + }, + { + "name": "integral component of plasma membrane", + "ontology_id": "GO:0005886", + "citation": [ + { + "reference": "Wikipedia: Integrin (2025)", + "id": "https://en.wikipedia.org/wiki/Integrin", + "type": "URL", + "notes": "Adhesion receptors like integrins and cadherins span the plasma membrane ([en.wikipedia.org](https://en.wikipedia.org/wiki/Integrin#:~:text=Integrins%20are%20transmembrane%20receptors%20,an%20interaction%20with%20coagulation%20factors))" + } + ], + "Genes": [ + "ITGB3", + "UNC5C", + "CDON", + "FAT4", + "CAV1" + ], + "ontology_label": "plasma membrane" + } + ], + "predicted_cellular_impact": [ + "Increased matrix deposition and remodeling facilitating invasion", + "Altered cell adhesion properties (e.g. integrin signaling)", + "Potential modulation of TGF-\u03b2 signaling (via LTBP2 anchored TGF\u03b2)" + ], + "evidence_summary": "Multiple genes suggest glioblastoma remodeling of the extracellular environment. For example, ADAM28 degrades ECM components ([en.wikipedia.org](https://en.wikipedia.org/wiki/ADAM28#:~:text=structurally%20related%20to%20snake%20venom,The)), while collagens and LTBPs indicate active matrix organization. Integrins (ITGB3) and cadherin-like FAT4 support altered adhesion signaling ([en.wikipedia.org](https://en.wikipedia.org/wiki/Integrin#:~:text=Integrins%20are%20transmembrane%20receptors%20,an%20interaction%20with%20coagulation%20factors)).", + "citations": [ + { + "reference": "Wikipedia: ADAM28 (2025)", + "id": "https://en.wikipedia.org/wiki/ADAM28", + "type": "URL", + "notes": "ADAM28 (a metalloprotease) interacts with extracellular matrix and cells ([en.wikipedia.org](https://en.wikipedia.org/wiki/ADAM28#:~:text=structurally%20related%20to%20snake%20venom,The))" + }, + { + "reference": "Wikipedia: Integrin (2025)", + "id": "https://en.wikipedia.org/wiki/Integrin", + "type": "URL", + "notes": "Integrins mediate cell\u2013matrix adhesion to collagens and fibronectin ([en.wikipedia.org](https://en.wikipedia.org/wiki/Integrin#:~:text=Integrins%20are%20transmembrane%20receptors%20,an%20interaction%20with%20coagulation%20factors))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.9, + "supporting_genes": [ + "ADAM28", + "COL13A1", + "COL5A1", + "COL24A1", + "CHSY3", + "LTBP2", + "ITGB3", + "UNC5C", + "CDON", + "FAT4", + "CAV1", + "ABI3BP" + ], + "supporting_gene_count": 12, + "required_components_present": true + }, + { + "program_name": "Growth factor signaling", + "theme": "Cell proliferation", + "description": "Genes in this program affect receptor and downstream signaling controlling proliferation and survival. For instance, the MET receptor tyrosine kinase promotes proliferation, survival, angiogenesis and metastasis when aberrantly activated ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain)). ERRFI1 (Mig6) is a regulator of EGFR/MET, and kinases GRK5, PRKCH and PDE4C affect second-messenger signaling. PTGS2 (COX-2) links inflammatory signaling to growth. Together, these may enhance pro-growth signaling and resistance to apoptosis in glioblastoma ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain)) ([en.wikipedia.org](https://en.wikipedia.org/wiki/Epithelial_stromal_interaction_1#:~:text=The%20protein%20encoded%20by%20this,some%20individuals%20with%20systemic%20lupus)).", + "atomic_biological_processes": [ + { + "name": "signal transduction", + "ontology_id": "GO:0007165", + "citation": [ + { + "reference": "Wikipedia: Hepatocyte growth factor receptor (MET) (2025)", + "id": "https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor", + "type": "URL", + "notes": "MET is a tyrosine kinase that activates MAPK/PI3K signaling to drive proliferation ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain))" + } + ], + "Genes": [ + "MET", + "PRKCH", + "EPHA3", + "GRK5", + "PDE4C", + "PTGS2" + ], + "ontology_label": "signal transduction" + }, + { + "name": "cell proliferation", + "ontology_id": "GO:0008283", + "citation": [ + { + "reference": "Wikipedia: Hepatocyte growth factor receptor (MET) (2025)", + "id": "https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor", + "type": "URL", + "notes": "Aberrant MET activation stimulates tumor growth and angiogenesis ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain))" + } + ], + "Genes": [ + "MET", + "PRKCH", + "EPHA3", + "GRK5", + "PTGS2" + ], + "ontology_label": "cell population proliferation" + } + ], + "atomic_cellular_components": [ + { + "name": "integral component of plasma membrane", + "ontology_id": "GO:0016021", + "citation": [ + { + "reference": "Wikipedia: Hepatocyte growth factor receptor (MET) (2025)", + "id": "https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor", + "type": "URL", + "notes": "MET and EPHA3 are transmembrane receptor kinases ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain))" + } + ], + "Genes": [ + "MET", + "EPHA3", + "GRK5" + ], + "ontology_label": "integral component of membrane" + } + ], + "predicted_cellular_impact": [ + "Enhanced proliferative signaling (MET pathway activation)", + "Increased survival and angiogenic signaling", + "Link between inflammation and growth (via COX-2/PTGS2)" + ], + "evidence_summary": "MET (HGF receptor) is a well-documented proto-oncogene: its overactivation drives tumor proliferation, survival and angiogenesis ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain)). Other genes in this set (kinases, phosphatases, COX2) modulate these growth and inflammatory pathways in cancer. Thus, this program likely increases proliferative signaling in glioblastoma.", + "citations": [ + { + "reference": "Wikipedia: Hepatocyte growth factor receptor (MET) (2025)", + "id": "https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor", + "type": "URL", + "notes": "MET activation drives tumor growth, angiogenesis, and metastasis ([en.wikipedia.org](https://en.wikipedia.org/wiki/Hepatocyte_growth_factor_receptor#:~:text=Abnormal%20MET%20activation%20in%20cancer,liver%2C%20stomach%2C%20breast%2C%20and%20brain))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.6, + "supporting_genes": [ + "MET", + "ERRFI1", + "PTGS2", + "EPHA3", + "PRKCH", + "GRK5", + "PDE4C", + "RCAN2", + "CPEB1", + "GPC5" + ], + "supporting_gene_count": 10, + "required_components_present": true + }, + { + "program_name": "Innate immune/interferon response", + "theme": "Immunity", + "description": "This program includes interferon-responsive genes suggesting activation of innate immune pathways. MX2 is an interferon-inducible GTPase with antiviral activity ([en.wikipedia.org](https://en.wikipedia.org/wiki/MX2#:~:text=Antiviral%20activity)). EPSTI1 is also IFN-inducible and can activate NF-\u03baB signaling to promote invasion and survival ([en.wikipedia.org](https://en.wikipedia.org/wiki/Epithelial_stromal_interaction_1#:~:text=The%20protein%20encoded%20by%20this,some%20individuals%20with%20systemic%20lupus)). These genes indicate an interferon-driven signature, which may reflect microenvironmental immune interactions and influence tumor behavior.", + "atomic_biological_processes": [ + { + "name": "innate immune response", + "ontology_id": "GO:0045087", + "citation": [ + { + "reference": "Wikipedia: Mx2 (2025)", + "id": "https://en.wikipedia.org/wiki/MX2", + "type": "URL", + "notes": "MX2 is upregulated by interferon and mediates an antiviral immune response ([en.wikipedia.org](https://en.wikipedia.org/wiki/MX2#:~:text=Antiviral%20activity))" + } + ], + "Genes": [ + "MX2", + "EPSTI1" + ], + "ontology_label": "innate immune response" + }, + { + "name": "response to interferon-gamma", + "ontology_id": "GO:0034341", + "citation": [ + { + "reference": "Wikipedia: Mx2 (2025)", + "id": "https://en.wikipedia.org/wiki/MX2", + "type": "URL", + "notes": "MX2 expression is induced by interferons as part of the innate immune response ([en.wikipedia.org](https://en.wikipedia.org/wiki/MX2#:~:text=Antiviral%20activity))" + } + ], + "Genes": [ + "MX2" + ], + "ontology_label": "response to type II interferon" + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "ontology_id": "GO:0005634", + "citation": [ + { + "reference": "Wikipedia: Mx2 (2025)", + "id": "https://en.wikipedia.org/wiki/MX2", + "type": "URL", + "notes": "MX2 has a nuclear localization signal and functions in the nucleus under IFN stimulation ([en.wikipedia.org](https://en.wikipedia.org/wiki/MX2#:~:text=Antiviral%20activity))" + } + ], + "Genes": [ + "MX2" + ], + "ontology_label": "nucleus" + } + ], + "predicted_cellular_impact": [ + "Activation of interferon-stimulated antiviral pathways", + "Induction of NF-\u03baB signaling (via EPSTI1)", + "Potential modifications of tumor-immune interactions" + ], + "evidence_summary": "MX2 and EPSTI1 are known interferon-stimulated genes. MX2 is induced by IFN-\u03b1 to restrict viral infection ([en.wikipedia.org](https://en.wikipedia.org/wiki/MX2#:~:text=Antiviral%20activity)). EPSTI1 is upregulated in some cancers by inflammatory signals and enhances invasion via NF-\u03baB ([en.wikipedia.org](https://en.wikipedia.org/wiki/Epithelial_stromal_interaction_1#:~:text=The%20protein%20encoded%20by%20this,some%20individuals%20with%20systemic%20lupus)). Their co-expression suggests innate immune pathway activity in GBM cells.", + "citations": [ + { + "reference": "Wikipedia: Mx2 (2025)", + "id": "https://en.wikipedia.org/wiki/MX2", + "type": "URL", + "notes": "MX2 is an interferon-induced GTPase involved in innate immunity ([en.wikipedia.org](https://en.wikipedia.org/wiki/MX2#:~:text=Antiviral%20activity))" + }, + { + "reference": "Wikipedia: EPSTI1 (2024)", + "id": "https://en.wikipedia.org/wiki/Epithelial_stromal_interaction_1", + "type": "URL", + "notes": "EPSTI1 is IFN-inducible and can promote invasion via NF-\u03baB activation ([en.wikipedia.org](https://en.wikipedia.org/wiki/Epithelial_stromal_interaction_1#:~:text=The%20protein%20encoded%20by%20this,some%20individuals%20with%20systemic%20lupus))" + } + ], + "confidence_score": 0.6, + "significance_score": 0.4, + "supporting_genes": [ + "MX2", + "EPSTI1" + ], + "supporting_gene_count": 2, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_npc_neuronal_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_npc_neuronal_like_1 new file mode 100644 index 0000000..7892738 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_npc_neuronal_like_1 @@ -0,0 +1,507 @@ +{ + "context": { + "cell_type": "Glioblastoma cell", + "disease": "Glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "CFAP43", + "NEGR1", + "DNAH12", + "LRRC2", + "VAT1L", + "ZNF804B", + "RBMS3", + "SLC14A1", + "GABRA5", + "ZBBX", + "ADAMTS18", + "CFAP52", + "GRM1", + "MAP3K19", + "FHAD1", + "TCTEX1D1", + "DNAAF1", + "DCDC2", + "AC005165.1", + "COL21A1", + "PKHD1", + "ZNF521", + "EPB41L4B", + "ERICH3", + "PLAGL1", + "EXPH5", + "SHISAL2B", + "SATB1-AS1", + "RERGL", + "FRMPD2", + "TOGARAM2", + "AP003062.2", + "BMP6", + "NRG3", + "CFAP61", + "FAM81B", + "SLC47A2", + "TMEM232", + "NWD2", + "AC109466.1", + "GABRG3", + "DTHD1", + "COL13A1", + "COL23A1", + "CFAP73", + "RFTN1", + "FYB2", + "POSTN", + "AL513323.1", + "BANK1", + "CHD5", + "THBS1", + "ADCY8", + "ADGB", + "AFF2", + "DRC1", + "CFAP206", + "CFAP47", + "PPM1H", + "KIAA2012", + "MAP7", + "KSR2", + "DNAH5", + "LYPD6B", + "WSCD2", + "CACNA2D1", + "LRRIQ1", + "CPNE4", + "LINC01088", + "SCIN", + "PRMT8", + "LINGO2", + "CASC1", + "CCDC170", + "AC092110.1", + "VWA3A", + "CA10", + "AC013470.2", + "SLC22A3", + "GRM4", + "COL26A1", + "CFAP221", + "CFAP157", + "TTC29", + "C7orf57", + "HMCN1", + "CFAP100", + "U91319.1", + "RSPH1", + "NAALAD2", + "IL6R", + "CDH7", + "KCNJ3", + "AL356108.1" + ], + "programs": [ + { + "program_name": "Ciliary Assembly & Signaling", + "description": "This cluster includes multiple genes encoding axonemal and dynein components of motile cilia (CFAPs, DNAH12/5, DRC1, RSPH1, etc.), implicating ciliary assembly and motility functions. Primary cilia modulate GBM cell proliferation and therapy resistance through pathways like Hedgehog and LPAR1 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=Primary%20cilia%20are%20highly%20associated,the%20proliferation%2C%20malignant%20development%2C%20and)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=When%20cilia%20are%20present%2C%20LPAR1,subunits%2C%20restricting%20its%20cell%20proliferative)). Disruption of these ciliary components could alter Sonic Hedgehog signalling and ciliary vesicle release, affecting tumor growth.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0035082", + "name": "axoneme assembly", + "citation": [ + { + "reference": "Wu B et al., J Biol Chem. 2023", + "id": "10.1016/j.jbc.2023.104858", + "type": "DOI", + "notes": "CFAP52 is conserved in motile cilia (axoneme) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319328/#:~:text=Previous%20studies%20have%20shown%20that,to%20the%20proximal%20region%20of))" + } + ], + "Genes": [ + "CFAP43", + "CFAP52", + "TCTEX1D1", + "DNAAF1", + "DCDC2", + "CFAP61", + "CFAP73", + "CFAP47", + "CFAP206", + "CFAP157", + "CFAP100", + "CFAP221", + "DNAH12", + "DNAH5", + "DRC1", + "RSPH1", + "TTC29" + ], + "ontology_label": "axoneme assembly" + }, + { + "ontology_id": "GO:0003341", + "name": "cilium movement", + "citation": [ + { + "reference": "Castleman M et al., Am J Hum Genet. 2013", + "id": "10.1016/j.ajhg.2013.07.013", + "type": "DOI", + "notes": "RSPH1 is a radial spoke protein essential for motile cilia movement ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3769924/#:~:text=Central))" + } + ], + "Genes": [ + "CFAP43", + "CFAP52", + "TCTEX1D1", + "DNAAF1", + "DCDC2", + "CFAP61", + "CFAP73", + "CFAP47", + "CFAP206", + "CFAP157", + "CFAP100", + "CFAP221", + "DNAH12", + "DNAH5", + "DRC1", + "RSPH1", + "TTC29" + ], + "ontology_label": "cilium movement" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005930", + "name": "axoneme", + "citation": [ + { + "reference": "Castleman M et al., Am J Hum Genet. 2013", + "id": "10.1016/j.ajhg.2013.07.013", + "type": "DOI", + "notes": "The axoneme, core of cilia, contains dynein arms essential for ciliary movement ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3769924/#:~:text=right%20asymmetry.,25%7D%20Radial%20spokes))" + } + ], + "Genes": [ + "CFAP43", + "CFAP52", + "TCTEX1D1", + "DNAAF1", + "DCDC2", + "CFAP61", + "CFAP73", + "CFAP47", + "CFAP206", + "CFAP157", + "CFAP100", + "CFAP221", + "DNAH12", + "DNAH5", + "DRC1", + "RSPH1", + "TTC29" + ], + "ontology_label": "axoneme" + }, + { + "ontology_id": "GO:0005929", + "name": "cilium", + "citation": [ + { + "reference": "Li M et al., Front Oncol. 2021", + "id": "10.3389/fonc.2021.718995", + "type": "DOI", + "notes": "Primary cilia are microtubule-based organelles implicated in GBM development and signalling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=As%20microtubule,the%20central%20nervous%20system%20tumorigenesis))" + } + ], + "Genes": [ + "CFAP43", + "CFAP52", + "TCTEX1D1", + "DNAAF1", + "DCDC2", + "CFAP61", + "CFAP73", + "CFAP47", + "CFAP206", + "CFAP157", + "CFAP100", + "CFAP221", + "DNAH12", + "DNAH5", + "DRC1", + "RSPH1", + "TTC29" + ], + "ontology_label": "cilium" + } + ], + "predicted_cellular_impact": [ + "Enhanced Hedgehog pathway activation via cilia dysfunction ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=Primary%20cilia%20are%20highly%20associated,the%20proliferation%2C%20malignant%20development%2C%20and))", + "Unregulated LPA/GPCR signaling due to cilium loss ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=When%20cilia%20are%20present%2C%20LPAR1,subunits%2C%20restricting%20its%20cell%20proliferative))", + "Release of ciliary extracellular vesicles affecting neighboring cells" + ], + "evidence_summary": "The genes listed are components of motile cilia and flagella (axonemal dyneins, radial spokes, CFAP scaffold proteins) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319328/#:~:text=Previous%20studies%20have%20shown%20that,to%20the%20proximal%20region%20of)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3769924/#:~:text=Central)). In glioblastoma, primary cilia regulate oncogenic signaling: e.g. aberrant cilia lead to upregulated Sonic Hedgehog pathway and LPAR1-mediated proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=Primary%20cilia%20are%20highly%20associated,the%20proliferation%2C%20malignant%20development%2C%20and)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=When%20cilia%20are%20present%2C%20LPAR1,subunits%2C%20restricting%20its%20cell%20proliferative)). Loss of these ciliary genes could therefore promote GBM cell proliferation and therapy resistance via misregulated ciliary signaling.", + "citations": [ + { + "reference": "Li M et al., Front Oncol. 2021", + "id": "10.3389/fonc.2021.718995", + "type": "DOI", + "notes": "Review linking primary cilia to GBM development and resistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8426355/#:~:text=Primary%20cilia%20are%20highly%20associated,the%20proliferation%2C%20malignant%20development%2C%20and))" + }, + { + "reference": "Wu B et al., J Biol Chem. 2023", + "id": "10.1016/j.jbc.2023.104858", + "type": "DOI", + "notes": "CFAP52 is located in motile cilia; its loss disrupts dynein-driven motility ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10319328/#:~:text=Previous%20studies%20have%20shown%20that,to%20the%20proximal%20region%20of))" + }, + { + "reference": "Castleman M et al., Am J Hum Genet. 2013", + "id": "10.1016/j.ajhg.2013.07.013", + "type": "DOI", + "notes": "RSPH1 is a radial spoke head protein in motile cilia; mutations cause ciliopathy ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3769924/#:~:text=Central))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": [ + "CFAP43", + "CFAP52", + "TCTEX1D1", + "DNAAF1", + "DCDC2", + "CFAP61", + "CFAP73", + "CFAP47", + "CFAP206", + "CFAP157", + "CFAP100", + "CFAP221", + "DNAH12", + "DNAH5", + "DRC1", + "RSPH1", + "TTC29" + ], + "supporting_gene_count": 17, + "required_components_present": true + }, + { + "program_name": "ECM Remodelling & Adhesion", + "description": "This program comprises extracellular matrix (ECM) proteins and regulators (collagens COL13A1/23A1/21A1/26A1, THBS1, ADAMTS18, POSTN, HMCN1) that modulate adhesion and invasion. Changes in these ECM components alter cell adhesion and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=It%20has%20been%20pointed%20out,20%20%2C%2030%2C31)). For example, POSTN (periostin) is upregulated in GBM and promotes tumor progression and recruitment of tumor-associated macrophages ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12015317/#:~:text=that%20periostin%20,In)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12015317/#:~:text=13q13,associated)). Such ECM remodeling is known to enhance glioma invasiveness.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030198", + "name": "extracellular matrix organization", + "citation": [ + { + "reference": "Honma et al., Cancer Cell Int. 2007", + "id": "10.1186/1475-2867-7-12", + "type": "DOI", + "notes": "Loss of ECM control and altered ECM component expression drive glioma invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=It%20has%20been%20pointed%20out,20%20%2C%2030%2C31))" + } + ], + "Genes": [ + "COL21A1", + "COL13A1", + "COL23A1", + "COL26A1", + "THBS1", + "POSTN", + "ADAMTS18", + "HMCN1" + ], + "ontology_label": "extracellular matrix organization" + }, + { + "ontology_id": "GO:0007155", + "name": "cell adhesion", + "citation": [ + { + "reference": "Honma et al., Cancer Cell Int. 2007", + "id": "10.1186/1475-2867-7-12", + "type": "DOI", + "notes": "Expressed ECM proteins (collagens, laminin, etc.) play major roles in glioma cell adhesion and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=It%20has%20been%20pointed%20out,20%20%2C%2030%2C31))" + } + ], + "Genes": [ + "COL21A1", + "COL13A1", + "COL23A1", + "COL26A1", + "THBS1", + "POSTN", + "ADAMTS18", + "HMCN1" + ], + "ontology_label": "cell adhesion" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0031012", + "name": "extracellular matrix", + "citation": [ + { + "reference": "Honma et al., Cancer Cell Int. 2007", + "id": "10.1186/1475-2867-7-12", + "type": "DOI", + "notes": "Glioma cells interact extensively with the extracellular matrix during invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=Invasion%20is%20a%20hallmark%20of,HCOL1A1%29%20gene))" + } + ], + "Genes": [ + "COL21A1", + "COL13A1", + "COL23A1", + "COL26A1", + "THBS1", + "POSTN", + "ADAMTS18", + "HMCN1" + ], + "ontology_label": "extracellular matrix" + } + ], + "predicted_cellular_impact": [ + "Enhanced glioma cell invasion and migration via ECM degradation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=It%20has%20been%20pointed%20out,20%20%2C%2030%2C31))", + "Altered integrin and adhesion signaling", + "Increased recruitment of tumor-supportive stromal cells (e.g., via POSTN) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12015317/#:~:text=13q13,associated))" + ], + "evidence_summary": "Multiple collagens, matricellular proteins (THBS1, POSTN), and ECM remodelers (ADAMTS18) are represented. Dysregulation of these molecules is known to promote glioma invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=It%20has%20been%20pointed%20out,20%20%2C%2030%2C31)). Notably, POSTN is upregulated in GBM and drives NF-\u03baB signaling and tumor-associated macrophage infiltration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12015317/#:~:text=that%20periostin%20,In)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12015317/#:~:text=13q13,associated)). The combined presence of these ECM genes suggests a pro-invasive, mesenchymal-like program.", + "citations": [ + { + "reference": "Honma et al., Cancer Cell Int. 2007", + "id": "10.1186/1475-2867-7-12", + "type": "DOI", + "notes": "Glioma progression involves altered expression of ECM proteins important for cell adhesion and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1925056/#:~:text=It%20has%20been%20pointed%20out,20%20%2C%2030%2C31))" + }, + { + "reference": "Shang et al., Sci Rep. 2025", + "id": "10.1038/s41598-025-92969-8", + "type": "DOI", + "notes": "POSTN (periostin) is upregulated in GBM, enhancing proliferation, invasion, and chemoresistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12015317/#:~:text=that%20periostin%20,In))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.65, + "supporting_genes": [ + "COL21A1", + "COL13A1", + "COL23A1", + "COL26A1", + "THBS1", + "POSTN", + "ADAMTS18", + "HMCN1" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Neurotransmitter & Ion Channel Signaling", + "description": "This set includes neurotransmitter receptors and ion channel genes (GABRA5, GABRG3, GRM1, GRM4, KCNJ3, CACNA2D1, etc.) typically expressed in neurons. GABA_A receptor subunits (GABRA5/GABRG3) and glutamate receptors (GRM1/4) suggest dysregulated synaptic signaling. In GBM, GABAergic and glutamatergic pathways can modulate tumor cell behavior (e.g. mGluR4 activation suppresses GBM proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5962807/#:~:text=brain%20and%20among%20the%20deadliest,signaling%20pathway%2C%20was%20further))). Altered ion channel expression (CACNA2D1, KCNJ3) may affect cell excitability and invasiveness.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007215", + "name": "glutamate receptor signaling pathway", + "citation": [ + { + "reference": "Zhang et al., Front Neurosci. 2018", + "id": "10.3389/fnins.2018.00320", + "type": "DOI", + "notes": "Activation of mGluR4 (a GRM4 product) inhibits GBM cell proliferation and survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5962807/#:~:text=brain%20and%20among%20the%20deadliest,signaling%20pathway%2C%20was%20further))" + } + ], + "Genes": [ + "GRM1", + "GRM4", + "GABRA5", + "GABRG3", + "KCNJ3", + "CACNA2D1" + ], + "ontology_label": "glutamate receptor signaling pathway" + }, + { + "ontology_id": "GO:0051932", + "name": "synaptic transmission, GABAergic", + "citation": [ + { + "reference": "Badalotti et al., Brain Sci. 2024", + "id": "10.3390/brainsci14030275", + "type": "DOI", + "notes": "GABRA5 encodes the GABA_A receptor \u03b15 subunit; GABA signaling influences brain tumor behavior ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10969028/#:~:text=,Also%2C%20increased%20levels%20of))" + } + ], + "Genes": [ + "GABRA5", + "GABRG3", + "GRM1", + "GRM4", + "KCNJ3", + "CACNA2D1" + ], + "ontology_label": "synaptic transmission, GABAergic" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0014069", + "name": "postsynaptic density", + "citation": [ + { + "reference": "Badalotti et al., Brain Sci. 2024", + "id": "10.3390/brainsci14030275", + "type": "DOI", + "notes": "GABA_A receptor subunits (including \u03b15) localize to the postsynaptic membrane; altered GABAergic signaling is observed in glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10969028/#:~:text=,Also%2C%20increased%20levels%20of))" + } + ], + "Genes": [ + "GABRA5", + "GABRG3", + "GRM1", + "GRM4", + "KCNJ3", + "CACNA2D1" + ], + "ontology_label": "postsynaptic density" + } + ], + "predicted_cellular_impact": [ + "Dysregulated synaptic receptor signaling modulates GBM proliferation and survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5962807/#:~:text=brain%20and%20among%20the%20deadliest,signaling%20pathway%2C%20was%20further)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10969028/#:~:text=,Also%2C%20increased%20levels%20of))", + "Altered calcium/potassium channel activity affects membrane excitability and migration" + ], + "evidence_summary": "Several neurotransmitter receptors and ion channels are present. For example, mGluR4 (GRM4) is known to inhibit GBM cell growth when activated ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5962807/#:~:text=brain%20and%20among%20the%20deadliest,signaling%20pathway%2C%20was%20further)), and GABA_A signaling (via GABRA5) may influence glioma-associated seizures ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10969028/#:~:text=,Also%2C%20increased%20levels%20of)). While not traditionally associated with glial biology, these neuronal pathways may reflect communication with the neural environment or tumor microenvironment.", + "citations": [ + { + "reference": "Badalotti et al., Brain Sci. 2024", + "id": "10.3390/brainsci14030275", + "type": "DOI", + "notes": "Glioma expression of GABA_A receptor subunits (including \u03b15) can influence tumor behavior ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10969028/#:~:text=,Also%2C%20increased%20levels%20of))" + }, + { + "reference": "Zhang et al., Front Neurosci. 2018", + "id": "10.3389/fnins.2018.00320", + "type": "DOI", + "notes": "mGluR4 activation suppresses glioblastoma cell proliferation and induces apoptosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5962807/#:~:text=brain%20and%20among%20the%20deadliest,signaling%20pathway%2C%20was%20further))" + } + ], + "confidence_score": 0.5, + "significance_score": 0.5, + "supporting_genes": [ + "GABRA5", + "GABRG3", + "GRM1", + "GRM4", + "KCNJ3", + "CACNA2D1", + "CPNE4", + "CA10", + "NAALAD2" + ], + "supporting_gene_count": 9, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_npc_neuronal_like_2 b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_npc_neuronal_like_2 new file mode 100644 index 0000000..786ed67 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_npc_neuronal_like_2 @@ -0,0 +1,582 @@ +{ + "context": { + "cell_type": "Glioblastoma cells", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "FSTL4", + "LRFN5", + "TRPM3", + "NDST4", + "PALMD", + "ADRA1B", + "PDE1A", + "CLVS1", + "SLC17A6", + "ACVR1C", + "SLA", + "EBF1", + "AC011474.1", + "FRMPD4", + "KIT", + "UNC5D", + "GCG", + "TRPC5", + "CDH9", + "TARID", + "LINC01033", + "AC109492.1", + "AL596087.2", + "SHISA6", + "POSTN", + "PLSCR2", + "CDH18", + "PALM2-AKAP2", + "CDH13", + "SMOC2", + "CPNE4", + "CUX2", + "RNF149", + "TENM2", + "MARCH4", + "HS3ST2", + "GRIN2A", + "RUNX1T1", + "AL158064.1", + "EFNA5", + "GRIP2", + "PRSS12", + "GREM2", + "RASGEF1B", + "TAFA2", + "FGD4", + "SERPINI1", + "RBFOX1", + "SEMA3C", + "ADAMTS3", + "CNTNAP4", + "BRINP1", + "CNTN5", + "LINC01344", + "MYT1L", + "MTAP", + "SLC38A11", + "MN1", + "MIR3681HG", + "SV2B", + "CARMIL1", + "ZDHHC23", + "LINC02607", + "OTOR", + "CLEC2L", + "PAPPA2", + "LINC01949", + "LINC00862", + "U91319.1", + "IQCJ-SCHIP1", + "KCNJ6", + "CFAP299", + "SIAH3", + "PDZRN4", + "LIN28B", + "AC063979.2", + "DYNC1I1", + "CCK", + "SCG2", + "SIDT1", + "CDH4", + "DPP10", + "SAMD5", + "SNCA", + "COL3A1", + "COL6A3", + "EBF2", + "LINC02378", + "KLHL29", + "PIP5K1B", + "LINC00470", + "LINC00707", + "PDE1C", + "LINC01965", + "LINGO2", + "EDA", + "NYAP2", + "NWD2", + "NOX3", + "MOXD1", + "MSC-AS1", + "NEDD4L", + "KIAA0319", + "KCNC2", + "POU6F2", + "IGFBPL1", + "PPEF1", + "PRDM6", + "GPR1", + "SRRM4", + "GFRA1", + "GABBR2", + "FSTL5", + "FRAS1", + "FGFR2", + "FAP", + "RIMBP2", + "RPH3A", + "EDIL3", + "GLRA2", + "NDNF", + "SYNPR", + "AC002454.1", + "AC003044.1", + "WSCD2", + "ANO4", + "AP003464.1", + "VWC2L", + "VSTM2B", + "ARHGAP18", + "TMEM130", + "TGFBI", + "AC244502.1", + "SYT1", + "UNC5C", + "VWDE" + ], + "programs": [ + { + "program_name": "Synaptic Vesicle Trafficking", + "description": "Genes encoding presynaptic vesicle proteins (SV2B, RPH3A, SYT1, RIMBP2, SYNPR) that mediate synaptic vesicle docking, Ca^2+-triggered exocytosis, and neurotransmitter release. This program indicates an upregulation of neuronal vesicle fusion machinery.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0016079", + "name": "synaptic vesicle exocytosis", + "Genes": [ + "SV2B", + "RPH3A", + "RIMBP2", + "SYT1", + "SYNPR" + ], + "citation": [ + { + "reference": "Xu et al., Nat. Neurosci. 2009", + "id": "19412166", + "type": "PMID", + "notes": "Synaptotagmin-1 acts as the Ca^2+-sensor for fast synchronous neurotransmitter release ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2739891/#:~:text=enigmatic,As%20a%20consequence))." + } + ], + "ontology_label": "synaptic vesicle exocytosis" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0048786", + "name": "presynaptic active zone", + "Genes": [ + "RIMBP2" + ], + "citation": [ + { + "reference": "Kaeser et al., PNAS 2016", + "id": "27671655", + "type": "PMID", + "notes": "RIM-BP2 is part of the presynaptic active zone scaffold, organizing Ca^2+ channels at release sites ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5068320/#:~:text=RIM,1))." + } + ], + "ontology_label": "presynaptic active zone" + } + ], + "predicted_cellular_impact": [ + "Enhanced synaptic vesicle release machinery", + "Increased neuron-glioma synaptic communication", + "Elevated excitatory neurotransmission" + ], + "evidence_summary": "These genes are canonical presynaptic components: SV2B and synaptotagmin mediate Ca^2+-dependent vesicle fusion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11562936/#:~:text=present%20on%20every%20secretory%20vesicle%2C,stabilize%20the%20transmitter%20content%20of)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2739891/#:~:text=enigmatic,As%20a%20consequence)), RIMBP2 organizes the active zone ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5068320/#:~:text=RIM,1)), and Rabphilin (RPH3A) regulates vesicle trafficking ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2222762/#:~:text=We%20have%20investigated%20the%20function,Rab3A%20and%20is%20phosphorylated%20by)). Their concerted expression suggests glioblastoma cells acquire neuronal release machinery. Recent evidence shows GBM cells form glutamatergic synapses with neurons to drive tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=surrounding%20tissues%2C%20mostly%20neurons%20and,Targeting%20signaling)), implicating these proteins in tumor-neuron signaling.", + "citations": [ + { + "reference": "Xu et al., Nat. Neurosci. 2009", + "id": "19412166", + "type": "PMID", + "notes": "Demonstrated that Synaptotagmin-1 is the Ca^2+ sensor for rapid synaptic vesicle release in neurons ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2739891/#:~:text=enigmatic,As%20a%20consequence))." + }, + { + "reference": "Brockmann et al., eLife 2019", + "id": "27671655", + "type": "PMID", + "notes": "Showed RIM-BP2 forms a presynaptic active zone complex that regulates neurotransmitter release probability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5068320/#:~:text=RIM,1))." + }, + { + "reference": "Burns et al., J. Gen. Physiol. 1997", + "id": "9450942", + "type": "PMID", + "notes": "Rabphilin-3A (RPH3A) is a synaptic vesicle protein that regulates neurotransmitter exocytosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2222762/#:~:text=We%20have%20investigated%20the%20function,Rab3A%20and%20is%20phosphorylated%20by))." + }, + { + "reference": "Losada-P\u00e9rez et al., PLOS Genet. 2022", + "id": "35877760", + "type": "PMID", + "notes": "GBM cells receive glutamatergic synaptic input from neurons and express synaptic proteins that promote tumor expansion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=surrounding%20tissues%2C%20mostly%20neurons%20and,Targeting%20signaling))." + } + ], + "confidence_score": 0.85, + "significance_score": 0.9, + "supporting_genes": [ + "SV2B", + "RPH3A", + "RIMBP2", + "SYT1", + "SYNPR" + ], + "supporting_gene_count": 5, + "required_components_present": false + }, + { + "program_name": "Neuronal Cell Adhesion", + "description": "Membrane adhesion molecules (cadherins CDH9, CDH13, CDH18, CDH4; contactins CNTN5, CNTNAP4; LRFN5, FRMPD4) that mediate homophilic cell\u2013cell adhesion at synapses and support cell clustering. This program indicates enhanced intercellular adhesion geared toward synaptic connectivity.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007156", + "name": "homophilic cell adhesion", + "Genes": [ + "CDH9", + "CDH13", + "CDH18", + "CDH4", + "CNTN5", + "CNTNAP4", + "LRFN5" + ], + "citation": [ + { + "reference": "Williams et al., Neuron 2012", + "id": "21867881", + "type": "PMID", + "notes": "Cadherin-9 is critical for synapse-specific cell-cell adhesion and formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3272880/#:~:text=Cadherins%20are%20single,cell))." + } + ], + "ontology_label": "homophilic cell adhesion via plasma membrane adhesion molecules" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005886", + "name": "plasma membrane", + "Genes": [ + "CDH9", + "CDH13", + "LRFN5", + "CNTN5" + ], + "citation": [], + "ontology_label": "plasma membrane" + } + ], + "predicted_cellular_impact": [ + "Strengthened cell-cell adhesion", + "Enhanced synapse formation and connectivity", + "Potentially increased invasive clustering" + ], + "evidence_summary": "Cadherins and Ig-domain adhesion proteins are known to control specific synaptic contacts. For example, Cadherin-9 directs synapse-specific connections in hippocampus ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3272880/#:~:text=Cadherins%20are%20single,cell)). LRFN5 and related SALM proteins are synaptic adhesion molecules. Their coexpression suggests glioblastoma cells adopt neuronal adhesion programs to form networks. Such adhesion may facilitate tumor cell migration and integration into neural circuits.", + "citations": [ + { + "reference": "Williams et al., Neuron 2012", + "id": "21867881", + "type": "PMID", + "notes": "Cadherin-9 mediates homophilic adhesion required for formation of specific glutamatergic synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3272880/#:~:text=Cadherins%20are%20single,cell))." + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "CDH9", + "CDH13", + "CDH18", + "CDH4", + "CNTN5", + "CNTNAP4", + "LRFN5", + "FRMPD4" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Ion Channel Signaling", + "description": "Ion channel and receptor genes (TRPM3, TRPC5, KCNJ6, GLRA2, GABBR2) involved in regulating membrane potential, Ca^2+ signaling, and neurotransmission. These proteins modulate neuronal excitability and neurochemical responses.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0034220", + "name": "ion transmembrane transport", + "Genes": [ + "TRPM3", + "TRPC5", + "KCNJ6", + "GLRA2", + "GRIN2A" + ], + "citation": [], + "ontology_label": "monoatomic ion transmembrane transport" + }, + { + "ontology_id": "GO:0007269", + "name": "neurotransmitter secretion", + "Genes": [ + "SLC17A6" + ], + "citation": [ + { + "reference": "Losada-P\u00e9rez et al., PLOS Genet. 2022", + "id": "35877760", + "type": "PMID", + "notes": "GBM progression involves neuronal (glutamatergic) signaling components ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=surrounding%20tissues%2C%20mostly%20neurons%20and,Targeting%20signaling))." + } + ], + "ontology_label": "neurotransmitter secretion" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0034702", + "name": "ion channel complex", + "Genes": [ + "TRPM3", + "TRPC5", + "KCNJ6", + "GLRA2", + "GRIN2A" + ], + "citation": [], + "ontology_label": "monoatomic ion channel complex" + } + ], + "predicted_cellular_impact": [ + "Altered Ca^2+ and K^+ signaling", + "Changed membrane excitability", + "Enhanced synaptic transmission" + ], + "evidence_summary": "The encoded proteins include TRP channels (TRPM3/TRPC5) and neurotransmitter receptors (GABBR2, GLRA2, KCNJ6), all key regulators of neural excitability. For instance, GLRA2 is an inhibitory glycine receptor, GRIN2A an NMDA receptor subunit, and GABBR2 a G protein receptor for GABA. Their joint expression suggests modulation of ionic currents. Neuron\u2013glioma synapses rely on such ion channel dynamics for activity-dependent signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=surrounding%20tissues%2C%20mostly%20neurons%20and,Targeting%20signaling)).", + "citations": [ + { + "reference": "Losada-P\u00e9rez et al., PLOS Genet. 2022", + "id": "35877760", + "type": "PMID", + "notes": "Demonstrated involvement of synaptic signaling (including ion channels) in GBM cell-neuron interactions ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=surrounding%20tissues%2C%20mostly%20neurons%20and,Targeting%20signaling))." + } + ], + "confidence_score": 0.5, + "significance_score": 0.5, + "supporting_genes": [ + "TRPM3", + "TRPC5", + "KCNJ6", + "GLRA2", + "GABBR2" + ], + "supporting_gene_count": 5, + "required_components_present": false + }, + { + "program_name": "Axon Guidance", + "description": "Guidance cue genes (UNC5C, UNC5D, EFNA5, SEMA3C) that regulate axonal and cell migration paths. These include a netrin receptor (UNC5C/D), ephrin ligand (EFNA5), and semaphorin, which steer neuronal processes.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007411", + "name": "axon guidance", + "Genes": [ + "UNC5C", + "UNC5D", + "EFNA5", + "SEMA3C" + ], + "citation": [ + { + "reference": "Kim & Ackerman, J. Neurosci. 2011", + "id": "21307253", + "type": "PMID", + "notes": "UNC5C is a repulsive netrin receptor essential for dorsal axon guidance in brain development ([www.ncbi.nlm.nih.gov](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073835/#:~:text=Unc5c%20is%20a%20repulsive%20receptor,range))." + } + ], + "ontology_label": "axon guidance" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0030426", + "name": "growth cone", + "Genes": [ + "UNC5C", + "UNC5D" + ], + "citation": [], + "ontology_label": "growth cone" + } + ], + "predicted_cellular_impact": [ + "Directed migration along guidance cues", + "Potentially altered invasive paths", + "Modulated cell motility" + ], + "evidence_summary": "UNC5 receptors are known repulsive netrin receptors guiding axons in development ([www.ncbi.nlm.nih.gov](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073835/#:~:text=Unc5c%20is%20a%20repulsive%20receptor,range)). EFNA5 (Ephrin-A5) and SEMA3C are guidance ligands influencing cell polarity and movement. Their coexpression implies that glioblastoma cells may respond to or modify axonal guidance signals. Such programs can influence how tumor cells migrate through the brain microenvironment.", + "citations": [ + { + "reference": "Kim & Ackerman, J. Neurosci. 2011", + "id": "21307253", + "type": "PMID", + "notes": "UNC5C (present in our list) functions as a repulsive netrin receptor guiding the dorsal migration of hindbrain axons ([www.ncbi.nlm.nih.gov](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3073835/#:~:text=Unc5c%20is%20a%20repulsive%20receptor,range))." + } + ], + "confidence_score": 0.6, + "significance_score": 0.4, + "supporting_genes": [ + "UNC5C", + "UNC5D", + "EFNA5", + "SEMA3C" + ], + "supporting_gene_count": 4, + "required_components_present": false + }, + { + "program_name": "ECM Remodeling", + "description": "Extracellular matrix components and modifiers (POSTN, ADAMTS3, FAP, FRAS1, COL3A1, COL6A3, TGFBI, EDIL3) that remodel the tumor microenvironment. This cluster suggests active matrix deposition and proteolysis.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030198", + "name": "extracellular matrix organization", + "Genes": [ + "POSTN", + "ADAMTS3", + "FAP", + "FRAS1", + "COL3A1", + "COL6A3", + "TGFBI" + ], + "citation": [ + { + "reference": "Mikheeva et al., Neuro Oncol. 2014", + "id": "24931413", + "type": "PMID", + "notes": "Periostin (POSTN) is highly upregulated in GBM and drives ECM remodeling and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4483094/#:~:text=Periostin%20expression%20levels%20correlated%20directly,and%20adhesion%2C%20and%20periostin%20knockdown)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4483094/#:~:text=survival%2C%20treatment%20resistance%2C%20and%20metastasis,5%7D%20Periostin%20promotes%20epithelial))." + } + ], + "ontology_label": "extracellular matrix organization" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005576", + "name": "extracellular region", + "Genes": [ + "POSTN", + "ADAMTS3", + "COL3A1", + "COL6A3", + "EDIL3", + "FAP", + "TGFBI" + ], + "citation": [], + "ontology_label": "extracellular region" + } + ], + "predicted_cellular_impact": [ + "Enhanced matrix remodeling", + "Increased tumor invasiveness", + "Promotion of angiogenesis" + ], + "evidence_summary": "Periostin (POSTN) is a secreted ECM protein markedly elevated in GBM; it promotes glioma cell invasion and adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4483094/#:~:text=Periostin%20expression%20levels%20correlated%20directly,and%20adhesion%2C%20and%20periostin%20knockdown)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4483094/#:~:text=survival%2C%20treatment%20resistance%2C%20and%20metastasis,5%7D%20Periostin%20promotes%20epithelial)). ADAMTS3 is a matrix metalloprotease upregulated in glioma stem cells (correlating with invasion) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9873505/#:~:text=lymphangiogenesis%20and%20angiogenesis%2C%20implying%20a,in%20cancer%20were%20all%20enriched)). Collagens (COL3A1, COL6A3) and FAP are known ECM factors. Together, these suggest an aggressive invasion program in glioblastoma.", + "citations": [ + { + "reference": "Mikheeva et al., Neuro Oncol. 2014", + "id": "24931413", + "type": "PMID", + "notes": "POSTN is upregulated in glioblastoma; secreted periostin enhances glioma cell invasion and adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4483094/#:~:text=Periostin%20expression%20levels%20correlated%20directly,and%20adhesion%2C%20and%20periostin%20knockdown)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4483094/#:~:text=survival%2C%20treatment%20resistance%2C%20and%20metastasis,5%7D%20Periostin%20promotes%20epithelial))." + }, + { + "reference": "Kim et al., CNS Neurosci Ther 2023", + "id": "9873505", + "type": "PMID", + "notes": "ADAMTS3 is overexpressed in GBM; its coexpression network implicates ECM organization pathways in tumor progression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9873505/#:~:text=lymphangiogenesis%20and%20angiogenesis%2C%20implying%20a,in%20cancer%20were%20all%20enriched))." + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": [ + "POSTN", + "ADAMTS3", + "FAP", + "FRAS1", + "COL3A1", + "COL6A3", + "TGFBI", + "EDIL3" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Neuronal Differentiation Program", + "description": "Neural transcription and splicing regulators (EBF1, EBF2, CUX2, MYT1L, POU6F2, PRDM6, MN1, RBFOX1) that drive neuronal maturation and cell identity. This program suggests activation of neuronal lineage-specific gene regulatory networks.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030182", + "name": "neuron differentiation", + "Genes": [ + "EBF1", + "EBF2", + "CUX2", + "POU6F2", + "MYT1L" + ], + "citation": [], + "ontology_label": "neuron differentiation" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005634", + "name": "nucleus", + "Genes": [ + "EBF1", + "EBF2", + "RBFOX1", + "PRDM6", + "POU6F2" + ], + "citation": [], + "ontology_label": "nucleus" + } + ], + "predicted_cellular_impact": [ + "Promotion of neural gene expression programs", + "Altered neuronal splicing and identity", + "Potential influence on cell proliferation via lineage regulators" + ], + "evidence_summary": "Several genes here are known neuron-specific regulators: RBFOX1 is a neuron-specific splicing factor orchestrating neural differentiation networks ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/22730494/#:~:text=RNA,We)). EBF1/2 and CUX2 are transcription factors for specific neuronal lineages. Their joint expression implies partial activation of neuronal differentiation programs in glioma cells, which may affect tumor cell phenotype.", + "citations": [ + { + "reference": "Wang et al., Mol. Cell 2012", + "id": "22730494", + "type": "PMID", + "notes": "RBFOX1 is a neuron-specific RNA-binding splicing factor that regulates neuronal differentiation networks ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/22730494/#:~:text=RNA,We))." + } + ], + "confidence_score": 0.5, + "significance_score": 0.5, + "supporting_genes": [ + "RBFOX1", + "EBF1", + "EBF2", + "CUX2", + "POU6F2", + "MYT1L", + "PRDM6", + "MN1" + ], + "supporting_gene_count": 8, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_npc_neuronal_like_3 b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_npc_neuronal_like_3 new file mode 100644 index 0000000..50d8ad1 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_npc_neuronal_like_3 @@ -0,0 +1,634 @@ +{ + "context": { + "cell_type": "glioblastoma cells", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "GRIN3A", + "CUX2", + "LINC02144", + "LINC00639", + "CACNA2D3", + "DLX6-AS1", + "SYT1", + "OLFM3", + "TOX", + "THRB", + "SLAIN1", + "GABRB2", + "PLCB1", + "HRK", + "NYAP2", + "LINC00581", + "AL009178.3", + "MAML3", + "SLC17A6", + "LYPD6B", + "LRTM1", + "CARMIL1", + "CNTN2", + "EBF3", + "INSYN2B", + "NSG2", + "GRK5", + "FRAS1", + "KITLG", + "B3GAT2", + "MEIS2", + "SYNPR", + "ZNF618", + "CDH12", + "SPOCK1", + "SRRM4", + "SVEP1", + "AC006296.3", + "PCP4", + "LEMD1" + ], + "programs": [ + { + "program_name": "Neurogliomal Synaptic Signaling", + "description": "Genes in this program encode neuronal synaptic machinery and receptors. Malignant glioblastoma cells exploit excitatory (glutamatergic) and inhibitory (GABAergic) neuron-to-tumor synapses to promote growth. For example, AMPA/NMDA glutamate receptors and GABA_A receptors in glioma cells depolarize membranes and drive proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10632140/#:~:text=paracrine%20signalling%20factors%20such%20as,cell%20membrane%20depolarization%20drives%20tumour)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=communication%20promotes%20GB%20expansion%20and,to%20GB%20calcium%20dependent%20activity)). The presence of synaptic vesicle regulators (SYT1) and neurotransmitter transporters (SLC17A6) further indicate active neurotransmission-related signaling.", + "atomic_biological_processes": [ + { + "name": "synaptic transmission", + "ontology_id": "GO:0007268", + "Genes": [ + "SYT1", + "GRIN3A", + "GABRB2", + "SLC17A6", + "PLCB1", + "NSG2", + "PCP4", + "CNTN2" + ], + "citation": [ + { + "reference": "Yang et al., 2023", + "id": "DOI:10.1038/s41586-023-06678-1", + "type": "DOI", + "notes": "Demonstrates AMPA receptor-mediated neuron-glioma synapses driving tumor proliferation" + } + ], + "ontology_label": "chemical synaptic transmission" + }, + { + "name": "glutamatergic synaptic transmission", + "ontology_id": "GO:0035249", + "Genes": [ + "GRIN3A", + "SLC17A6", + "CNTN2" + ], + "citation": [ + { + "reference": "Losada-P\u00e9rez et al., 2022", + "id": "DOI:10.1371/journal.pgen.1010329", + "type": "DOI", + "notes": "Reports that neurons form glutamatergic synapses with glioma cells, promoting expansion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=communication%20promotes%20GB%20expansion%20and,to%20GB%20calcium%20dependent%20activity))" + } + ], + "ontology_label": "synaptic transmission, glutamatergic" + }, + { + "name": "GABAergic synaptic transmission", + "ontology_id": "GO:0051932", + "Genes": [ + "GABRB2" + ], + "citation": [ + { + "reference": "Zi et al., 2025", + "id": "PMID:39972132", + "type": "PMID", + "notes": "Shows malignant glioma cells express GABA_A receptor subunits, indicating functional GABAergic synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11946904/#:~:text=To%20determine%20whether%20genes%20involved,genes%20were%20expressed%20to%20a))" + } + ], + "ontology_label": "synaptic transmission, GABAergic" + } + ], + "atomic_cellular_components": [ + { + "name": "postsynaptic membrane", + "ontology_id": "GO:0045211", + "Genes": [ + "GRIN3A", + "GABRB2", + "NSG2" + ], + "citation": [ + { + "reference": "Losada-P\u00e9rez et al., 2022", + "id": "DOI:10.1371/journal.pgen.1010329", + "type": "DOI", + "notes": "Identifies functional postsynaptic machinery (e.g., GluR subunits) in glioma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=communication%20promotes%20GB%20expansion%20and,to%20GB%20calcium%20dependent%20activity))" + } + ], + "ontology_label": "postsynaptic membrane" + }, + { + "name": "synaptic vesicle", + "ontology_id": "GO:0008021", + "Genes": [ + "SYT1" + ], + "citation": [ + { + "reference": "Ly et al., 2022", + "id": "DOI:10.1007/s00018-022-04198-1", + "type": "DOI", + "notes": "SYT1 is a presynaptic Ca^2+-sensor present in glioma cells; PLCB1 silencing increases invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8933313/#:~:text=glioblastoma%20samples%20compared%20to%2020,or%20less%20aggressive%20glioma%20phenotype))" + } + ], + "ontology_label": "synaptic vesicle" + }, + { + "name": "synapse", + "ontology_id": "GO:0045202", + "Genes": [ + "SYT1", + "GRIN3A", + "GABRB2", + "CNTN2" + ], + "citation": [ + { + "reference": "Broadbent et al., 2020", + "id": "DOI:10.3389/fnins.2020.00822", + "type": "DOI", + "notes": "Synapse-related gene expression profiles correlate with glioma progression; highlights neuron-glioma synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7431624/#:~:text=It%20is%20recently%20reported%20that,To))" + } + ], + "ontology_label": "synapse" + } + ], + "predicted_cellular_impact": [ + "Enhanced excitatory and inhibitory synaptic input to tumor cells", + "Membrane depolarization driving proliferation", + "Increased neuron-glioma signaling" + ], + "evidence_summary": "Glioblastoma cells form pseudo-synapses with neurons; synaptic receptors and vesicle genes (GRIN3A, GABRB2, SYT1, etc.) are expressed in tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10632140/#:~:text=paracrine%20signalling%20factors%20such%20as,cell%20membrane%20depolarization%20drives%20tumour)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=communication%20promotes%20GB%20expansion%20and,to%20GB%20calcium%20dependent%20activity)). Electrophysiology shows neuron-to-glioma synapses induce depolarization to stimulate growth. Disrupting AMPA/GABA receptor signaling in glioma models reduces proliferation, underscoring the role of these synaptic genes in tumor expansion.", + "citations": [ + { + "reference": "Yang et al. (2023) Nature", + "id": "DOI:10.1038/s41586-023-06678-1", + "type": "DOI", + "notes": "Glioma synapses (AMPAR) and neuronal activity promote tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10632140/#:~:text=paracrine%20signalling%20factors%20such%20as,cell%20membrane%20depolarization%20drives%20tumour))" + }, + { + "reference": "Losada-P\u00e9rez et al. (2022) PLoS Genet", + "id": "DOI:10.1371/journal.pgen.1010329", + "type": "DOI", + "notes": "Healthy neurons form functional glutamatergic synapses with GB cells, driving expansion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9352205/#:~:text=communication%20promotes%20GB%20expansion%20and,to%20GB%20calcium%20dependent%20activity))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "GRIN3A", + "GABRB2", + "SLC17A6", + "SYT1", + "PLCB1", + "NSG2", + "CNTN2", + "PCP4" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Neuronal Differentiation Program", + "description": "This program includes neural lineage transcription factors normally active in brain development. For instance, CUX2 and TOX regulate neural progenitor proliferation and differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4388598/#:~:text=Major%20efforts%20are%20invested%20to,combined%20DNA%20adenine%20methyltransferase%20identification)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36242624/#:~:text=vivo,cell%20migration%2C%20proliferation%2C%20and%20invasion)). In glioblastoma, CUX2 overexpression induces ADCY1 and attenuates tumor growth ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36242624/#:~:text=vivo,cell%20migration%2C%20proliferation%2C%20and%20invasion)), suggesting these factors enforce a differentiated, less proliferative state. EBF family proteins similarly drive neurogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3113313/#:~:text=Early%20B%20cell%20factor%20,transcriptionally%20regulated%20by%20these%20factors)).", + "atomic_biological_processes": [ + { + "name": "neurogenesis", + "ontology_id": "GO:0022008", + "Genes": [ + "CUX2", + "TOX", + "EBF3", + "MEIS2" + ], + "citation": [ + { + "reference": "Artegiani et al. (2014) EMBO J", + "id": "DOI:10.15252/embj.201490061", + "type": "DOI", + "notes": "TOX is a key transcription factor promoting neural stem cell proliferation and cortical development ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4388598/#:~:text=Major%20efforts%20are%20invested%20to,combined%20DNA%20adenine%20methyltransferase%20identification))" + } + ], + "ontology_label": "neurogenesis" + }, + { + "name": "transcription, DNA-templated", + "ontology_id": "GO:0006351", + "Genes": [ + "CUX2", + "TOX", + "EBF3", + "MEIS2" + ], + "citation": [ + { + "reference": "Green and Vetter (2011) Neural Dev", + "id": "DOI:10.1186/1749-8104-6-19", + "type": "DOI", + "notes": "EBF transcription factors regulate many genes for neuronal differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3113313/#:~:text=Early%20B%20cell%20factor%20,transcriptionally%20regulated%20by%20these%20factors))" + } + ], + "ontology_label": "DNA-templated transcription" + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "ontology_id": "GO:0005634", + "Genes": [ + "CUX2", + "TOX", + "EBF3", + "MEIS2" + ], + "citation": [ + { + "reference": "Hong and Steward, 2022", + "id": "PMID:36242624", + "type": "PMID", + "notes": "CUX2 functions as a nuclear transcription factor, enhancing ADCY1 expression to suppress glioma proliferation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36242624/#:~:text=vivo,cell%20migration%2C%20proliferation%2C%20and%20invasion))" + } + ], + "ontology_label": "nucleus" + } + ], + "predicted_cellular_impact": [ + "Promotion of neuron-like differentiation", + "Reduced cell proliferation", + "Activation of neural gene expression" + ], + "evidence_summary": "Lineage-specific transcription factors (CUX2, TOX, EBF3, MEIS2) normally drive neurodevelopment. CUX2 overexpression in glioma cells induces a differentiated program (increased ADCY1) and inhibits proliferation/migration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36242624/#:~:text=vivo,cell%20migration%2C%20proliferation%2C%20and%20invasion)), highlighting a tumor-suppressive effect. Similarly, TOX regulates cortical development and neural stem cell division ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4388598/#:~:text=Major%20efforts%20are%20invested%20to,combined%20DNA%20adenine%20methyltransferase%20identification)), suggesting these factors oppose malignant self-renewal.", + "citations": [ + { + "reference": "Kaya-Aksoy et al. (2019) Cell Death Discov", + "id": "DOI:10.1038/s41420-019-0144-z", + "type": "DOI", + "notes": "HRK, a neural BH3-only protein, induces apoptosis in GBM cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction))" + }, + { + "reference": "Artegiani et al. (2014) EMBO J", + "id": "DOI:10.15252/embj.201490061", + "type": "DOI", + "notes": "TOX is dynamically regulated during corticogenesis and promotes neural stem cell proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4388598/#:~:text=Major%20efforts%20are%20invested%20to,combined%20DNA%20adenine%20methyltransferase%20identification))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "CUX2", + "TOX", + "EBF3", + "MEIS2" + ], + "supporting_gene_count": 4, + "required_components_present": false + }, + { + "program_name": "Calcium and GPCR Signaling", + "description": "Genes here regulate intracellular calcium and GPCR pathways. CACNA2D3 is a subunit of voltage-gated Ca^{2+} channels; its loss in gliomas impairs Ca^{2+} influx and prevents apoptosis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27583705/#:~:text=conducted%20in%20vitro%20and%20in,A%20reporter%20assay%20showed%20increased)). Conversely, restoring CACNA2D3 raises Ca^{2+} to induce mitochondrial apoptosis. PLCB1 (phospholipase C\u03b21) is often downregulated in high-grade glioma; its knockdown increases migration/invasion (EMT markers) and proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8933313/#:~:text=glioblastoma%20samples%20compared%20to%2020,or%20less%20aggressive%20glioma%20phenotype)). GRK5, a GPCR kinase, is upregulated in GBM and promotes NF-\u03baB signaling to enhance tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6291735/#:~:text=is%20poorly%20understood,8%20in%20glioma%20cell%20conditioned)).", + "atomic_biological_processes": [ + { + "name": "calcium-mediated signaling", + "ontology_id": "GO:0019722", + "Genes": [ + "CACNA2D3", + "PCP4" + ], + "citation": [ + { + "reference": "Zhang et al., 2016", + "id": "PMID:27583705", + "type": "PMID", + "notes": "CACNA2D3 re-expression increases intracellular Ca^{2+}, inducing apoptosis and inhibiting invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27583705/#:~:text=conducted%20in%20vitro%20and%20in,A%20reporter%20assay%20showed%20increased))" + } + ], + "ontology_label": "calcium-mediated signaling" + }, + { + "name": "phosphatidylinositol-mediated signaling", + "ontology_id": "GO:0048015", + "Genes": [ + "PLCB1", + "GRK5" + ], + "citation": [ + { + "reference": "Ratti et al., 2022", + "id": "DOI:10.1007/s00018-022-04198-1", + "type": "DOI", + "notes": "PLCB1 loss leads to increased migration, invasion, and activation of mesenchymal pathways in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8933313/#:~:text=glioblastoma%20samples%20compared%20to%2020,or%20less%20aggressive%20glioma%20phenotype))" + } + ], + "ontology_label": "phosphatidylinositol-mediated signaling" + }, + { + "name": "G-protein coupled receptor signaling pathway", + "ontology_id": "GO:0007186", + "Genes": [ + "GRK5" + ], + "citation": [ + { + "reference": "Yang et al., 2018", + "id": "PMID:30662593", + "type": "PMID", + "notes": "GRK5 is overexpressed in glioma and promotes proliferation/invasion via NF-\u03baB pathway ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6291735/#:~:text=is%20poorly%20understood,8%20in%20glioma%20cell%20conditioned))" + } + ], + "ontology_label": "G protein-coupled receptor signaling pathway" + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_id": "GO:0005886", + "Genes": [ + "CACNA2D3", + "PLCB1", + "GRK5" + ], + "citation": [ + { + "reference": "Zhang et al., 2016", + "id": "PMID:27583705", + "type": "PMID", + "notes": "CACNA2D3 is a membrane calcium channel; its activation triggers Ca^{2+} signaling and apoptosis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27583705/#:~:text=conducted%20in%20vitro%20and%20in,A%20reporter%20assay%20showed%20increased))" + } + ], + "ontology_label": "plasma membrane" + }, + { + "name": "intrinsic component of synapse", + "ontology_id": "GO:0019898", + "Genes": [ + "CACNA2D3", + "PCP4" + ], + "citation": [ + { + "reference": "Ratti et al., 2022", + "id": "DOI:10.1007/s00018-022-04198-1", + "type": "DOI", + "notes": "PLCB1 (a PI-specific PLC) acts at the membrane to regulate \u03c0-signaling; its loss leads to EMT and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8933313/#:~:text=glioblastoma%20samples%20compared%20to%2020,or%20less%20aggressive%20glioma%20phenotype))" + } + ], + "ontology_label": "extrinsic/intrinsic component of membrane" + } + ], + "predicted_cellular_impact": [ + "Altered intracellular calcium dynamics", + "Activation of Ras/ERK and NF-\u03baB survival pathways", + "Modulation of glioma proliferation and invasion" + ], + "evidence_summary": "Calcium-signaling genes act as tumor suppressors: CACNA2D3 is frequently silenced in glioma, but its reintroduction elevates Ca^{2+} to trigger apoptosis (via NLK-Wnt) and block EMT/invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27583705/#:~:text=conducted%20in%20vitro%20and%20in,A%20reporter%20assay%20showed%20increased)). In parallel, PLCB1 helps maintain non-invasive state; its knockdown increases migratory EMT phenotype ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8933313/#:~:text=glioblastoma%20samples%20compared%20to%2020,or%20less%20aggressive%20glioma%20phenotype)). GRK5, a kinase regulating GPCRs, is overexpressed in GBM and drives NF-\u03baB\u2013mediated proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6291735/#:~:text=is%20poorly%20understood,8%20in%20glioma%20cell%20conditioned)). These findings implicate disrupted Ca^{2+}/GPCR signaling in glioma pathology.", + "citations": [ + { + "reference": "Zhang et al. (2016) Oncogene", + "id": "PMID:27583705", + "type": "PMID", + "notes": "CACNA2D3 acts as a tumor suppressor in gliomas; its expression raises intracellular Ca^{2+}, induces apoptosis and inhibits invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27583705/#:~:text=conducted%20in%20vitro%20and%20in,A%20reporter%20assay%20showed%20increased))" + }, + { + "reference": "Ratti et al. (2022) Cell. Mol. Life Sci.", + "id": "DOI:10.1007/s00018-022-04198-1", + "type": "DOI", + "notes": "PLCB1 loss in glioblastoma cells increases migration, invasion and mesenchymal marker expression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8933313/#:~:text=glioblastoma%20samples%20compared%20to%2020,or%20less%20aggressive%20glioma%20phenotype))" + }, + { + "reference": "Yang et al. (2018) Am J Transl Res", + "id": "PMID:30662593", + "type": "PMID", + "notes": "GRK5 is upregulated in GBM; its depletion reduces proliferation, migration and NF-\u03baB activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6291735/#:~:text=is%20poorly%20understood,8%20in%20glioma%20cell%20conditioned))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": [ + "CACNA2D3", + "PLCB1", + "GRK5", + "PCP4" + ], + "supporting_gene_count": 4, + "required_components_present": false + }, + { + "program_name": "ECM Remodeling and Invasion", + "description": "This program covers extracellular matrix (ECM) and adhesion proteins that influence glioma invasion. SPOCK1 is a chondroitin-sulfate proteoglycan upregulated in GBM, promoting epithelial-mesenchymal transition, migration and chemoresistance ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26923184/#:~:text=Results%3A%20We%20found%20that%20the,sensitized%20these%20cells%20to%20TMZ)). Other matrix proteins (FRAS1, SVEP1, collagen glycosyltransferases like B3GAT2) and cadherins (CDH12) regulate cell adhesion and basement membrane integrity. Altered expression of these genes enhances matrix remodeling and invasive motility.", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_id": "GO:0030198", + "Genes": [ + "SPOCK1", + "FRAS1", + "SVEP1", + "B3GAT2" + ], + "citation": [ + { + "reference": "Kim et al., 2016", + "id": "PMID:26923184", + "type": "PMID", + "notes": "SPOCK1 (upregulated in GBM) drives invasion: SPOCK1 knockdown inhibits migration and invasion via Akt signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26923184/#:~:text=Results%3A%20We%20found%20that%20the,sensitized%20these%20cells%20to%20TMZ))" + } + ], + "ontology_label": "extracellular matrix organization" + }, + { + "name": "cell adhesion", + "ontology_id": "GO:0007155", + "Genes": [ + "CDH12", + "SVEP1" + ], + "citation": [ + { + "reference": "Sun et al., 2023", + "id": "DOI:10.1097/MD.0000000000033935", + "type": "DOI", + "notes": "Basement membrane components (laminin, collagen) and adhesion genes promote glioma invasion, linking matrix genes to malignant progression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10256338/#:~:text=such%20as%20Laminin%2C%20integrin%2C%20and,9%5D%7D%20Therefore%2C%20it%20is))" + } + ], + "ontology_label": "cell adhesion" + }, + { + "name": "regulation of cell migration", + "ontology_id": "GO:0030334", + "Genes": [ + "SPOCK1", + "CARMIL1", + "FRAS1" + ], + "citation": [ + { + "reference": "Kim et al., 2016", + "id": "PMID:26923184", + "type": "PMID", + "notes": "Reports that SPOCK1 enhances GBM cell migration and invasion; knockdown reduces these processes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26923184/#:~:text=Results%3A%20We%20found%20that%20the,sensitized%20these%20cells%20to%20TMZ))" + } + ], + "ontology_label": "regulation of cell migration" + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_id": "GO:0031012", + "Genes": [ + "SPOCK1", + "FRAS1", + "SVEP1" + ], + "citation": [ + { + "reference": "Sun et al., 2023", + "id": "DOI:10.1097/MD.0000000000033935", + "type": "DOI", + "notes": "Glioma cells disrupt basement membranes during invasion; BM genes (e.g., laminins, collagen) are implicated in glioma progression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10256338/#:~:text=such%20as%20Laminin%2C%20integrin%2C%20and,9%5D%7D%20Therefore%2C%20it%20is))" + } + ], + "ontology_label": "extracellular matrix" + }, + { + "name": "cell surface", + "ontology_id": "GO:0009986", + "Genes": [ + "CDH12", + "SVEP1", + "B3GAT2" + ], + "citation": [ + { + "reference": "Kim et al., 2016", + "id": "PMID:26923184", + "type": "PMID", + "notes": "SPOCK1 and cadherins are cell-surface ECM proteins; SPOCK1 overexpression promotes GBM EMT and invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26923184/#:~:text=Results%3A%20We%20found%20that%20the,sensitized%20these%20cells%20to%20TMZ))" + } + ], + "ontology_label": "cell surface" + } + ], + "predicted_cellular_impact": [ + "Increased extracellular matrix degradation and remodeling", + "Enhanced invasion and migration", + "Promotion of mesenchymal transition" + ], + "evidence_summary": "Extracellular and adhesion genes in the list are linked to glioma invasiveness. Notably, SPOCK1 is highly expressed in aggressive GBM and its knockdown reduces motility and EMT markers ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26923184/#:~:text=Results%3A%20We%20found%20that%20the,sensitized%20these%20cells%20to%20TMZ)). Basement membrane proteins like FRAS1 maintain tissue integrity, and alterations can facilitate infiltration. Overall, the combined presence of multiple ECM-related genes suggests a program for matrix remodeling and cell invasion in glioblastoma.", + "citations": [ + { + "reference": "Kim et al. (2016) Int J Oncol", + "id": "PMID:26923184", + "type": "PMID", + "notes": "SPOCK1 is upregulated in invasive GBM; its knockdown inhibits migration, invasion and Akt signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26923184/#:~:text=Results%3A%20We%20found%20that%20the,sensitized%20these%20cells%20to%20TMZ))" + }, + { + "reference": "Sun et al. (2023) Medicine (Baltimore)", + "id": "DOI:10.1097/MD.0000000000033935", + "type": "DOI", + "notes": "Basement membrane and matrix-associated genes are enriched in glioma; these promote invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10256338/#:~:text=such%20as%20Laminin%2C%20integrin%2C%20and,9%5D%7D%20Therefore%2C%20it%20is))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.8, + "supporting_genes": [ + "SPOCK1", + "FRAS1", + "SVEP1", + "CDH12", + "CARMIL1", + "B3GAT2" + ], + "supporting_gene_count": 6, + "required_components_present": false + }, + { + "program_name": "Apoptotic Regulation", + "description": "This program reflects tumor-intrinsic cell death pathways. HRK (Harakiri) is a pro-apoptotic BH3-only Bcl-2 protein normally expressed in neurons. In glioblastoma, HRK induction triggers mitochondrial apoptosis: HRK overexpression activates caspases, cooperates with TRAIL, and suppresses tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction)). Thus, loss of HRK expression allows glioma cells to evade programmed cell death.", + "atomic_biological_processes": [ + { + "name": "regulation of apoptotic process", + "ontology_id": "GO:0042981", + "Genes": [ + "HRK" + ], + "citation": [ + { + "reference": "Kaya-Aksoy et al., 2019", + "id": "DOI:10.1038/s41420-019-0144-z", + "type": "DOI", + "notes": "HRK expression induces caspase activation and apoptosis in glioblastoma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction))" + } + ], + "ontology_label": "regulation of apoptotic process" + }, + { + "name": "intrinsic apoptotic signaling pathway", + "ontology_id": "GO:0097193", + "Genes": [ + "HRK" + ], + "citation": [ + { + "reference": "Kaya-Aksoy et al., 2019", + "id": "DOI:10.1038/s41420-019-0144-z", + "type": "DOI", + "notes": "HRK disrupts Bcl-2/Bcl-xL function to promote mitochondrial apoptosis in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction))" + } + ], + "ontology_label": "intrinsic apoptotic signaling pathway" + } + ], + "atomic_cellular_components": [ + { + "name": "mitochondrial outer membrane", + "ontology_id": "GO:0005741", + "Genes": [ + "HRK" + ], + "citation": [ + { + "reference": "Kaya-Aksoy et al., 2019", + "id": "DOI:10.1038/s41420-019-0144-z", + "type": "DOI", + "notes": "HRK localizes to mitochondria and initiates apoptosis by antagonizing anti-apoptotic Bcl-2 proteins ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction))" + } + ], + "ontology_label": "mitochondrial outer membrane" + } + ], + "predicted_cellular_impact": [ + "Enhanced apoptotic sensitivity", + "Promotion of caspase-mediated cell death" + ], + "evidence_summary": "HRK is a neural BH3-only protein that sensitizes glioblastoma cells to apoptosis. Overexpressing HRK in GBM models activates caspases and cooperates with apoptosis-inducing agents like TRAIL ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction)). Thus, genes in this program reflect the reactivation of intrinsic cell death pathways, which could counteract tumor survival.", + "citations": [ + { + "reference": "Kaya-Aksoy et al. (2019) Cell Death Discov", + "id": "DOI:10.1038/s41420-019-0144-z", + "type": "DOI", + "notes": "Describes HRK as a pro-apoptotic factor whose expression in GBM cells induces apoptosis and reduces tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6368544/#:~:text=Harakiri%20%28HRK%29%20is%20a%20BH3,xL%2C%20suggesting%20the%20functional%20interaction))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.6, + "supporting_genes": [ + "HRK" + ], + "supporting_gene_count": 1, + "required_components_present": false + } + ], + "version": "1.0.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_ac_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_ac_like_1 new file mode 100644 index 0000000..3f57e33 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_ac_like_1 @@ -0,0 +1,445 @@ +{ + "context": { + "cell_type": "Glioblastoma cells", + "disease": "Glioblastoma", + "tissue": "Brain" + }, + "input_genes": [ + "LINC01727", + "AC117464.1", + "XYLT1", + "MMD2", + "EEPD1", + "AC013265.1", + "MYO5B", + "PLA2G4A", + "KCNIP1", + "ITGB4", + "AC019068.1", + "UNC5D", + "MIR3681HG", + "LINC02125", + "LINC02246", + "LRRC4C", + "LUCAT1", + "MDGA2", + "AC077690.1", + "CTXND1", + "AL353138.1", + "CDH18", + "MN1", + "AL356737.2", + "NKAIN3", + "CD44", + "NLRC5", + "LINC01776", + "LINC01117", + "DAB1", + "GFAP", + "DCHS2", + "DIPK1C", + "COL20A1", + "ELMOD1", + "ERICH3", + "ADAMTS5", + "GPC5", + "CHST8", + "AC233296.1", + "AC124254.2", + "NPR3", + "HRH1", + "INPP4B", + "AL159156.1", + "LINC02328", + "ARC", + "PDZRN4", + "AC007344.1", + "RGMA", + "PPARGC1A", + "TNR", + "ST8SIA5", + "ST8SIA1", + "SLC7A11" + ], + "programs": [ + { + "program_name": "ECM glycosylation & remodeling", + "theme": "Extracellular Matrix", + "description": "Genes linked to extracellular matrix composition and glycosylation suggest enhanced ECM remodeling in glioblastoma. This includes enzymes initiating glycosaminoglycan chains (XYLT1, CHST8), sialyltransferases (ST8SIA1, ST8SIA5), and proteases modifying ECM (ADAMTS5, GPC5, COL20A1, TNR). This program may increase invasive capacity of tumor cells via altered cell\u2013matrix interactions.", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_id": "GO:0030198", + "citation": [ + { + "reference": "Yamada et al., Acta Neuropathologica 2005", + "id": "PMID:16133547", + "type": "PMID", + "notes": "ADAMTS5 cleaves brevican, an ECM proteoglycan, promoting glioma invasion." + } + ], + "Genes": [ + "ADAMTS5", + "COL20A1", + "TNR", + "GPC5" + ], + "ontology_label": "extracellular matrix organization" + }, + { + "name": "glycosaminoglycan biosynthetic process", + "ontology_id": "GO:0006024", + "citation": [ + { + "reference": "Veillon et al., ACS Chem Neurosci 2017", + "id": "PMID:28982002", + "type": "PMID", + "notes": "Review highlights aberrant glycosylation (ECM glycoproteins) promoting brain tumor invasion." + } + ], + "Genes": [ + "XYLT1", + "CHST8" + ], + "ontology_label": "glycosaminoglycan biosynthetic process" + }, + { + "name": "protein sialylation", + "ontology_id": "GO:1990743", + "citation": [ + { + "reference": "Veillon et al., ACS Chem Neurosci 2017", + "id": "PMID:28982002", + "type": "PMID", + "notes": "Upregulation of sialic acid on glycoproteins is a cancer hallmark in gliomas." + } + ], + "Genes": [ + "ST8SIA1", + "ST8SIA5" + ], + "ontology_label": "protein sialylation" + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_id": "GO:0031012", + "citation": [ + { + "reference": "Veillon et al., ACS Chem Neurosci 2017", + "id": "PMID:28982002", + "type": "PMID", + "notes": "ECM glycoprotein glycosylation alterations support tumor cell invasion." + } + ], + "Genes": [ + "ADAMTS5", + "COL20A1", + "TNR", + "GPC5" + ], + "ontology_label": "extracellular matrix" + } + ], + "predicted_cellular_impact": [ + "Enhanced ECM degradation and remodeling", + "Altered glycan composition of cell surface", + "Increased invasive/migratory potential" + ], + "evidence_summary": "ADAMTS5 is overexpressed in glioblastomas and degrades ECM proteoglycans (brevican), promoting cell invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16133547/#:~:text=transfectants,through%20the%20cleavage%20of%20brevican)). Broadly, aberrant glycosylation of ECM proteins is linked to glioma invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5771830/#:~:text=surface%20and%20%2For%20secreted%20proteins,the%20upregulation%20of%20sialic%20acid)). Presence of multiple glycosyltransferases (XYLT1, CHST8, ST8SIA1/5) and ECM proteins (COL20A1, TNR, GPC5) suggests coordinated ECM modifications in tumor progression.", + "citations": [ + { + "reference": "Yamada K. et al., 'Human glioblastomas overexpress ADAMTS-5 that degrades brevican', Acta Neuropathologica, 2005", + "id": "PMID:16133547", + "type": "PMID", + "notes": "Demonstrates ADAMTS5 cleavage of brevican and GBM invasion." + }, + { + "reference": "Veillon L. et al., 'Glycosylation Changes in Brain Cancer', ACS Chem Neurosci, 2017", + "id": "PMID:28982002", + "type": "PMID", + "notes": "Review of aberrant glycosylation in gliomas and its role in invasion." + } + ], + "confidence_score": 0.8, + "significance_score": 0.9, + "supporting_genes": [ + "XYLT1", + "CHST8", + "ST8SIA1", + "ST8SIA5", + "ADAMTS5", + "COL20A1", + "TNR", + "GPC5" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Cell adhesion & migration", + "theme": "Cell Motility", + "description": "This cluster includes cell-surface adhesion receptors and guidance molecules that regulate glioblastoma cell motility. Integrin (ITGB4), cadherins (CD44, CDH18, DCHS2), and repulsive guidance signals (UNC5D, RGMA) suggest enhanced cell\u2013matrix adhesion and directional migration. Dysregulation of these molecules could increase invasive migration in tumor cells.", + "atomic_biological_processes": [ + { + "name": "cell adhesion", + "ontology_id": "GO:0007155", + "citation": [ + { + "reference": "Chen et al., Sci Rep 2024", + "id": "PMID:38172503", + "type": "PMID", + "notes": "ITGB4 (integrin \u03b24) mediates cell adhesion to ECM via fibronectin/collagen." + } + ], + "Genes": [ + "ITGB4", + "CDH18", + "CD44", + "DCHS2" + ], + "ontology_label": "cell adhesion" + }, + { + "name": "positive regulation of cell migration", + "ontology_id": "GO:0030335", + "citation": [ + { + "reference": "Inoue et al., Cancers (Basel) 2023", + "id": "PMID:37835592", + "type": "PMID", + "notes": "CD44-high glioma stem cells are highly invasive (migration) in GBM." + } + ], + "Genes": [ + "ITGB4", + "CD44" + ], + "ontology_label": "positive regulation of cell migration" + }, + { + "name": "axon guidance", + "ontology_id": "GO:0007411", + "citation": [], + "Genes": [ + "UNC5D", + "RGMA" + ], + "ontology_label": "axon guidance" + } + ], + "atomic_cellular_components": [ + { + "name": "integrin complex", + "ontology_id": "GO:0008305", + "citation": [ + { + "reference": "Chen et al., Sci Rep 2024", + "id": "PMID:38172503", + "type": "PMID", + "notes": "Integrins (including ITGB4) form adhesion complexes interacting with ECM." + } + ], + "Genes": [ + "ITGB4" + ], + "ontology_label": "integrin complex" + } + ], + "predicted_cellular_impact": [ + "Enhanced cell\u2013ECM adhesion via integrins and cadherins", + "Increased cell migration and invasion", + "Altered guidance cue signaling" + ], + "evidence_summary": "Integrin \u03b24 (ITGB4) is upregulated in glioma and promotes adhesion to ECM components (fibronectin, collagen) and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10764336/#:~:text=functions%2C%20including%20tumor%20proliferation%2C%20migration%2C,5%7D.%20ITGB4%20has%20been)). CD44 is highly expressed on glioma stem-like cells, driving both invasion and proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10572085/#:~:text=As%20recurrence%20in%20glioblastoma%20is,pathways%20show%20reciprocal%20activation%20of)). Together with cadherins and guidance molecules (RGMA/UNC5D), this program likely enhances glioblastoma migratory potential.", + "citations": [ + { + "reference": "Chen P. et al., 'ITGB4 upregulation is associated with progression of lower grade glioma', Sci Rep, 2024", + "id": "PMID:38172503", + "type": "PMID", + "notes": "Shows ITGB4's role in cell adhesion and glioma progression." + }, + { + "reference": "Inoue A. et al., 'CD44\u2019s Role in Glioblastoma Invasion, Proliferation, and Recurrence', Cancers (Basel), 2023", + "id": "PMID:37835592", + "type": "PMID", + "notes": "Reviews how CD44-high GBM cells are invasive and therapy-resistant." + } + ], + "confidence_score": 0.75, + "significance_score": 0.8, + "supporting_genes": [ + "ITGB4", + "CD44", + "CDH18", + "DCHS2", + "UNC5D", + "RGMA" + ], + "supporting_gene_count": 6, + "required_components_present": false + }, + { + "program_name": "Hypoxia/stemness adaptation", + "theme": "Stem Cell Phenotype", + "description": "Key regulators of glioma stem-like cell (GSC) maintenance under hypoxia. Long noncoding RNA LUCAT1 and ganglioside-synthesizing enzyme ST8SIA1 (GD3 synthase) are linked to HIF1\u03b1 signaling and stem cell properties. This program likely enhances survival and self-renewal of GBM cells in hypoxic niches.", + "atomic_biological_processes": [ + { + "name": "cellular response to hypoxia", + "ontology_id": "GO:0071456", + "citation": [ + { + "reference": "Huang et al., Neuro Oncol 2024", + "id": "PMID:38456228", + "type": "PMID", + "notes": "LUCAT1 is induced by HIF-1\u03b1 in hypoxic glioma stem cells." + } + ], + "Genes": [ + "LUCAT1" + ], + "ontology_label": "cellular response to hypoxia" + }, + { + "name": "stem cell population maintenance", + "ontology_id": "GO:0019827", + "citation": [ + { + "reference": "Huang et al., Neuro Oncol 2024", + "id": "PMID:38456228", + "type": "PMID", + "notes": "LUCAT1 promotes self-renewal of GBM stem-like cells under hypoxia." + } + ], + "Genes": [ + "LUCAT1" + ], + "ontology_label": "stem cell population maintenance" + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Enhanced GSC self-renewal and survival under hypoxia", + "Amplified HIF-1\u03b1 signaling feedback", + "Increased resistance to therapy" + ], + "evidence_summary": "LUCAT1 is strongly induced by hypoxia in GBM and interacts with HIF1\u03b1 to maintain glioma stem cell self-renewal ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=glioblastoma%20%28GBM%29%20and%20glioma%20stem,dependent%20manner)). ST8SIA1 (GD3 synthase) expression in GBM stem-like cells is required for their proliferation, migration, and tumorigenicity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12224360/#:~:text=We%20showed%20that%20GD3%20is,pathways%20and%20more%20specifically%20the)). Together, these suggest hypoxia and glycosylation programs support GBM stemness.", + "citations": [ + { + "reference": "Huang H. et al., 'lncRNA LUCAT1 promotes glioblastoma progression via HIF-1\u03b1', Neuro Oncol, 2024", + "id": "PMID:38456228", + "type": "PMID", + "notes": "Shows LUCAT1-HIF1\u03b1 loop critical for GBM stem cell maintenance." + }, + { + "reference": "Hein V. et al., 'GD3 ganglioside promotes glioblastoma stem-like properties', Cancer Cell Int, 2025", + "id": "PMID:40604768", + "type": "PMID", + "notes": "Demonstrates ST8SIA1/GD3 maintains GBM stem cell proliferation and migration." + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "LUCAT1", + "ST8SIA1" + ], + "supporting_gene_count": 2, + "required_components_present": false + }, + { + "program_name": "Metabolic plasticity & redox", + "theme": "Metabolism", + "description": "Genes involved in metabolic adaptation and antioxidant defense in GBM. PPARGC1A (PGC-1\u03b1) regulates mitochondrial metabolism under nutrient stress, while SLC7A11 (xCT) drives cystine uptake/glutathione synthesis and glutamate release. This program likely sustains energy flexibility and redox homeostasis, aiding tumor growth and survival.", + "atomic_biological_processes": [ + { + "name": "glutathione metabolic process", + "ontology_id": "GO:0006749", + "citation": [ + { + "reference": "Robert et al., Sci Transl Med 2015", + "id": "PMID:26019222", + "type": "PMID", + "notes": "High SLC7A11 in gliomas increases GSH production and accelerates tumor growth." + } + ], + "Genes": [ + "SLC7A11" + ], + "ontology_label": "glutathione metabolic process" + }, + { + "name": "mitochondrial electron transport", + "ontology_id": "GO:0042775", + "citation": [ + { + "reference": "Sauer et al., Clin Transl Med 2024", + "id": "PMID:39552019", + "type": "PMID", + "notes": "AMPK-PGC-1\u03b1 axis enables glioma cells to use alternative fuels (mitochondrial metabolism)." + } + ], + "Genes": [ + "PPARGC1A" + ], + "ontology_label": "mitochondrial ATP synthesis coupled electron transport" + } + ], + "atomic_cellular_components": [ + { + "name": "mitochondrion", + "ontology_id": "GO:0005739", + "citation": [ + { + "reference": "Sauer et al., Clin Transl Med 2024", + "id": "PMID:39552019", + "type": "PMID", + "notes": "PGC-1\u03b1 activation increases mitochondrial metabolic activity in GBM." + } + ], + "Genes": [ + "PPARGC1A" + ], + "ontology_label": "mitochondrion" + } + ], + "predicted_cellular_impact": [ + "Enhanced antioxidant/glutathione synthesis", + "Increased fatty acid and oxidative metabolism under stress", + "Resistance to oxidative damage" + ], + "evidence_summary": "Approximately 50% of gliomas overexpress SLC7A11 (xCT), driving glutathione production and glutamate release, which accelerates tumor growth and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=expression%20of%20SLC7A11%2FxCT%2C%20the%20catalytic,mediated%20glutamate)). Additionally, AMPK-mediated induction of PGC-1\u03b1 fosters metabolic flexibility (oxidative phosphorylation) under nutrient deprivation in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11570551/#:~:text=A%20switch%20from%20glucose%20to,defining%20a%20specific%20metabolic%20compartment)). These pathways together bolster tumor survival and energy production.", + "citations": [ + { + "reference": "Robert S.M. et al., 'SLC7A11 expression predicts poor survival in malignant glioma', Sci Transl Med, 2015", + "id": "PMID:26019222", + "type": "PMID", + "notes": "Links xCT expression to glutamate-driven tumor growth and poor prognosis." + }, + { + "reference": "Sauer B. et al., 'AMPK-PGC-1\u03b1 axis mediates metabolic plasticity in glioblastoma', Clin Transl Med, 2024", + "id": "PMID:39552019", + "type": "PMID", + "notes": "Shows PGC-1\u03b1 is essential for metabolic adaptation to nutrient stress." + } + ], + "confidence_score": 0.65, + "significance_score": 0.6, + "supporting_genes": [ + "SLC7A11", + "PPARGC1A" + ], + "supporting_gene_count": 2, + "required_components_present": false + } + ], + "method": { + "clustering_basis": [ + "Pathway and literature curation", + "Gene function and co-expression" + ], + "notes": "Programs derived by grouping genes with related functions and known interactions; evidence from published glioma biology." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_ac_like_2 b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_ac_like_2 new file mode 100644 index 0000000..d4b3d37 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_ac_like_2 @@ -0,0 +1,403 @@ +{ + "context": { + "cell_type": "astrocytes", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "AC007402.1", + "LINC02397", + "DLL3", + "PRR5L", + "MYO5C", + "UNC13C", + "EGFR", + "AL359546.1", + "SLC24A3", + "INKA2", + "AC003991.1", + "ZNF804B", + "LINC01902", + "AC087854.1", + "DUSP10", + "SWAP70", + "LUZP2", + "RAB27B", + "AC117464.1", + "DLL1", + "AC013265.1", + "NKD1", + "KLRC2", + "SLC22A3", + "BX284613.2", + "CREM", + "AC002069.2", + "HES6", + "HIP1", + "GRM5", + "DPF3", + "MIR4300HG", + "CNTN6", + "HRH2", + "COL20A1", + "ANKFN1", + "MCTP1", + "GLYCTK-AS1", + "CHST9", + "CASZ1" + ], + "programs": [ + { + "program_name": "Synaptic Vesicle Exocytosis", + "theme": "Neuronal signaling", + "description": "Genes in this program (UNC13C, RAB27B, HIP1, MYO5C, CNTN6, GRM5, SLC24A3, MCTP1) are involved in synaptic vesicle trafficking and neurotransmission. In GBM cells, Rab27b is upregulated after irradiation and mediates secretion of epiregulin (EREG), activating EGFR signaling and supporting cell survival. UNC13C and MCTP1 regulate synaptic vesicle priming and neurotransmitter release, suggesting enhanced excitatory signaling and neuro-gliomal communication.", + "atomic_biological_processes": [ + { + "name": "synaptic vesicle exocytosis", + "citation": [ + { + "reference": "Nishioka S et al. Rab27b contributes to radioresistance via EREG secretion in glioblastoma. Neuro Oncol Adv. 2020.", + "id": "DOI:10.1093/noajnl/vdaa091", + "type": "DOI", + "notes": "Rab27b is a secretory GTPase that mediates EREG secretion and EGFR activation in GBM" + } + ], + "Genes": [ + "UNC13C", + "RAB27B", + "HIP1", + "MCTP1" + ], + "ontology_label": "synaptic vesicle exocytosis", + "ontology_id": "GO:0016079" + }, + { + "name": "neurotransmitter secretion", + "citation": [ + { + "reference": "Gen\u010d O et al. MCTP is an ER-resident Ca2+ sensor that stabilizes synaptic transmission. eLife. 2017.", + "id": "DOI:10.7554/eLife.22904", + "type": "DOI", + "notes": "MCTP1 localizes to presynaptic terminals and is essential for neurotransmitter release" + } + ], + "Genes": [ + "UNC13C", + "RAB27B", + "MCTP1" + ], + "ontology_label": "neurotransmitter secretion", + "ontology_id": "GO:0007269" + } + ], + "atomic_cellular_components": [ + { + "name": "presynaptic active zone", + "citation": [ + { + "reference": "Gen\u010d O et al. MCTP is an ER-resident Ca2+ sensor that stabilizes synaptic transmission. eLife. 2017.", + "id": "DOI:10.7554/eLife.22904", + "type": "DOI", + "notes": "MCTP1 functions at presynaptic terminals to coordinate neurotransmitter release" + } + ], + "Genes": [ + "UNC13C", + "MCTP1", + "HIP1" + ], + "ontology_label": "presynaptic active zone", + "ontology_id": "GO:0048786" + }, + { + "name": "synapse", + "citation": [ + { + "reference": "Gen\u010d O et al. MCTP is an ER-resident Ca2+ sensor that stabilizes synaptic transmission. eLife. 2017.", + "id": "DOI:10.7554/eLife.22904", + "type": "DOI", + "notes": "MCTP1 is distributed throughout the presynaptic region supporting neurotransmission" + } + ], + "Genes": [ + "UNC13C", + "RAB27B", + "MCTP1", + "HIP1" + ], + "ontology_label": "synapse", + "ontology_id": "GO:0045202" + } + ], + "predicted_cellular_impact": [ + "Enhanced neurotransmitter release", + "Increased synaptic connectivity", + "Elevated autocrine/paracrine growth signaling" + ], + "evidence_summary": "Rab27b (from this gene list) is upregulated in irradiated GBM cells and promotes secretion of EREG, driving EGFR signaling and cell survival. MCTP1 acts as an ER Ca2+ sensor necessary for stable neurotransmission in neurons. Together, these gene functions imply increased synaptic signaling and secretory communication in glioblastoma cells.", + "citations": [ + { + "reference": "Nishioka S et al. Rab27b contributes to radioresistance via EREG secretion in glioblastoma. Neuro Oncol Adv. 2020.", + "id": "DOI:10.1093/noajnl/vdaa091", + "type": "DOI", + "notes": "Rab27b mediates vesicle-mediated release of EREG, which activates EGFR signaling in GBM (supports enhanced secretion)" + } + ], + "confidence_score": 0.85, + "significance_score": 0.9, + "supporting_genes": [ + "UNC13C", + "RAB27B", + "HIP1", + "MYO5C", + "CNTN6", + "GRM5", + "SLC24A3", + "MCTP1" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Notch Signaling", + "theme": "Developmental pathway", + "description": "This program includes Notch pathway genes (DLL1, DLL3, HES6). Notch signaling in GBM supports stem/progenitor identities and regulates differentiation. Altered expression of Notch ligands and targets can affect GBM growth: e.g., modulating DLL1/3 levels influences proliferation and cell fate.", + "atomic_biological_processes": [ + { + "name": "Notch signaling pathway", + "citation": [ + { + "reference": "Drakulic D et al. Review of dysregulated neurodevelopmental pathways in glioblastoma. Cells. 2022.", + "id": "PMID:36010607", + "type": "PMID", + "notes": "Notch signaling (via DLL ligands and HES genes) maintains glioma stem cells and promotes proliferation" + } + ], + "Genes": [ + "DLL1", + "DLL3", + "HES6" + ], + "ontology_label": "Notch signaling pathway", + "ontology_id": "GO:0007219" + }, + { + "name": "cell differentiation", + "citation": [ + { + "reference": "Drakulic D et al. Review of dysregulated neurodevelopmental pathways in glioblastoma. Cells. 2022.", + "id": "PMID:36010607", + "type": "PMID", + "notes": "Notch influences neural progenitor differentiation in GBM" + } + ], + "Genes": [ + "DLL1", + "DLL3" + ], + "ontology_label": "cell differentiation", + "ontology_id": "GO:0030154" + } + ], + "atomic_cellular_components": [ + { + "name": "integral component of membrane", + "citation": [ + { + "reference": "Drakulic D et al. Review of dysregulated neurodevelopmental pathways in glioblastoma. Cells. 2022.", + "id": "PMID:36010607", + "type": "PMID", + "notes": "DLL1 and DLL3 encode transmembrane Notch ligands" + } + ], + "Genes": [ + "DLL1", + "DLL3" + ], + "ontology_label": null, + "ontology_id": null + } + ], + "predicted_cellular_impact": [ + "Maintenance of progenitor-like state", + "Suppressed differentiation", + "Enhanced glioma stemness" + ], + "evidence_summary": "The presence of DLL1/DLL3 and HES6 suggests active Notch signaling. Notch activity can maintain GBM stemness; its inhibition reduces proliferation in glioma models. Therefore, this program likely supports a less differentiated, stem-like state in GBM cells.", + "citations": [ + { + "reference": "Drakulic D et al. Review of dysregulated neurodevelopmental pathways in glioblastoma. Cells. 2022.", + "id": "PMID:36010607", + "type": "PMID", + "notes": "Activation of Notch signaling (ligands DLL1/DLL3 and targets like HES family) promotes self-renewal of GBM stem-like cells and impacts differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9406959/#:~:text=oncogenic%20function%20of%20Notch%20signaling,Activation%20of%20the%20Notch))." + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "DLL1", + "DLL3", + "HES6" + ], + "supporting_gene_count": 3, + "required_components_present": false + }, + { + "program_name": "EGFR Signaling", + "theme": "Growth factor signaling", + "description": "Genes EGFR and RAB27B indicate an RTK signaling program. Rab27b-mediated secretion of the EGFR ligand epiregulin can activate EGFR in a paracrine loop, driving GBM cell proliferation and therapy resistance. EGFR itself is a key oncogene in glioblastoma.", + "atomic_biological_processes": [ + { + "name": "EGFR signaling pathway", + "citation": [ + { + "reference": "Nishioka S et al. Rab27b contributes to GBM radioresistance via EREG secretion. Neuro Oncol Adv. 2020.", + "id": "PMID:33409495", + "type": "PMID", + "notes": "Rab27b upregulation drives EREG secretion, leading to EGFR activation in GBM" + } + ], + "Genes": [ + "EGFR", + "RAB27B" + ], + "ontology_label": "epidermal growth factor receptor signaling pathway", + "ontology_id": "GO:0007173" + }, + { + "name": "MAPK cascade", + "citation": [ + { + "reference": "Nishioka S et al. Rab27b contributes to GBM radioresistance via EREG secretion. Neuro Oncol Adv. 2020.", + "id": "PMID:33409495", + "type": "PMID", + "notes": "EGFR activation triggers downstream MAPK signaling to enhance GBM cell survival" + } + ], + "Genes": [ + "EGFR" + ], + "ontology_label": "MAPK cascade", + "ontology_id": "GO:0000165" + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane receptor complex", + "citation": [ + { + "reference": "Nishioka S et al. Rab27b contributes to GBM radioresistance via EREG secretion. Neuro Oncol Adv. 2020.", + "id": "PMID:33409495", + "type": "PMID", + "notes": "EGFR is a membrane-bound receptor activated by secreted EGF-like ligands (e.g., EREG)" + } + ], + "Genes": [ + "EGFR" + ], + "ontology_label": "plasma membrane signaling receptor complex", + "ontology_id": "GO:0098802" + } + ], + "predicted_cellular_impact": [ + "Increased cell proliferation", + "Enhanced therapeutic resistance", + "Autocrine/paracrine growth signaling" + ], + "evidence_summary": "Rab27b from the gene list is shown to upregulate secretion of EREG, activating EGFR signaling and contributing to radioresistance. EGFR is a known driver of GBM growth. This program likely amplifies MAPK pathway signaling and survival in tumor cells.", + "citations": [ + { + "reference": "Nishioka S et al. Rab27b contributes to GBM radioresistance via EREG secretion. Neuro Oncol Adv. 2020.", + "id": "PMID:33409495", + "type": "PMID", + "notes": "Rab27b-mediated secretion of EREG activates EGFR signaling in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7770522/#:~:text=recipient%20mice.%20Interestingly%2C%20the%20co,mechanism%2C%20activated%20EGF%20receptor%20and)), driving proliferation and survival" + } + ], + "confidence_score": 0.9, + "significance_score": 0.95, + "supporting_genes": [ + "EGFR", + "RAB27B" + ], + "supporting_gene_count": 2, + "required_components_present": false + }, + { + "program_name": "Oncogenic Transcription", + "theme": "Transcriptional regulation", + "description": "This program includes transcriptional regulators (CASZ1, CREM, DPF3). CASZ1 is an oncogenic transcription factor overexpressed in glioma, promoting proliferation via target genes like p75NTR. Altered transcription regulation by these factors can shift GBM cell identity and growth.", + "atomic_biological_processes": [ + { + "name": "regulation of transcription, DNA-templated", + "citation": [ + { + "reference": "Mao C et al. CASZ1 is an oncogenic transcription factor in glioma. MedComm. 2022.", + "id": "PMID:36276925", + "type": "PMID", + "notes": "CASZ1 drives transcription of target genes (e.g., p75NTR) in glioma cells" + } + ], + "Genes": [ + "CASZ1", + "CREM", + "DPF3" + ], + "ontology_label": "regulation of DNA-templated transcription", + "ontology_id": "GO:0006355" + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "citation": [ + { + "reference": "Mao C et al. CASZ1 is an oncogenic transcription factor in glioma. MedComm. 2022.", + "id": "PMID:36276925", + "type": "PMID", + "notes": "CASZ1 functions in the nucleus to regulate gene expression" + } + ], + "Genes": [ + "CASZ1", + "CREM", + "DPF3" + ], + "ontology_label": "nucleus", + "ontology_id": "GO:0005634" + } + ], + "predicted_cellular_impact": [ + "Upregulated oncogenic gene expression", + "Activation of proliferation programs", + "Altered differentiation gene networks" + ], + "evidence_summary": "CASZ1 is highly expressed in glioma and acts as an oncogene by promoting transcription of growth-related genes; its knockdown reduces proliferation. CREM and DPF3 likely modulate gene expression too. The combined effect is a shift toward oncogenic transcriptional programs in GBM cells.", + "citations": [ + { + "reference": "Mao C et al. CASZ1 is an oncogenic transcription factor in glioma. MedComm. 2022.", + "id": "PMID:36276925", + "type": "PMID", + "notes": "CASZ1 overexpression correlates with poor glioma prognosis and drives proliferation through transcriptional activation of p75NTR" + } + ], + "confidence_score": 0.6, + "significance_score": 0.6, + "supporting_genes": [ + "CASZ1", + "CREM", + "DPF3" + ], + "supporting_gene_count": 3, + "required_components_present": false + } + ], + "method": { + "clustering_basis": [ + "pathway databases", + "literature curation", + "gene co-expression" + ], + "notes": "Genes were grouped based on known pathways and coordinated functions in neural and cancer contexts." + }, + "version": "1.0.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_like_1 new file mode 100644 index 0000000..6c2dd93 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_like_1 @@ -0,0 +1,586 @@ +{ + "context": { + "cell_type": "astrocytes", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "AFAP1L2", + "COL4A3", + "FERMT1", + "VIPR2", + "AL512308.1", + "CALCRL", + "REPS2", + "FGF12", + "CCDC26", + "OTOGL", + "ELMO1", + "PCDH15", + "COL4A4", + "THSD4", + "FA2H", + "LRRC7", + "PLPP4", + "PLA2G4A", + "AR", + "LINC00689", + "TNS3", + "BCAS1", + "DLL3", + "KCNIP3", + "MIR503HG", + "ANO3", + "PLAAT1", + "MEGF11", + "GSG1L", + "UGT8", + "COL20A1", + "ALCAM", + "C2orf27A", + "LHFPL3-AS1", + "CA10", + "SLC5A4", + "ADAMTS17", + "DCT", + "CHST9", + "NRSN1", + "AC110285.1", + "CCND1", + "TRPC4", + "TACR1", + "TNR", + "SOX6", + "PDE4A", + "GPR17", + "ARPP21", + "MYRF" + ], + "programs": [ + { + "program_name": "ECM Remodeling & Adhesion", + "description": "Multiple collagen IV chains (COL4A3, COL4A4), other ECM proteins (THSD4, COL20A1) and ECM regulators (ADAMTS17, CHST9) suggest active extracellular matrix organization. Adhesion molecules (ALCAM, PCDH15, FERMT1, TNS3) and integrin-associated factors indicate enhanced cell adhesion. In malignant glioblastoma, elevated ECM deposition and remodeling drive tumor invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10046791/#:~:text=blockage%20%20,great%20interest%20in%20GBM%20treatment)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3452333/#:~:text=Downregulation%20of%20ALCAM%20expression%20on,ALCAM%20siRNA%E2%80%93transfected%20and%20negative%20control)).", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030198", + "name": "extracellular matrix organization", + "citation": [ + { + "reference": "Caffo et al. Collagen IV in GBM.", + "id": "", + "type": "", + "notes": "Glioblastoma cells produce type IV collagen, indicating active ECM assembly ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10046791/#:~:text=blockage%20%20,great%20interest%20in%20GBM%20treatment))" + } + ], + "Genes": [ + "COL4A3", + "COL4A4", + "COL20A1", + "THSD4", + "ADAMTS17", + "CHST9" + ], + "ontology_label": "extracellular matrix organization" + }, + { + "ontology_id": "GO:0007155", + "name": "cell adhesion", + "citation": [ + { + "reference": "Kijima et al., Neuro Oncol 2011", + "id": "", + "type": "", + "notes": "ALCAM knockdown increases GBM invasion, implicating ALCAM in cell adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3452333/#:~:text=Downregulation%20of%20ALCAM%20expression%20on,ALCAM%20siRNA%E2%80%93transfected%20and%20negative%20control))" + } + ], + "Genes": [ + "ALCAM", + "PCDH15", + "FERMT1", + "TNS3" + ], + "ontology_label": "cell adhesion" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0031012", + "name": "extracellular matrix", + "citation": [ + { + "reference": "Caffo et al. 2004", + "id": "", + "type": "", + "notes": "Glioblastoma cells produce collagen IV in vitro, contributing to the ECM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10046791/#:~:text=blockage%20%20,great%20interest%20in%20GBM%20treatment))" + } + ], + "Genes": [ + "COL4A3", + "COL4A4", + "COL20A1", + "THSD4" + ], + "ontology_label": "extracellular matrix" + }, + { + "ontology_id": "GO:0005925", + "name": "focal adhesion", + "citation": [ + { + "reference": "Fust\u00e9 et al., Sci Rep 2019", + "id": "", + "type": "", + "notes": "Cyclin D1 induces focal adhesion kinase and paxillin, linking adhesion to invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=activates%20the%20invasion%20of%20primary,GBM%20dissemination%20through%20cytoplasmic%20and))" + } + ], + "Genes": [ + "FERMT1", + "TNS3" + ], + "ontology_label": "focal adhesion" + } + ], + "predicted_cellular_impact": [ + "increased ECM deposition enabling tumor invasion", + "enhanced focal adhesion signaling" + ], + "evidence_summary": "Glioblastoma cells characteristically overproduce type IV collagens and other matrix proteins, increasing ECM density ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10046791/#:~:text=blockage%20%20,great%20interest%20in%20GBM%20treatment)). Adhesion receptors like ALCAM and integrin regulators (FERMT1, TNS3) are present; ALCAM downregulation enhances invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3452333/#:~:text=Downregulation%20of%20ALCAM%20expression%20on,ALCAM%20siRNA%E2%80%93transfected%20and%20negative%20control)). Together these suggest heightened cell-ECM interactions and motility.", + "citations": [ + { + "reference": "Caffo et al., J Neurooncol 2004", + "id": "", + "type": "", + "notes": "Evidence of collagen IV production by GBM cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10046791/#:~:text=blockage%20%20,great%20interest%20in%20GBM%20treatment))." + }, + { + "reference": "Kijima et al., Neuro Oncol 2011", + "id": "", + "type": "", + "notes": "ALCAM involvement in GBM invasion via cell adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3452333/#:~:text=Downregulation%20of%20ALCAM%20expression%20on,ALCAM%20siRNA%E2%80%93transfected%20and%20negative%20control))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "COL4A3", + "COL4A4", + "COL20A1", + "THSD4", + "ADAMTS17", + "CHST9", + "ALCAM", + "PCDH15", + "FERMT1", + "TNS3", + "PLA2G4A" + ], + "supporting_gene_count": 11, + "required_components_present": true + }, + { + "program_name": "GPCR/Ca2+ Signaling", + "description": "G-protein coupled receptors (VIPR2, CALCRL, TACR1) and ion channels (TRPC4, ANO3, KCNIP3) suggest active GPCR/Ca^{2+}-mediated signaling. VIPR2 and CALCRL activation drives PI3K/Akt and proliferation pathways, while GPR17 (in clustered program) modulates survival ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36237322/#:~:text=MCF,related%20protein%203%2C%20and%20actin)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36618798/#:~:text=CALCRL%20expression%20was%20highest%20in,apoptosis%20rate%20was%20significantly%20increased)). Altered intracellular Ca^{2+} (via TRP channels, ANO3 chloride channel) likely impacts migration. ", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007186", + "name": "G-protein coupled receptor signaling pathway", + "citation": [ + { + "reference": "Asano et al., Cancers 2022", + "id": "", + "type": "", + "notes": "VIPR2 (GPCR) activation promotes tumor cell migration via PI3K/WAVE2 actin signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36237322/#:~:text=MCF,related%20protein%203%2C%20and%20actin))" + } + ], + "Genes": [ + "VIPR2", + "CALCRL", + "TACR1" + ], + "ontology_label": "G protein-coupled receptor signaling pathway" + }, + { + "ontology_id": "GO:0019722", + "name": "calcium-mediated signaling", + "citation": [ + { + "reference": "Doan et al., Cancers 2021", + "id": "", + "type": "", + "notes": "GPR17 (a GPCR) triggers MAPK/PI3K pathways and cell cycle arrest in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8345100/#:~:text=mechanism%20of%20action%20of%20the,barrier%20and%20reduces%20tumor%20volume))" + } + ], + "Genes": [ + "TRPC4", + "ANO3", + "KCNIP3" + ], + "ontology_label": "calcium-mediated signaling" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005886", + "name": "plasma membrane", + "citation": [ + { + "reference": "Asano et al., Cancers 2022", + "id": "", + "type": "", + "notes": "VIPR2 and other receptors localize to membrane to drive signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36237322/#:~:text=MCF,related%20protein%203%2C%20and%20actin))" + } + ], + "Genes": [ + "VIPR2", + "CALCRL", + "TACR1", + "TRPC4", + "ANO3" + ], + "ontology_label": "plasma membrane" + } + ], + "predicted_cellular_impact": [ + "enhanced chemotactic migration via GPCR-PI3K signaling", + "modulated Ca^{2+}-dependent signaling affecting proliferation" + ], + "evidence_summary": "VIPR2 activation in cancer cells promotes migration through PI3K and actin remodeling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36237322/#:~:text=MCF,related%20protein%203%2C%20and%20actin)). In glioma, high CALCRL drives proliferation and survival ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36618798/#:~:text=CALCRL%20expression%20was%20highest%20in,apoptosis%20rate%20was%20significantly%20increased)). Together, multiple GPCRs and Ca^{2+}/Cl^{-} channels suggest dysregulated cAMP/Ca^{2+} signaling influencing GBM growth and motility.", + "citations": [ + { + "reference": "Asano et al., Cancers 2022", + "id": "", + "type": "", + "notes": "VIPR2 induces PI3K-mediated migration in cancer cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36237322/#:~:text=MCF,related%20protein%203%2C%20and%20actin))." + }, + { + "reference": "Gu et al., Ann Transl Med 2021", + "id": "", + "type": "", + "notes": "CALCRL knockdown reduces glioma proliferation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/36618798/#:~:text=CALCRL%20expression%20was%20highest%20in,apoptosis%20rate%20was%20significantly%20increased))." + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": [ + "VIPR2", + "CALCRL", + "TACR1", + "TRPC4", + "ANO3", + "KCNIP3" + ], + "supporting_gene_count": 6, + "required_components_present": true + }, + { + "program_name": "Oligodendrocyte Differentiation", + "description": "Genes associated with oligodendrocyte lineage and myelination are enriched. MYRF is a master regulator of myelin gene expression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3742440/#:~:text=induced%20during%20oligodendrocyte%20differentiation,terms%20for%20genes%20proximal%20to)). Lipid enzymes (UGT8, FA2H) and marker BCAS1 indicate myelin synthesis. Extracellular protein TNR (Tenascin-R) promotes oligodendrocyte maturation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6573339/#:~:text=expression%20and%20the%20upregulation%20of,for%20CNS%20myelination%20and%20remyelination)). This program reflects an oligodendrocyte-like differentiation state in GBM cells.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0042552", + "name": "myelination", + "citation": [ + { + "reference": "Bujalka et al., PLoS Biol 2013", + "id": "", + "type": "", + "notes": "MYRF directly activates myelin genes during oligodendrocyte differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3742440/#:~:text=induced%20during%20oligodendrocyte%20differentiation,terms%20for%20genes%20proximal%20to))" + } + ], + "Genes": [ + "MYRF", + "BCAS1", + "FA2H", + "UGT8" + ], + "ontology_label": "myelination" + }, + { + "ontology_id": "GO:0048709", + "name": "oligodendrocyte differentiation", + "citation": [ + { + "reference": "Pesheva et al., J Neurosci 1997", + "id": "", + "type": "", + "notes": "Tenascin-R stimulates oligodendrocyte differentiation in vitro ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6573339/#:~:text=expression%20and%20the%20upregulation%20of,for%20CNS%20myelination%20and%20remyelination))" + } + ], + "Genes": [ + "MYRF", + "BCAS1", + "TNR", + "GPR17", + "SOX6", + "FA2H", + "UGT8" + ], + "ontology_label": "oligodendrocyte differentiation" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0043209", + "name": "myelin sheath", + "citation": [ + { + "reference": "Bujalka et al., PLoS Biol 2013", + "id": "", + "type": "", + "notes": "MYRF upregulates myelin-related genes (e.g. MAG, MBP) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3742440/#:~:text=induced%20during%20oligodendrocyte%20differentiation,terms%20for%20genes%20proximal%20to))" + } + ], + "Genes": [ + "UGT8", + "FA2H" + ], + "ontology_label": "myelin sheath" + } + ], + "predicted_cellular_impact": [ + "enhanced myelin-specific gene expression", + "promotion of oligodendrocyte-like differentiation" + ], + "evidence_summary": "Several genes (MYRF, BCAS1, UGT8, FA2H) are canonical oligodendrocyte/myelination markers ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3742440/#:~:text=induced%20during%20oligodendrocyte%20differentiation,terms%20for%20genes%20proximal%20to)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6573339/#:~:text=expression%20and%20the%20upregulation%20of,for%20CNS%20myelination%20and%20remyelination)). Tenascin-R (TNR) is a known autocrine promoter of oligodendrocyte maturation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6573339/#:~:text=expression%20and%20the%20upregulation%20of,for%20CNS%20myelination%20and%20remyelination)). This constellation suggests GBM cells may adopt an oligodendrocyte-like program, potentially altering metabolism (lipid-rich myelin) and growth behavior.", + "citations": [ + { + "reference": "Pesheva et al., J Neurosci 1997", + "id": "", + "type": "", + "notes": "Tenascin-R promotes oligodendrocyte maturation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6573339/#:~:text=expression%20and%20the%20upregulation%20of,for%20CNS%20myelination%20and%20remyelination))." + }, + { + "reference": "Bujalka et al., PLoS Biol 2013", + "id": "", + "type": "", + "notes": "MYRF drives expression of myelin and ensheathment genes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3742440/#:~:text=induced%20during%20oligodendrocyte%20differentiation,terms%20for%20genes%20proximal%20to))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": [ + "MYRF", + "BCAS1", + "TNR", + "GPR17", + "UGT8", + "FA2H", + "SOX6" + ], + "supporting_gene_count": 7, + "required_components_present": true + }, + { + "program_name": "Cell Cycle Progression", + "description": "CCND1 (Cyclin D1) is a key cell-cycle regulator. In GBM, Cyclin D1 overexpression drives proliferation and also unexpectedly promotes invasion via cytoplasmic signaling to RalA/paxillin ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=activates%20the%20invasion%20of%20primary,GBM%20dissemination%20through%20cytoplasmic%20and)). This program indicates highly active G1/S progression and linked motility signaling in tumor cells.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007049", + "name": "cell cycle", + "citation": [ + { + "reference": "Fust\u00e9 et al., Sci Rep 2019", + "id": "", + "type": "", + "notes": "Cyclin D1/Cdk4 axis is frequently altered in GBM, leading to overproliferation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=to%20overproliferation%20by%20RB1%20deletion,acting%20upstream%20of%20those%20regulators))" + } + ], + "Genes": [ + "CCND1" + ], + "ontology_label": "cell cycle" + }, + { + "ontology_id": "GO:0030334", + "name": "regulation of cell migration", + "citation": [ + { + "reference": "Fust\u00e9 et al., Sci Rep 2019", + "id": "", + "type": "", + "notes": "Cytoplasmic Cyclin D1 activates RalA and paxillin to enhance GBM cell invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=activates%20the%20invasion%20of%20primary,GBM%20dissemination%20through%20cytoplasmic%20and))" + } + ], + "Genes": [ + "CCND1" + ], + "ontology_label": "regulation of cell migration" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005634", + "name": "nucleus", + "citation": [ + { + "reference": "Fust\u00e9 et al., Sci Rep 2019", + "id": "", + "type": "", + "notes": "Cyclin D1 functions as a nuclear cell-cycle regulator ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=to%20overproliferation%20by%20RB1%20deletion,acting%20upstream%20of%20those%20regulators))" + } + ], + "Genes": [ + "CCND1" + ], + "ontology_label": "nucleus" + }, + { + "ontology_id": "GO:0005829", + "name": "cytosol", + "citation": [ + { + "reference": "Fust\u00e9 et al., Sci Rep 2019", + "id": "", + "type": "", + "notes": "Cyclin D1 can act in the cytoplasm to regulate invasion via RalA ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=activates%20the%20invasion%20of%20primary,GBM%20dissemination%20through%20cytoplasmic%20and))" + } + ], + "Genes": [ + "CCND1" + ], + "ontology_label": "cytosol" + } + ], + "predicted_cellular_impact": [ + "accelerated proliferation", + "enhanced invasiveness via RalA/paxillin signaling" + ], + "evidence_summary": "Cyclin D1 is overexpressed in GBM and drives the G1/S transition. Elevated CCND1 not only promotes proliferation but also increases cytoplasmic signaling that activates RalA and paxillin, augmenting tumor cell invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=activates%20the%20invasion%20of%20primary,GBM%20dissemination%20through%20cytoplasmic%20and)).", + "citations": [ + { + "reference": "Fust\u00e9 et al., Sci Rep 2019", + "id": "", + "type": "", + "notes": "Cyclin D1/Cdk4 activation leads to GBM overproliferation; Cyclin D1 induces RalA/paxillin to promote invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=to%20overproliferation%20by%20RB1%20deletion,acting%20upstream%20of%20those%20regulators)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/30957234/#:~:text=activates%20the%20invasion%20of%20primary,GBM%20dissemination%20through%20cytoplasmic%20and))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": [ + "CCND1" + ], + "supporting_gene_count": 1, + "required_components_present": true + }, + { + "program_name": "Androgen Receptor Signaling", + "description": "Androgen receptor (AR) is highly expressed in GBM and contributes to tumor growth. AR can be activated via EGFR/AKT signaling even without ligand ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8535837/#:~:text=Androgen%20receptor%20,correlation%20between%20AR%20and%20EGFR)). Active AR translocates to the nucleus to drive proliferation and survival gene programs, collaborating with oncogenic kinase pathways.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0043401", + "name": "steroid hormone mediated signaling pathway", + "citation": [ + { + "reference": "Zalcman et al., Int J Mol Sci 2021", + "id": "", + "type": "", + "notes": "AR is overexpressed in most GBMs; EGFR signaling increases AR activation and nuclear translocation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8535837/#:~:text=Androgen%20receptor%20,correlation%20between%20AR%20and%20EGFR))" + } + ], + "Genes": [ + "AR" + ], + "ontology_label": "steroid hormone receptor signaling pathway" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005634", + "name": "nucleus", + "citation": [ + { + "reference": "Zalcman et al., Int J Mol Sci 2021", + "id": "", + "type": "", + "notes": "Activated AR localizes to the nucleus to regulate transcription ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8535837/#:~:text=Androgen%20receptor%20,correlation%20between%20AR%20and%20EGFR))" + } + ], + "Genes": [ + "AR" + ], + "ontology_label": "nucleus" + } + ], + "predicted_cellular_impact": [ + "enhanced proliferation and survival via cross-talk with RTK pathways" + ], + "evidence_summary": "AR is amplified in glioblastoma and correlates with EGFR levels. EGFR or EGFRvIII overexpression in GBM cells induces AR phosphorylation and nuclear localization, promoting cell growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8535837/#:~:text=Androgen%20receptor%20,correlation%20between%20AR%20and%20EGFR)). Thus androgen receptor signaling supports GBM proliferation independent of androgens.", + "citations": [ + { + "reference": "Zalcman et al., Int J Mol Sci 2021", + "id": "", + "type": "", + "notes": "EGFR signaling activates AR in GBM, suggesting AR-driven transcription aids tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8535837/#:~:text=Androgen%20receptor%20,correlation%20between%20AR%20and%20EGFR))." + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": [ + "AR" + ], + "supporting_gene_count": 1, + "required_components_present": false + }, + { + "program_name": "Notch Signaling Modulation", + "description": "DLL3 is an inhibitory ligand of the Notch pathway. In gliomas, high DLL3 expression is associated with better prognosis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33713320/#:~:text=between%20DLL3%20gene%20expression%20and,targeted%20therapies)), suggesting that DLL3 attenuates Notch signaling. This program may influence cell differentiation and the immune microenvironment in GBM.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007219", + "name": "Notch signaling pathway", + "citation": [ + { + "reference": "Wang et al., J Cancer 2021", + "id": "", + "type": "", + "notes": "DLL3 expression stratifies glioma prognosis; low DLL3 links to shorter survival, implicating DLL3 in Notch pathway inhibition ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33713320/#:~:text=between%20DLL3%20gene%20expression%20and,targeted%20therapies))" + } + ], + "Genes": [ + "DLL3" + ], + "ontology_label": "Notch signaling pathway" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0009986", + "name": "cell surface", + "citation": [ + { + "reference": "Zhang et al., Biochim Biophys Acta 2013", + "id": "", + "type": "", + "notes": "DLL3 is a transmembrane Notch ligand; its surface expression modulates signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33713320/#:~:text=between%20DLL3%20gene%20expression%20and,targeted%20therapies))" + } + ], + "Genes": [ + "DLL3" + ], + "ontology_label": "cell surface" + } + ], + "predicted_cellular_impact": [ + "modulation of differentiation via Notch inhibition", + "altered immune response" + ], + "evidence_summary": "In malignant glioma, DLL3 acts as a Notch inhibitor and its high expression predicts longer survival ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33713320/#:~:text=between%20DLL3%20gene%20expression%20and,targeted%20therapies)). Lower DLL3 correlates with enhanced immune and inflammatory pathways. Thus DLL3 likely influences tumor cell fate by dampening Notch signaling.", + "citations": [ + { + "reference": "Wang et al., J Cancer 2021", + "id": "", + "type": "", + "notes": "DLL3 stratifies patient survival; lower DLL3 is linked to more aggressive GBM and upregulated immune pathways ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33713320/#:~:text=between%20DLL3%20gene%20expression%20and,targeted%20therapies))." + } + ], + "confidence_score": 0.7, + "significance_score": 0.5, + "supporting_genes": [ + "DLL3" + ], + "supporting_gene_count": 1, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_like_2 b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_like_2 new file mode 100644 index 0000000..29ebd28 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_like_2 @@ -0,0 +1,525 @@ +{ + "context": { + "cell_type": "glioblastoma cells", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "PPP1R16B", + "BCAS1", + "AC008080.4", + "MOG", + "GLRA3", + "ENPP6", + "ADAM33", + "GPC3", + "CLDN11", + "PLD1", + "SEMA4D", + "MYRF", + "MBP", + "GPR17", + "KCNS3", + "TNS3", + "RASGEF1B", + "AC069209.2", + "ADRA1A", + "CD22", + "FA2H", + "CDK18", + "ST18", + "FERMT1", + "NOS1", + "TMEM235", + "AC110285.1", + "ACAN", + "MAG", + "PRICKLE1", + "AL512308.1", + "FAM83D", + "BMP2", + "BMPER", + "COL18A1", + "LINC01447", + "P2RX7", + "ZNF536", + "ATP6V0A4", + "AMPD3" + ], + "programs": [ + { + "program_name": "Oligodendrocyte Myelination", + "description": "This program comprises canonical oligodendrocyte and myelin genes. MOG, MBP, MAG, CLDN11, FA2H, ENPP6 and BCAS1 are all known myelin/oligodendrocyte markers, often co-expressed in oligodendrocyte precursor cell (OPC) differentiation. MYRF and GPR17 are oligodendrocyte lineage regulators (GPR17 as a myelination timer ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2783566/#:~:text=intrinsic%20timer%20of%20myelination%20,intrinsic%20timer%20of)), MYRF a master TF). In normal brain these drive myelin sheath assembly. In GBM, expression suggests a proneural/OPC-like differentiation state ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3100315/#:~:text=match%20at%20L126%20tumors%20closely,genes%20that%20are%20differentially%20expressed)).", + "atomic_biological_processes": [ + { + "name": "myelination", + "citation": [ + { + "reference": "Chen Y et al. GPR17 is a cell-intrinsic timer of myelination. Nat Neurosci. 2009.", + "id": "19838178", + "type": "PMID", + "notes": "GPR17 is oligodendrocyte-specific and controls timing of CNS myelination ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2783566/#:~:text=intrinsic%20timer%20of%20myelination%20,intrinsic%20timer%20of))" + } + ], + "Genes": [ + "GPR17", + "MOG", + "MBP", + "MAG", + "CLDN11", + "FA2H", + "ENPP6", + "BCAS1" + ], + "ontology_label": "myelination", + "ontology_id": "GO:0042552" + } + ], + "atomic_cellular_components": [ + { + "name": "myelin sheath", + "citation": [ + { + "reference": "Fulton D et al. Multiple roles of myelin protein genes in oligodendrocyte development. ASN Neuro. 2010.", + "id": "20017732", + "type": "PMID", + "notes": "MBP and MAG localize to myelin sheaths and are critical for compact myelin structure ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2814326/#:~:text=MBP%20are%20distributed%20within%20the,interactions%20between%20myelin%20and%20axonal))" + } + ], + "Genes": [ + "MOG", + "MBP", + "MAG", + "CLDN11", + "FA2H" + ], + "ontology_label": "myelin sheath", + "ontology_id": "GO:0043209" + } + ], + "predicted_cellular_impact": [ + "Adoption of oligodendrocyte-like differentiation signature", + "Ectopic myelin protein expression in tumor cells", + "Altered cell-cell/axon interactions via myelin components" + ], + "evidence_summary": "MOG, MBP, MAG, CLDN11, ENPP6, FA2H and BCAS1 are classic oligodendrocyte/myelin proteins highly expressed during myelination. GPR17 is an oligodendrocyte-specific GPCR that times myelination ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2783566/#:~:text=intrinsic%20timer%20of%20myelination%20,intrinsic%20timer%20of)). MYRF is a master regulator of oligodendrocyte differentiation. Together these indicate activation of an oligodendrocyte/myelination program. Such signatures are known in the proneural GBM subtype, reflecting an OPC-like state ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3100315/#:~:text=match%20at%20L126%20tumors%20closely,genes%20that%20are%20differentially%20expressed)). Thus, tumor cells may aberrantly activate myelin gene expression (influencing membrane properties or cell interactions).", + "citations": [ + { + "reference": "Chen Y et al. The oligodendrocyte-specific G-protein coupled receptor GPR17 is a cell-intrinsic timer of myelination. Nat Neurosci. 2009.", + "id": "19838178", + "type": "PMID", + "notes": "Supports GPR17 in oligodendrocyte myelination ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2783566/#:~:text=intrinsic%20timer%20of%20myelination%20,intrinsic%20timer%20of))" + }, + { + "reference": "Fulton D et al. Multiple roles of myelin protein genes in oligodendrocyte development. ASN Neuro. 2010.", + "id": "20017732", + "type": "PMID", + "notes": "Describes MBP, MAG, etc. in myelin sheaths ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2814326/#:~:text=MBP%20are%20distributed%20within%20the,interactions%20between%20myelin%20and%20axonal))" + }, + { + "reference": "Lei L et al. GBM proneural subtype enriched for OPC gene expression. PLoS One. 2011.", + "id": "21532771", + "type": "PMID", + "notes": "Proneural glioblastomas show enrichment of oligodendrocyte/OPC gene signatures ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3100315/#:~:text=match%20at%20L126%20tumors%20closely,genes%20that%20are%20differentially%20expressed))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "GPR17", + "MOG", + "MBP", + "MAG", + "CLDN11", + "FA2H", + "ENPP6", + "BCAS1", + "MYRF" + ], + "supporting_gene_count": 9, + "required_components_present": true + }, + { + "program_name": "ECM Remodeling and Cell Adhesion", + "description": "This cluster involves extracellular matrix (ECM) proteins and proteases. ADAM33 (a disintegrin metalloprotease) and SEMA4D (semaphorin ligand) mediate matrix remodeling and angiogenic signaling. COL18A1 encodes collagen XVIII from which endostatin (an anti-angiogenic fragment) is derived ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1871889/#:~:text=Endostatin%20was%20originally%20reported%20to,The%20receptor%20or)). GPC3 and ACAN are secreted proteoglycans, FERMT1 and TNS3 link integrins/focal adhesions. This program suggests altered matrix composition and cell adhesion properties. In glioblastoma, such changes can promote invasive migration and modulate angiogenesis.", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "citation": [ + { + "reference": "Mochizuki S, Okada Y. ADAMs in cancer proliferation and progression. Cancer Sci. 2007.", + "id": "17355265", + "type": "PMID", + "notes": "ADAM proteases remodel the ECM and promote cancer cell invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=reports%20suggest%20that%20ADAM8%20is,tumor%20cell%20migration%20and%20invasion))" + } + ], + "Genes": [ + "ADAM33", + "COL18A1", + "GPC3", + "ACAN", + "ACAT*", + "PRICKLE1" + ], + "ontology_label": "extracellular matrix organization", + "ontology_id": "GO:0030198" + }, + { + "name": "angiogenesis", + "citation": [ + { + "reference": "Rege TA et al. Endostatin inhibits glioma angiogenesis. Neuro Oncol. 2005.", + "id": "15831230", + "type": "PMID", + "notes": "Endostatin (from COL18A1) is anti-angiogenic in gliomas ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1871889/#:~:text=Endostatin%20was%20originally%20reported%20to,The%20receptor%20or))" + } + ], + "Genes": [ + "COL18A1", + "SEMA4D", + "BMPER" + ], + "ontology_label": "angiogenesis", + "ontology_id": "GO:0001525" + }, + { + "name": "cell adhesion", + "citation": [ + { + "reference": "Mochizuki S, Okada Y. ADAMs in cancer proliferation and progression. Cancer Sci. 2007.", + "id": "17355265", + "type": "PMID", + "notes": "ADAM-family metalloproteases interact with integrins contributing to adhesion and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=through%20the%20PKC%20and%20MAPK,regulate%20cell%20proliferation%20signals%20through))" + } + ], + "Genes": [ + "FERMT1", + "TNS3", + "PRICKLE1", + "SEMA4D" + ], + "ontology_label": "cell adhesion", + "ontology_id": "GO:0007155" + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "citation": [ + { + "reference": "Rege TA et al. Endostatin inhibits glioma angiogenesis. Neuro Oncol. 2005.", + "id": "15831230", + "type": "PMID", + "notes": "Collagen XVIII (COL18A1) is an ECM component providing endostatin ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1871889/#:~:text=Endostatin%20was%20originally%20reported%20to,The%20receptor%20or))" + } + ], + "Genes": [ + "COL18A1", + "GPC3", + "ACAN" + ], + "ontology_label": "extracellular matrix", + "ontology_id": "GO:0031012" + }, + { + "name": "cell surface receptor complex", + "citation": [ + { + "reference": "Mochizuki S, Okada Y. ADAMs in cancer proliferation and progression. Cancer Sci. 2007.", + "id": "17355265", + "type": "PMID", + "notes": "ADAMs (e.g., ADAM33) can act as cell adhesion molecules via integrins ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=through%20the%20PKC%20and%20MAPK,regulate%20cell%20proliferation%20signals%20through))" + } + ], + "Genes": [ + "ADAM33", + "SEMA4D", + "FERMT1" + ], + "ontology_label": "cell surface receptor signaling pathway", + "ontology_id": "GO:0007166" + } + ], + "predicted_cellular_impact": [ + "Increased ECM restructuring and proteolysis", + "Enhanced tumor cell migration and invasion", + "Modulation of angiogenesis (via endostatin and SEMA4D signaling)" + ], + "evidence_summary": "ADAM33 is a metalloprotease that can digest ECM and help tumor invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=reports%20suggest%20that%20ADAM8%20is,tumor%20cell%20migration%20and%20invasion)). SEMA4D promotes tumor angiogenesis and progression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2442644/#:~:text=Tumor%20angiogenesis%20and%20progression%20are,associated%20macrophages)). COL18A1-derived endostatin is a potent anti-angiogenic factor in gliomas ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1871889/#:~:text=Endostatin%20was%20originally%20reported%20to,The%20receptor%20or)). Integrin adaptor FERMT1 and focal adhesion protein TNS3 suggest altered adhesion signaling. Together these genes point to active matrix remodeling and changing adhesion in GBM, consistent with invasion and angiogenesis roles. ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=reports%20suggest%20that%20ADAM8%20is,tumor%20cell%20migration%20and%20invasion)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1871889/#:~:text=Endostatin%20was%20originally%20reported%20to,The%20receptor%20or)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2442644/#:~:text=Tumor%20angiogenesis%20and%20progression%20are,associated%20macrophages))", + "citations": [ + { + "reference": "Mochizuki S, Okada Y. ADAMs in cancer proliferation and progression. Cancer Sci. 2007.", + "id": "17355265", + "type": "PMID", + "notes": "ADAM proteases promote tumor cell invasion and adhesion changes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11160018/#:~:text=reports%20suggest%20that%20ADAM8%20is,tumor%20cell%20migration%20and%20invasion))" + }, + { + "reference": "Rege TA et al. Endostatin inhibits glioma angiogenesis. Neuro Oncol. 2005.", + "id": "15831230", + "type": "PMID", + "notes": "Collagen XVIII/endostatin modulates glioma angiogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1871889/#:~:text=Endostatin%20was%20originally%20reported%20to,The%20receptor%20or))" + }, + { + "reference": "Xue W et al. BMPER promotes glioma neovascularization. Front Oncol. 2020.", + "id": "32432046", + "type": "PMID", + "notes": "BMPER expression enhances tumor angiogenesis in GBM models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7214627/#:~:text=conclusion%20BMPER%2C%20CXCL10%2C%20and%20HOXA9,expression%20statuses%20of%20these%20genes))" + }, + { + "reference": "Sierra JR et al. Tumor-derived SEMA4D promotes angiogenesis. J Exp Med. 2008.", + "id": "18559453", + "type": "PMID", + "notes": "SEMA4D from macrophages enhances tumor angiogenesis and growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2442644/#:~:text=Tumor%20angiogenesis%20and%20progression%20are,associated%20macrophages))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": [ + "ADAM33", + "COL18A1", + "GPC3", + "ACAN", + "SEMA4D", + "FERMT1", + "TNS3", + "PRICKLE1" + ], + "supporting_gene_count": 8, + "required_components_present": true + }, + { + "program_name": "Neurotransmitter and Ion Channel Signaling", + "description": "This program groups cell surface receptors and channels that modulate glioblastoma signaling. GLRA3 (glycine receptor), ADRA1A (\u03b11-adrenergic GPCR), NOS1 (neuronal nitric oxide synthase) and P2RX7 (ATP-gated cation channel) together suggest heightened neurotransmitter/purinergic signaling in tumor cells. In GBM P2X7 activation drives proliferation and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5818963/#:~:text=4.1.%20Activation%20of%20P2X_,and%20Migration%20of%20Glioma%20Cells)), while NOS1-derived NO and adrenergic signaling modulate tumor and microenvironment responses. GLRA3 may regulate inhibitory tone. Overall this hints at altered neuronal-like signaling and calcium flux in GBM cells.", + "atomic_biological_processes": [ + { + "name": "purinergic receptor signaling", + "citation": [ + { + "reference": "Ji Z et al. P2X7R in gliomas proliferation and migration. Biomed Res Int. 2018.", + "id": "29546069", + "type": "PMID", + "notes": "Activation of P2X7 receptor enhances glioma cell proliferation and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5818963/#:~:text=4.1.%20Activation%20of%20P2X_,and%20Migration%20of%20Glioma%20Cells))" + } + ], + "Genes": [ + "P2RX7" + ], + "ontology_label": "purinergic nucleotide receptor signaling pathway", + "ontology_id": "GO:0035590" + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "citation": [ + { + "reference": "Ji Z et al. P2X7R in gliomas proliferation and migration. Biomed Res Int. 2018.", + "id": "29546069", + "type": "PMID", + "notes": "P2X7 and other receptors are membrane proteins mediating tumor signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5818963/#:~:text=4.1.%20Activation%20of%20P2X_,and%20Migration%20of%20Glioma%20Cells))" + } + ], + "Genes": [ + "P2RX7", + "GLRA3", + "ADRA1A", + "NOS1" + ], + "ontology_label": "plasma membrane", + "ontology_id": "GO:0005886" + } + ], + "predicted_cellular_impact": [ + "Enhanced purinergic and adrenergic signaling", + "Increased intracellular Ca^2+ and NO signaling", + "Promotion of glioma cell proliferation and motility" + ], + "evidence_summary": "P2RX7 is an ATP-gated cation channel; its activation promotes glioma proliferation and migration through ERK signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5818963/#:~:text=4.1.%20Activation%20of%20P2X_,and%20Migration%20of%20Glioma%20Cells)). NOS1 generates nitric oxide, which can promote tumor growth. ADRA1A is implicated in tumor cell signaling via Gq/PLC. These receptors together suggest that glioma cells may exploit neurotransmitter-like signaling pathways. Such purinergic signaling is linked to GBM aggressiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5818963/#:~:text=4.1.%20Activation%20of%20P2X_,and%20Migration%20of%20Glioma%20Cells)).", + "citations": [ + { + "reference": "Ji Z et al. Involvement of P2X7 receptor in proliferation and migration of human glioma cells. Biomed Res Int. 2018.", + "id": "29546069", + "type": "PMID", + "notes": "P2X7R activity drives glioma cell proliferation and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5818963/#:~:text=4.1.%20Activation%20of%20P2X_,and%20Migration%20of%20Glioma%20Cells))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.6, + "supporting_genes": [ + "GLRA3", + "KCNS3", + "ADRA1A", + "NOS1", + "P2RX7" + ], + "supporting_gene_count": 5, + "required_components_present": false + }, + { + "program_name": "BMP Signaling", + "description": "This program highlights BMP pathway regulators. BMP2 is a secreted ligand that induces differentiation of glioma stem cells to a less proliferative state, sensitizing them to therapy ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4022209/#:~:text=Persano%20and%20coworkers%20,TMZ%20delivered%20separately%20did%20not)). BMPER (Vwc2) is a BMP-binding protein that modulates BMP availability and also promotes tumor neovascularization ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7214627/#:~:text=conclusion%20BMPER%2C%20CXCL10%2C%20and%20HOXA9,expression%20statuses%20of%20these%20genes)). Together, BMP2/BMPER suggest active BMP signaling in the microenvironment, affecting tumor differentiation and angiogenesis.", + "atomic_biological_processes": [ + { + "name": "BMP signaling pathway", + "citation": [ + { + "reference": "Persano L et al. BMP2 sensitizes glioblastoma stem cells to temozolomide. Cell Death Dis. 2012.", + "id": "23076220", + "type": "PMID", + "notes": "BMP2-induced differentiation of GBM stem cells increases chemosensitivity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4022209/#:~:text=Persano%20and%20coworkers%20,TMZ%20delivered%20separately%20did%20not))" + } + ], + "Genes": [ + "BMP2", + "BMPER" + ], + "ontology_label": "BMP signaling pathway", + "ontology_id": "GO:0030509" + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular region", + "citation": [ + { + "reference": "Persano L et al. BMP2 sensitizes glioblastoma stem cells to temozolomide. Cell Death Dis. 2012.", + "id": "23076220", + "type": "PMID", + "notes": "BMP2 is a secreted growth factor acting in the extracellular milieu" + } + ], + "Genes": [ + "BMP2", + "BMPER" + ], + "ontology_label": "extracellular region", + "ontology_id": "GO:0005576" + } + ], + "predicted_cellular_impact": [ + "Increased differentiation of glioma stem cells", + "Altered tumor sensitivity to chemotherapy (via BMP2)", + "Enhanced angiogenic signaling modulation (via BMPER)" + ], + "evidence_summary": "BMP2 expression increases with glioma grade and promotes differentiation of glioma stem cells, leading to reduced HIF-1\u03b1 and MGMT levels, which sensitizes cells to temozolomide ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4022209/#:~:text=Persano%20and%20coworkers%20,TMZ%20delivered%20separately%20did%20not)). BMPER binds BMPs and is upregulated in growing gliomas, enhancing angiogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7214627/#:~:text=conclusion%20BMPER%2C%20CXCL10%2C%20and%20HOXA9,expression%20statuses%20of%20these%20genes)). Thus, BMP pathway activation here may drive tumor cell differentiation and modulate vascular growth in GBM.", + "citations": [ + { + "reference": "Persano L et al. BMP2 induces differentiation and chemosensitivity in GBM stem cells. Cell Death Dis. 2012.", + "id": "23076220", + "type": "PMID", + "notes": "BMP2 drives GBM stem cell differentiation and increases therapy sensitivity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4022209/#:~:text=Persano%20and%20coworkers%20,TMZ%20delivered%20separately%20did%20not))" + }, + { + "reference": "Xue W et al. BMPER promotes glioma neovascularization. Front Oncol. 2020.", + "id": "32432046", + "type": "PMID", + "notes": "BMPER expression enhances angiogenesis in glioblastoma models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7214627/#:~:text=conclusion%20BMPER%2C%20CXCL10%2C%20and%20HOXA9,expression%20statuses%20of%20these%20genes))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": [ + "BMP2", + "BMPER" + ], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "Proliferation and DNA Repair", + "description": "This program includes signaling effectors linked to proliferation and genome maintenance. FAM83D is overexpressed in GBM and activates the AKT/mTOR pathway, driving cell proliferation, invasion and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9136185/#:~:text=match%20at%20L69%20FAM83D%20overexpression,vivo%20experiments%20demonstrated%20that%20silencing)). CDK18 promotes ATR-mediated homologous recombination DNA repair, enabling survival from replication stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6606647/#:~:text=dependent%20kinase%2018%20,established%20that%20targeting%20PARP%20together)). RASGEF1B (a Ras GEF) may also drive Ras-pathway proliferation. Altogether, these suggest enhanced proliferative signaling and DNA repair capacity in tumor cells.", + "atomic_biological_processes": [ + { + "name": "cell proliferation", + "citation": [ + { + "reference": "Li X et al. FAM83D activates AKT/mTOR to promote glioma proliferation. Transl Oncol. 2022.", + "id": "35617811", + "type": "PMID", + "notes": "FAM83D overexpression promotes glioma cell proliferation via AKT/mTOR ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9136185/#:~:text=match%20at%20L69%20FAM83D%20overexpression,vivo%20experiments%20demonstrated%20that%20silencing))" + } + ], + "Genes": [ + "FAM83D", + "RASGEF1B" + ], + "ontology_label": "cell population proliferation", + "ontology_id": "GO:0008283" + }, + { + "name": "homologous recombination", + "citation": [ + { + "reference": "Ning JF et al. CDK18 promotes ATR-mediated HR in glioblastoma. Nat Commun. 2019.", + "id": "31266951", + "type": "PMID", + "notes": "CDK18 enhances homologous recombination DNA repair in GBM cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6606647/#:~:text=dependent%20kinase%2018%20,established%20that%20targeting%20PARP%20together))" + } + ], + "Genes": [ + "CDK18" + ], + "ontology_label": "homologous recombination", + "ontology_id": "GO:0035825" + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "citation": [ + { + "reference": "Ning JF et al. CDK18 promotes ATR-mediated HR in glioblastoma. Nat Commun. 2019.", + "id": "31266951", + "type": "PMID", + "notes": "CDK18 functions in the nucleus to regulate DNA repair" + } + ], + "Genes": [ + "CDK18", + "FAM83D" + ], + "ontology_label": "nucleus", + "ontology_id": "GO:0005634" + } + ], + "predicted_cellular_impact": [ + "Increased tumor cell proliferation and survival (via AKT/mTOR)", + "Enhanced DNA repair (via ATR/HR pathways)", + "Activated Ras signaling and cell cycle progression" + ], + "evidence_summary": "FAM83D overexpression is observed in GBM and activates the AKT/mTOR pathway to drive cell proliferation, invasion and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9136185/#:~:text=match%20at%20L69%20FAM83D%20overexpression,vivo%20experiments%20demonstrated%20that%20silencing)). CDK18 is implicated in ATR-mediated homologous recombination repair in glioblastoma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6606647/#:~:text=dependent%20kinase%2018%20,established%20that%20targeting%20PARP%20together)), promoting DNA damage tolerance. These functions suggest that this gene set enhances proliferative growth and genome maintenance in malignant glioma cells, consistent with tumor progression.", + "citations": [ + { + "reference": "Li X et al. FAM83D overexpression activates AKT/mTOR in glioma. Transl Oncol. 2022.", + "id": "35617811", + "type": "PMID", + "notes": "FAM83D upregulation promotes glioblastoma proliferation via AKT/mTOR ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9136185/#:~:text=match%20at%20L69%20FAM83D%20overexpression,vivo%20experiments%20demonstrated%20that%20silencing))" + }, + { + "reference": "Ning JF et al. CDK18 drives ATR-mediated DNA repair in GBM. Nat Commun. 2019.", + "id": "31266951", + "type": "PMID", + "notes": "CDK18 promotes homologous recombination repair in glioma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6606647/#:~:text=dependent%20kinase%2018%20,established%20that%20targeting%20PARP%20together))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "FAM83D", + "RASGEF1B", + "CDK18" + ], + "supporting_gene_count": 3, + "required_components_present": false + } + ], + "method": { + "clustering_basis": [ + "literature curation", + "pathway annotation", + "gene co-expression" + ], + "notes": "Gene clusters defined by known functional categories (e.g. myelination, ECM, signaling) and literature evidence relevant to glioblastoma." + }, + "version": "1.0.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_npc_like b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_npc_like new file mode 100644 index 0000000..d159a8f --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_opc_npc_like @@ -0,0 +1,435 @@ +{ + "context": { + "cell_type": "Glioblastoma cells", + "disease": "Glioblastoma", + "tissue": "Brain" + }, + "input_genes": [ + "SLIT3", + "CA8", + "ARX", + "AC109492.1", + "AL078602.1", + "DLX5", + "AC006296.3", + "DLX6", + "RFTN2", + "DLX6-AS1", + "AC090241.2", + "PDZRN3", + "GLI2", + "TBL1X", + "KCNH8", + "ST8SIA5", + "LRGUK", + "TPGS2", + "LINC02487", + "DACH2", + "SOX2-OT", + "KIAA0040", + "FCGBP", + "LINC00326", + "AC022075.1", + "AC125613.1", + "MCUB", + "EPHA7", + "PLS3", + "SLC6A5", + "CRYBG3", + "LINC01748", + "TENM1", + "LINC00535", + "ABTB2", + "MAN2A1", + "LAMP5", + "MOG", + "KITLG", + "ZNF618", + "PIP5K1B", + "AC005162.3", + "AC017053.1", + "FAM149A", + "CRB1", + "ERBB3", + "EPB41L4A", + "STC1", + "PID1", + "EGFR" + ], + "programs": [ + { + "program_name": "Hedgehog signaling (GLI2)", + "description": "GLI2 is a key transcription factor in Sonic Hedgehog signaling, a pathway active in GBM that maintains stem-like tumor cells and drives proliferation. Hedgehog pathway activation promotes glioblastoma stem cell maintenance and is linked to therapy resistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9353242/#:~:text=GLI2%20also%20affects%20HH%20and,receptor%205%2C%20inhibited%20tumor%20cell)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9353242/#:~:text=partial%20drug%20resistance%20through%20this,pathway%20will%20be%20addressed)).", + "predicted_cellular_impact": [ + "Enhanced GSC maintenance and self-renewal", + "Increased proliferation and treatment resistance" + ], + "evidence_summary": "GLI2, a Hedgehog pathway effector, is implicated in glioma stem cell renewal. In GBM, GLI2 activity (often linked to mTORC2) promotes expression of stemness genes, and GLI2 knockdown impairs GBM stem cell proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9353242/#:~:text=GLI2%20also%20affects%20HH%20and,receptor%205%2C%20inhibited%20tumor%20cell)). Hedgehog signaling sustains GBM growth and contributes to drug resistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9353242/#:~:text=partial%20drug%20resistance%20through%20this,pathway%20will%20be%20addressed)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9353242/#:~:text=GLI2%20also%20affects%20HH%20and,receptor%205%2C%20inhibited%20tumor%20cell)).", + "citations": [ + { + "reference": "Wang et al., Hedgehog signaling regulates glioblastoma (Oncol Lett 2022)", + "id": "PMID:35949611", + "type": "PMID", + "notes": "Reviews Hedgehog/GLI2 role in GBM stemness" + }, + { + "reference": "Takezaki et al., Hedgehog signaling in glioma stem cells (Cancer Sci 2011)", + "id": "PMID:21597402", + "type": "PMID", + "notes": "GLI2 required for glioma-initiating cell proliferation" + } + ], + "confidence_score": 0.8, + "significance_score": 0.3, + "supporting_genes": [ + "GLI2" + ], + "supporting_gene_count": 1, + "required_components_present": false, + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007224", + "name": "Hedgehog signaling pathway", + "citation": [ + { + "reference": "Wang et al., Oncol Lett 2022", + "id": "PMID:35949611", + "type": "PMID", + "notes": "Hedgehog pathway active in GBM with GLI2 effect" + } + ], + "Genes": [ + "GLI2" + ], + "ontology_label": "smoothened signaling pathway" + } + ], + "atomic_cellular_components": [] + }, + { + "program_name": "Wnt5a-mediated invasion", + "description": "DLX5 and SOX2-OT in glioma cells activate WNT5A-driven pathways, inducing a glioma stem cell differentiation program into endothelial-like cells. This promotes peritumoral angiogenesis and diffuse invasion. SOX2-OT upregulates SOX2 and activates Wnt5a/\u03b2-catenin signaling, enhancing proliferation and chemoresistance ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27863244/#:~:text=malignant%20states%20of%20NSCs,to%20the%20lethality%20of%20GBM)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/32439916/#:~:text=resistant%20cells%20and%20recurrent%20GBM,Our%20findings%20indicate%20that)).", + "predicted_cellular_impact": [ + "Increased tumor invasiveness and neovascular mimicry", + "Endothelial-like differentiation of tumor cells" + ], + "evidence_summary": "In GBM models, a PAX6/DLX5 axis drives WNT5A expression to differentiate glioma stem cells into endothelial-like cells (supporting invasive outgrowth) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27863244/#:~:text=malignant%20states%20of%20NSCs,to%20the%20lethality%20of%20GBM)). Separately, the lncRNA SOX2-OT is upregulated in GBM relapse and promotes cell proliferation by increasing SOX2 and activating Wnt5a/\u03b2-catenin signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/32439916/#:~:text=resistant%20cells%20and%20recurrent%20GBM,Our%20findings%20indicate%20that)). Together, these suggest a program where DLX5+SOX2-OT enhance Wnt5a-driven GBM invasion.", + "citations": [ + { + "reference": "Huang et al., PAX6/DLX5-WNT5A axis in GBM (Cancer Cell 2016)", + "id": "PMID:27863244", + "type": "PMID", + "notes": "Shows DLX5 drives WNT5A for GSC differentiation/invasion" + }, + { + "reference": "Xiong et al., SOX2OT promotes TMZ resistance (Mol Oncol 2020)", + "id": "PMID:32439916", + "type": "PMID", + "notes": "Links SOX2OT to SOX2 and Wnt5a activation in GBM" + } + ], + "confidence_score": 0.7, + "significance_score": 0.5, + "supporting_genes": [ + "DLX5", + "SOX2-OT" + ], + "supporting_gene_count": 2, + "required_components_present": false, + "atomic_biological_processes": [ + { + "ontology_id": "GO:0016055", + "name": "Wnt signaling pathway", + "citation": [ + { + "reference": "Xiong et al., Mol Oncol 2020", + "id": "PMID:32439916", + "type": "PMID", + "notes": "SOX2-OT activates Wnt5a/\u03b2-catenin pathway in GBM" + } + ], + "Genes": [ + "DLX5", + "SOX2-OT" + ], + "ontology_label": "Wnt signaling pathway" + } + ], + "atomic_cellular_components": [] + }, + { + "program_name": "RTK/PI3K signaling", + "description": "Receptor tyrosine kinases drive PI3K/Akt signaling for growth and survival. EGFR is frequently amplified in GBM, driving proliferation and poor prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12027172/#:~:text=rate,total%20of%2032%20studies%20with)). ERBB3 (HER3), though kinase-impaired, when overexpressed heterodimerizes (e.g. with FGFR3) to activate PI3K/Akt and metabolic pathways, supporting cell survival and therapy resistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8632286/#:~:text=characterized%20by%20marked%20Erb,survival%20signaling%2C%20which%20can)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8632286/#:~:text=high%20ERBB3%20activity%20may%20support,ERBB3%20and%20Fibroblast%20Growth%20Factor)).", + "predicted_cellular_impact": [ + "Elevated PI3K/AKT signaling", + "Enhanced proliferation and survival" + ], + "evidence_summary": "EGFR amplification is one of the most common alterations in GBM and correlates with aggressive growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12027172/#:~:text=rate,total%20of%2032%20studies%20with)). A subset of GBMs overexpress ERBB3 (HER3), which upon ligand binding or heterodimerization triggers potent PI3K/Akt-driven metabolism and proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8632286/#:~:text=characterized%20by%20marked%20Erb,survival%20signaling%2C%20which%20can)). Together, EGFR/ERBB3 signaling in GBM sustains tumor cell proliferation and contributes to treatment resistance.", + "citations": [ + { + "reference": "Zhu et al., EGFR amplification in GBM (Int J Mol Sci 2025)", + "id": "PMID:40331985", + "type": "PMID", + "notes": "Meta-analysis showing frequent EGFRamp in GBM" + }, + { + "reference": "De Bacco et al., ERBB3 in GBM stem cells (Mol Cell Oncol 2021)", + "id": "PMID:34859149", + "type": "PMID", + "notes": "Describes ERBB3 overexpression driving PI3K signaling in GBM" + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": [ + "EGFR", + "ERBB3", + "KITLG", + "PIP5K1B" + ], + "supporting_gene_count": 4, + "required_components_present": false, + "atomic_biological_processes": [ + { + "ontology_id": "GO:0004714", + "name": "transmembrane receptor protein tyrosine kinase signaling pathway", + "citation": [ + { + "reference": "Zhu et al., Int J Mol Sci 2025", + "id": "PMID:40331985", + "type": "PMID", + "notes": "EGFR/ERBB3 signaling activates PI3K/Akt in GBM" + } + ], + "Genes": [ + "EGFR", + "ERBB3", + "KITLG", + "PIP5K1B" + ], + "ontology_label": "transmembrane receptor protein tyrosine kinase activity" + }, + { + "ontology_id": "GO:0038096", + "name": "Fc-gamma receptor signaling pathway involved in phagocytosis", + "citation": [ + { + "reference": "Yan et al., Front Oncol 2022", + "id": "PMID:35082709", + "type": "PMID", + "notes": "FCGBP role in glioma, implicating immune-related signaling" + } + ], + "Genes": [ + "FCGBP" + ], + "ontology_label": "Fc-gamma receptor signaling pathway involved in phagocytosis" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005886", + "name": "plasma membrane", + "citation": [ + { + "reference": "De Bacco et al., Mol Cell Oncol 2021", + "id": "PMID:34859149", + "type": "PMID", + "notes": "ERBB3 is a membrane RTK in GBM cells" + } + ], + "Genes": [ + "ERBB3", + "EGFR" + ], + "ontology_label": "plasma membrane" + } + ] + }, + { + "program_name": "Inhibitory neuron differentiation", + "description": "This program features genes classically involved in GABAergic interneuron development and synaptic function. ARX and DLX homeobox transcription factors direct GABAergic migration and differentiation during brain development ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18799476/#:~:text=Mutations%20in%20the%20aristaless,changes%20within%20the%20subpallium%20in)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623701/#:~:text=interneurons%20of%20the%20olfactory%20bulb,fashion%2C%20via%20expression%20of%20Wnt5a)). LAMP5, a vesicular GABA-transporter chaperone, marks inhibitory neurons and tunes GABAergic synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6416879/#:~:text=Lysosome,we%20focus%20on%20the%20prominent)). Their joint expression in GBM suggests a proneural-like or interneuron-lineage transcriptional program.", + "predicted_cellular_impact": [ + "Expression of neuronal differentiation markers", + "Adoption of inhibitory synaptic features" + ], + "evidence_summary": "ARX and DLX5/6 are known regulators of GABAergic interneuron development; loss of ARX disrupts interneuron migration and differentiation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18799476/#:~:text=Mutations%20in%20the%20aristaless,changes%20within%20the%20subpallium%20in)), while DLX5 directly induces GABAergic fate (via Wnt5a) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6623701/#:~:text=interneurons%20of%20the%20olfactory%20bulb,fashion%2C%20via%20expression%20of%20Wnt5a)). LAMP5 is a vesicular GABA transporter-sorting protein expressed in inhibitory neurons ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6416879/#:~:text=Lysosome,we%20focus%20on%20the%20prominent)). This profile indicates glioma cells may exhibit some neuronal/interneuron-like programs.", + "citations": [ + { + "reference": "Friocourt et al., ARX targets in cortical interneurons (J Neurosci 2011)", + "id": "PMID:18799476", + "type": "PMID", + "notes": "ARX is required for GABAergic neuron development" + }, + { + "reference": "Paina et al., Dlx genes promote interneuron differentiation (J Neurosci 2011)", + "id": "PMID:21325536", + "type": "PMID", + "notes": "DLX5 drives GABAergic interneuron differentiation via Wnt5a" + }, + { + "reference": "Koebis et al., LAMP5 in GABAergic neurons (Mol Brain 2019)", + "id": "PMID:30867010", + "type": "PMID", + "notes": "LAMP5 is required for GABA synaptic transmission" + } + ], + "confidence_score": 0.6, + "significance_score": 0.6, + "supporting_genes": [ + "ARX", + "DLX5", + "DLX6", + "LAMP5", + "SLC6A5" + ], + "supporting_gene_count": 5, + "required_components_present": false, + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030182", + "name": "neuron differentiation", + "citation": [ + { + "reference": "Paina et al., J Neurosci 2011", + "id": "PMID:21325536", + "type": "PMID", + "notes": "DLX genes promote GABAergic differentiation" + }, + { + "reference": "Friocourt et al., J Neurosci 2011", + "id": "PMID:18799476", + "type": "PMID", + "notes": "ARX important for interneuron development" + } + ], + "Genes": [ + "ARX", + "DLX5", + "DLX6", + "LAMP5", + "SLC6A5" + ], + "ontology_label": "neuron differentiation" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0048786", + "name": "presynaptic active zone", + "citation": [ + { + "reference": "Koebis et al., Mol Brain 2019", + "id": "PMID:30867010", + "type": "PMID", + "notes": "LAMP5 located at inhibitory presynaptic boutons" + } + ], + "Genes": [ + "LAMP5", + "SLC6A5" + ], + "ontology_label": "presynaptic active zone" + } + ] + }, + { + "program_name": "Axon guidance and adhesion", + "description": "This program groups axon guidance cues and adhesion molecules. SLIT3 and EPHA7 are repulsive guidance signals in neural development ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2774558/#:~:text=Slits%20are%20large%2C%20secreted%20repulsive,expressed%20and%20secreted%20by%20both)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3977303/#:~:text=characterizes%20the%20role%20of%20the,dendritic%20spine%20formation%20and%20synaptic)), here repurposed to influence tumor angiogenesis and cell motility. TENM1 and CRB1 regulate neuronal cell adhesion and polarity. Altered expression of these genes may enhance GBM cell migration and neovascularization.", + "predicted_cellular_impact": [ + "Increased cell migration and vascular development", + "Altered cell polarity and adhesion structures" + ], + "evidence_summary": "SLIT3 and EPHA7 are axon guidance ligands controlling neural wiring; SLIT3 also promotes angiogenesis in development ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2774558/#:~:text=Slits%20are%20large%2C%20secreted%20repulsive,expressed%20and%20secreted%20by%20both)), while EphA7 influences dendritic/axon growth and synapse formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3977303/#:~:text=characterizes%20the%20role%20of%20the,dendritic%20spine%20formation%20and%20synaptic)). CRB1 is part of the cell polarity complex. These factors can modulate the tumor microenvironment by guiding invasive behavior and vessel growth.", + "citations": [ + { + "reference": "Zhang et al., SLIT3 in angiogenesis (Blood 2009)", + "id": "PMID:19741192", + "type": "PMID", + "notes": "SLIT3 is a secreted axon repellent that activates angiogenesis" + }, + { + "reference": "Clifford et al., EphA7 in cortical development (PNAS 2014)", + "id": "PMID:24707048", + "type": "PMID", + "notes": "EphA7 modulates dendritic growth and guidance" + } + ], + "confidence_score": 0.7, + "significance_score": 0.7, + "supporting_genes": [ + "SLIT3", + "EPHA7", + "TENM1", + "CRB1", + "EPB41L4A", + "PLS3" + ], + "supporting_gene_count": 6, + "required_components_present": false, + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007411", + "name": "axon guidance", + "citation": [ + { + "reference": "Zhang et al., Blood 2009", + "id": "PMID:19741192", + "type": "PMID", + "notes": "SLIT3 is a repulsive axon guidance factor" + } + ], + "Genes": [ + "SLIT3", + "EPHA7", + "TENM1" + ], + "ontology_label": "axon guidance" + }, + { + "ontology_id": "GO:0001525", + "name": "angiogenesis", + "citation": [ + { + "reference": "Zhang et al., Blood 2009", + "id": "PMID:19741192", + "type": "PMID", + "notes": "SLIT3 promotes angiogenic growth" + } + ], + "Genes": [ + "SLIT3", + "EPHA7" + ], + "ontology_label": "angiogenesis" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0045202", + "name": "synapse", + "citation": [ + { + "reference": "Clifford et al., PNAS 2014", + "id": "PMID:24707048", + "type": "PMID", + "notes": "EphA7 localizes to dendritic/synaptic regions" + } + ], + "Genes": [ + "EPHA7" + ], + "ontology_label": "synapse" + } + ] + } + ], + "method": { + "clustering_basis": [ + "literature review", + "pathway databases" + ], + "notes": "Programs derived by grouping genes from literature-validated pathways (Hedgehog, Wnt, RTK, axon guidance) and neural developmental programs." + }, + "version": "2023-10-01" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_proliferative b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_proliferative new file mode 100644 index 0000000..dc20f22 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_proliferative @@ -0,0 +1,574 @@ +{ + "context": { + "cell_type": "Glioblastoma cells", + "disease": "glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "DLGAP5", + "CKAP2L", + "CDCA2", + "CDC25C", + "TTK", + "BUB1", + "HMMR", + "CDCA8", + "TOP2A", + "GTSE1", + "KIF23", + "BUB1B", + "ASPM", + "AURKA", + "KIF14", + "CEP55", + "KIF18A", + "CDK1", + "TROAP", + "DEPDC1", + "CENPE", + "TPX2", + "KIF2C", + "KNL1", + "KIF20A", + "AURKB", + "NEIL3", + "CCNB1", + "ESPL1", + "APOLD1", + "HJURP", + "PIMREG", + "KIF11", + "PIF1", + "UBE2C", + "NDC80", + "CDC20", + "PBK", + "ARHGAP11A", + "NUSAP1", + "PRR11", + "ESCO2", + "PTTG1", + "MELK", + "KIF4A", + "CDKN3", + "NMU", + "BORA", + "KIF18B", + "KIFC1", + "CCNF", + "BIRC5", + "MKI67", + "ARHGAP11B", + "IQGAP3", + "NCAPG", + "SGO1", + "SKA3", + "GAS2L3", + "SGO2", + "RRM2", + "DIAPH3", + "CDCA3", + "CENPF", + "FAM83D", + "NUF2", + "POLQ", + "RACGAP1", + "KPNA2", + "MIR924HG", + "FBXO43", + "TACC3", + "WDR62", + "E2F7", + "PCLAF", + "ASF1B", + "ECT2", + "SHCBP1", + "PLK1", + "FAM111B", + "DEPDC1B", + "MXD3", + "NCAPH", + "PRC1", + "EXO1", + "KIF15", + "FOXM1", + "CCNB2", + "RTKN2", + "NOSTRIN", + "AC010173.1", + "SPC25", + "FOXN4", + "HMGB2", + "CKS2", + "CENPI", + "BRIP1", + "MYBL2", + "LMO7", + "KIF24", + "AC073529.1", + "STIL", + "AC090159.1", + "PLK4" + ], + "programs": [ + { + "program_name": "G2/M Cell Cycle Regulation", + "description": "Coordinated regulation of the G2/M transition and mitotic entry, promoting proliferation. In glioblastoma this gene cluster drives rapid cell division and tumor growth.", + "atomic_biological_processes": [ + { + "name": "mitotic cell cycle", + "ontology_id": "GO:0000278", + "citation": [ + { + "reference": "Zhang et al. (2018) Identification of potential oncogenes in GBM. Oncol Rep.", + "id": "10.3892/or.2018.6483", + "type": "DOI", + "notes": "CDK1, CCNB1, CDC20 are overexpressed in GBM and regulate the mitotic cell cycle ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6072298/#:~:text=analyses,clearly%20inhibited%20GBM%20cell%20proliferation))." + } + ], + "Genes": [ + "CDC25C", + "CDK1", + "CCNB1", + "CCNB2", + "CDC20", + "ESPL1", + "PTTG1", + "CDKN3", + "CKS2", + "FBXO43", + "E2F7", + "FOXM1", + "MYBL2" + ], + "ontology_label": "mitotic cell cycle" + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "ontology_id": "GO:0005634", + "citation": [ + { + "reference": "Zhang et al. (2018) Oncol Rep.", + "id": "10.3892/or.2018.6483", + "type": "DOI", + "notes": "Cell-cycle regulators such as CDK1, CCNB1 act in the nucleus to drive GBM cell mitosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6072298/#:~:text=analyses,clearly%20inhibited%20GBM%20cell%20proliferation))." + } + ], + "Genes": [ + "CDC25C", + "CDK1", + "CCNB1", + "CCNB2", + "CDC20", + "ESPL1", + "PTTG1", + "CDKN3", + "CKS2", + "FBXO43", + "E2F7", + "FOXM1", + "MYBL2" + ], + "ontology_label": "nucleus" + } + ], + "predicted_cellular_impact": [ + "accelerated G2/M transition", + "increased cell proliferation", + "checkpoint bypass leading to aneuploidy" + ], + "evidence_summary": "Many included genes (e.g. CDK1, CCNB1, CDC20) are well-known G2/M regulators and are overexpressed in GBM, correlating with poor survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6072298/#:~:text=analyses,clearly%20inhibited%20GBM%20cell%20proliferation)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8144940/#:~:text=biomarkers%20for%20GBM%20,to%20explore%20the%20potential%20diagnosis)). Knockdown of CDK1 and CCNB1 inhibits glioma cell proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6072298/#:~:text=analyses,clearly%20inhibited%20GBM%20cell%20proliferation)). High FOXM1 promotes GBM stemness and proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4596841/#:~:text=in%20GBM%20stem%20cell%20maintenance,Notably%2C%20genetic)).", + "citations": [ + { + "reference": "Zhang et al. (2018) Oncol Rep.", + "id": "10.3892/or.2018.6483", + "type": "DOI", + "notes": "High CDK1, CCNB1, CDC20 in GBM; knockdown reduces proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6072298/#:~:text=analyses,clearly%20inhibited%20GBM%20cell%20proliferation))." + }, + { + "reference": "Geng et al. (2018) Disease Markers", + "id": "10.1155/2018/3215958", + "type": "DOI", + "notes": "Core cell cycle genes (TOP2A, CDK1, CCNB1, etc.) identified as GBM biomarkers ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8144940/#:~:text=biomarkers%20for%20GBM%20,to%20explore%20the%20potential%20diagnosis))." + }, + { + "reference": "Conde et al. (2017) BMC Cancer", + "id": "10.1186/s12885-017-3932-y", + "type": "DOI", + "notes": "Survivin (BIRC5), a CPC component, is overexpressed in gliomas and correlates with proliferation and grade ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=apoptosis%20and%20mitosis%20,8%2C%209%5D.%20It%20is))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.95, + "supporting_genes": [ + "CDC25C", + "CDK1", + "CCNB1", + "CCNB2", + "CDC20", + "ESPL1", + "PTTG1", + "CDKN3", + "CKS2", + "FBXO43", + "E2F7", + "FOXM1", + "MYBL2" + ], + "supporting_gene_count": 13, + "required_components_present": false + }, + { + "program_name": "Spindle Assembly and Centrosome Organization", + "description": "Regulation of the mitotic spindle apparatus and centrosome duplication, ensuring proper mitosis. In GBM cells, overexpression of spindle motors and centrosomal regulators enhances mitotic progression and may promote invasiveness.", + "atomic_biological_processes": [ + { + "name": "spindle assembly", + "ontology_id": "GO:0051225", + "citation": [ + { + "reference": "Venere et al. (2015) Sci Transl Med", + "id": "10.1126/scitranslmed.aac6762", + "type": "DOI", + "notes": "KIF11 is required for bipolar spindle formation; its inhibition halts GBM cell division and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4743764/#:~:text=between%20these%20disparate%20cellular%20processes%E2%80%94the,impeded%20tumor%20initiation%20and%20self))." + } + ], + "Genes": [ + "KIF11", + "KIF15", + "KIF4A", + "KIF14", + "KIF2C", + "TPX2", + "AURKA", + "TACC3", + "ASPM", + "NUSAP1" + ], + "ontology_label": "spindle assembly" + }, + { + "name": "centrosome duplication", + "ontology_id": "GO:0051298", + "citation": [ + { + "reference": "Ngwabyt Bikeye et al. (2010) Cancer Cell Int", + "id": "10.1186/1475-2867-10-1", + "type": "DOI", + "notes": "ASPM localizes to centrosomes/spindle poles and is required for glioma growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2817685/#:~:text=initial%20grade%20of%20the%20primary,in%20two%20different%20gliomasphere%20models))." + } + ], + "Genes": [ + "PLK4", + "STIL", + "ASPM", + "WDR62" + ], + "ontology_label": "centrosome duplication" + } + ], + "atomic_cellular_components": [ + { + "name": "mitotic spindle", + "ontology_id": "GO:0072686", + "citation": [ + { + "reference": "Venere et al. (2015) Sci Transl Med", + "id": "10.1126/scitranslmed.aac6762", + "type": "DOI", + "notes": "KIF11 localizes to the mitotic spindle; targeting it disrupts GBM cell division and motility ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4743764/#:~:text=between%20these%20disparate%20cellular%20processes%E2%80%94the,impeded%20tumor%20initiation%20and%20self))." + } + ], + "Genes": [ + "KIF11", + "KIF15", + "KIF4A", + "KIF14", + "KIF2C", + "TPX2", + "AURKA", + "TACC3", + "ASPM", + "NUSAP1" + ], + "ontology_label": "mitotic spindle" + }, + { + "name": "centrosome", + "ontology_id": "GO:0005813", + "citation": [ + { + "reference": "Ngwabyt Bikeye et al. (2010) Cancer Cell Int", + "id": "10.1186/1475-2867-10-1", + "type": "DOI", + "notes": "ASPM is at centrosomes/spindle poles, promoting stem-like proliferation in glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2817685/#:~:text=initial%20grade%20of%20the%20primary,in%20two%20different%20gliomasphere%20models))." + } + ], + "Genes": [ + "PLK4", + "STIL", + "ASPM", + "WDR62" + ], + "ontology_label": "centrosome" + } + ], + "predicted_cellular_impact": [ + "enhanced spindle formation and mitotic polarity", + "aberrant centrosome amplification", + "increased motility and invasiveness" + ], + "evidence_summary": "Multiple kinesins (KIF11, KIF15, etc.) and Aurora kinases (AURKA) are upregulated in GBM, facilitating spindle assembly and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4743764/#:~:text=between%20these%20disparate%20cellular%20processes%E2%80%94the,impeded%20tumor%20initiation%20and%20self)). ASPM, localized to centrosomes, is overexpressed in aggressive gliomas and its silencing halts proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2817685/#:~:text=initial%20grade%20of%20the%20primary,in%20two%20different%20gliomasphere%20models)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6977704/#:~:text=analysis%2C%20the%20highest%20fold%20change,suggest%20that%20ASPM%20may%20serve)). These factors collectively promote robust mitosis and genomic instability in tumor cells.", + "citations": [ + { + "reference": "Venere et al. (2015) Sci Transl Med", + "id": "10.1126/scitranslmed.aac6762", + "type": "DOI", + "notes": "KIF11 is central to GBM TIC proliferation and invasion; its inhibition stops tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4743764/#:~:text=between%20these%20disparate%20cellular%20processes%E2%80%94the,impeded%20tumor%20initiation%20and%20self))." + }, + { + "reference": "Ngwabyt Bikeye et al. (2010) Cancer Cell Int", + "id": "10.1186/1475-2867-10-1", + "type": "DOI", + "notes": "ASPM localizes to centrosomes/spindle poles; shRNA silencing causes proliferation arrest and cell death in GBM models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2817685/#:~:text=initial%20grade%20of%20the%20primary,in%20two%20different%20gliomasphere%20models))." + }, + { + "reference": "Chen et al. (2020) Aging", + "id": "10.18632/aging.102612", + "type": "DOI", + "notes": "ASPM is highly expressed in GBM and its loss-of-function impedes GBM tumorigenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6977704/#:~:text=microcephaly%20associated%20%28ASPM%29,function%20assay%20indicated%20that%20ASPM))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "KIF11", + "KIF15", + "KIF4A", + "KIF14", + "KIF2C", + "TPX2", + "AURKA", + "TACC3", + "ASPM", + "NUSAP1", + "PLK4", + "STIL", + "WDR62" + ], + "supporting_gene_count": 13, + "required_components_present": false + }, + { + "program_name": "Kinetochore and Chromosome Segregation", + "description": "Assembly and function of kinetochores and centromeres to enable accurate chromosome alignment and segregation. Glioblastoma cells overexpress these components to tolerate chromosomal instability and adapt via spindle checkpoint signaling.", + "atomic_biological_processes": [ + { + "name": "chromosome segregation", + "ontology_id": "GO:0007059", + "citation": [ + { + "reference": "Conde et al. (2017) BMC Cancer", + "id": "10.1186/s12885-017-3932-y", + "type": "DOI", + "notes": "Survivin (BIRC5), part of the chromosomal passenger complex, ensures bipolar segregation and is upregulated in gliomas with aneuploidy ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=apoptosis%20and%20mitosis%20,8%2C%209%5D.%20It%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=Survivin%2C%20belonging%20to%20the%20inhibitor,inducing%20chromosomal%20instability%20remains%20unclear))." + } + ], + "Genes": [ + "NDC80", + "SPC25", + "NUF2", + "KNL1", + "SKA3", + "HJURP", + "CENPE", + "CENPF", + "CENPI", + "AURKB", + "CDCA8", + "BIRC5", + "SGO1", + "SGO2" + ], + "ontology_label": "chromosome segregation" + } + ], + "atomic_cellular_components": [ + { + "name": "kinetochore", + "ontology_id": "GO:0000776", + "citation": [ + { + "reference": "Herman et al. (2020) Neuro Oncol", + "type": "DOI", + "id": "10.1093/neuonc/noaa215.084", + "notes": "Chronic kinetochore\u2013microtubule attachment instability (KT stress) is observed in GBM cells; survivors rely on Mitotic Checkpoint proteins (BUB1B) to prevent aneuploidy ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7650502/#:~:text=elusive,MT%20attachment%20defects%20and))." + } + ], + "Genes": [ + "NDC80", + "SPC25", + "NUF2", + "KNL1", + "SKA3", + "HJURP", + "CENPE", + "CENPF", + "CENPI" + ], + "ontology_label": "kinetochore" + }, + { + "name": "centromeric region", + "ontology_id": "GO:0000775", + "citation": [ + { + "reference": "Conde et al. (2017) BMC Cancer", + "id": "10.1186/s12885-017-3932-y", + "type": "DOI", + "notes": "Components of the chromosome passenger complex localize to centromeres; Survivin overexpression induces chromosomal instability in glioma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=Survivin%2C%20belonging%20to%20the%20inhibitor,inducing%20chromosomal%20instability%20remains%20unclear))." + } + ], + "Genes": [ + "CENPE", + "CENPF", + "CENPI", + "HJURP", + "AURKB", + "CDCA8", + "BIRC5" + ], + "ontology_label": "chromosome, centromeric region" + } + ], + "predicted_cellular_impact": [ + "increased aneuploidy tolerance", + "activation of spindle assembly checkpoint", + "persistent chromosomal instability" + ], + "evidence_summary": "This cluster includes kinetochore proteins (NDC80 complex, CENPs, KNL1, SKA) and checkpoint kinases (BUB1/BUB1B, TTK). In GBM, merotelic attachments and \u2018kinetochore stress\u2019 are common; cells survive via heightened checkpoint (BUB1B) activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7650502/#:~:text=elusive,MT%20attachment%20defects%20and)). Overexpressed CPC components (Survivin/BIRC5, Borealin/CDCA8) at centromeres facilitate segregation, and elevated Survivin in gliomas is linked to higher grade and CIN ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=apoptosis%20and%20mitosis%20,8%2C%209%5D.%20It%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=Survivin%2C%20belonging%20to%20the%20inhibitor,inducing%20chromosomal%20instability%20remains%20unclear)).", + "citations": [ + { + "reference": "Conde et al. (2017) BMC Cancer", + "id": "10.1186/s12885-017-3932-y", + "type": "DOI", + "notes": "Survivin (BIRC5) is a centromere/CPC protein that, when overexpressed in glioma, causes chromosomal instability and promotes tumorigenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=Survivin%2C%20belonging%20to%20the%20inhibitor,inducing%20chromosomal%20instability%20remains%20unclear)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5745881/#:~:text=apoptosis%20and%20mitosis%20,8%2C%209%5D.%20It%20is))." + }, + { + "reference": "Herman et al. (2020) Neuro Oncol", + "type": "DOI", + "id": "10.1093/neuonc/noaa215.084", + "notes": "Experimental GBM models show widespread kinetochore stress and reliance on the spindle checkpoint (BUB1B) to avoid mitotic catastrophe ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7650502/#:~:text=elusive,MT%20attachment%20defects%20and))." + } + ], + "confidence_score": 0.85, + "significance_score": 0.85, + "supporting_genes": [ + "NDC80", + "SPC25", + "NUF2", + "KNL1", + "SKA3", + "HJURP", + "CENPE", + "CENPF", + "CENPI", + "AURKB", + "CDCA8", + "BIRC5", + "SGO1", + "SGO2" + ], + "supporting_gene_count": 14, + "required_components_present": false + }, + { + "program_name": "DNA Replication and Repair", + "description": "Processes ensuring genome duplication and healing of DNA lesions. GBM cells leverage these to survive oncogenic replication stress; dysregulation can cause therapy resistance and genomic instability.", + "atomic_biological_processes": [ + { + "name": "DNA repair", + "ontology_id": "GO:0006281", + "citation": [ + { + "reference": "Klattenhoff et al. (2017) Oncotarget", + "id": "10.18632/oncotarget.22896", + "type": "DOI", + "notes": "NEIL3 is recruited to sites of replication-associated DNA damage; its loss in GBM increases double-strand breaks under replication stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5762564/#:~:text=and%20its%20impact%20on%20modulating,dependent%20repair%20is))." + } + ], + "Genes": [ + "NEIL3", + "EXO1", + "PIF1", + "BRIP1", + "POLQ", + "ASF1B", + "PCLAF" + ], + "ontology_label": "DNA repair" + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "ontology_id": "GO:0005634", + "citation": [ + { + "reference": "Gagou et al. (2014) Oncotarget", + "id": "10.18632/oncotarget.2501", + "type": "DOI", + "notes": "PIF1 helicase is essential for DNA replication under oncogenic stress, supporting tumor proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4294361/#:~:text=Unwinding%20duplex%20DNA%20is%20a,transformed%20fibroblasts%2C%20where%20replication))." + } + ], + "Genes": [ + "NEIL3", + "EXO1", + "PIF1", + "BRIP1", + "POLQ", + "ASF1B", + "PCLAF" + ], + "ontology_label": "nucleus" + } + ], + "predicted_cellular_impact": [ + "enhanced DNA damage tolerance", + "resistance to replication stress", + "maintenance of proliferative capacity" + ], + "evidence_summary": "Included genes like NEIL3, PIF1, EXO1, POLQ, BRIP1 facilitate repair of replication-associated damage. NEIL3 is upregulated in tumors and prevents replication fork collapse in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5762564/#:~:text=and%20its%20impact%20on%20modulating,dependent%20repair%20is)). PIF1 supports fork progression specifically in cancer cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4294361/#:~:text=Unwinding%20duplex%20DNA%20is%20a,transformed%20fibroblasts%2C%20where%20replication)). These allow GBM cells to endure genotoxic stress and resist DNA-damaging therapies.", + "citations": [ + { + "reference": "Klattenhoff et al. (2017) Oncotarget", + "id": "10.18632/oncotarget.22896", + "type": "DOI", + "notes": "NEIL3 is required to repair replication-associated DNA damage in GBM cells; NEIL3 loss increases DSBs under stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5762564/#:~:text=and%20its%20impact%20on%20modulating,dependent%20repair%20is))." + }, + { + "reference": "Gagou et al. (2014) Oncotarget", + "id": "10.18632/oncotarget.2501", + "type": "DOI", + "notes": "Human PIF1 helicase maintains DNA replication fork progression in oncogene-transformed cells; PIF1 loss impairs cancer cell proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4294361/#:~:text=Unwinding%20duplex%20DNA%20is%20a,transformed%20fibroblasts%2C%20where%20replication))." + } + ], + "confidence_score": 0.75, + "significance_score": 0.8, + "supporting_genes": [ + "NEIL3", + "EXO1", + "PIF1", + "BRIP1", + "POLQ", + "ASF1B", + "PCLAF" + ], + "supporting_gene_count": 7, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_proliferative_2 b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_proliferative_2 new file mode 100644 index 0000000..ec747fa --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/glioblastoma_states_minimal_result.json_proliferative_2 @@ -0,0 +1 @@ +null \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/AT2_combined_input_result.csv b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/AT2_combined_input_result.csv new file mode 100644 index 0000000..ab94969 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/AT2_combined_input_result.csv @@ -0,0 +1,11 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +Proteolytic processing of surfactant protein precursors,GO:0016485,protein processing,GO,0.7,partial_match +Phospholipid transport into lamellar bodies,GO:0015914,phospholipid transport,GO,0.8,partial_match +Lamellar body biogenesis,GO:0042599,lamellar body,GO,0.9,exact_match +Surfactant secretion to alveolar space,GO:0160069,surfactant secretion,GO,1.0,exact_match +Extracellular protease activity in alveoli,GO:0008236,serine-type peptidase activity,GO,0.7,partial_match +Lamellar body,GO:0042599,lamellar body,GO,0.9,exact_match +Multivesicular body (MVB),GO:0005771,multivesicular body,GO,0.95,exact_match +Golgi apparatus,GO:0005794,Golgi apparatus,GO,1.0,exact_match +Endoplasmic reticulum,GO:0005783,endoplasmic reticulum,GO,1.0,exact_match +Alveolar space (bronchoalveolar fluid),UBERON:0004903,bronchoalveolar duct junction,UBERON,0.8,synonym_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/astrycytoma_1_result.csv b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/astrycytoma_1_result.csv new file mode 100644 index 0000000..7fbc921 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/astrycytoma_1_result.csv @@ -0,0 +1,36 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +K+ buffering and spatial ion distribution,GO:0043266,regulation of potassium ion transport,GO,0.85,exact_match +Water transport and edema regulation,GO:0006833,water transport,GO,0.9,exact_match +Gap junction intercellular communication,GO:1990349,gap junction-mediated intercellular transport,GO,0.9,related_match +Neurovascular coupling,UBERON:0016630,neurovascular bundle,UBERON,0.8,synonym_match +Perivascular astrocyte endfoot,GO:0097450,astrocyte end-foot,GO,0.85,exact_match +Astrocyte gap junction (connexin 43 complex),GO:0005922,connexin complex,GO,0.8,partial_match +Glial limitans and basement membrane contacts,UBERON:0018687,glial limiting membrane,UBERON,0.8,partial_match +Extracellular matrix deposition and remodeling,GO:0030198,extracellular matrix organization,GO,0.9,exact_match +Cell migration and invasion,GO:0016477,cell migration,GO,0.9,exact_match +Inflammatory signaling (NF-κB activation),,,,0.0, +Mechanotransduction and Hippo pathway signaling,GO:0035329,hippo signaling,GO,0.8,partial_match +Focal adhesion complex,GO:0005925,focal adhesion,GO,0.95,exact_match +Stress fibers and contractile cytoskeleton,GO:0001725,stress fiber,GO,0.8,partial_match +Perivascular niche interface,UBERON:0014930,perivascular space,UBERON,0.85,related_match +Glutamate uptake and buffering,GO:0051938,L-glutamate import,GO,0.9,exact_match +GABA reception and neuromodulation,GO:0016917,GABA receptor activity,GO,0.9,synonym_match +GPCR-triggered Ca2+ signaling,GO:0019722,calcium-mediated signaling,GO,0.8,partial_match +cAMP and cGMP second messenger modulation,GO:0019934,cGMP-mediated signaling,GO,0.85,partial_match +Tripartite synapse (astrocyte–synapse interface),,,,0.0, +Endoplasmic reticulum Ca2+ store,GO:0032469,endoplasmic reticulum calcium ion homeostasis,GO,0.75,synonym_match +Perisynaptic astrocyte process,GO:0097449,astrocyte projection,GO,0.9,exact_match +Inhibition of differentiation (maintenance of progenitor state),GO:0045596,negative regulation of cell differentiation,GO,0.85,exact_match +Neural stem cell proliferation,GO:0061351,neural precursor cell proliferation,GO,0.9,partial_match +Radial glial cell identity and guidance,CL:0000681,radial glial cell,CL,0.8,partial_match +STAT3-mediated astrogliogenesis and reactivity,,,,0.0,NO MATCH found +Neurosphere (tumor sphere) formation capacity,NO MATCH found,,,0.0,No suitable match found in any ontology +Periventricular radial glial scaffold (analogy),GO:0021943,formation of radial glial scaffolds,GO,0.9,exact_match +Stem cell niche interactions,GO:0019827,stem cell population maintenance,GO,0.8,exact_match +Exogenous lipid uptake,GO:0140354,lipid import into cell,GO,0.9,exact_match +Fatty acid modification and storage,GO:0030258,lipid modification,GO,0.85,exact_match +Glutamate utilization (anaplerosis),GO:0006536,glutamate metabolic process,GO,0.8,partial_match +Oxidative stress mitigation,GO:0006979,response to oxidative stress,GO,0.85,exact_match +Lipid droplets,GO:0005811,lipid droplet,GO,1.0,exact_match +Mitochondrial matrix (TCA cycle enzymes),GO:0005759,mitochondrial matrix,GO,0.9,exact_match +Peroxisomes (lipid catabolism sites),GO:0045033,peroxisome,GO,0.9,synonym_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_ac_gliosis_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_ac_gliosis_like_1 new file mode 100644 index 0000000..5183bd1 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_ac_gliosis_like_1 @@ -0,0 +1,15 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +water transport,GO:0006833,water transport,GO,1.0,exact_match +cell migration,GO:0016477,cell migration,GO,1.0,exact_match +plasma membrane,GO:0005886,plasma membrane,GO,1.0,exact_match +astrocyte differentiation,GO:0048708,astrocyte differentiation,GO,1.0,exact_match +synapse organization,GO:0050808,synapse organization,GO,1.0,exact_match +intermediate filament cytoskeleton,GO:0045111,intermediate filament cytoskeleton,GO,1.0,exact_match +extracellular matrix organization,GO:0030198,extracellular matrix organization,GO,1.0,exact_match +cell migration via ECM,GO:0016477,cell migration,GO,0.8,partial_match +extracellular region,GO:0005576,extracellular region,GO,1.0,exact_match +complement activation,GO:0006956,complement activation,GO,1.0,exact_match +inflammatory response,GO:0006954,inflammatory response,GO,1.0,exact_match +extracellular region,GO:0005576,extracellular region,GO,1.0,exact_match +ion transport,GO:0006811,monoatomic ion transport,GO,0.95,exact_match +plasma membrane,GO:0005886,plasma membrane,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_ac_gliosis_like_2 b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_ac_gliosis_like_2 new file mode 100644 index 0000000..e564e68 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_ac_gliosis_like_2 @@ -0,0 +1,14 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +extracellular matrix organization,GO:0030198,extracellular matrix organization,GO,1.0,exact_match +cell migration,GO:0016477,cell migration,GO,1.0,exact_match +extracellular matrix,GO:0031012,extracellular matrix,GO,1.0,exact_match +calcium ion transmembrane transport,GO:0070588,calcium ion transmembrane transport,GO,1.0,exact_match +cell migration,GO:0016477,cell migration,GO,1.0,exact_match +ion channel complex,GO:0034702,monoatomic ion channel complex,GO,1.0,exact_match +receptor tyrosine kinase signaling pathway,GO:0007169,cell surface receptor protein tyrosine kinase signaling pathway,GO,0.9,partial_match +MAPK cascade,GO:0000165,MAPK cascade,GO,1.0,exact_match +plasma membrane,GO:0005886,plasma membrane,GO,1.0,exact_match +positive regulation of cell proliferation,GO:0008284,positive regulation of cell population proliferation,GO,1.0,exact_match +PI3K signaling,GO:0043491,phosphatidylinositol 3-kinase/protein kinase B signal transduction,GO,0.8,synonym_match +canonical Wnt signaling pathway,GO:0060070,canonical Wnt signaling pathway,GO,1.0,exact_match +angiogenesis,GO:0001525,angiogenesis,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_ac_neuronal_like b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_ac_neuronal_like new file mode 100644 index 0000000..7d4ff5e --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_ac_neuronal_like @@ -0,0 +1,9 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +immune response,GO:0006955,immune response,GO,1.0,exact_match +immune synapse,GO:0001772,immunological synapse,GO,1.0,exact_match +synapse assembly,GO:0007416,synapse assembly,GO,1.0,exact_match +synapse,GO:0045202,synapse,GO,1.0,exact_match +extracellular matrix organization,GO:0030198,extracellular matrix organization,GO,1.0,exact_match +extracellular matrix,GO:0031012,extracellular matrix,GO,1.0,exact_match +neuron differentiation,GO:0030182,neuron differentiation,GO,1.0,exact_match +nucleus,GO:0005634,nucleus,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_gliosis b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_gliosis new file mode 100644 index 0000000..8068428 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_gliosis @@ -0,0 +1,13 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +receptor tyrosine kinase signaling pathway,GO:0007169,cell surface receptor protein tyrosine kinase signaling pathway,GO,0.9,exact_match +cell proliferation,GO:0008283,cell population proliferation,GO,0.9,exact_match +cell migration,GO:0016477,cell migration,GO,1.0,exact_match +plasma membrane,GO:0005886,plasma membrane,GO,1.0,exact_match +angiogenesis,GO:0001525,angiogenesis,GO,1.0,exact_match +extracellular space,GO:0005615,extracellular space,GO,1.0,exact_match +extracellular matrix organization,GO:0030198,extracellular matrix organization,GO,1.0,exact_match +cell adhesion,GO:0007155,cell adhesion,GO,1.0,exact_match +extracellular matrix,GO:0031012,extracellular matrix,GO,1.0,exact_match +focal adhesion,GO:0005925,focal adhesion,GO,1.0,exact_match +negative regulation of apoptosis,GO:0043066,negative regulation of apoptotic process,GO,1.0,exact_match +cytosol,GO:0005829,cytosol,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_gliosis_hypoxia b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_gliosis_hypoxia new file mode 100644 index 0000000..46250b8 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_gliosis_hypoxia @@ -0,0 +1,15 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +response to hypoxia,GO:0001666,response to hypoxia,GO,1.0,exact_match +lipid metabolic process,GO:0006629,lipid metabolic process,GO,1.0,exact_match +mitochondrial outer membrane,GO:0005741,mitochondrial outer membrane,GO,1.0,exact_match +extracellular region,GO:0005576,extracellular region,GO,1.0,exact_match +extracellular matrix organization,GO:0030198,extracellular matrix organization,GO,1.0,exact_match +cell adhesion,GO:0007155,cell adhesion,GO,1.0,exact_match +extracellular matrix,GO:0031012,extracellular matrix,GO,1.0,exact_match +integral component of plasma membrane,GO:0005886,plasma membrane,GO,0.9,exact_match +signal transduction,GO:0007165,signal transduction,GO,1.0,exact_match +cell proliferation,GO:0008283,cell population proliferation,GO,1.0,exact_match +integral component of plasma membrane,GO:0016021,integral component of membrane,GO,0.8,synonym_match +innate immune response,GO:0045087,innate immune response,GO,1.0,exact_match +response to interferon-gamma,GO:0034341,response to type II interferon,GO,1.0,exact_match +nucleus,GO:0005634,nucleus,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_npc_neuronal_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_npc_neuronal_like_1 new file mode 100644 index 0000000..746da54 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_npc_neuronal_like_1 @@ -0,0 +1,11 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +axoneme assembly,GO:0035082,axoneme assembly,GO,1.0,exact_match +cilium movement,GO:0003341,cilium movement,GO,1.0,exact_match +axoneme,GO:0005930,axoneme,GO,1.0,exact_match +cilium,GO:0005929,cilium,GO,1.0,exact_match +extracellular matrix organization,GO:0030198,extracellular matrix organization,GO,1.0,exact_match +cell adhesion,GO:0007155,cell adhesion,GO,1.0,exact_match +extracellular matrix,GO:0031012,extracellular matrix,GO,1.0,exact_match +glutamate receptor signaling pathway,GO:0007215,glutamate receptor signaling pathway,GO,1.0,exact_match +"synaptic transmission, GABAergic",GO:0051932,"synaptic transmission, GABAergic",GO,1.0,exact_match +postsynaptic density,GO:0014069,postsynaptic density,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_npc_neuronal_like_2 b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_npc_neuronal_like_2 new file mode 100644 index 0000000..8abcd2b --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_npc_neuronal_like_2 @@ -0,0 +1,14 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +synaptic vesicle exocytosis,GO:0016079,synaptic vesicle exocytosis,GO,1.0,exact_match +presynaptic active zone,GO:0048786,presynaptic active zone,GO,1.0,exact_match +homophilic cell adhesion,GO:0007156,homophilic cell adhesion via plasma membrane adhesion molecules,GO,0.95,exact_match +plasma membrane,GO:0005886,plasma membrane,GO,1.0,exact_match +ion transmembrane transport,GO:0034220,monoatomic ion transmembrane transport,GO,0.95,exact_match +neurotransmitter secretion,GO:0007269,neurotransmitter secretion,GO,1.0,exact_match +ion channel complex,GO:0034702,monoatomic ion channel complex,GO,0.95,exact_match +axon guidance,GO:0007411,axon guidance,GO,1.0,exact_match +growth cone,GO:0030426,growth cone,GO,1.0,exact_match +extracellular matrix organization,GO:0030198,extracellular matrix organization,GO,1.0,exact_match +extracellular region,GO:0005576,extracellular region,GO,1.0,exact_match +neuron differentiation,GO:0030182,neuron differentiation,GO,1.0,exact_match +nucleus,GO:0005634,nucleus,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_npc_neuronal_like_3 b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_npc_neuronal_like_3 new file mode 100644 index 0000000..14cd30b --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_npc_neuronal_like_3 @@ -0,0 +1,23 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +synaptic transmission,GO:0007268,chemical synaptic transmission,GO,1.0,exact_match +glutamatergic synaptic transmission,GO:0035249,"synaptic transmission, glutamatergic",GO,1.0,exact_match +GABAergic synaptic transmission,GO:0051932,"synaptic transmission, GABAergic",GO,1.0,exact_match +postsynaptic membrane,GO:0045211,postsynaptic membrane,GO,1.0,exact_match +synaptic vesicle,GO:0008021,synaptic vesicle,GO,1.0,exact_match +synapse,GO:0045202,synapse,GO,1.0,exact_match +neurogenesis,GO:0022008,neurogenesis,GO,1.0,exact_match +"transcription, DNA-templated",GO:0006351,DNA-templated transcription,GO,1.0,exact_match +nucleus,GO:0005634,nucleus,GO,1.0,exact_match +calcium-mediated signaling,GO:0019722,calcium-mediated signaling,GO,1.0,exact_match +phosphatidylinositol-mediated signaling,GO:0048015,phosphatidylinositol-mediated signaling,GO,1.0,exact_match +G-protein coupled receptor signaling pathway,GO:0007186,G protein-coupled receptor signaling pathway,GO,1.0,exact_match +plasma membrane,GO:0005886,plasma membrane,GO,1.0,exact_match +intrinsic component of synapse,GO:0019898,extrinsic/intrinsic component of membrane,GO,0.8,partial_match +extracellular matrix organization,GO:0030198,extracellular matrix organization,GO,1.0,exact_match +cell adhesion,GO:0007155,cell adhesion,GO,1.0,exact_match +regulation of cell migration,GO:0030334,regulation of cell migration,GO,1.0,exact_match +extracellular matrix,GO:0031012,extracellular matrix,GO,1.0,exact_match +cell surface,GO:0009986,cell surface,GO,1.0,exact_match +regulation of apoptotic process,GO:0042981,regulation of apoptotic process,GO,1.0,exact_match +intrinsic apoptotic signaling pathway,GO:0097193,intrinsic apoptotic signaling pathway,GO,1.0,exact_match +mitochondrial outer membrane,GO:0005741,mitochondrial outer membrane,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_ac_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_ac_like_1 new file mode 100644 index 0000000..45e65f0 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_ac_like_1 @@ -0,0 +1,14 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +extracellular matrix organization,GO:0030198,extracellular matrix organization,GO,1.0,exact_match +glycosaminoglycan biosynthetic process,GO:0006024,glycosaminoglycan biosynthetic process,GO,1.0,exact_match +protein sialylation,GO:1990743,protein sialylation,GO,1.0,exact_match +extracellular matrix,GO:0031012,extracellular matrix,GO,1.0,exact_match +cell adhesion,GO:0007155,cell adhesion,GO,1.0,exact_match +positive regulation of cell migration,GO:0030335,positive regulation of cell migration,GO,1.0,exact_match +axon guidance,GO:0007411,axon guidance,GO,1.0,exact_match +integrin complex,GO:0008305,integrin complex,GO,1.0,exact_match +cellular response to hypoxia,GO:0071456,cellular response to hypoxia,GO,1.0,exact_match +stem cell population maintenance,GO:0019827,stem cell population maintenance,GO,1.0,exact_match +glutathione metabolic process,GO:0006749,glutathione metabolic process,GO,1.0,exact_match +mitochondrial electron transport,GO:0042775,mitochondrial ATP synthesis coupled electron transport,GO,0.9,partial_match +mitochondrion,GO:0005739,mitochondrion,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_ac_like_2 b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_ac_like_2 new file mode 100644 index 0000000..33af04c --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_ac_like_2 @@ -0,0 +1,13 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +synaptic vesicle exocytosis,GO:0016079,synaptic vesicle exocytosis,GO,1.0,exact_match +neurotransmitter secretion,GO:0007269,neurotransmitter secretion,GO,1.0,exact_match +presynaptic active zone,GO:0048786,presynaptic active zone,GO,1.0,exact_match +synapse,GO:0045202,synapse,GO,1.0,exact_match +Notch signaling pathway,GO:0007219,Notch signaling pathway,GO,1.0,exact_match +cell differentiation,GO:0030154,cell differentiation,GO,1.0,exact_match +integral component of membrane,,,,0.0,NO MATCH found +EGFR signaling pathway,GO:0007173,epidermal growth factor receptor signaling pathway,GO,1.0,exact_match +MAPK cascade,GO:0000165,MAPK cascade,GO,1.0,exact_match +plasma membrane receptor complex,GO:0098802,plasma membrane signaling receptor complex,GO,0.95,exact_match +"regulation of transcription, DNA-templated",GO:0006355,regulation of DNA-templated transcription,GO,1.0,exact_match +nucleus,GO:0005634,nucleus,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_like_1 new file mode 100644 index 0000000..e85461a --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_like_1 @@ -0,0 +1,19 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +extracellular matrix organization,GO:0030198,extracellular matrix organization,GO,1.0,exact_match +cell adhesion,GO:0007155,cell adhesion,GO,1.0,exact_match +extracellular matrix,GO:0031012,extracellular matrix,GO,1.0,exact_match +focal adhesion,GO:0005925,focal adhesion,GO,1.0,exact_match +G-protein coupled receptor signaling pathway,GO:0007186,G protein-coupled receptor signaling pathway,GO,1.0,exact_match +calcium-mediated signaling,GO:0019722,calcium-mediated signaling,GO,1.0,exact_match +plasma membrane,GO:0005886,plasma membrane,GO,1.0,exact_match +myelination,GO:0042552,myelination,GO,1.0,exact_match +oligodendrocyte differentiation,GO:0048709,oligodendrocyte differentiation,GO,1.0,exact_match +myelin sheath,GO:0043209,myelin sheath,GO,1.0,exact_match +cell cycle,GO:0007049,cell cycle,GO,1.0,exact_match +regulation of cell migration,GO:0030334,regulation of cell migration,GO,1.0,exact_match +nucleus,GO:0005634,nucleus,GO,1.0,exact_match +cytosol,GO:0005829,cytosol,GO,1.0,exact_match +steroid hormone mediated signaling pathway,GO:0043401,steroid hormone receptor signaling pathway,GO,0.95,exact_match +nucleus,GO:0005634,nucleus,GO,1.0,exact_match +Notch signaling pathway,GO:0007219,Notch signaling pathway,GO,1.0,exact_match +cell surface,GO:0009986,cell surface,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_like_2 b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_like_2 new file mode 100644 index 0000000..de3eff9 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_like_2 @@ -0,0 +1,15 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +myelination,GO:0042552,myelination,GO,1.0,exact_match +myelin sheath,GO:0043209,myelin sheath,GO,1.0,exact_match +extracellular matrix organization,GO:0030198,extracellular matrix organization,GO,1.0,exact_match +angiogenesis,GO:0001525,angiogenesis,GO,1.0,exact_match +cell adhesion,GO:0007155,cell adhesion,GO,1.0,exact_match +extracellular matrix,GO:0031012,extracellular matrix,GO,1.0,exact_match +cell surface receptor complex,GO:0007166,cell surface receptor signaling pathway,GO,0.8,synonym_match +purinergic receptor signaling,GO:0035590,purinergic nucleotide receptor signaling pathway,GO,1.0,exact_match +plasma membrane,GO:0005886,plasma membrane,GO,1.0,exact_match +BMP signaling pathway,GO:0030509,BMP signaling pathway,GO,1.0,exact_match +extracellular region,GO:0005576,extracellular region,GO,1.0,exact_match +cell proliferation,GO:0008283,cell population proliferation,GO,1.0,exact_match +homologous recombination,GO:0035825,homologous recombination,GO,1.0,exact_match +nucleus,GO:0005634,nucleus,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_npc_like b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_npc_like new file mode 100644 index 0000000..8c23493 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_opc_npc_like @@ -0,0 +1,11 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +Hedgehog signaling pathway,GO:0007224,smoothened signaling pathway,GO,1.0,exact_match +Wnt signaling pathway,GO:0016055,Wnt signaling pathway,GO,1.0,exact_match +transmembrane receptor protein tyrosine kinase signaling pathway,GO:0004714,transmembrane receptor protein tyrosine kinase activity,GO,0.9,exact_match +Fc-gamma receptor signaling pathway involved in phagocytosis,GO:0038096,Fc-gamma receptor signaling pathway involved in phagocytosis,GO,1.0,exact_match +plasma membrane,GO:0005886,plasma membrane,GO,1.0,exact_match +neuron differentiation,GO:0030182,neuron differentiation,GO,1.0,exact_match +presynaptic active zone,GO:0048786,presynaptic active zone,GO,1.0,exact_match +axon guidance,GO:0007411,axon guidance,GO,1.0,exact_match +angiogenesis,GO:0001525,angiogenesis,GO,1.0,exact_match +synapse,GO:0045202,synapse,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_proliferative b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_proliferative new file mode 100644 index 0000000..07ca01e --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/glioblastoma_states_minimal_result.csv_proliferative @@ -0,0 +1,12 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +mitotic cell cycle,GO:0000278,mitotic cell cycle,GO,1.0,exact_match +nucleus,GO:0005634,nucleus,GO,1.0,exact_match +spindle assembly,GO:0051225,spindle assembly,GO,1.0,exact_match +centrosome duplication,GO:0051298,centrosome duplication,GO,1.0,exact_match +mitotic spindle,GO:0072686,mitotic spindle,GO,1.0,exact_match +centrosome,GO:0005813,centrosome,GO,1.0,exact_match +chromosome segregation,GO:0007059,chromosome segregation,GO,1.0,exact_match +kinetochore,GO:0000776,kinetochore,GO,1.0,exact_match +centromeric region,GO:0000775,"chromosome, centromeric region",GO,0.95,exact_match +DNA repair,GO:0006281,DNA repair,GO,1.0,exact_match +nucleus,GO:0005634,nucleus,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/neutrophil_combined_input_result.csv b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/neutrophil_combined_input_result.csv new file mode 100644 index 0000000..0e40781 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/neutrophil_combined_input_result.csv @@ -0,0 +1,22 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +neutrophil chemotaxis,GO:0030593,neutrophil chemotaxis,GO,1.0,exact_match +chemokine receptor signaling,GO:0070098,chemokine-mediated signaling pathway,GO,0.9,partial_match +extracellular chemokine milieu,GO:0005576,extracellular region,GO,0.9,exact_match +neutrophil plasma membrane (chemokine receptors),GO:0005886,plasma membrane,GO,0.7,partial_match +NF-κB pathway activation,GO:0007250,activation of NF-kappaB-inducing kinase activity,GO,0.9,exact_match +proinflammatory cytokine secretion (e.g. IL-1β),GO:0001816,cytokine production,GO,0.85,synonym_match +neutrophil activation and adhesion (integrin upregulation),GO:0042119,neutrophil activation,GO,0.9,exact_match +neutrophil extracellular trap (NET) formation,GO:0140645,neutrophil extracellular trap formation,GO,1.0,exact_match +neutrophil cytosol,GO:0005829,cytosol,GO,0.8,exact_match within broader context +extracellular space (almighty DAMP release),GO:0005615,extracellular space,GO,0.6,"partial_match, main term is extracellular space" +neutrophil transepithelial migration,GO:0072672,neutrophil extravasation,GO,0.9,exact_match +neutrophil transendothelial migration,GO:0072672,neutrophil extravasation,GO,0.9,exact_match +leukocyte adhesion to endothelium,GO:0061756,leukocyte adhesion to vascular endothelial cell,GO,0.9,exact_match +epithelial tight junction (subepithelial),GO:0070160,tight junction,GO,0.85,exact_match +endothelial cell junction,GO:0030054,cell junction,GO,0.8,exact_match +neutrophil plasma membrane (adhesion complex),GO:0098636,protein complex involved in cell adhesion,GO,0.7,partial_match +neutrophil degranulation (azurophil granule exocytosis),GO:0043312,neutrophil degranulation,GO,0.9,exact_match +serine-type endopeptidase (proteolytic) activity,GO:0004252,serine-type endopeptidase activity,GO,1.0,exact_match +neutrophil azurophilic granule lumen,GO:0035578,azurophil granule lumen,GO,0.9,exact_match +neutrophil plasma membrane (granule fusion site),GO:0005886,plasma membrane,GO,0.7,partial_match +extracellular space,GO:0005615,extracellular space,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/osteoclast_combined_input_result.csv b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/osteoclast_combined_input_result.csv new file mode 100644 index 0000000..78cf1d7 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/mappings/osteoclast_combined_input_result.csv @@ -0,0 +1,15 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +osteoclast differentiation,GO:0030316,osteoclast differentiation,GO,1.0,exact_match +NFATc1-mediated gene transcription,NO MATCH found,,,0.0, +NF-κB signaling,,,,0.0, +proliferation of myeloid precursors,GO:0035726,common myeloid progenitor cell proliferation,GO,0.9,partial_match +RANK receptor (TNFRSF11A),PR:000001954,tumor necrosis factor receptor superfamily member 11A,PR,1.0,exact_match +CSF1 receptor (c-FMS) complex,GO:1990682,CSF1-CSF1R complex,GO,1.0,exact_match +ITAM signal transduction,GO:0007165,signal transduction,GO,0.9,partial_match +osteoclast precursor cell fusion,GO:0072675,osteoclast fusion,GO,0.95,exact_match +osteoclast migration and resorption,GO:0045453,bone resorption,GO,0.85,partial_match +DAP12 (TYROBP) adaptor complex,NO MATCH found,No label found,N/A,0.0,No suitable match found after exhaustive query across multiple ontologies. +dephosphorylation of bone matrix proteins,GO:0006470,protein dephosphorylation,GO,0.8,partial_match +acidification of resorption lacuna,GO:0007035,vacuolar acidification,GO,0.7,partial_match +mineralized bone matrix resorption,GO:0045453,bone resorption,GO,0.9,exact_match +bone extracellular matrix,UBERON:4000020,mineralized extracellular matrix,UBERON,0.9,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/neutrophil_combined_input_result.json b/cellsem_agent/graphs/gene_annotator/output/experiment1/neutrophil_combined_input_result.json new file mode 100644 index 0000000..6f38346 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/neutrophil_combined_input_result.json @@ -0,0 +1,553 @@ +{ + "context": { + "cell_type": "Neutrophil", + "disease": "Inflammatory condition", + "tissue": "unspecified" + }, + "input_genes": [ + "CXCL8", + "CXCR2", + "CXCL6", + "CTSG", + "S100A9", + "S100A8", + "CXCR1", + "JAML", + "FCER1G", + "ITGB2", + "CSF3R", + "IL1B", + "TREM1", + "ANXA3", + "PECAM1", + "CD177", + "PRTN3" + ], + "programs": [ + { + "program_name": "Chemokine-Mediated Neutrophil Recruitment", + "theme": "Chemotaxis/Inflammation", + "description": "This program centers on CXCL8/IL-8 and CXCL6 chemokine production by neutrophils or surrounding stroma, engaging CXCR1 and CXCR2 on the same or adjacent neutrophils. The resulting autocrine/paracrine loop drives directed neutrophil migration into tissues. High local IL-8/CXCL6 induces chemotaxis and, at higher concentrations, neutrophil activation (including NET release) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2577773/#:~:text=CXCL6%20is%20a%20potent%20pro,AF%29%20and%20if%20CXCL6)). The net effect is amplified recruitment and accumulation of neutrophils in inflamed tissue.", + "atomic_biological_processes": [ + { + "name": "neutrophil chemotaxis", + "citation": [ + { + "reference": "Planagum\u00e0 A et al. Differential IL-8 thresholds... J Leukoc Biol (2021)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "IL-8 (CXCL8) is a key chemokine driving neutrophil chemotaxis via CXCR1/2 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as))" + } + ], + "Genes": [ + "CXCL8", + "CXCL6" + ], + "ontology_label": "neutrophil chemotaxis", + "ontology_id": "GO:0030593" + }, + { + "name": "chemokine receptor signaling", + "citation": [ + { + "reference": "Planagum\u00e0 A et al. Differential IL-8 thresholds... J Leukoc Biol (2021)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "IL-8 signals through CXCR1/CXCR2 to induce directional migration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as))" + } + ], + "Genes": [ + "CXCR1", + "CXCR2" + ], + "ontology_label": "chemokine-mediated signaling pathway", + "ontology_id": "GO:0070098" + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular chemokine milieu", + "citation": [ + { + "reference": "Simard JC et al. PLoS One (2013)", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "Chemokines like CXCL8 are secreted DAMPs mediating inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + } + ], + "Genes": [ + "CXCL8", + "CXCL6" + ], + "ontology_label": "extracellular region", + "ontology_id": "GO:0005576" + }, + { + "name": "neutrophil plasma membrane (chemokine receptors)", + "citation": [ + { + "reference": "Planagum\u00e0 A et al. Differential IL-8 thresholds... J Leukoc Biol (2021)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "CXCR1/CXCR2 are cell surface GPCRs for IL-8 on neutrophils ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as))" + } + ], + "Genes": [ + "CXCR1", + "CXCR2" + ], + "ontology_label": "plasma membrane", + "ontology_id": "GO:0005886" + } + ], + "predicted_cellular_impact": [ + "Enhanced neutrophil chemotaxis toward inflammatory signals", + "Autocrine amplification of neutrophil activation", + "Greater recruitment and accumulation of neutrophils" + ], + "evidence_summary": "CXCL8/IL-8 and CXCL6 are potent neutrophil chemoattractants. Planagum\u00e0 et al. confirmed that human IL-8 engages CXCR1/CXCR2 to drive PMN chemotaxis and NET release ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as)). CXCL6 is similarly a strong neutrophil chemoattractant ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2577773/#:~:text=CXCL6%20is%20a%20potent%20pro,AF%29%20and%20if%20CXCL6)). These ligands and receptors together create a feed-forward loop of neutrophil recruitment and activation in inflamed tissues.", + "citations": [ + { + "reference": "Planagum\u00e0 A et al. Differential IL-8 thresholds for chemotaxis and netosis in human neutrophils.", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "IL-8 (CXCL8) is a key chemokine driving neutrophil migration through CXCR1/CXCR2 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as))" + }, + { + "reference": "Simard JC et al. S100A8/A9 induce IL-8 secretion via NF-\u03baB in phagocytes (PLOS One, 2013).", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "Demonstrates IL-8 (CXCL8) is produced as part of an innate inflammatory loop ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + }, + { + "reference": "Espinoza J et al. CXCL6 is a potent neutrophil chemoattractant (Am J Reprod Immunol, 2008).", + "id": "10.1111/j.1600-0897.2008.00637.x", + "type": "DOI", + "notes": "CXCL6 described as a strong neutrophil chemoattractant and activator ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2577773/#:~:text=CXCL6%20is%20a%20potent%20pro,AF%29%20and%20if%20CXCL6))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "CXCL8", + "CXCL6", + "CXCR1", + "CXCR2" + ], + "supporting_gene_count": 4, + "required_components_present": true + }, + { + "program_name": "Calprotectin-Driven Inflammatory Amplification", + "theme": "DAMP signaling/Inflammation", + "description": "S100A8 and S100A9 (calprotectin) are abundant cytosolic proteins that are released as alarmins by activated neutrophils (especially with NETosis). Extracellular S100A8/A9 engages TLR4/RAGE, triggering NF-\u03baB activation and secretion of cytokines (e.g. IL-1\u03b2, IL-8) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=biomarker%20for%20several%20inflammatory%20diseases,upon%20the%20formation%20of%20neutrophil)). They further upregulate neutrophil adhesion molecules (CD11b/ITGB2) and enhance ROS production ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=%28PMA%29,DAMP%20might%20amplify%20neutrophil%20activation)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=examined%20the%20effects%20of%20S100A8,by%20ATP%2C%20a%20known%20inflammasome)). This creates a positive feedback loop amplifying neutrophil-driven inflammation.", + "atomic_biological_processes": [ + { + "name": "NF-\u03baB pathway activation", + "citation": [ + { + "reference": "Simard JC et al. PLoS One (2013)", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "S100A8/A9 activate NF-\u03baB, inducing expression of IL-8 and IL-1\u03b2 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ], + "ontology_label": "activation of NF-kappaB-inducing kinase activity", + "ontology_id": "GO:0007250" + }, + { + "name": "proinflammatory cytokine secretion (e.g. IL-1\u03b2)", + "citation": [ + { + "reference": "Simard JC et al. PLoS One (2013)", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "S100A8/A9 induce secretion of IL-1\u03b2 and IL-8 via NF-\u03baB ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ], + "ontology_label": "cytokine production", + "ontology_id": "GO:0001816" + }, + { + "name": "neutrophil activation and adhesion (integrin upregulation)", + "citation": [ + { + "reference": "Sprenkeler EG et al. Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "Extracellular S100A8/A9 induces neutrophil adhesion and upregulation of CD11b (ITGB2) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=%28PMA%29,DAMP%20might%20amplify%20neutrophil%20activation))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ], + "ontology_label": "neutrophil activation", + "ontology_id": "GO:0042119" + }, + { + "name": "neutrophil extracellular trap (NET) formation", + "citation": [ + { + "reference": "Sprenkeler EG et al. Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "S100A8/A9 are released during NETosis and can propagate NET formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=biomarker%20for%20several%20inflammatory%20diseases,upon%20the%20formation%20of%20neutrophil))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ], + "ontology_label": "neutrophil extracellular trap formation", + "ontology_id": "GO:0140645" + } + ], + "atomic_cellular_components": [ + { + "name": "neutrophil cytosol", + "citation": [ + { + "reference": "Sprenkeler EG et al. Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "S100A8/A9 are highly abundant in the neutrophil cytosol (not in granules) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=biomarker%20for%20several%20inflammatory%20diseases,upon%20the%20formation%20of%20neutrophil))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ], + "ontology_label": "cytosol", + "ontology_id": "GO:0005829" + }, + { + "name": "extracellular space (almighty DAMP release)", + "citation": [ + { + "reference": "Sprenkeler EG et al. Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "S100A8/A9 are released extracellularly (via NETs) and act as DAMPs ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=biomarker%20for%20several%20inflammatory%20diseases,upon%20the%20formation%20of%20neutrophil))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ], + "ontology_label": "extracellular space", + "ontology_id": "GO:0005615" + } + ], + "predicted_cellular_impact": [ + "Enhanced inflammatory signaling via NF-\u03baB", + "Increased IL-1\u03b2 and IL-8 production", + "Upregulated neutrophil adhesion (CD11b/ITGB2 expression)", + "Positive feedback on neutrophil activation" + ], + "evidence_summary": "S100A8/A9 (calprotectin) are released by activated neutrophils and bind TLR4/RAGE, leading to NF-\u03baB-dependent expression of proinflammatory cytokines (IL-1\u03b2, IL-8) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using)). Sprenkeler et al. demonstrated that purified S100A8/A9 promote neutrophil activation including CD11b upregulation and adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=%28PMA%29,DAMP%20might%20amplify%20neutrophil%20activation)). These DAMPs therefore amplify neutrophil-driven inflammation and recruitment.", + "citations": [ + { + "reference": "Simard JC et al., PLoS One (2013)", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "Shows S100A8/A9 induce IL-1\u03b2 and IL-8 via NF-\u03baB signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + }, + { + "reference": "Sprenkeler EG et al., Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "Reports that S100A8/A9 trigger neutrophil activation and CD11b (ITGB2) upregulation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=%28PMA%29,DAMP%20might%20amplify%20neutrophil%20activation))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": [ + "S100A8", + "S100A9" + ], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "Neutrophil Adhesion and Transmigration", + "theme": "Adhesion/Migration", + "description": "JAML on neutrophils binds epithelial CAR at tight junctions, enabling transepithelial migration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies)). Similarly, \u03b22-integrins (CD11/CD18; ITGB2) mediate firm adhesion to endothelial ICAMs, and PECAM1 on endothelial junctions facilitates diapedesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate)). Together these molecules drive neutrophil extravasation into tissues. High expression of these adhesion genes suggests this cell cluster is primed for tissue infiltration and barrier traversal.", + "atomic_biological_processes": [ + { + "name": "neutrophil transepithelial migration", + "citation": [ + { + "reference": "Zen K et al., Mol Biol Cell (2005)", + "id": "10.1091/mbc.e05-01-0036", + "type": "DOI", + "notes": "JAML binding to epithelial CAR is required for neutrophil migration across tight junctions ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies))" + } + ], + "Genes": [ + "JAML" + ], + "ontology_label": "neutrophil extravasation", + "ontology_id": "GO:0072672" + }, + { + "name": "neutrophil transendothelial migration", + "citation": [ + { + "reference": "Woodfin A et al., Blood (2007)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "PECAM1 is a key endothelial junction molecule that mediates neutrophil transmigration into inflamed tissue ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate))" + } + ], + "Genes": [ + "ITGB2", + "PECAM1" + ], + "ontology_label": "neutrophil extravasation", + "ontology_id": "GO:0072672" + }, + { + "name": "leukocyte adhesion to endothelium", + "citation": [ + { + "reference": "Pulikkottil S et al., Cells (2022)", + "id": "10.3390/cells11132025", + "type": "DOI", + "notes": "\u03b22 integrins (ITGB2) are critical for neutrophil adhesion and recruitment to sites of inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin))" + } + ], + "Genes": [ + "ITGB2" + ], + "ontology_label": "leukocyte adhesion to vascular endothelial cell", + "ontology_id": "GO:0061756" + } + ], + "atomic_cellular_components": [ + { + "name": "epithelial tight junction (subepithelial)", + "citation": [ + { + "reference": "Zen K et al., Mol Biol Cell (2005)", + "id": "10.1091/mbc.e05-01-0036", + "type": "DOI", + "notes": "JAML on neutrophils binds CAR on epithelial tight junctions during transmigration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies))" + } + ], + "Genes": [ + "JAML" + ], + "ontology_label": "tight junction", + "ontology_id": "GO:0070160" + }, + { + "name": "endothelial cell junction", + "citation": [ + { + "reference": "Woodfin A et al., Blood (2007)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "PECAM1 at endothelial junctions facilitates neutrophil diapedesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate))" + } + ], + "Genes": [ + "PECAM1" + ], + "ontology_label": "cell junction", + "ontology_id": "GO:0030054" + }, + { + "name": "neutrophil plasma membrane (adhesion complex)", + "citation": [ + { + "reference": "Pulikkottil S et al., Cells (2022)", + "id": "10.3390/cells11132025", + "type": "DOI", + "notes": "\u03b22 integrins (containing ITGB2) localize to the neutrophil plasma membrane and mediate firm adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin))" + } + ], + "Genes": [ + "ITGB2" + ], + "ontology_label": "protein complex involved in cell adhesion", + "ontology_id": "GO:0098636" + } + ], + "predicted_cellular_impact": [ + "Increased adhesion to endothelium and epithelium", + "Efficient transendothelial and transepithelial migration", + "Enhanced tissue infiltration and recruitment to inflamed sites" + ], + "evidence_summary": "Neutrophil JAML has been shown to bind CAR on epithelial tight junctions, promoting transepithelial migration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies)). \u03b22-integrins (e.g. LFA-1/Mac-1) mediate firm adhesion to endothelium, while PECAM1 at endothelial junctions is required for transmigration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin)). Pulikkottil et al. review highlights integrins (including ITGB2) as essential for neutrophil recruitment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin)). These molecules together enable neutrophils to exit vessels and enter tissues.", + "citations": [ + { + "reference": "Zen K et al. Mol Biol Cell (2005)", + "id": "10.1091/mbc.e05-01-0036", + "type": "DOI", + "notes": "Establishes that neutrophil JAML binding to epithelial CAR mediates migration across tight junctions ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies))" + }, + { + "reference": "Woodfin A et al. Blood (2007)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "Shows PECAM1 at endothelial junctions is critical for neutrophil transmigration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate))" + }, + { + "reference": "Pulikkottil S et al. Cells (2022)", + "id": "10.3390/cells11132025", + "type": "DOI", + "notes": "Review confirming \u03b22-integrins (ITGB2) are crucial for neutrophil adhesion and migration during inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "JAML", + "ITGB2", + "PECAM1" + ], + "supporting_gene_count": 3, + "required_components_present": true + }, + { + "program_name": "Granule-Mediated Antimicrobial Activity", + "theme": "Defense/Proteolysis", + "description": "This program reflects neutrophil azurophilic granule exocytosis. PRTN3 (proteinase 3) and CTSG (cathepsin G) are serine proteases stored in neutrophil azurophilic granules ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the)). Upon activation, these enzymes are released to kill pathogens and degrade extracellular matrix. Annexin A3 (ANXA3) is associated with specific granules and regulates granule\u2013membrane fusion during exocytosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of)). Together, these components drive potent proteolytic and microbicidal responses (and can generate autoantigens on the neutrophil surface).", + "atomic_biological_processes": [ + { + "name": "neutrophil degranulation (azurophil granule exocytosis)", + "citation": [ + { + "reference": "Le Cabec V et al., Biochem J (1994)", + "id": "10.1042/bj3030481", + "type": "DOI", + "notes": "Annexin A3 is localized to neutrophil granules and may mediate granule fusion with the membrane ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of))" + } + ], + "Genes": [ + "ANXA3", + "PRTN3", + "CTSG" + ], + "ontology_label": "neutrophil degranulation", + "ontology_id": "GO:0043312" + }, + { + "name": "serine-type endopeptidase (proteolytic) activity", + "citation": [ + { + "reference": "Pepper RJ et al., Am J Pathol (2015)", + "id": "10.1016/j.ajpath.2015.01.015", + "type": "DOI", + "notes": "Describes proteinase 3 (PRTN3) as a neutrophil azurophilic granule protease with microbicidal activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the))" + } + ], + "Genes": [ + "PRTN3", + "CTSG" + ], + "ontology_label": "serine-type endopeptidase activity", + "ontology_id": "GO:0004252" + } + ], + "atomic_cellular_components": [ + { + "name": "neutrophil azurophilic granule lumen", + "citation": [ + { + "reference": "Pepper RJ et al., Am J Pathol (2015)", + "id": "10.1016/j.ajpath.2015.01.015", + "type": "DOI", + "notes": "PRTN3 (proteinase 3) is stored in neutrophil azurophil granules ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the))" + } + ], + "Genes": [ + "PRTN3", + "CTSG" + ], + "ontology_label": "azurophil granule lumen", + "ontology_id": "GO:0035578" + }, + { + "name": "neutrophil plasma membrane (granule fusion site)", + "citation": [ + { + "reference": "Le Cabec V et al., Biochem J (1994)", + "id": "10.1042/bj3030481", + "type": "DOI", + "notes": "Annexin A3 translocates from granules to the plasma membrane upon activation, implicating it in granule fusion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of))" + } + ], + "Genes": [ + "ANXA3" + ], + "ontology_label": "plasma membrane", + "ontology_id": "GO:0005886" + }, + { + "name": "extracellular space", + "citation": [ + { + "reference": "Pepper RJ et al., Am J Pathol (2015)", + "id": "10.1016/j.ajpath.2015.01.015", + "type": "DOI", + "notes": "Azurophil proteases like PRTN3 and CTSG are released extracellularly to enact microbicidal effects ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the))" + } + ], + "Genes": [ + "PRTN3", + "CTSG" + ], + "ontology_label": "extracellular space", + "ontology_id": "GO:0005615" + } + ], + "predicted_cellular_impact": [ + "Potent antimicrobial killing via protease release", + "Extracellular matrix degradation and tissue remodeling", + "Generation of inflammatory mediators/autoantigens (e.g. membrane PR3)" + ], + "evidence_summary": "PRTN3 and CTSG are major azurophilic granule proteases in neutrophils ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the)). They mediate pathogen killing and contribute to extracellular matrix degradation. Le Cabec et al. showed Annexin A3 localizes to neutrophil granules and translocates to the plasma membrane during activation, suggesting it facilitates granule fusion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of)). Together these proteins drive degranulation and proteolytic antimicrobial activity.", + "citations": [ + { + "reference": "Pepper RJ et al., Am J Pathol (2015)", + "id": "10.1016/j.ajpath.2015.01.015", + "type": "DOI", + "notes": "Confirms that proteinase 3 is a neutrophil azurophil granule protease with microbicidal activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the))" + }, + { + "reference": "Le Cabec V et al., Biochem J (1994)", + "id": "10.1042/bj3030481", + "type": "DOI", + "notes": "Shows Annexin A3 is granule-associated in neutrophils and moves to membrane upon activation, implying a role in degranulation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": [ + "CTSG", + "PRTN3", + "ANXA3" + ], + "supporting_gene_count": 3, + "required_components_present": true + } + ], + "method": { + "clustering_basis": [ + "known pathway interactions", + "literature co-citation" + ], + "notes": "Gene programs identified by grouping input genes with related functions (e.g. chemotaxis, adhesion, degranulation) based on literature and pathway context" + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment1/osteoclast_combined_input_result.json b/cellsem_agent/graphs/gene_annotator/output/experiment1/osteoclast_combined_input_result.json new file mode 100644 index 0000000..239a4bd --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment1/osteoclast_combined_input_result.json @@ -0,0 +1,342 @@ +{ + "context": { + "cell_type": "osteoclast", + "disease": "Bone remodeling (normal physiology)", + "tissue": "bone" + }, + "input_genes": [ + "TNFRSF11A", + "Csf1r", + "TYROBP", + "ACP5", + "Acp5" + ], + "programs": [ + { + "program_name": "Osteoclast Differentiation Signaling (RANK/CSF1R)", + "theme": "Bone remodeling", + "description": "A program driven by M-CSF/CSF1R and RANKL/RANK signaling that directs monocyte/macrophage precursors to differentiate into mature, multinucleated osteoclasts. CSF1R activation by M-CSF promotes survival and proliferation of myeloid precursors and induces expression of RANK (TNFRSF11A). Subsequent binding of RANKL to RANK triggers NF-\u03baB and MAPK cascades, culminating in NFATc1 activation and transcription of osteoclast-specific genes (e.g., ACP5/TRAP, cathepsin K, integrins). This cascade is essential for osteoclastogenesis and maintenance of osteoclast viability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cancer,proliferation%20and%20differentiation%20from%20precursor)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10097072/#:~:text=RANK%20extracellular%20domain%20promotes%20osteoclastogenesis,RANK%20on%20osteoclast%20precursor%20cells)).", + "atomic_biological_processes": [ + { + "name": "osteoclast differentiation", + "citation": [ + { + "reference": "Mun S-H et al. The M-CSF receptor in osteoclasts and beyond. Exp Mol Med. 2020;52(8):1239-1254.", + "id": "10.1038/s12276-020-0484-z", + "type": "DOI", + "notes": "CSF1R and RANK signaling drive differentiation of precursors into osteoclasts ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cancer,proliferation%20and%20differentiation%20from%20precursor)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10097072/#:~:text=RANK%20extracellular%20domain%20promotes%20osteoclastogenesis,RANK%20on%20osteoclast%20precursor%20cells))" + } + ], + "Genes": [ + "TNFRSF11A", + "Csf1r" + ], + "ontology_label": "osteoclast differentiation", + "ontology_id": "GO:0030316" + }, + { + "name": "NFATc1-mediated gene transcription", + "citation": [ + { + "reference": "Mun S-H et al. Exp Mol Med. 2020.", + "id": "10.1038/s12276-020-0484-z", + "type": "DOI", + "notes": "CSF1R-induced RANK expression and RANKL binding activate NFATc1, a master regulator of osteoclast genes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cells,induction%20of%20metabolic%20reprogramming%20and))" + } + ], + "Genes": [ + "TNFRSF11A", + "Csf1r" + ], + "ontology_label": null, + "ontology_id": "NO MATCH found" + }, + { + "name": "NF-\u03baB signaling", + "citation": [ + { + "reference": "Mun S-H et al. Exp Mol Med. 2020.", + "id": "10.1038/s12276-020-0484-z", + "type": "DOI", + "notes": "RANK-RANKL interaction activates NF-\u03baB pathways in osteoclast precursors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cells,induction%20of%20metabolic%20reprogramming%20and))" + } + ], + "Genes": [ + "TNFRSF11A" + ], + "ontology_label": "", + "ontology_id": "" + }, + { + "name": "proliferation of myeloid precursors", + "citation": [ + { + "reference": "Mun S-H et al. Exp Mol Med. 2020.", + "id": "10.1038/s12276-020-0484-z", + "type": "DOI", + "notes": "CSF1R signaling is essential for proliferation and survival of osteoclast precursors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cancer,proliferation%20and%20differentiation%20from%20precursor))" + } + ], + "Genes": [ + "Csf1r" + ], + "ontology_label": "common myeloid progenitor cell proliferation", + "ontology_id": "GO:0035726" + } + ], + "atomic_cellular_components": [ + { + "name": "RANK receptor (TNFRSF11A)", + "citation": [ + { + "reference": "Takahashi N et al. Biochem Biophys Res Commun. 1999;256(3):449-455.", + "id": "10080918", + "type": "PMID", + "notes": "Describes binding of RANKL (OPGL) to RANK on osteoclast precursors ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10097072/#:~:text=RANK%20extracellular%20domain%20promotes%20osteoclastogenesis,RANK%20on%20osteoclast%20precursor%20cells))" + } + ], + "Genes": [ + "TNFRSF11A" + ], + "ontology_label": "tumor necrosis factor receptor superfamily member 11A", + "ontology_id": "PR:000001954" + }, + { + "name": "CSF1 receptor (c-FMS) complex", + "citation": [ + { + "reference": "Mun S-H et al. Exp Mol Med. 2020.", + "id": "10.1038/s12276-020-0484-z", + "type": "DOI", + "notes": "CSF1R (c-Fms) on precursors mediates M-CSF signaling for osteoclast development ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cancer,proliferation%20and%20differentiation%20from%20precursor))" + } + ], + "Genes": [ + "Csf1r" + ], + "ontology_label": "CSF1-CSF1R complex", + "ontology_id": "GO:1990682" + } + ], + "predicted_cellular_impact": [ + "Enhanced differentiation of monocytes into multinucleated osteoclasts", + "Increased survival and proliferation of osteoclast precursor cells", + "Upregulation of osteoclast-specific markers and enzymes (e.g., TRAP/ACP5, cathepsin K)", + "Activation of NF-\u03baB and NFATc1 transcriptional programs" + ], + "evidence_summary": "CSF1R (c-Fms) and RANK (TNFRSF11A) are essential receptors for osteoclastogenesis. CSF1R signaling induces RANK expression in myeloid precursors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cancer,proliferation%20and%20differentiation%20from%20precursor)); binding of RANKL to RANK activates NF-\u03baB/MAPK cascades and NFATc1, driving osteoclast-specific gene expression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cells,induction%20of%20metabolic%20reprogramming%20and)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10097072/#:~:text=RANK%20extracellular%20domain%20promotes%20osteoclastogenesis,RANK%20on%20osteoclast%20precursor%20cells)). Genetic ablation of RANK or CSF1R leads to osteopetrosis from failed osteoclast formation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10097072/#:~:text=RANK%20extracellular%20domain%20promotes%20osteoclastogenesis,RANK%20on%20osteoclast%20precursor%20cells)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=receptor%20activator%20of%20NF,proliferation%20and%20differentiation%20from%20precursor)). Thus, coordinated M-CSF and RANK signals underlie osteoclast differentiation and function in bone.", + "citations": [ + { + "reference": "Mun S-H et al. The M-CSF receptor in osteoclasts and beyond. Exp Mol Med. 2020;52(8):1239-1254.", + "id": "10.1038/s12276-020-0484-z", + "type": "DOI", + "notes": "CSF1R signaling promotes osteoclast precursor proliferation and RANK expression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=cancer,proliferation%20and%20differentiation%20from%20precursor)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8080670/#:~:text=induced%20NFATc1%20expression,24))" + }, + { + "reference": "Takahashi N et al. Biochem Biophys Res Commun. 1999;256(3):449-455.", + "id": "10080918", + "type": "PMID", + "notes": "Demonstrated that RANK mediates osteoclast differentiation induced by RANKL (OPGL) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10097072/#:~:text=RANK%20extracellular%20domain%20promotes%20osteoclastogenesis,RANK%20on%20osteoclast%20precursor%20cells))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "TNFRSF11A", + "Csf1r" + ], + "supporting_gene_count": 2, + "required_components_present": false + }, + { + "program_name": "ITAM-mediated Co-stimulatory Signaling", + "theme": "Osteoclast activation", + "description": "TyroBP (DAP12) is an immunoreceptor adaptor that transmits ITAM signals via associated receptors (e.g. TREM2) to enhance osteoclast development and activity. Activation of DAP12 potentiates RANKL-induced differentiation and promotes cytoskeletal organization. DAP12/TREM2 signaling is required for efficient fusion of precursors into large, multinucleated osteoclasts and for full bone-resorptive capacity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These)). Loss of DAP12 (TYROBP) leads to small, TRAP+ osteoclasts with impaired resorption ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These)).", + "atomic_biological_processes": [ + { + "name": "ITAM signal transduction", + "citation": [ + { + "reference": "Paloneva J et al. J Exp Med. 2003;198(4):669-675.", + "id": "10.1084/jem.20030027", + "type": "DOI", + "notes": "Shows that DAP12/TREM2 signaling complex is essential for osteoclast differentiation and function ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These))" + } + ], + "Genes": [ + "TYROBP" + ], + "ontology_label": "signal transduction", + "ontology_id": "GO:0007165" + }, + { + "name": "osteoclast precursor cell fusion", + "citation": [ + { + "reference": "Paloneva J et al. J Exp Med. 2003.", + "id": "10.1084/jem.20030027", + "type": "DOI", + "notes": "DAP12-deficient cells show inefficient fusion and reduced multinuclear osteoclasts ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These))" + } + ], + "Genes": [ + "TYROBP" + ], + "ontology_label": "osteoclast fusion", + "ontology_id": "GO:0072675" + }, + { + "name": "osteoclast migration and resorption", + "citation": [ + { + "reference": "Paloneva J et al. J Exp Med. 2003.", + "id": "10.1084/jem.20030027", + "type": "DOI", + "notes": "DAP12/TREM2 loss causes smaller osteoclasts with greatly reduced bone resorption in vitro ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These))" + } + ], + "Genes": [ + "TYROBP" + ], + "ontology_label": "bone resorption", + "ontology_id": "GO:0045453" + } + ], + "atomic_cellular_components": [ + { + "name": "DAP12 (TYROBP) adaptor complex", + "citation": [ + { + "reference": "Paloneva J et al. J Exp Med. 2003.", + "id": "10.1084/jem.20030027", + "type": "DOI", + "notes": "DAP12 is an ITAM-bearing adaptor protein required for osteoclast maturation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These))" + } + ], + "Genes": [ + "TYROBP" + ], + "ontology_label": "No label found", + "ontology_id": "NO MATCH found" + } + ], + "predicted_cellular_impact": [ + "Enhanced fusion of osteoclast precursors into large, multinucleated cells", + "Increased osteoclast motility and cytoskeletal reorganization (podosome/sealing zone formation)", + "Amplification of RANKL-induced signaling to promote bone resorption" + ], + "evidence_summary": "DAP12 (TYROBP) is a key co-stimulatory adaptor in osteoclasts. Mutations in DAP12 (TYROBP) or its receptor TREM2 cause Nasu-Hakola disease with bone cysts and impaired osteoclastogenesis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16418779/#:~:text=Deficiency%20of%20the%20signaling%20adapter,evidence%20that%20TREM2%20regulates%20OC)). DAP12-deficient cells form small TRAP-positive osteoclasts with drastically reduced resorptive activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These)). These findings indicate that ITAM-mediated DAP12 signaling is necessary for efficient fusion of osteoclast precursors and full osteoclastic bone degradation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These)).", + "citations": [ + { + "reference": "Paloneva J et al. DAP12/TREM2 deficiency impairs osteoclast differentiation and causes osteoporotic features. J Exp Med. 2003;198(4):669-675.", + "id": "10.1084/jem.20030027", + "type": "DOI", + "notes": "Loss-of-function mutations in DAP12 (TYROBP) severely blunt osteoclast fusion and bone resorption capability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2194176/#:~:text=of%20peripheral%20blood%20mononuclear%20cells,These))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": [ + "TYROBP" + ], + "supporting_gene_count": 1, + "required_components_present": false + }, + { + "program_name": "Bone Matrix Degradation (TRAP/ACP5 Enzymatic Activity)", + "theme": "Bone resorption", + "description": "Tartrate-resistant acid phosphatase (TRAP, encoded by ACP5) is an enzyme secreted by active osteoclasts into the resorption lacuna. TRAP dephosphorylates bone matrix proteins (e.g. osteopontin, bone sialoprotein), facilitating the dissolution of mineralized matrix ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et)). This enzyme contributes to the acidified environment that dissolves hydroxyapatite during resorption. ACP5 is highly upregulated in mature osteoclasts and is a marker of their activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et)). ACP5 deficiency leads to excessive bone retention and mild osteopetrosis, indicating its role in matrix remodeling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et)).", + "atomic_biological_processes": [ + { + "name": "dephosphorylation of bone matrix proteins", + "citation": [ + { + "reference": "Blumer MJ et al. Mech Dev. 2013;130(5-6):97-108.", + "id": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419267", + "type": "URL", + "notes": "TRAP (ACP5) dephosphorylates osteopontin and bone sialoprotein in the matrix, aiding bone remodeling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et))" + } + ], + "Genes": [ + "ACP5" + ], + "ontology_label": "protein dephosphorylation", + "ontology_id": "GO:0006470" + }, + { + "name": "acidification of resorption lacuna", + "citation": [ + { + "reference": "Blumer MJ et al. Mech Dev. 2013.", + "id": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419267", + "type": "URL", + "notes": "Osteoclasts create a highly acidic milieu for mineral dissolution; TRAP contributes by acting in this environment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et))" + } + ], + "Genes": [ + "ACP5" + ], + "ontology_label": "vacuolar acidification", + "ontology_id": "GO:0007035" + }, + { + "name": "mineralized bone matrix resorption", + "citation": [ + { + "reference": "Blumer MJ et al. Mech Dev. 2013.", + "id": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419267", + "type": "URL", + "notes": "TRAP activity is essential for normal bone resorption; TRAP-knockout mice show increased bone mass and osteopetrotic features ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et))" + } + ], + "Genes": [ + "ACP5" + ], + "ontology_label": "bone resorption", + "ontology_id": "GO:0045453" + } + ], + "atomic_cellular_components": [ + { + "name": "bone extracellular matrix", + "citation": [ + { + "reference": "Blumer MJ et al. Mech Dev. 2013.", + "id": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419267", + "type": "URL", + "notes": "ACP5 acts on bone matrix proteins during resorption ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et))" + } + ], + "Genes": [ + "ACP5" + ], + "ontology_label": "mineralized extracellular matrix", + "ontology_id": "UBERON:4000020" + } + ], + "predicted_cellular_impact": [ + "Enhanced dephosphorylation and breakdown of bone matrix proteins", + "Formation of an acidic resorption compartment facilitating mineral dissolution", + "Increased osteoclast bone degradation activity" + ], + "evidence_summary": "ACP5 (TRAP) is a signature osteoclast enzyme. It dephosphorylates and helps degrade phosphoproteins in bone matrix ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et)). TRAP-deficient mice have impaired bone resorption and develop osteopetrotic features (excess bone mass and malformed growth plates) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et)). Thus, ACP5 activity is required for efficient extracellular matrix degradation by osteoclasts.", + "citations": [ + { + "reference": "Blumer MJ et al. Role of TRAP (ACP5) in long bone development. Mech Dev. 2013.", + "id": "https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3419267", + "type": "URL", + "notes": "Describes TRAP\u2019s role in dephosphorylating bone matrix proteins and shows TRAP knockout leads to osteopetrotic phenotype ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3419267/#:~:text=osteoclasts%20participate%20in%20the%20resorption,Rylander%20et))" + } + ], + "confidence_score": 0.85, + "significance_score": 0.9, + "supporting_genes": [ + "ACP5", + "Acp5" + ], + "supporting_gene_count": 2, + "required_components_present": false + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment2/README.md b/cellsem_agent/graphs/gene_annotator/output/experiment2/README.md new file mode 100644 index 0000000..dd113fb --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment2/README.md @@ -0,0 +1,4 @@ + +Deepsearch model: "o3-deep-research-2025-06-26" +Annotator agent model: "openai:gpt-5" +Schema: https://github.com/Cellular-Semantics/cellsem-agent/blob/4a9aef6f9c6402ec321380b1044f57e2a400cf09/cellsem_agent/services/gene_list_contextual_deepsearch/schema/deepsearch_results_schema.json \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment2/astrycytoma_1_result.json b/cellsem_agent/graphs/gene_annotator/output/experiment2/astrycytoma_1_result.json new file mode 100644 index 0000000..c33bf27 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment2/astrycytoma_1_result.json @@ -0,0 +1,1119 @@ +{ + "context": { + "cell_type": "Astrocyte (IDH-mutant astrocytoma malignant subset)", + "disease": "IDH-mutant diffuse astrocytoma", + "tissue": "Brain (central nervous system white/gray matter)" + }, + "input_genes": [ + "FAM189A2", + "OGFRL1", + "MAP3K5", + "ITPR2", + "ETNPPL", + "NRG3", + "CD38", + "FMN2", + "LINC01088", + "KCNN3", + "DAAM2", + "AC002429.2", + "OBI1-AS1", + "NTRK2", + "SYTL4", + "WDR49", + "ADGRV1", + "LIFR", + "AQP4", + "ID3", + "OSBPL11", + "DPP10", + "SERPINI2", + "TLR4", + "NAA11", + "MGAT4C", + "AC026316.5", + "EEPD1", + "RASSF4", + "AL392086.3", + "SLC4A4", + "EDNRB", + "SLC39A11", + "ATP1A2", + "SLCO1C1", + "AHCYL2", + "SPON1", + "SLC1A3", + "GRAMD2B", + "DTNA", + "AC012405.1", + "NKAIN3", + "NTM", + "SLC14A1", + "DCLK2", + "DCLK1", + "ID4", + "AC124854.1", + "LINC01094", + "PCDH9", + "GABBR2", + "PARD3B", + "PDE8A", + "LRIG1", + "C5ORF64", + "RNF19A", + "SPARCL1", + "AC093535.1", + "FADS2", + "PLEKHA5", + "ASTN2", + "ADAMTS9", + "AC073941.1", + "SLC24A4", + "PAPPA", + "AC068587.4", + "FARP1", + "SORL1", + "ARHGAP26", + "CADPS", + "ST3GAL6", + "ITPKB", + "GABRB1", + "FAM107A", + "MIR99AHG", + "ANK2", + "AC107223.1", + "PPP2R2B", + "LPL", + "AL589935.1", + "MRVI1", + "TNIK", + "AL160272.1", + "AC016766.1", + "RANBP3L", + "ARHGEF4", + "ADCY2", + "NPL", + "KCNQ5", + "AC079352.1", + "LIX1", + "APOE", + "SLC25A48", + "ADCYAP1R1", + "AHCYL1", + "RASL12", + "GINS3", + "PTPRG", + "AL096709.1", + "BMP2K", + "MCF2L2", + "RBMS3", + "SLCO3A1", + "AL445426.1", + "CARMIL1", + "CACNA2D3", + "CDHR3", + "NAV3", + "UTRN", + "NRP2", + "DNAH7", + "KIAA1671", + "HPSE2", + "COL4A5", + "AC083864.5", + "L3MBTL4", + "AC092131.1", + "PCSK6", + "AC097450.1", + "ANOS1", + "SYNPO2", + "LINC00836", + "MAPK4", + "AL365259.1", + "WNK2", + "LMO3", + "SSBP2", + "SLC1A4", + "PPP2R5A", + "LINC00299", + "SLC15A2", + "CNTN1", + "FKBP5", + "GREB1L", + "LUZP2", + "MAP7", + "AC023095.1", + "IGFBP7", + "ALDH1A1", + "GRAMD1C", + "RHBDL3", + "DAPK1", + "LINC02058", + "TENM4", + "RTN1", + "LINC01138", + "GLUD1", + "NEBL", + "LINC01117", + "AC092691.1", + "TJP2", + "PCDH9-AS2", + "YAP1", + "ABCC9", + "LAMA1", + "AL137024.1", + "ERBB4", + "ADRA1A", + "MYBPC1", + "NT5DC3", + "AQP1", + "NKAIN4", + "ARAP2", + "RHOB", + "AQP4-AS1", + "CDH20", + "RGMA", + "OSGIN2", + "PRKG1", + "MROH7", + "PRRX1", + "MAST4", + "CHL1", + "PAPLN", + "OSBPL3", + "RFX4", + "CD44", + "ATP13A4", + "COL5A3", + "ITGA6", + "DOCK7", + "CPE", + "DPF3", + "ZNF521", + "DHRS3", + "AC006148.1", + "LMNTD1", + "AC092924.2", + "LHFPL6", + "AC024145.1", + "LIMCH1", + "SRPX2", + "AL590999.1", + "ADCY8", + "AC008957.2", + "TTYH2", + "GJA1", + "SHROOM3", + "USH1C", + "AC007262.2" + ], + "programs": [ + { + "program_name": "Astrocyte Homeostasis & Neurovascular Coupling", + "theme": "Homeostatic Support", + "description": "This program encompasses classic astrocytic functions that regulate the brain microenvironment, particularly water and ion balance at vascular and synaptic interfaces. Malignant astrocytoma cells expressing these genes retain an astrocyte-like capability for K+ buffering, water transport, and gap junction coupling, positioning themselves at blood vessels and around neurons. In the tumor context, this may help malignant cells modulate extracellular K+ and glutamate levels, sustain local blood flow (neurovascular coupling), and survive hypoxic stress by efficiently clearing excess ions and preserving osmotic balance. The program mirrors normal astrocyte roles in supporting neurons and vessels but in a dysregulated tumor setting, it could influence peritumoral edema, seizure propensity, and adaptation of tumor cells to metabolic demands.", + "atomic_biological_processes": [ + { + "name": "K+ buffering and spatial ion distribution", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytic endfeet use channels (AQP4, Kir4.1) to remove K+ and water, maintaining ionic balance in brain ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=the%20CNS%2C%20AQP4%20is%20predominantly,cell)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in))." + } + ], + "Genes": [ + "AQP4", + "SLC1A3", + "ABCC9", + "SLC4A4", + "KCNQ5" + ], + "ontology_label": "potassium ion homeostasis", + "ontology_id": "GO:0055075" + }, + { + "name": "Water transport and edema regulation", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "AQP4 water channels in astrocyte endfeet facilitate fluid clearance and are crucial for neurovascular fluid exchange ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Polarized%20expression%20of%20AQP4%20in,49%5D.%20Furthermore%2C%20AQP4))." + } + ], + "Genes": [ + "AQP4", + "AQP1" + ], + "ontology_label": "water transport", + "ontology_id": "GO:0006833" + }, + { + "name": "Gap junction intercellular communication", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes form networks via gap junctions (connexin 43) allowing ion and metabolite sharing to buffer activity and metabolic stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": [ + "GJA1" + ], + "ontology_label": "gap junction-mediated intercellular transport", + "ontology_id": "GO:1990349" + }, + { + "name": "Neurovascular coupling", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocyte endfeet with AQP4 and K+ channels at capillaries regulate blood flow in response to neural activity, matching perfusion to metabolic demand ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=reciprocal%20regulation%20involves%20coordinated%20actions,in%20astrocytic%20endfeet%2C%20whereas%20some)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=regulatory%20effects%20at%20both%20blood,vessels%20and%20synapses))." + } + ], + "Genes": [ + "AQP4", + "ABCC9", + "EDNRB" + ], + "ontology_label": "neurovascular bundle", + "ontology_id": "UBERON:0016630" + } + ], + "atomic_cellular_components": [ + { + "name": "Perivascular astrocyte endfoot", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "AQP4 and Kir channels are highly concentrated in astrocytic endfeet abutting blood vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=the%20CNS%2C%20AQP4%20is%20predominantly,their%20functional%20role%20in%20this)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in))." + } + ], + "Genes": [ + "AQP4", + "AQP1", + "ABCC9" + ], + "ontology_label": "astrocyte end-foot", + "ontology_id": "GO:0097450" + }, + { + "name": "Astrocyte gap junction (connexin 43 complex)", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes are coupled by connexin-43 gap junctions, enabling intercellular signaling and distribution of ions across the glial network ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": [ + "GJA1" + ], + "ontology_label": "connexin complex", + "ontology_id": "GO:0005922" + }, + { + "name": "Glial limitans and basement membrane contacts", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes form the glial limiting membrane and contact basement membranes via specialized endfeet enriched in AQP4 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses))." + } + ], + "Genes": [ + "AQP4", + "TJP2", + "ITGA6", + "LAMA1" + ], + "ontology_label": "glial limiting membrane", + "ontology_id": "UBERON:0018687" + } + ], + "predicted_cellular_impact": [ + "Enhanced clearance of extracellular K+ and glutamate, reducing hyperexcitability", + "Efficient removal of excess water, potentially mitigating peritumoral edema", + "Coupling of tumor cells into functional networks via gap junctions", + "Ability to modulate local blood flow in response to neuronal activity and metabolic needs" + ], + "evidence_summary": "Multiple genes in this program encode hallmark astrocytic channels and transporters that maintain CNS homeostasis. AQP4 is localized to astrocyte endfeet and greatly increases water permeability at the blood\u2013brain interface, facilitating fluid clearance and K+ siphoning ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses)). Co-expressed K+ handling mechanisms (e.g., KCN channels and transporters) allow astrocytic processes to buffer extracellular K+ from active neurons, preventing neuronal hyperexcitability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in)). Connexin-43 (GJA1) gap junctions electrically and metabolically couple astrocytoma cells, enabling the distribution of ions and signaling molecules through tumor cell networks ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339)). Expression of EDNRB (endothelin B receptor) in these cells suggests they can respond to vascular endothelin signals, potentially constricting or dilating nearby vessels and participating in neurovascular coupling, akin to reactive astrocytes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Correspondingly%2C%20patient%20glioblastoma%20tissues%20express,were%20those%20involved%20in%20cytoskeleton)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=role%20of%20autocrine%20EDN3%2FEDNRB%20system,mediated%20tumor%20recurrence)). Overall, this program indicates that a subset of malignant cells retains an astrocyte-like supportive phenotype, regulating ions and water to influence neuronal activity and blood flow around the tumor.", + "citations": [ + { + "reference": "Jukkola & Gu (2014) Regulation of Neurovascular Coupling in Autoimmunity to Water and Ion Channels, Autoimmun Rev.", + "id": "PMC4303502", + "type": "PMID", + "notes": "Details AQP4, Kir4.1 channel localization in astrocyte endfeet and their roles in water & K+ homeostasis." + }, + { + "reference": "Shao et al. (2011) Autocrine EDN3/EDNRB signaling maintains GSC properties, Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Shows EDNRB supports glial stem-like cells, implying astrocytoma cells with EDNRB can influence survival and migration in a radial glial-like manner." + } + ], + "confidence_score": 0.9, + "significance_score": 0.6, + "supporting_genes": [ + "AQP4", + "AQP1", + "GJA1", + "SLC1A3", + "SLC4A4", + "ABCC9", + "EDNRB", + "KCNQ5", + "TJP2" + ], + "supporting_gene_count": 9, + "required_components_present": false + }, + { + "program_name": "Mesenchymal Transformation & ECM Remodeling", + "theme": "Invasive Mesenchymal State", + "description": "This program reflects a shift of tumor cells toward a reactive, mesenchymal-like phenotype with enhanced motility, stress response, and extracellular matrix (ECM) interaction. Genes in this cluster encode cell-surface receptors and signaling molecules (e.g., TLR4, CD44, integrin \u03b16, YAP1, PRRX1) that collectively promote an inflammatory and migratory state. Malignant astrocytes with this program secrete and remodel ECM components (e.g., SPARC-like 1, ADAMTS9, papilin, collagens) and upregulate cytoskeletal regulators (Rho GTPase regulators and actin-binding proteins) to acquire fibroblast-like morphology and invasive behavior. Functionally, this enables tumor cells to invade surrounding brain tissue (often along blood vessels via integrin \u03b16-laminin interactions), resist apoptosis, and communicate with immune cells through cytokine and Toll-like receptor pathways. It mirrors aspects of reactive astrogliosis and epithelial\u2013mesenchymal transition: cells become highly migratory, secrete matrix, and activate NF-\u03baB and YAP/TAZ signaling to sustain proliferation and survival in a hostile microenvironment.", + "atomic_biological_processes": [ + { + "name": "Extracellular matrix deposition and remodeling", + "citation": [ + { + "reference": "Ferr\u00e1ndez et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "TLR4 activation in differentiating glioma cells triggers NF-\u03baB and upregulates genes like IL-6 and likely ECM modifiers, linking inflammatory signaling to a mesenchymal gene expression profile ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=an%20important%20event%20in%20tumor,cells%20has%20been%20poorly%20studied))." + } + ], + "Genes": [ + "SPARCL1", + "ASTN2", + "LAMA1", + "COL4A5", + "COL5A3", + "PAPLN", + "ADAMTS9" + ], + "ontology_label": "extracellular matrix organization", + "ontology_id": "GO:0030198" + }, + { + "name": "Cell migration and invasion", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Integrin \u03b16 on glioma stem cells mediates adhesion to laminin in perivascular niches, promoting self-renewal and invasion along blood vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Immunostaining%20of%20GBM%20surgical%20biopsies,varying%20overlap%20with%20CD133%20expression))." + } + ], + "Genes": [ + "ITGA6", + "DOCK7", + "ARHGEF4", + "ARHGAP26", + "CARMIL1", + "SYNPO2", + "LIMCH1" + ], + "ontology_label": "cell migration", + "ontology_id": "GO:0016477" + }, + { + "name": "Inflammatory signaling (NF-\u03baB activation)", + "ontology_label": "", + "citation": [ + { + "reference": "Ferr\u00e1ndez et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "Hyaluronic acid produced by glioma cells engages TLR4 to activate NF-\u03baB, preventing full differentiation and maintaining proliferation of these cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=transcriptional%20activation%20of%20NF%CE%BAB%2C%20which,and%20consequently%20their%20tumorigenic%20capacity))." + } + ], + "Genes": [ + "TLR4", + "CD44" + ], + "ontology_id": "" + }, + { + "name": "Mechanotransduction and Hippo pathway signaling", + "citation": [ + { + "reference": "Guo et al. (2020) J. Neurosci.", + "id": "32066583", + "type": "PMID", + "notes": "YAP is upregulated in reactive astrocytes after injury, driving astrocyte proliferation and scar formation via RhoA-p27^Kip1 signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytes%20of%20C57BL%2F6%20male%20mice,Finally%2C%20bFGF)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytic%20proliferation%2C%20impaired%20the%20formation,findings%20suggest%20that%20YAP%20promotes))." + } + ], + "Genes": [ + "YAP1", + "MAPK4" + ], + "ontology_label": "hippo signaling", + "ontology_id": "GO:0035329" + } + ], + "atomic_cellular_components": [ + { + "name": "Focal adhesion complex", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Glioblastoma cells with high integrin \u03b16 form tight adhesions with vascular basement membrane laminin, linking them to niches that support invasion and stemness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Immunostaining%20of%20GBM%20surgical%20biopsies,varying%20overlap%20with%20CD133%20expression))." + } + ], + "Genes": [ + "ITGA6", + "LAMA1" + ], + "ontology_label": "focal adhesion", + "ontology_id": "GO:0005925" + }, + { + "name": "Stress fibers and contractile cytoskeleton", + "citation": [ + { + "reference": "Ferr\u00e1ndez et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "NF-\u03baB activation by TLR4 in tumor cells is associated with morphological changes to an elongated shape with stress-fiber-like processes when TLR4 is blocked ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=expression%20of%20NF%CE%BAB%20target%20genes,18))." + } + ], + "Genes": [ + "SYNPO2", + "LIMCH1", + "DOCK7" + ], + "ontology_label": "stress fiber", + "ontology_id": "GO:0001725" + }, + { + "name": "Perivascular niche interface", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Integrin \u03b16^high tumor cells accumulate within 5 \u03bcm of blood vessels, indicating localization at the perivascular compartment for growth and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly))." + } + ], + "Genes": [ + "ITGA6", + "CD44", + "SPARCL1" + ], + "ontology_label": "perivascular space", + "ontology_id": "UBERON:0014930" + } + ], + "predicted_cellular_impact": [ + "Increased cell motility and brain parenchyma invasion along ECM-rich tracks (e.g., blood vessels)", + "Elevated secretion and reorganization of extracellular matrix components to form a supportive stroma", + "Chronic activation of inflammatory pathways (NF-\u03baB, cytokine production) promoting tumor cell survival and immune evasion", + "Acquisition of fibroblast-like morphology with enhanced contractility and mechanosensing" + ], + "evidence_summary": "Malignant astrocytes displaying this program adopt features akin to reactive astrocytes and mesenchymal glioma cells. TLR4 and CD44 are upregulated, enabling cells to respond to damage-associated matrix fragments (like hyaluronan) and activate NF-\u03baB signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=which%20promoted%20further%20differentiation%20and,maintain%20their%20proliferative%20potential%20and)). This results in secretion of interleukins (e.g., IL-6) and other factors that sustain an inflammatory, proliferative loop and prevent terminal differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=process%20of%20differentiation%2C%20GSCs%20upregulate,and%20consequently%20their%20tumorigenic%20capacity)). Concurrently, transcriptional regulators such as PRRX1 and YAP1 shift gene expression toward a mesenchymal program. YAP1, a mechanosensitive oncogene, is known to drive astrocyte proliferation after injury by overcoming cell-cycle arrest (via p27^Kip1) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytic%20proliferation%2C%20impaired%20the%20formation,findings%20suggest%20that%20YAP%20promotes)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=after%20SCI,p27%5E%7BKip1%7D%20pathway%20positively%20regulates%20astrocytic)). Here, YAP1 likely promotes growth and survival under the stiffer, fibrosis-like conditions created by tumor ECM. Integrin \u03b16 (ITGA6), highly expressed in this cluster, complexes with laminin in vascular basement membranes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Of%20particular%20interest%20to%20stem,importance%20of%20integrin%20%CE%B16%20in)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)). This integrin-mediated adhesion anchors tumor cells in perivascular niches, enhancing their self-renewal and invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=of%20tumor%20specimens%20with%20integrin,negative%7D%20populations)). Matrix remodeling enzymes and glycoproteins (ADAMTS9, SPON1, PAPLN, collagens) are co-expressed, indicating active restructuring of the tumor microenvironment to facilitate cell migration and create tracks of permissive ECM. Altogether, this gene program confers a motile, ECM-invasive phenotype with an inflammatory, stem-cell-supportive microenvironment characteristic of higher-grade progression in IDH-mutant astrocytomas.", + "citations": [ + { + "reference": "Ferr\u00e1ndez et al. (2018) Hyaluronic acid-TLR4 signaling promotes NF-\u03baB activation in differentiating GBM cells, Sci Rep.", + "id": "PMC5910430", + "type": "PMID", + "notes": "Demonstrates TLR4 drives NF-\u03baB and maintains proliferative, undifferentiated state in glioma cells with HA fragment signals." + }, + { + "reference": "Lathia et al. (2010) Integrin \u03b16 regulates glioblastoma stem cells, Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Shows integrin \u03b16 enriches for invasive, stem-like GBM cells that reside in perivascular niches and are critical for tumor propagation." + }, + { + "reference": "Guo et al. (2020) Astrocytic YAP promotes glial scar formation, J Neurosci.", + "id": "32066583", + "type": "PMID", + "notes": "Finds YAP activation in reactive astrocytes increases proliferation and scar formation, highlighting YAP's role in astrocyte plasticity under stress." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "TLR4", + "CD44", + "ITGA6", + "YAP1", + "PRRX1", + "DOCK7", + "ARHGEF4", + "ARHGAP26", + "SPARCL1", + "LAMA1", + "COL4A5", + "ADAMTS9", + "PAPLN" + ], + "supporting_gene_count": 13, + "required_components_present": true + }, + { + "program_name": "Neurotransmitter Signaling & Calcium Dynamics", + "theme": "Neuron-Glial Interaction", + "description": "This program comprises genes enabling malignant astrocytoma cells to engage in neuronal communication and intracellular Ca\u00b2\u207a signaling, resembling normal astrocyte-neuron interactions. Key components include neurotransmitter transporters and receptors (for glutamate, GABA, etc.), G-protein-coupled receptors responding to neuromodulators (adrenergic, peptidergic), and modulators of second messengers (adenylyl cyclases, phosphodiesterases, and the IP3 calcium release pathway via ITPR2). By expressing these, tumor cells can sense and modulate synaptic activity: for instance, by clearing excess glutamate from synapses (via SLC1A3/4) or responding to norepinephrine surges with Ca\u00b2\u207a waves (via ADRA1A and ITPR2). This may influence neuronal firing patterns (potentially contributing to tumor-associated epilepsy) and allow tumor cells to adapt metabolically to neural activity. It also indicates that these cells maintain aspects of astrocytic Ca\u00b2\u207a excitability and gliotransmission which, in the context of disease, could feedback to promote a tumor-supportive microenvironment or dampen cytotoxic neural inputs.", + "atomic_biological_processes": [ + { + "name": "Glutamate uptake and buffering", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Impaired astrocytic K+ and glutamate uptake (via Kir4.1 and EAAT transporters) leads to hyperexcitability and seizures, highlighting the importance of astrocyte glutamate buffering ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=dysfunction%20and%20seizure%20activity%2C%20as,1%20channel%20expression%20and%20function))." + } + ], + "Genes": [ + "SLC1A3", + "SLC1A4" + ], + "ontology_label": "glutamate reuptake", + "ontology_id": "GO:0051935" + }, + { + "name": "GABA reception and neuromodulation", + "citation": [ + { + "reference": "Xiong et al. (2018) Front Cell Neurosci.", + "id": "27825285", + "type": "PMID", + "notes": "Astrocytes express various neurotransmitter receptors including GABA_B which modulate their intracellular signaling and can influence neuronal network excitability (implied by reactive astrocyte studies)." + } + ], + "Genes": [ + "GABBR2", + "GABRB1" + ], + "ontology_label": "GABA-ergic synapse", + "ontology_id": "GO:0098982" + }, + { + "name": "GPCR-triggered Ca2+ signaling", + "citation": [ + { + "reference": "Ding et al. (2013) Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Cortical astrocytes exhibit rapid, widespread Ca2+ transients in vivo in response to locus coeruleus norepinephrine release, mediated by astrocytic \u03b11-adrenergic receptors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=vivo%20and%20in%20anesthetized%20animals,specific%20neurotoxin)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=cerebral%20cortex%20mediate%20long,4%29%2C%20which%20reduced%20cortical%20NE))." + } + ], + "Genes": [ + "ADRA1A", + "ADCYAP1R1", + "ITPR2" + ], + "ontology_label": "G protein-coupled receptor signaling pathway", + "ontology_id": "GO:0007186" + }, + { + "name": "cAMP and cGMP second messenger modulation", + "citation": [ + { + "reference": "Ferr\u00e1ndez et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "Differentiating glioma cells rely on sustained NF-\u03baB signaling; by analogy, modulating cyclic nucleotide pathways (via PDEs and ACs) in tumor astrocytes could adjust their reactivity and proliferation (supported indirectly by literature on cAMP effects on Id gene expression) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10066362/#:~:text=Id4%20expression%20induces%20apoptosis%20in,on%20Id%20gene%20expression%20in))." + } + ], + "Genes": [ + "ADCY2", + "ADCY8", + "PDE8A", + "CD38", + "PRKG1" + ], + "ontology_label": "G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger", + "ontology_id": "GO:0007187" + } + ], + "atomic_cellular_components": [ + { + "name": "Tripartite synapse (astrocyte\u2013synapse interface)", + "ontology_label": "", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocyte processes envelop synapses and nodes, expressing transporters (e.g., GLAST) that remove neurotransmitters and channels that sense synaptic activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=reciprocal%20regulation%20involves%20coordinated%20actions,in%20astrocytic%20endfeet%2C%20whereas%20some)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": [ + "SLC1A3", + "SLC1A4", + "GABBR2" + ], + "ontology_id": "" + }, + { + "name": "Endoplasmic reticulum Ca2+ store", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytic Ca2+ waves require coordinated activity of channels on both the plasma membrane and endoplasmic reticulum (IP3 receptors) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": [ + "ITPR2", + "ITPKB" + ], + "ontology_label": "perinuclear endoplasmic reticulum", + "ontology_id": "GO:0097038" + }, + { + "name": "Perisynaptic astrocyte process", + "citation": [ + { + "reference": "Ding et al. (2013) Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Astrocyte processes distributed across cortex show synchronized Ca2+ signals upon neuromodulatory input (NE via \u03b11-AR), indicating a network of responsive perisynaptic astroglial processes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=Astrocyte%20Ca,The)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=cerebral%20cortex%20mediate%20long,4%29%2C%20which%20reduced%20cortical%20NE))." + } + ], + "Genes": [ + "ADRA1A", + "ADCYAP1R1" + ], + "ontology_label": "perisynaptic space", + "ontology_id": "GO:0099544" + } + ], + "predicted_cellular_impact": [ + "Active removal of excitatory neurotransmitters from the extracellular space, potentially dampening neuron firing and excitotoxicity", + "Propagation of calcium waves among tumor astrocytes in response to neuromodulators, possibly coordinating tumor cell activity with neuronal cues", + "Modulation of local synaptic activity and plasticity (which could manifest as seizures or cognitive changes in patients)", + "Adjustment of tumor cell metabolism and gene expression in response to neurotransmitters (through cAMP/PKA and Ca2+-dependent pathways)" + ], + "evidence_summary": "Several hallmark astrocytic communication pathways are retained. For instance, high-affinity glutamate transporters (SLC1A3, SLC1A4) in tumor cells would remove glutamate from synapses, as normal astrocytes do to prevent excitotoxicity. In astrocytes, loss of K^+ and glutamate uptake causes hyperexcitability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=susceptibility%20have%20impaired%20astrocytic%20K,and%20inhibition%20or)), suggesting these tumor cells might mitigate excitatory buildup around them. The presence of GABA_B (GABBR2) and GABA_A (GABRB1) receptor subunits implies the tumor cells can respond to inhibitory neurotransmitters, potentially altering their Ca^2+ or cAMP levels in response to neuronal activity (analogous to how astrocytes modulate their function upon GABA sensing). Importantly, ITPR2 (inositol trisphosphate receptor 2) is the astrocyte-specific ER Ca^2+ release channel required for astrocytic Ca^2+ waves ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339)). Its expression suggests these tumor cells propagate Ca^2+ signals internally and between each other, especially when triggered by GPCRs like ADRA1A (\u03b11-adrenergic receptor) and ADCYAP1R1 (PAC1 receptor). Indeed, in vivo studies show astrocytic \u03b11-adrenergic receptors orchestrate global Ca^2+ elevations in response to locus coeruleus noradrenaline release ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=vivo%20and%20in%20anesthetized%20animals,well%20as%20the%20frequently%20observed)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=physiological%20sensory%20,2%2B%7D%20signals%20in%20awake%20mice)). Malignant cells with this machinery could similarly react to stress signals (e.g., high norepinephrine in the tumor milieu) with synchronized Ca^2+ surges, potentially promoting their survival or motility. Additionally, multiple adenylyl cyclases (ADCY2, ADCY8) and PDE8A hint at tight regulation of cyclic AMP, which integrates with Ca^2+ signals to control astrocyte physiology. Through CD38, they can produce messengers like cyclic ADP-ribose, further modulating Ca^2+ release and possibly enhancing pro-inflammatory phenotypes (as CD38 activity in reactive astrocytes is linked to cytokine release) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9436380/#:~:text=nervous%20system%20autoimmunity%20,controls%20astrocyte%20proinflammatory%20transcriptional%20reprogramming)). In summary, this program endows tumor cells with quasi-neuronal communication abilities: they sense and respond to neural activity and neuromodulators, which might allow the tumor to co-opt neural circuits and protect itself from excitotoxic damage.", + "citations": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Describes astrocytic glutamate uptake and Kir4.1 roles in preventing hyperexcitability, and need for ER Ca channels in glial Ca waves." + }, + { + "reference": "Ding et al. (2013) Astrocytic \u03b11-adrenergic receptors mediate coordinated Ca2+ signals in awake mice, Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Demonstrates global astrocyte Ca2+ waves triggered by NE via \u03b11-AR, highlighting astrocytes' responsiveness to neuromodulators." + }, + { + "reference": "Sontheimer (2008) Nature Rev Neurosci (review).", + "id": "PMID", + "type": "PMID", + "notes": "Reviews neuron\u2013astrocyte signaling interactions, including roles of astrocytic GABA and glutamate receptors in brain tumors (providing context to these findings)." + } + ], + "confidence_score": 0.8, + "significance_score": 0.5, + "supporting_genes": [ + "SLC1A3", + "SLC1A4", + "GABBR2", + "GABRB1", + "ADRA1A", + "ADCYAP1R1", + "ITPR2", + "ITPKB", + "ADCY2", + "ADCY8", + "PDE8A", + "CD38" + ], + "supporting_gene_count": 12, + "required_components_present": true + }, + { + "program_name": "Developmental Stem-like Program", + "theme": "Undifferentiated Progenitor State", + "description": "This program reflects the reactivation of developmental pathways and maintenance of a stem/progenitor-like state in a subset of tumor cells. Key features include high expression of Inhibitor of Differentiation genes (ID3, ID4) which block differentiation and sustain a neural stem-like gene profile, and receptors for developmental growth factors like LIFR (leukemia inhibitory factor receptor) and NTRK2 (TrkB for neurotrophins). These cells also express guidance and adhesion molecules (e.g., CHL1, CNTN1, NTM, teneurins) reminiscent of radial glia that scaffold neuronal migration. Functionally, this program would keep cells in a less differentiated, highly proliferative state with the capacity for multipotency. These cells likely exhibit slower cell-cycle exit (due to ID-mediated cell cycle gene effects) and can self-renew and give rise to diverse lineages within the tumor. In the context of IDH-mutant astrocytoma, this program aligns with the 'proneural' signature often seen in these tumors, and it may be linked to their origin from neural precursor cells. It also provides a reservoir of therapy-resistant cells that can drive recurrence, while simultaneously recapitulating some aspects of normal astrocyte development (for example, delayed maturation and persistent expression of embryonic cell adhesion cues).", + "atomic_biological_processes": [ + { + "name": "Inhibition of differentiation (maintenance of progenitor state)", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Enforced Id4 expression in astrocytes upregulates stem cell markers (Nestin, Sox2, CD133) and induces neurosphere-forming, stem-like properties ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Conversion%20of%20Ink4a%2FArf,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=astrocytes,20%20%CE%BCm%29%20of%20vector))." + } + ], + "Genes": [ + "ID4", + "ID3", + "LMO3" + ], + "ontology_label": "negative regulation of cell differentiation", + "ontology_id": "GO:0045596" + }, + { + "name": "Neural stem cell proliferation", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Id4 drives hyperproliferation in astrocytes via upregulation of cyclin E, facilitating a transition to a neural stem-like, tumorigenic state ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=primary%20murine%20Ink4a%2FArf%28,cycle%20and%20differentiation%20regulatory%20molecules)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=is%20responsible%20for%20elevated%20growth,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and%20cyclin))." + } + ], + "Genes": [ + "ID4", + "CCNE1 (Cyclin E, via ID4 upregulation)", + "CD44" + ], + "ontology_label": "neural precursor cell proliferation", + "ontology_id": "GO:0061351" + }, + { + "name": "Radial glial cell identity and guidance", + "citation": [ + { + "reference": "Shao et al. (2011) Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Glioma stem cells co-express radial glial markers and neural crest pathways; EDN3/EDNRB signaling is identified as maintaining a radial glial-like migratory, undifferentiated state in these cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Glioblastoma%20stem%20cells%20,or%20EDN3%20RNA%20interference)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=downregulated%20by%20EDN3%2FEDNRB%20blockade%20were,These%20data%20suggest%20that%20autocrine))." + } + ], + "Genes": [ + "LIFR", + "NTRK2", + "CHL1", + "CNTN1", + "TENM4" + ], + "ontology_label": "radial glial cell", + "ontology_id": "CL:0000681" + }, + { + "name": "STAT3-mediated astrogliogenesis and reactivity", + "citation": [ + { + "reference": "Xiong et al. (2018) J Neurotrauma.", + "id": "27825285", + "type": "PMID", + "notes": "After CNS injury, LIF-activated STAT3 signaling in astrocytes promotes their proliferation and reactive gliosis, indicating LIF/LIFR fosters an astroglial progenitor response ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=Moreover%2C%20LIF%20increased%20the%20number,via%20activation%20of%20STAT3%20signaling))." + } + ], + "Genes": [ + "LIFR", + "STAT3 (downstream)", + "SOX2" + ], + "ontology_label": "STAT3 inhibitor", + "ontology_id": "CHEBI:87183" + } + ], + "atomic_cellular_components": [ + { + "name": "Neurosphere (tumor sphere) formation capacity", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Id4-overexpressing astrocytes form free-floating neurospheres in stem cell media, demonstrating acquisition of neurosphere architecture typical of neural stem cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and%20Id4,one%20cell%20per%20square%20millimeter))." + } + ], + "Genes": [ + "ID4", + "SOX2", + "NES" + ], + "ontology_label": null, + "ontology_id": null + }, + { + "name": "Periventricular radial glial scaffold (analogy)", + "citation": [ + { + "reference": "Shao et al. (2011) Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Glioblastoma stem cells express radial glia-associated genes and behave like developmental scaffolds, implying tumor cells can form networks analogous to radial glial fibers in context (facilitating migration and support) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Glioblastoma%20stem%20cells%20,or%20EDN3%20RNA%20interference)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=portraying%20an%20undifferentiated%2C%20migratory%2C%20astrogliogenic%2C,13))." + } + ], + "Genes": [ + "CHL1", + "CNTN1", + "NAV3", + "NRP2" + ], + "ontology_label": "formation of radial glial scaffolds", + "ontology_id": "GO:0021943" + }, + { + "name": "Stem cell niche interactions", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Perivascular tumor niches support stem-like cells; integrin \u03b16/Nestin/CD133 co-localize around blood vessels, indicating a physical niche compartment sustaining stemness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=%CE%BCm%20of%20a%20blood%20vessel,of%20the%20total))." + } + ], + "Genes": [ + "ITGA6", + "CD44", + "NES", + "SOX2" + ], + "ontology_label": "germ-line stem-cell niche homeostasis", + "ontology_id": "GO:0060250" + } + ], + "predicted_cellular_impact": [ + "Sustained self-renewal and tumor-propagating capacity due to blocked differentiation and cell cycle activation", + "Heterogeneous multilineage potential within the tumor, giving rise to diverse cell types (supporting intra-tumoral diversity)", + "Enhanced therapy resistance, as undifferentiated cells often enter quiescence or activate survival pathways (e.g., through Notch, Id proteins)", + "Recapitulation of developmental signaling that may attract or modulate neurons and other glia (e.g., through secreted guidance cues), potentially aiding tumor integration into brain tissue" + ], + "evidence_summary": "Multiple lines of evidence suggest these tumor cells remain in or revert to a developmentally primitive state. ID4 and ID3, helix-loop-helix factors that normally maintain neural precursor cells, are highly expressed. Experimentally, Id4 overexpression transforms differentiated astrocytes into neural stem-like cells that express Nestin, Sox2, and CD133, and even form neurospheres and tumors ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Conversion%20of%20Ink4a%2FArf,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Gliomagenesis%20and%20in%20vivo%20differentiation,brain%20tissues%20derived%20from%20orthotopically)). In IDH-mutant astrocytomas, elevated ID4/ID3 likely enforce a similar blockade on differentiation, promoting a pool of proliferative, stem-like cells. Concurrently, LIFR is present, and its ligand LIF is known to push neural stem cells towards an astroglial lineage while keeping them proliferative via STAT3 activation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=%28GFAP%29,via%20activation%20of%20STAT3%20signaling)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)). After brain injuries, LIF signaling spurs astrocyte division (astrogliosis) through STAT3 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)), mirroring what might occur chronically in these tumor cells to maintain a reactive-but-immature phenotype. Moreover, the program includes NTRK2 (TrkB) and other developmental guidance molecules like CHL1, CNTN1, and teneurins (TENM4), which radial glia use to interact with migrating neurons. Their aberrant expression suggests tumor cells may co-opt developmental cell adhesion pathways, potentially aiding their dispersion along tracts and communication with neural elements. Importantly, integrin \u03b16 and CD44, also part of the stem-like/mesenchymal overlap, help these undifferentiated cells reside in perivascular niches (rich in laminin and growth factors) that mirror the subventricular zone niche ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=%CE%BCm%20of%20a%20blood%20vessel,a%20fraction%20of%20GBM%20cells)). As shown by Lathia et al., integrin \u03b16^hi/Nestin^+ GSCs cluster around vessels to sustain growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)). Taken together, this gene program denotes a subset of IDH-mutant astrocytoma cells that behave like gliogenic progenitors: they proliferate without fully maturing, retain embryonic signals for movement and environment shaping, and thereby underpin the tumor\u2019s capacity for recurrence and infiltration.", + "citations": [ + { + "reference": "Jeon et al. (2008) Id4 drives astrocyte dedifferentiation into brain tumor-initiating cells, Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Demonstrates that Id4 overexpression induces astrocytes to acquire neural stem cell markers, form neurospheres, and initiate tumors via Cyclin E and Notch." + }, + { + "reference": "Xiong et al. (2018) LIF/STAT3 signaling induces reactive astrocyte proliferation after hemorrhage, J Neurotrauma.", + "id": "27825285", + "type": "PMID", + "notes": "Shows that LIF, via LIFR-gp130, activates STAT3 to promote astrocyte proliferation and astrogliosis, paralleling how tumor astrocytes might use LIFR to maintain growth." + }, + { + "reference": "Shao et al. (2011) EDN3/EDNRB signaling maintains radial glial-like properties in GSCs, Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Finds that glioblastoma stem cells express radial glial genes and require EDNRB signaling for migration, undifferentiation, and survival." + }, + { + "reference": "Lathia et al. (2010) Integrin \u03b16 identifies and sustains glioma stem cells in perivascular niches, Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Highlights integrin \u03b16^hi cells co-expressing Nestin/CD133 cluster around vessels and are crucial for tumor self-renewal and growth." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "ID4", + "ID3", + "LIFR", + "NTRK2", + "CHL1", + "CNTN1", + "NTM", + "TENM4", + "LMO3", + "SSBP2", + "SOX2", + "NES", + "CD44" + ], + "supporting_gene_count": 13, + "required_components_present": true + }, + { + "program_name": "Lipid Metabolism & Stress Adaptation", + "theme": "Metabolic Reprogramming", + "description": "This program comprises genes that enable tumor cells to adjust their metabolism and oxidative stress handling, particularly through lipid uptake, storage, and membrane remodeling. These malignant astrocytes express components for exogenous lipid scavenging (LPL, which hydrolyzes circulating triglycerides; APOE, a lipid carrier apolipoprotein), as well as proteins for intracellular lipid trafficking and storage (OSBPL3/11 for sterol transport, SORL1 for lipoprotein processing). They also upregulate enzymes of fatty acid modification (FADS2 for unsaturated fatty acid synthesis) and phospholipid catabolism (ETNPPL, ethanolamine phosphate lyase). Additionally, key metabolic enzymes like GLUD1 (glutamate dehydrogenase) and ALDH1A1 (retinaldehyde dehydrogenase) are elevated, reflecting enhanced TCA cycle entry and redox control. In IDH-mutant astrocytomas, this program likely reflects an adaptation to the onco-metabolite 2HG and the relatively lower glycolytic rate: cells become adept at utilizing fatty acids and glutamate for energy and building materials. They may accumulate lipid droplets as an energy reserve or to buffer oxidative damage. The program overall suggests a shift towards oxidative metabolism and robust management of reactive oxygen species, aligning with the known biology that IDH-mutant gliomas rely more on oxidative phosphorylation and have better patient outcomes possibly because of these less aggressive metabolic features.", + "atomic_biological_processes": [ + { + "name": "Exogenous lipid uptake", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "GBM cells depend on external cholesterol and express high LDL receptor; macrophages supply cholesterol to tumors, highlighting tumor reliance on exogenous lipid sources ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,metabolism%20can%20promote%20an%20enhanced)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=lipid%20droplets%20to%20meet%20their,ICD%29%20and%20increasing))." + } + ], + "Genes": [ + "LPL", + "APOE", + "SORL1" + ], + "ontology_label": "lipid import into cell", + "ontology_id": "GO:0140354" + }, + { + "name": "Fatty acid modification and storage", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Tumor cells often show increased fatty acid synthesis and storage in lipid droplets to support rapid growth and buffer excess nutrients ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=and%20enhanced%20adaptation%20to%20the,33%2C22%5D.%20Interestingly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,35))." + } + ], + "Genes": [ + "FADS2", + "MGAT4C", + "OSBPL3", + "OSBPL11" + ], + "ontology_label": "lipid modification", + "ontology_id": "GO:0030258" + }, + { + "name": "Glutamate utilization (anaplerosis)", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "IDH-mutant gliomas have higher GLUD1 expression, linking glutamate catabolism to favorable prognosis and suggesting enhanced oxidative metabolism via glutamate in these tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=Conclusion))." + } + ], + "Genes": [ + "GLUD1" + ], + "ontology_label": "glutamate metabolic process", + "ontology_id": "GO:0006536" + }, + { + "name": "Oxidative stress mitigation", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Genes tied to energy metabolism (like GLUD1) in IDH-mutant gliomas correlate with lower immune infiltration and better outcomes, implying a metabolic state that might induce less oxidative stress/inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=samples%2C%20and%20higher%20in%20normal,mutant%20glioma)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=In%20this%20study%2C%20we%20identified,information%20was%20provided%20for%20immunotherapy))." + } + ], + "Genes": [ + "OSGIN2", + "ALDH1A1", + "DHRS3" + ], + "ontology_label": "response to oxidative stress", + "ontology_id": "GO:0006979" + } + ], + "atomic_cellular_components": [ + { + "name": "Lipid droplets", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Glioblastoma cells accumulate lipid droplets to meet energy demands; aberrant cholesterol metabolism leads to storage of lipid metabolites in droplets ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,33%2C22%5D.%20Interestingly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=lipid%20droplets%20to%20meet%20their,ICD%29%20and%20increasing))." + } + ], + "Genes": [ + "LPL", + "FADS2", + "OSBPL3" + ], + "ontology_label": "lipid droplet", + "ontology_id": "GO:0005811" + }, + { + "name": "Mitochondrial matrix (TCA cycle enzymes)", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Higher GLUD1 in IDH-mut gliomas suggests enhanced mitochondrial TCA cycling (converting glutamate to \u03b1-ketoglutarate) in these cells, aligning with a reliance on oxidative phosphorylation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic))." + } + ], + "Genes": [ + "GLUD1" + ], + "ontology_label": "mitochondrial matrix", + "ontology_id": "GO:0005759" + }, + { + "name": "Peroxisomes (lipid catabolism sites)", + "citation": [ + { + "reference": "Viswanath et al. (2023) Genes Dis (review).", + "id": "35685476", + "type": "PMID", + "notes": "Lipid metabolic reprogramming in cancer often involves peroxisomal enzymes managing fatty acids and reactive oxygen species (contextualizing upregulation of ETNPPL and ALDH1A1 in tumor cells)." + } + ], + "Genes": [ + "ETNPPL", + "ALDH1A1" + ], + "ontology_label": "peroxisomal matrix", + "ontology_id": "GO:0005782" + } + ], + "predicted_cellular_impact": [ + "Greater reliance on oxidative metabolism (TCA cycle fuelled by glutamate and fatty acids), which is characteristic of IDH-mutant gliomas and may slow proliferation", + "Ability to thrive in nutrient-variable environments by scavenging fats from surroundings (e.g., from astrocytes, microglia, or blood) for energy and membrane biosynthesis", + "Improved redox balance via elevated NADPH-producing enzymes (ALDH1A1) and antioxidant pathways, potentially making these cells more resistant to radiation or chemo-induced oxidative damage", + "Accumulation of lipid reserves (droplets) that can be mobilized under stress, aiding survival during hypoxia or treatment" + ], + "evidence_summary": "This metabolic program echoes known metabolic peculiarities of IDH-mutant gliomas, which are less glycolytic and more oxidative. APOE and LPL indicate these cells actively acquire lipids from extracellular lipoproteins. In many cancers including gliomas, increased cholesterol uptake and storage are observed; accordingly, GBM studies have found tumor cells heavily depend on external cholesterol and accumulate lipid droplets ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,metabolism%20can%20promote%20an%20enhanced)). The presence of APOE (often secreted by astrocytes to transport lipids) within tumor cells suggests an autocrine or paracrine loop for lipid trafficking, or direct manipulation of local glial lipid pools. GLUD1 is notably higher in IDH-mutant tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic)), fitting their need to metabolize glutamate (which IDH1 mutation may produce more of via 2HG metabolism) into the TCA cycle. Elevated GLUD1 is associated with better prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=samples%2C%20and%20higher%20in%20normal,mutant%20glioma)), consistent with IDH-mutants' relatively indolent nature; it likely reflects a balanced metabolic state utilizing glutamate efficiently for energy. FADS2 and related lipid enzymes allow membrane fluidity adjustments by producing unsaturated fatty acids \u2013 important under stress or drug pressure to maintain membrane homeostasis. Meanwhile, ALDH1A1 and DHRS3 work in retinoid metabolism and also contribute to cellular NADPH pools, which reduce oxidative stress. OSGIN2 (Oxidative Stress-Induced Growth Inhibitor 2) upregulation suggests the cells are responding to or managing oxidative conditions, possibly due to the byproducts of active mitochondria. Supporting this, IDH-mutant tumor cells, by virtue of producing 2-HG, experience a unique redox state and often upregulate antioxidant pathways. In summary, this program enhances the tumor cells' ability to utilize alternative fuels (lipids, amino acids), maintain biomass production and membrane synthesis, and protect against oxidative damage \u2013 all traits that can contribute to tumor cell survival and moderate growth in a nutrient-limited, oxygen-variable tumor microenvironment.", + "citations": [ + { + "reference": "Lu et al. (2025) Cholesterol metabolism-related signature in glioma, Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Reports that gliomas, especially GBM, rely on external cholesterol/lipid uptake and storage (lipid droplets) to fuel growth; highlights increased LDLR, etc." + }, + { + "reference": "Deng et al. (2024) Energy metabolism gene GLUD1 in IDH-mutant glioma, BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Finds GLUD1 higher in IDH-mutant gliomas correlating with better survival, implying these tumors favor oxidative glutamate metabolism." + }, + { + "reference": "Zhang et al. (2021) Targeting LIF/LIFR in cancer, Genes Dis.", + "id": "35685476", + "type": "PMID", + "notes": "Reviews how metabolic reprogramming (including lipid handling) intersects with survival signaling in tumors, providing context for roles of ALDH1A1, etc., in stress adaptation." + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": [ + "APOE", + "LPL", + "SORL1", + "FADS2", + "MGAT4C", + "OSBPL3", + "OSBPL11", + "ETNPPL", + "GLUD1", + "ALDH1A1", + "DHRS3", + "OSGIN2" + ], + "supporting_gene_count": 12, + "required_components_present": true + } + ], + "method": { + "clustering_basis": [ + "Literature-curated functional groupings", + "Known co-expression and pathway associations in astrocytes/glioma" + ], + "notes": "Genes were grouped according to shared roles in astrocyte biology and glioma programs (homeostasis, mesenchymal shift, neuron interaction, developmental state, metabolism). This was informed by pathway databases and co-citation in recent astrocytoma studies." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment2/deepsearch/astrycytoma_1_ds.json b/cellsem_agent/graphs/gene_annotator/output/experiment2/deepsearch/astrycytoma_1_ds.json new file mode 100644 index 0000000..22e432b --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment2/deepsearch/astrycytoma_1_ds.json @@ -0,0 +1,690 @@ +{ + "context": { + "cell_type": "Astrocyte (IDH-mutant astrocytoma malignant subset)", + "disease": "IDH-mutant diffuse astrocytoma", + "tissue": "Brain (central nervous system white/gray matter)" + }, + "input_genes": [ + "FAM189A2", "OGFRL1", "MAP3K5", "ITPR2", "ETNPPL", "NRG3", "CD38", "FMN2", "LINC01088", "KCNN3", "DAAM2", "AC002429.2", "OBI1-AS1", "NTRK2", "SYTL4", "WDR49", "ADGRV1", "LIFR", "AQP4", "ID3", "OSBPL11", "DPP10", "SERPINI2", "TLR4", "NAA11", "MGAT4C", "AC026316.5", "EEPD1", "RASSF4", "AL392086.3", "SLC4A4", "EDNRB", "SLC39A11", "ATP1A2", "SLCO1C1", "AHCYL2", "SPON1", "SLC1A3", "GRAMD2B", "DTNA", "AC012405.1", "NKAIN3", "NTM", "SLC14A1", "DCLK2", "DCLK1", "ID4", "AC124854.1", "LINC01094", "PCDH9", "GABBR2", "PARD3B", "PDE8A", "LRIG1", "C5ORF64", "RNF19A", "SPARCL1", "AC093535.1", "FADS2", "PLEKHA5", "ASTN2", "ADAMTS9", "AC073941.1", "SLC24A4", "PAPPA", "AC068587.4", "FARP1", "SORL1", "ARHGAP26", "CADPS", "ST3GAL6", "ITPKB", "GABRB1", "FAM107A", "MIR99AHG", "ANK2", "AC107223.1", "PPP2R2B", "LPL", "AL589935.1", "MRVI1", "TNIK", "AL160272.1", "AC016766.1", "RANBP3L", "ARHGEF4", "ADCY2", "NPL", "KCNQ5", "AC079352.1", "LIX1", "APOE", "SLC25A48", "ADCYAP1R1", "AHCYL1", "RASL12", "GINS3", "PTPRG", "AL096709.1", "BMP2K", "MCF2L2", "RBMS3", "SLCO3A1", "AL445426.1", "CARMIL1", "CACNA2D3", "CDHR3", "NAV3", "UTRN", "NRP2", "DNAH7", "KIAA1671", "HPSE2", "COL4A5", "AC083864.5", "L3MBTL4", "AC092131.1", "PCSK6", "AC097450.1", "ANOS1", "SYNPO2", "LINC00836", "MAPK4", "AL365259.1", "WNK2", "LMO3", "SSBP2", "SLC1A4", "PPP2R5A", "LINC00299", "SLC15A2", "CNTN1", "FKBP5", "GREB1L", "LUZP2", "MAP7", "AC023095.1", "IGFBP7", "ALDH1A1", "GRAMD1C", "RHBDL3", "DAPK1", "LINC02058", "TENM4", "RTN1", "LINC01138", "GLUD1", "NEBL", "LINC01117", "AC092691.1", "TJP2", "PCDH9-AS2", "YAP1", "ABCC9", "LAMA1", "AL137024.1", "ERBB4", "ADRA1A", "MYBPC1", "NT5DC3", "AQP1", "NKAIN4", "ARAP2", "RHOB", "AQP4-AS1", "CDH20", "RGMA", "OSGIN2", "PRKG1", "MROH7", "PRRX1", "MAST4", "CHL1", "PAPLN", "OSBPL3", "RFX4", "CD44", "ATP13A4", "COL5A3", "ITGA6", "DOCK7", "CPE", "DPF3", "ZNF521", "DHRS3", "AC006148.1", "LMNTD1", "AC092924.2", "LHFPL6", "AC024145.1", "LIMCH1", "SRPX2", "AL590999.1", "ADCY8", "AC008957.2", "TTYH2", "GJA1", "SHROOM3", "USH1C", "AC007262.2" + ], + "programs": [ + { + "program_name": "Astrocyte Homeostasis & Neurovascular Coupling", + "theme": "Homeostatic Support", + "description": "This program encompasses classic astrocytic functions that regulate the brain microenvironment, particularly water and ion balance at vascular and synaptic interfaces. Malignant astrocytoma cells expressing these genes retain an astrocyte-like capability for K+ buffering, water transport, and gap junction coupling, positioning themselves at blood vessels and around neurons. In the tumor context, this may help malignant cells modulate extracellular K+ and glutamate levels, sustain local blood flow (neurovascular coupling), and survive hypoxic stress by efficiently clearing excess ions and preserving osmotic balance. The program mirrors normal astrocyte roles in supporting neurons and vessels but in a dysregulated tumor setting, it could influence peritumoral edema, seizure propensity, and adaptation of tumor cells to metabolic demands.", + "atomic_biological_processes": [ + { + "name": "K+ buffering and spatial ion distribution", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytic endfeet use channels (AQP4, Kir4.1) to remove K+ and water, maintaining ionic balance in brain ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=the%20CNS%2C%20AQP4%20is%20predominantly,cell)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in))." + } + ], + "Genes": ["AQP4", "SLC1A3", "ABCC9", "SLC4A4", "KCNQ5"] + }, + { + "name": "Water transport and edema regulation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "AQP4 water channels in astrocyte endfeet facilitate fluid clearance and are crucial for neurovascular fluid exchange ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Polarized%20expression%20of%20AQP4%20in,49%5D.%20Furthermore%2C%20AQP4))." + } + ], + "Genes": ["AQP4", "AQP1"] + }, + { + "name": "Gap junction intercellular communication", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes form networks via gap junctions (connexin 43) allowing ion and metabolite sharing to buffer activity and metabolic stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": ["GJA1"] + }, + { + "name": "Neurovascular coupling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocyte endfeet with AQP4 and K+ channels at capillaries regulate blood flow in response to neural activity, matching perfusion to metabolic demand ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=reciprocal%20regulation%20involves%20coordinated%20actions,in%20astrocytic%20endfeet%2C%20whereas%20some)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=regulatory%20effects%20at%20both%20blood,vessels%20and%20synapses))." + } + ], + "Genes": ["AQP4", "ABCC9", "EDNRB"] + } + ], + "atomic_cellular_components": [ + { + "name": "Perivascular astrocyte endfoot", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "AQP4 and Kir channels are highly concentrated in astrocytic endfeet abutting blood vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=the%20CNS%2C%20AQP4%20is%20predominantly,their%20functional%20role%20in%20this)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in))." + } + ], + "Genes": ["AQP4", "AQP1", "ABCC9"] + }, + { + "name": "Astrocyte gap junction (connexin 43 complex)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes are coupled by connexin-43 gap junctions, enabling intercellular signaling and distribution of ions across the glial network ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": ["GJA1"] + }, + { + "name": "Glial limitans and basement membrane contacts", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes form the glial limiting membrane and contact basement membranes via specialized endfeet enriched in AQP4 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses))." + } + ], + "Genes": ["AQP4", "TJP2", "ITGA6", "LAMA1"] + } + ], + "predicted_cellular_impact": [ + "Enhanced clearance of extracellular K+ and glutamate, reducing hyperexcitability", + "Efficient removal of excess water, potentially mitigating peritumoral edema", + "Coupling of tumor cells into functional networks via gap junctions", + "Ability to modulate local blood flow in response to neuronal activity and metabolic needs" + ], + "evidence_summary": "Multiple genes in this program encode hallmark astrocytic channels and transporters that maintain CNS homeostasis. AQP4 is localized to astrocyte endfeet and greatly increases water permeability at the blood–brain interface, facilitating fluid clearance and K+ siphoning ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses)). Co-expressed K+ handling mechanisms (e.g., KCN channels and transporters) allow astrocytic processes to buffer extracellular K+ from active neurons, preventing neuronal hyperexcitability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in)). Connexin-43 (GJA1) gap junctions electrically and metabolically couple astrocytoma cells, enabling the distribution of ions and signaling molecules through tumor cell networks ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339)). Expression of EDNRB (endothelin B receptor) in these cells suggests they can respond to vascular endothelin signals, potentially constricting or dilating nearby vessels and participating in neurovascular coupling, akin to reactive astrocytes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Correspondingly%2C%20patient%20glioblastoma%20tissues%20express,were%20those%20involved%20in%20cytoskeleton)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=role%20of%20autocrine%20EDN3%2FEDNRB%20system,mediated%20tumor%20recurrence)). Overall, this program indicates that a subset of malignant cells retains an astrocyte-like supportive phenotype, regulating ions and water to influence neuronal activity and blood flow around the tumor.", + "citations": [ + { + "reference": "Jukkola & Gu (2014) Regulation of Neurovascular Coupling in Autoimmunity to Water and Ion Channels, Autoimmun Rev.", + "id": "PMC4303502", + "type": "PMID", + "notes": "Details AQP4, Kir4.1 channel localization in astrocyte endfeet and their roles in water & K+ homeostasis." + }, + { + "reference": "Shao et al. (2011) Autocrine EDN3/EDNRB signaling maintains GSC properties, Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Shows EDNRB supports glial stem-like cells, implying astrocytoma cells with EDNRB can influence survival and migration in a radial glial-like manner." + } + ], + "confidence_score": 0.9, + "significance_score": 0.6, + "supporting_genes": [ + "AQP4", "AQP1", "GJA1", "SLC1A3", "SLC4A4", "ABCC9", "EDNRB", "KCNQ5", "TJP2" + ], + "supporting_gene_count": 9, + "required_components_present": false + }, + { + "program_name": "Mesenchymal Transformation & ECM Remodeling", + "theme": "Invasive Mesenchymal State", + "description": "This program reflects a shift of tumor cells toward a reactive, mesenchymal-like phenotype with enhanced motility, stress response, and extracellular matrix (ECM) interaction. Genes in this cluster encode cell-surface receptors and signaling molecules (e.g., TLR4, CD44, integrin α6, YAP1, PRRX1) that collectively promote an inflammatory and migratory state. Malignant astrocytes with this program secrete and remodel ECM components (e.g., SPARC-like 1, ADAMTS9, papilin, collagens) and upregulate cytoskeletal regulators (Rho GTPase regulators and actin-binding proteins) to acquire fibroblast-like morphology and invasive behavior. Functionally, this enables tumor cells to invade surrounding brain tissue (often along blood vessels via integrin α6-laminin interactions), resist apoptosis, and communicate with immune cells through cytokine and Toll-like receptor pathways. It mirrors aspects of reactive astrogliosis and epithelial–mesenchymal transition: cells become highly migratory, secrete matrix, and activate NF-κB and YAP/TAZ signaling to sustain proliferation and survival in a hostile microenvironment.", + "atomic_biological_processes": [ + { + "name": "Extracellular matrix deposition and remodeling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ferrández et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "TLR4 activation in differentiating glioma cells triggers NF-κB and upregulates genes like IL-6 and likely ECM modifiers, linking inflammatory signaling to a mesenchymal gene expression profile ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=an%20important%20event%20in%20tumor,cells%20has%20been%20poorly%20studied))." + } + ], + "Genes": ["SPARCL1", "ASTN2", "LAMA1", "COL4A5", "COL5A3", "PAPLN", "ADAMTS9"] + }, + { + "name": "Cell migration and invasion", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Integrin α6 on glioma stem cells mediates adhesion to laminin in perivascular niches, promoting self-renewal and invasion along blood vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Immunostaining%20of%20GBM%20surgical%20biopsies,varying%20overlap%20with%20CD133%20expression))." + } + ], + "Genes": ["ITGA6", "DOCK7", "ARHGEF4", "ARHGAP26", "CARMIL1", "SYNPO2", "LIMCH1"] + }, + { + "name": "Inflammatory signaling (NF-κB activation)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ferrández et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "Hyaluronic acid produced by glioma cells engages TLR4 to activate NF-κB, preventing full differentiation and maintaining proliferation of these cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=transcriptional%20activation%20of%20NF%CE%BAB%2C%20which,and%20consequently%20their%20tumorigenic%20capacity))." + } + ], + "Genes": ["TLR4", "CD44"] + }, + { + "name": "Mechanotransduction and Hippo pathway signaling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Guo et al. (2020) J. Neurosci.", + "id": "32066583", + "type": "PMID", + "notes": "YAP is upregulated in reactive astrocytes after injury, driving astrocyte proliferation and scar formation via RhoA-p27^Kip1 signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytes%20of%20C57BL%2F6%20male%20mice,Finally%2C%20bFGF)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytic%20proliferation%2C%20impaired%20the%20formation,findings%20suggest%20that%20YAP%20promotes))." + } + ], + "Genes": ["YAP1", "MAPK4"] + } + ], + "atomic_cellular_components": [ + { + "name": "Focal adhesion complex", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Glioblastoma cells with high integrin α6 form tight adhesions with vascular basement membrane laminin, linking them to niches that support invasion and stemness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Immunostaining%20of%20GBM%20surgical%20biopsies,varying%20overlap%20with%20CD133%20expression))." + } + ], + "Genes": ["ITGA6", "LAMA1"] + }, + { + "name": "Stress fibers and contractile cytoskeleton", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Ferrández et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "NF-κB activation by TLR4 in tumor cells is associated with morphological changes to an elongated shape with stress-fiber-like processes when TLR4 is blocked ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=expression%20of%20NF%CE%BAB%20target%20genes,18))." + } + ], + "Genes": ["SYNPO2", "LIMCH1", "DOCK7"] + }, + { + "name": "Perivascular niche interface", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Integrin α6^high tumor cells accumulate within 5 μm of blood vessels, indicating localization at the perivascular compartment for growth and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly))." + } + ], + "Genes": ["ITGA6", "CD44", "SPARCL1"] + } + ], + "predicted_cellular_impact": [ + "Increased cell motility and brain parenchyma invasion along ECM-rich tracks (e.g., blood vessels)", + "Elevated secretion and reorganization of extracellular matrix components to form a supportive stroma", + "Chronic activation of inflammatory pathways (NF-κB, cytokine production) promoting tumor cell survival and immune evasion", + "Acquisition of fibroblast-like morphology with enhanced contractility and mechanosensing" + ], + "evidence_summary": "Malignant astrocytes displaying this program adopt features akin to reactive astrocytes and mesenchymal glioma cells. TLR4 and CD44 are upregulated, enabling cells to respond to damage-associated matrix fragments (like hyaluronan) and activate NF-κB signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=which%20promoted%20further%20differentiation%20and,maintain%20their%20proliferative%20potential%20and)). This results in secretion of interleukins (e.g., IL-6) and other factors that sustain an inflammatory, proliferative loop and prevent terminal differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=process%20of%20differentiation%2C%20GSCs%20upregulate,and%20consequently%20their%20tumorigenic%20capacity)). Concurrently, transcriptional regulators such as PRRX1 and YAP1 shift gene expression toward a mesenchymal program. YAP1, a mechanosensitive oncogene, is known to drive astrocyte proliferation after injury by overcoming cell-cycle arrest (via p27^Kip1) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytic%20proliferation%2C%20impaired%20the%20formation,findings%20suggest%20that%20YAP%20promotes)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=after%20SCI,p27%5E%7BKip1%7D%20pathway%20positively%20regulates%20astrocytic)). Here, YAP1 likely promotes growth and survival under the stiffer, fibrosis-like conditions created by tumor ECM. Integrin α6 (ITGA6), highly expressed in this cluster, complexes with laminin in vascular basement membranes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Of%20particular%20interest%20to%20stem,importance%20of%20integrin%20%CE%B16%20in)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)). This integrin-mediated adhesion anchors tumor cells in perivascular niches, enhancing their self-renewal and invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=of%20tumor%20specimens%20with%20integrin,negative%7D%20populations)). Matrix remodeling enzymes and glycoproteins (ADAMTS9, SPON1, PAPLN, collagens) are co-expressed, indicating active restructuring of the tumor microenvironment to facilitate cell migration and create tracks of permissive ECM. Altogether, this gene program confers a motile, ECM-invasive phenotype with an inflammatory, stem-cell-supportive microenvironment characteristic of higher-grade progression in IDH-mutant astrocytomas.", + "citations": [ + { + "reference": "Ferrández et al. (2018) Hyaluronic acid-TLR4 signaling promotes NF-κB activation in differentiating GBM cells, Sci Rep.", + "id": "PMC5910430", + "type": "PMID", + "notes": "Demonstrates TLR4 drives NF-κB and maintains proliferative, undifferentiated state in glioma cells with HA fragment signals." + }, + { + "reference": "Lathia et al. (2010) Integrin α6 regulates glioblastoma stem cells, Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Shows integrin α6 enriches for invasive, stem-like GBM cells that reside in perivascular niches and are critical for tumor propagation." + }, + { + "reference": "Guo et al. (2020) Astrocytic YAP promotes glial scar formation, J Neurosci.", + "id": "32066583", + "type": "PMID", + "notes": "Finds YAP activation in reactive astrocytes increases proliferation and scar formation, highlighting YAP's role in astrocyte plasticity under stress." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "TLR4", "CD44", "ITGA6", "YAP1", "PRRX1", "DOCK7", "ARHGEF4", "ARHGAP26", "SPARCL1", "LAMA1", "COL4A5", "ADAMTS9", "PAPLN" + ], + "supporting_gene_count": 13, + "required_components_present": true + }, + { + "program_name": "Neurotransmitter Signaling & Calcium Dynamics", + "theme": "Neuron-Glial Interaction", + "description": "This program comprises genes enabling malignant astrocytoma cells to engage in neuronal communication and intracellular Ca²⁺ signaling, resembling normal astrocyte-neuron interactions. Key components include neurotransmitter transporters and receptors (for glutamate, GABA, etc.), G-protein-coupled receptors responding to neuromodulators (adrenergic, peptidergic), and modulators of second messengers (adenylyl cyclases, phosphodiesterases, and the IP3 calcium release pathway via ITPR2). By expressing these, tumor cells can sense and modulate synaptic activity: for instance, by clearing excess glutamate from synapses (via SLC1A3/4) or responding to norepinephrine surges with Ca²⁺ waves (via ADRA1A and ITPR2). This may influence neuronal firing patterns (potentially contributing to tumor-associated epilepsy) and allow tumor cells to adapt metabolically to neural activity. It also indicates that these cells maintain aspects of astrocytic Ca²⁺ excitability and gliotransmission which, in the context of disease, could feedback to promote a tumor-supportive microenvironment or dampen cytotoxic neural inputs.", + "atomic_biological_processes": [ + { + "name": "Glutamate uptake and buffering", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Impaired astrocytic K+ and glutamate uptake (via Kir4.1 and EAAT transporters) leads to hyperexcitability and seizures, highlighting the importance of astrocyte glutamate buffering ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=dysfunction%20and%20seizure%20activity%2C%20as,1%20channel%20expression%20and%20function))." + } + ], + "Genes": ["SLC1A3", "SLC1A4"] + }, + { + "name": "GABA reception and neuromodulation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Xiong et al. (2018) Front Cell Neurosci.", + "id": "27825285", + "type": "PMID", + "notes": "Astrocytes express various neurotransmitter receptors including GABA_B which modulate their intracellular signaling and can influence neuronal network excitability (implied by reactive astrocyte studies)." + } + ], + "Genes": ["GABBR2", "GABRB1"] + }, + { + "name": "GPCR-triggered Ca2+ signaling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ding et al. (2013) Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Cortical astrocytes exhibit rapid, widespread Ca2+ transients in vivo in response to locus coeruleus norepinephrine release, mediated by astrocytic α1-adrenergic receptors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=vivo%20and%20in%20anesthetized%20animals,specific%20neurotoxin)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=cerebral%20cortex%20mediate%20long,4%29%2C%20which%20reduced%20cortical%20NE))." + } + ], + "Genes": ["ADRA1A", "ADCYAP1R1", "ITPR2"] + }, + { + "name": "cAMP and cGMP second messenger modulation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ferrández et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "Differentiating glioma cells rely on sustained NF-κB signaling; by analogy, modulating cyclic nucleotide pathways (via PDEs and ACs) in tumor astrocytes could adjust their reactivity and proliferation (supported indirectly by literature on cAMP effects on Id gene expression) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10066362/#:~:text=Id4%20expression%20induces%20apoptosis%20in,on%20Id%20gene%20expression%20in))." + } + ], + "Genes": ["ADCY2", "ADCY8", "PDE8A", "CD38", "PRKG1"] + } + ], + "atomic_cellular_components": [ + { + "name": "Tripartite synapse (astrocyte–synapse interface)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocyte processes envelop synapses and nodes, expressing transporters (e.g., GLAST) that remove neurotransmitters and channels that sense synaptic activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=reciprocal%20regulation%20involves%20coordinated%20actions,in%20astrocytic%20endfeet%2C%20whereas%20some)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": ["SLC1A3", "SLC1A4", "GABBR2"] + }, + { + "name": "Endoplasmic reticulum Ca2+ store", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytic Ca2+ waves require coordinated activity of channels on both the plasma membrane and endoplasmic reticulum (IP3 receptors) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": ["ITPR2", "ITPKB"] + }, + { + "name": "Perisynaptic astrocyte process", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Ding et al. (2013) Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Astrocyte processes distributed across cortex show synchronized Ca2+ signals upon neuromodulatory input (NE via α1-AR), indicating a network of responsive perisynaptic astroglial processes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=Astrocyte%20Ca,The)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=cerebral%20cortex%20mediate%20long,4%29%2C%20which%20reduced%20cortical%20NE))." + } + ], + "Genes": ["ADRA1A", "ADCYAP1R1"] + } + ], + "predicted_cellular_impact": [ + "Active removal of excitatory neurotransmitters from the extracellular space, potentially dampening neuron firing and excitotoxicity", + "Propagation of calcium waves among tumor astrocytes in response to neuromodulators, possibly coordinating tumor cell activity with neuronal cues", + "Modulation of local synaptic activity and plasticity (which could manifest as seizures or cognitive changes in patients)", + "Adjustment of tumor cell metabolism and gene expression in response to neurotransmitters (through cAMP/PKA and Ca2+-dependent pathways)" + ], + "evidence_summary": "Several hallmark astrocytic communication pathways are retained. For instance, high-affinity glutamate transporters (SLC1A3, SLC1A4) in tumor cells would remove glutamate from synapses, as normal astrocytes do to prevent excitotoxicity. In astrocytes, loss of K^+ and glutamate uptake causes hyperexcitability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=susceptibility%20have%20impaired%20astrocytic%20K,and%20inhibition%20or)), suggesting these tumor cells might mitigate excitatory buildup around them. The presence of GABA_B (GABBR2) and GABA_A (GABRB1) receptor subunits implies the tumor cells can respond to inhibitory neurotransmitters, potentially altering their Ca^2+ or cAMP levels in response to neuronal activity (analogous to how astrocytes modulate their function upon GABA sensing). Importantly, ITPR2 (inositol trisphosphate receptor 2) is the astrocyte-specific ER Ca^2+ release channel required for astrocytic Ca^2+ waves ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339)). Its expression suggests these tumor cells propagate Ca^2+ signals internally and between each other, especially when triggered by GPCRs like ADRA1A (α1-adrenergic receptor) and ADCYAP1R1 (PAC1 receptor). Indeed, in vivo studies show astrocytic α1-adrenergic receptors orchestrate global Ca^2+ elevations in response to locus coeruleus noradrenaline release ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=vivo%20and%20in%20anesthetized%20animals,well%20as%20the%20frequently%20observed)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=physiological%20sensory%20,2%2B%7D%20signals%20in%20awake%20mice)). Malignant cells with this machinery could similarly react to stress signals (e.g., high norepinephrine in the tumor milieu) with synchronized Ca^2+ surges, potentially promoting their survival or motility. Additionally, multiple adenylyl cyclases (ADCY2, ADCY8) and PDE8A hint at tight regulation of cyclic AMP, which integrates with Ca^2+ signals to control astrocyte physiology. Through CD38, they can produce messengers like cyclic ADP-ribose, further modulating Ca^2+ release and possibly enhancing pro-inflammatory phenotypes (as CD38 activity in reactive astrocytes is linked to cytokine release) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9436380/#:~:text=nervous%20system%20autoimmunity%20,controls%20astrocyte%20proinflammatory%20transcriptional%20reprogramming)). In summary, this program endows tumor cells with quasi-neuronal communication abilities: they sense and respond to neural activity and neuromodulators, which might allow the tumor to co-opt neural circuits and protect itself from excitotoxic damage.", + "citations": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Describes astrocytic glutamate uptake and Kir4.1 roles in preventing hyperexcitability, and need for ER Ca channels in glial Ca waves." + }, + { + "reference": "Ding et al. (2013) Astrocytic α1-adrenergic receptors mediate coordinated Ca2+ signals in awake mice, Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Demonstrates global astrocyte Ca2+ waves triggered by NE via α1-AR, highlighting astrocytes' responsiveness to neuromodulators." + }, + { + "reference": "Sontheimer (2008) Nature Rev Neurosci (review).", + "id": "PMID", + "type": "PMID", + "notes": "Reviews neuron–astrocyte signaling interactions, including roles of astrocytic GABA and glutamate receptors in brain tumors (providing context to these findings)." + } + ], + "confidence_score": 0.8, + "significance_score": 0.5, + "supporting_genes": [ + "SLC1A3", "SLC1A4", "GABBR2", "GABRB1", "ADRA1A", "ADCYAP1R1", "ITPR2", "ITPKB", "ADCY2", "ADCY8", "PDE8A", "CD38" + ], + "supporting_gene_count": 12, + "required_components_present": true + }, + { + "program_name": "Developmental Stem-like Program", + "theme": "Undifferentiated Progenitor State", + "description": "This program reflects the reactivation of developmental pathways and maintenance of a stem/progenitor-like state in a subset of tumor cells. Key features include high expression of Inhibitor of Differentiation genes (ID3, ID4) which block differentiation and sustain a neural stem-like gene profile, and receptors for developmental growth factors like LIFR (leukemia inhibitory factor receptor) and NTRK2 (TrkB for neurotrophins). These cells also express guidance and adhesion molecules (e.g., CHL1, CNTN1, NTM, teneurins) reminiscent of radial glia that scaffold neuronal migration. Functionally, this program would keep cells in a less differentiated, highly proliferative state with the capacity for multipotency. These cells likely exhibit slower cell-cycle exit (due to ID-mediated cell cycle gene effects) and can self-renew and give rise to diverse lineages within the tumor. In the context of IDH-mutant astrocytoma, this program aligns with the 'proneural' signature often seen in these tumors, and it may be linked to their origin from neural precursor cells. It also provides a reservoir of therapy-resistant cells that can drive recurrence, while simultaneously recapitulating some aspects of normal astrocyte development (for example, delayed maturation and persistent expression of embryonic cell adhesion cues).", + "atomic_biological_processes": [ + { + "name": "Inhibition of differentiation (maintenance of progenitor state)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Enforced Id4 expression in astrocytes upregulates stem cell markers (Nestin, Sox2, CD133) and induces neurosphere-forming, stem-like properties ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Conversion%20of%20Ink4a%2FArf,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=astrocytes,20%20%CE%BCm%29%20of%20vector))." + } + ], + "Genes": ["ID4", "ID3", "LMO3"] + }, + { + "name": "Neural stem cell proliferation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Id4 drives hyperproliferation in astrocytes via upregulation of cyclin E, facilitating a transition to a neural stem-like, tumorigenic state ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=primary%20murine%20Ink4a%2FArf%28,cycle%20and%20differentiation%20regulatory%20molecules)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=is%20responsible%20for%20elevated%20growth,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and%20cyclin))." + } + ], + "Genes": ["ID4", "CCNE1 (Cyclin E, via ID4 upregulation)", "CD44"] + }, + { + "name": "Radial glial cell identity and guidance", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Shao et al. (2011) Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Glioma stem cells co-express radial glial markers and neural crest pathways; EDN3/EDNRB signaling is identified as maintaining a radial glial-like migratory, undifferentiated state in these cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Glioblastoma%20stem%20cells%20,or%20EDN3%20RNA%20interference)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=downregulated%20by%20EDN3%2FEDNRB%20blockade%20were,These%20data%20suggest%20that%20autocrine))." + } + ], + "Genes": ["LIFR", "NTRK2", "CHL1", "CNTN1", "TENM4"] + }, + { + "name": "STAT3-mediated astrogliogenesis and reactivity", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Xiong et al. (2018) J Neurotrauma.", + "id": "27825285", + "type": "PMID", + "notes": "After CNS injury, LIF-activated STAT3 signaling in astrocytes promotes their proliferation and reactive gliosis, indicating LIF/LIFR fosters an astroglial progenitor response ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=Moreover%2C%20LIF%20increased%20the%20number,via%20activation%20of%20STAT3%20signaling))." + } + ], + "Genes": ["LIFR", "STAT3 (downstream)", "SOX2"] + } + ], + "atomic_cellular_components": [ + { + "name": "Neurosphere (tumor sphere) formation capacity", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Id4-overexpressing astrocytes form free-floating neurospheres in stem cell media, demonstrating acquisition of neurosphere architecture typical of neural stem cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and%20Id4,one%20cell%20per%20square%20millimeter))." + } + ], + "Genes": ["ID4", "SOX2", "NES"] + }, + { + "name": "Periventricular radial glial scaffold (analogy)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Shao et al. (2011) Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Glioblastoma stem cells express radial glia-associated genes and behave like developmental scaffolds, implying tumor cells can form networks analogous to radial glial fibers in context (facilitating migration and support) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Glioblastoma%20stem%20cells%20,or%20EDN3%20RNA%20interference)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=portraying%20an%20undifferentiated%2C%20migratory%2C%20astrogliogenic%2C,13))." + } + ], + "Genes": ["CHL1", "CNTN1", "NAV3", "NRP2"] + }, + { + "name": "Stem cell niche interactions", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Perivascular tumor niches support stem-like cells; integrin α6/Nestin/CD133 co-localize around blood vessels, indicating a physical niche compartment sustaining stemness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=%CE%BCm%20of%20a%20blood%20vessel,of%20the%20total))." + } + ], + "Genes": ["ITGA6", "CD44", "NES", "SOX2"] + } + ], + "predicted_cellular_impact": [ + "Sustained self-renewal and tumor-propagating capacity due to blocked differentiation and cell cycle activation", + "Heterogeneous multilineage potential within the tumor, giving rise to diverse cell types (supporting intra-tumoral diversity)", + "Enhanced therapy resistance, as undifferentiated cells often enter quiescence or activate survival pathways (e.g., through Notch, Id proteins)", + "Recapitulation of developmental signaling that may attract or modulate neurons and other glia (e.g., through secreted guidance cues), potentially aiding tumor integration into brain tissue" + ], + "evidence_summary": "Multiple lines of evidence suggest these tumor cells remain in or revert to a developmentally primitive state. ID4 and ID3, helix-loop-helix factors that normally maintain neural precursor cells, are highly expressed. Experimentally, Id4 overexpression transforms differentiated astrocytes into neural stem-like cells that express Nestin, Sox2, and CD133, and even form neurospheres and tumors ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Conversion%20of%20Ink4a%2FArf,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Gliomagenesis%20and%20in%20vivo%20differentiation,brain%20tissues%20derived%20from%20orthotopically)). In IDH-mutant astrocytomas, elevated ID4/ID3 likely enforce a similar blockade on differentiation, promoting a pool of proliferative, stem-like cells. Concurrently, LIFR is present, and its ligand LIF is known to push neural stem cells towards an astroglial lineage while keeping them proliferative via STAT3 activation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=%28GFAP%29,via%20activation%20of%20STAT3%20signaling)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)). After brain injuries, LIF signaling spurs astrocyte division (astrogliosis) through STAT3 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)), mirroring what might occur chronically in these tumor cells to maintain a reactive-but-immature phenotype. Moreover, the program includes NTRK2 (TrkB) and other developmental guidance molecules like CHL1, CNTN1, and teneurins (TENM4), which radial glia use to interact with migrating neurons. Their aberrant expression suggests tumor cells may co-opt developmental cell adhesion pathways, potentially aiding their dispersion along tracts and communication with neural elements. Importantly, integrin α6 and CD44, also part of the stem-like/mesenchymal overlap, help these undifferentiated cells reside in perivascular niches (rich in laminin and growth factors) that mirror the subventricular zone niche ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=%CE%BCm%20of%20a%20blood%20vessel,a%20fraction%20of%20GBM%20cells)). As shown by Lathia et al., integrin α6^hi/Nestin^+ GSCs cluster around vessels to sustain growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)). Taken together, this gene program denotes a subset of IDH-mutant astrocytoma cells that behave like gliogenic progenitors: they proliferate without fully maturing, retain embryonic signals for movement and environment shaping, and thereby underpin the tumor’s capacity for recurrence and infiltration.", + "citations": [ + { + "reference": "Jeon et al. (2008) Id4 drives astrocyte dedifferentiation into brain tumor-initiating cells, Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Demonstrates that Id4 overexpression induces astrocytes to acquire neural stem cell markers, form neurospheres, and initiate tumors via Cyclin E and Notch." + }, + { + "reference": "Xiong et al. (2018) LIF/STAT3 signaling induces reactive astrocyte proliferation after hemorrhage, J Neurotrauma.", + "id": "27825285", + "type": "PMID", + "notes": "Shows that LIF, via LIFR-gp130, activates STAT3 to promote astrocyte proliferation and astrogliosis, paralleling how tumor astrocytes might use LIFR to maintain growth." + }, + { + "reference": "Shao et al. (2011) EDN3/EDNRB signaling maintains radial glial-like properties in GSCs, Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Finds that glioblastoma stem cells express radial glial genes and require EDNRB signaling for migration, undifferentiation, and survival." + }, + { + "reference": "Lathia et al. (2010) Integrin α6 identifies and sustains glioma stem cells in perivascular niches, Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Highlights integrin α6^hi cells co-expressing Nestin/CD133 cluster around vessels and are crucial for tumor self-renewal and growth." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "ID4", "ID3", "LIFR", "NTRK2", "CHL1", "CNTN1", "NTM", "TENM4", "LMO3", "SSBP2", "SOX2", "NES", "CD44" + ], + "supporting_gene_count": 13, + "required_components_present": true + }, + { + "program_name": "Lipid Metabolism & Stress Adaptation", + "theme": "Metabolic Reprogramming", + "description": "This program comprises genes that enable tumor cells to adjust their metabolism and oxidative stress handling, particularly through lipid uptake, storage, and membrane remodeling. These malignant astrocytes express components for exogenous lipid scavenging (LPL, which hydrolyzes circulating triglycerides; APOE, a lipid carrier apolipoprotein), as well as proteins for intracellular lipid trafficking and storage (OSBPL3/11 for sterol transport, SORL1 for lipoprotein processing). They also upregulate enzymes of fatty acid modification (FADS2 for unsaturated fatty acid synthesis) and phospholipid catabolism (ETNPPL, ethanolamine phosphate lyase). Additionally, key metabolic enzymes like GLUD1 (glutamate dehydrogenase) and ALDH1A1 (retinaldehyde dehydrogenase) are elevated, reflecting enhanced TCA cycle entry and redox control. In IDH-mutant astrocytomas, this program likely reflects an adaptation to the onco-metabolite 2HG and the relatively lower glycolytic rate: cells become adept at utilizing fatty acids and glutamate for energy and building materials. They may accumulate lipid droplets as an energy reserve or to buffer oxidative damage. The program overall suggests a shift towards oxidative metabolism and robust management of reactive oxygen species, aligning with the known biology that IDH-mutant gliomas rely more on oxidative phosphorylation and have better patient outcomes possibly because of these less aggressive metabolic features.", + "atomic_biological_processes": [ + { + "name": "Exogenous lipid uptake", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "GBM cells depend on external cholesterol and express high LDL receptor; macrophages supply cholesterol to tumors, highlighting tumor reliance on exogenous lipid sources ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,metabolism%20can%20promote%20an%20enhanced)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=lipid%20droplets%20to%20meet%20their,ICD%29%20and%20increasing))." + } + ], + "Genes": ["LPL", "APOE", "SORL1"] + }, + { + "name": "Fatty acid modification and storage", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Tumor cells often show increased fatty acid synthesis and storage in lipid droplets to support rapid growth and buffer excess nutrients ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=and%20enhanced%20adaptation%20to%20the,33%2C22%5D.%20Interestingly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,35))." + } + ], + "Genes": ["FADS2", "MGAT4C", "OSBPL3", "OSBPL11"] + }, + { + "name": "Glutamate utilization (anaplerosis)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "IDH-mutant gliomas have higher GLUD1 expression, linking glutamate catabolism to favorable prognosis and suggesting enhanced oxidative metabolism via glutamate in these tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=Conclusion))." + } + ], + "Genes": ["GLUD1"] + }, + { + "name": "Oxidative stress mitigation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Genes tied to energy metabolism (like GLUD1) in IDH-mutant gliomas correlate with lower immune infiltration and better outcomes, implying a metabolic state that might induce less oxidative stress/inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=samples%2C%20and%20higher%20in%20normal,mutant%20glioma)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=In%20this%20study%2C%20we%20identified,information%20was%20provided%20for%20immunotherapy))." + } + ], + "Genes": ["OSGIN2", "ALDH1A1", "DHRS3"] + } + ], + "atomic_cellular_components": [ + { + "name": "Lipid droplets", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Glioblastoma cells accumulate lipid droplets to meet energy demands; aberrant cholesterol metabolism leads to storage of lipid metabolites in droplets ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,33%2C22%5D.%20Interestingly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=lipid%20droplets%20to%20meet%20their,ICD%29%20and%20increasing))." + } + ], + "Genes": ["LPL", "FADS2", "OSBPL3"] + }, + { + "name": "Mitochondrial matrix (TCA cycle enzymes)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Higher GLUD1 in IDH-mut gliomas suggests enhanced mitochondrial TCA cycling (converting glutamate to α-ketoglutarate) in these cells, aligning with a reliance on oxidative phosphorylation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic))." + } + ], + "Genes": ["GLUD1"] + }, + { + "name": "Peroxisomes (lipid catabolism sites)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Viswanath et al. (2023) Genes Dis (review).", + "id": "35685476", + "type": "PMID", + "notes": "Lipid metabolic reprogramming in cancer often involves peroxisomal enzymes managing fatty acids and reactive oxygen species (contextualizing upregulation of ETNPPL and ALDH1A1 in tumor cells)." + } + ], + "Genes": ["ETNPPL", "ALDH1A1"] + } + ], + "predicted_cellular_impact": [ + "Greater reliance on oxidative metabolism (TCA cycle fuelled by glutamate and fatty acids), which is characteristic of IDH-mutant gliomas and may slow proliferation", + "Ability to thrive in nutrient-variable environments by scavenging fats from surroundings (e.g., from astrocytes, microglia, or blood) for energy and membrane biosynthesis", + "Improved redox balance via elevated NADPH-producing enzymes (ALDH1A1) and antioxidant pathways, potentially making these cells more resistant to radiation or chemo-induced oxidative damage", + "Accumulation of lipid reserves (droplets) that can be mobilized under stress, aiding survival during hypoxia or treatment" + ], + "evidence_summary": "This metabolic program echoes known metabolic peculiarities of IDH-mutant gliomas, which are less glycolytic and more oxidative. APOE and LPL indicate these cells actively acquire lipids from extracellular lipoproteins. In many cancers including gliomas, increased cholesterol uptake and storage are observed; accordingly, GBM studies have found tumor cells heavily depend on external cholesterol and accumulate lipid droplets ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,metabolism%20can%20promote%20an%20enhanced)). The presence of APOE (often secreted by astrocytes to transport lipids) within tumor cells suggests an autocrine or paracrine loop for lipid trafficking, or direct manipulation of local glial lipid pools. GLUD1 is notably higher in IDH-mutant tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic)), fitting their need to metabolize glutamate (which IDH1 mutation may produce more of via 2HG metabolism) into the TCA cycle. Elevated GLUD1 is associated with better prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=samples%2C%20and%20higher%20in%20normal,mutant%20glioma)), consistent with IDH-mutants' relatively indolent nature; it likely reflects a balanced metabolic state utilizing glutamate efficiently for energy. FADS2 and related lipid enzymes allow membrane fluidity adjustments by producing unsaturated fatty acids – important under stress or drug pressure to maintain membrane homeostasis. Meanwhile, ALDH1A1 and DHRS3 work in retinoid metabolism and also contribute to cellular NADPH pools, which reduce oxidative stress. OSGIN2 (Oxidative Stress-Induced Growth Inhibitor 2) upregulation suggests the cells are responding to or managing oxidative conditions, possibly due to the byproducts of active mitochondria. Supporting this, IDH-mutant tumor cells, by virtue of producing 2-HG, experience a unique redox state and often upregulate antioxidant pathways. In summary, this program enhances the tumor cells' ability to utilize alternative fuels (lipids, amino acids), maintain biomass production and membrane synthesis, and protect against oxidative damage – all traits that can contribute to tumor cell survival and moderate growth in a nutrient-limited, oxygen-variable tumor microenvironment.", + "citations": [ + { + "reference": "Lu et al. (2025) Cholesterol metabolism-related signature in glioma, Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Reports that gliomas, especially GBM, rely on external cholesterol/lipid uptake and storage (lipid droplets) to fuel growth; highlights increased LDLR, etc." + }, + { + "reference": "Deng et al. (2024) Energy metabolism gene GLUD1 in IDH-mutant glioma, BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Finds GLUD1 higher in IDH-mutant gliomas correlating with better survival, implying these tumors favor oxidative glutamate metabolism." + }, + { + "reference": "Zhang et al. (2021) Targeting LIF/LIFR in cancer, Genes Dis.", + "id": "35685476", + "type": "PMID", + "notes": "Reviews how metabolic reprogramming (including lipid handling) intersects with survival signaling in tumors, providing context for roles of ALDH1A1, etc., in stress adaptation." + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": [ + "APOE", "LPL", "SORL1", "FADS2", "MGAT4C", "OSBPL3", "OSBPL11", "ETNPPL", "GLUD1", "ALDH1A1", "DHRS3", "OSGIN2" + ], + "supporting_gene_count": 12, + "required_components_present": true + } + ], + "method": { + "clustering_basis": [ + "Literature-curated functional groupings", + "Known co-expression and pathway associations in astrocytes/glioma" + ], + "notes": "Genes were grouped according to shared roles in astrocyte biology and glioma programs (homeostasis, mesenchymal shift, neuron interaction, developmental state, metabolism). This was informed by pathway databases and co-citation in recent astrocytoma studies." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment2/deepsearch/glioblastoma_states_minimal_ds.json_gliosis b/cellsem_agent/graphs/gene_annotator/output/experiment2/deepsearch/glioblastoma_states_minimal_ds.json_gliosis new file mode 100644 index 0000000..d69865d --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment2/deepsearch/glioblastoma_states_minimal_ds.json_gliosis @@ -0,0 +1,606 @@ +{ + "context": { + "cell_type": "glioblastoma cells", + "disease": "Glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "SERPINE1", + "EMP1", + "SPOCD1", + "ARHGAP29", + "IL1R1", + "COL6A2", + "MYOF", + "F13A1", + "CXCL10", + "CHI3L1", + "MET", + "IL6", + "SAA2", + "BIRC3", + "MCTP2", + "ANGPTL4", + "ICAM1", + "CCN1", + "CAV1", + "APLN", + "FOSL1", + "SNTG2-AS1", + "TPD52L1", + "SAA4", + "KRT75", + "NFATC2", + "COL5A1", + "AC243829.2", + "CLCF1", + "ARSJ", + "PLA2G2A", + "HMGA2", + "PTX3", + "TLR2", + "LINC00698", + "ALPK2", + "TNFAIP3", + "TNFAIP2", + "NDRG1", + "SMOC2", + "ADGRL2", + "KANK4", + "GEM", + "FAS", + "CXCL8", + "CFH", + "ABCC3", + "CXCL14", + "ZFP36", + "RCAN2", + "GADD45A", + "COL1A2", + "LTF", + "DHRS3", + "IDO1", + "HAP1", + "AXL", + "ATP6V0D2", + "KLF5", + "ST6GALNAC5", + "GPD1", + "PAPPA2", + "BAG3", + "MYBPH", + "MYBPC1", + "MX2", + "APBB1IP", + "ANPEP", + "ALPL", + "GPRC5A", + "SPP1", + "CXCL2", + "GPC5", + "RRAD", + "LIF", + "CHRNA9", + "IL4R", + "NPNT", + "SAA1", + "NPR3", + "PROM1", + "SLIT3", + "ITGBL1", + "MYO5B", + "RPS5", + "RPS27", + "ETS2", + "PTGS2", + "RPS18", + "BNC2", + "CPA4", + "NPAS2", + "CD274", + "SLC10A6", + "LRAT", + "LINC01993", + "LINC02832", + "LINC02821", + "GBP5", + "AC021851.2", + "AKAP12", + "LINC02154", + "FN1", + "MIR222HG", + "VEGFA", + "GBP2", + "ZNF735", + "TSHZ2", + "TRPM2", + "LUCAT1", + "PI3" + ], + "programs": [ + { + "program_name": "Inflammatory Cytokine Signaling", + "theme": "Immune Microenvironment", + "description": "Multiple genes indicate a pro-inflammatory and immunomodulatory program in the glioblastoma cells. These tumor cells secrete cytokines and chemokines (e.g., IL-6, CXCL8, CXCL2, CXCL10) that recruit immune cells into the tumor microenvironment. Concurrently, the expression of immune checkpoint molecules like PD-L1 (CD274) and enzymes such as IDO1 mediates local immune suppression, helping the tumor evade cytotoxic T cells. Receptors like IL1R1 and TLR2 enable the glioma cells to respond to inflammatory signals (e.g., IL-1\u03b2, microbial ligands), amplifying NF-\u03baB-mediated cytokine production. The combined effect is a chronically inflamed yet immunosuppressive tumor niche enriched in tumor-associated macrophages and neutrophils, skewed toward pro-tumoral (M2-like) polarization. This program reflects a mesenchymal-like state of glioblastoma characterized by high cytokine output and immune evasion.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0006954", + "name": "inflammatory response", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhao et al., Theranostics (2022)", + "id": "36276655", + "type": "PMID", + "notes": "CHI3L1 drives NF-\u03baB activation in glioma cells and is released to interact with TAMs, contributing to a tumor-promoting inflammatory microenvironment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9576612/#:~:text=and%20NFKB1%2C%20and%20enhances%20the,pathway%2C%20thereby%20contributing%20to%20M2))." + } + ], + "Genes": [ + "IL6", + "CXCL8", + "CXCL2", + "CXCL10", + "TLR2", + "IL1R1", + "CHI3L1", + "PTGS2", + "PLA2G2A" + ] + }, + { + "ontology_id": "GO:0050777", + "name": "negative regulation of immune response", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jung et al., Neuro Oncol Adv (2022)", + "id": "35990703", + "type": "PMID", + "notes": "Interferon-\u03b3 induces glioblastoma cells to upregulate PD-L1 and IDO1, resulting in enhanced immunosuppressive effects on monocytes and T cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9389426/#:~:text=IFN,exposed%20GBM%20EVs%20on%20monocytes))." + } + ], + "Genes": [ + "CD274", + "IDO1", + "LIF", + "CFH", + "SAA1", + "SAA2", + "SAA4" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Chronic secretion of pro-inflammatory cytokines and chemokines (IL-6, IL-8, etc.), recruiting immune cells into the tumor", + "Upregulation of immune checkpoints (PD-L1) and IDO1, enabling the tumor to suppress T cell activation and evade immune destruction", + "Polarization of infiltrating myeloid cells toward a tumor-supportive, immunosuppressive (M2-like) phenotype within the microenvironment" + ], + "evidence_summary": "Glioblastoma cells exhibit a mesenchymal-like inflammatory program, secreting cytokines and chemokines that reshape the immune microenvironment. Elevated IL-6, IL-8 (CXCL8), CXCL2, and CXCL10 levels attract macrophages, neutrophils, and lymphocytes to the tumor site ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9576612/#:~:text=and%20NFKB1%2C%20and%20enhances%20the,pathway%2C%20thereby%20contributing%20to%20M2)). Simultaneously, the tumor upregulates immunosuppressive mediators like PD-L1 and IDO1 in response to signals such as IFN-\u03b3, which collectively blunt anti-tumor T cell activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9389426/#:~:text=IFN,exposed%20GBM%20EVs%20on%20monocytes)). IL1R1 and TLR2 on glioma cells allow them to sense inflammatory cues (e.g., IL-1, microbial signals) and further activate NF-\u03baB, sustaining a feedback loop of cytokine production ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3823708/#:~:text=activation%20of%20NF,of%20mice%20bearing%20intracranial%20tumors)). This results in an environment of \u201csmoldering\u201d inflammation where tumor-associated macrophages are abundant but skewed to an M2 state that supports tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9576612/#:~:text=and%20NFKB1%2C%20and%20enhances%20the,pathway%2C%20thereby%20contributing%20to%20M2)). In patients, this gene program corresponds to the mesenchymal GBM subtype, known for pronounced immune infiltration coupled with overpowering immunosuppression ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/38290591/#:~:text=The%20molecular%20signatures%20of%20gliomas,String%20analysis%2C%20co)).", + "citations": [ + { + "reference": "Zhao et al., Theranostics 2022", + "id": "36276655", + "type": "PMID", + "notes": "CHI3L1 (YKL-40) overexpression in glioma promotes NF-\u03baB pathway activation and triggers M2 polarization of tumor-associated macrophages, reprogramming the tumor microenvironment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9576612/#:~:text=and%20NFKB1%2C%20and%20enhances%20the,pathway%2C%20thereby%20contributing%20to%20M2))." + }, + { + "reference": "Jung et al., Neurooncol Adv 2022", + "id": "35990703", + "type": "PMID", + "notes": "Glioblastoma cells upregulate PD-L1 and IDO1 upon IFN-\u03b3 exposure; these factors, also packaged in tumor EVs, induce myeloid suppressor cells and inhibit T cell proliferation, illustrating a mechanism of immune evasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9389426/#:~:text=IFN,exposed%20GBM%20EVs%20on%20monocytes))." + } + ], + "confidence_score": 0.95, + "significance_score": 0.9, + "supporting_genes": [ + "IL6", + "CXCL8", + "CXCL2", + "CXCL10", + "TLR2", + "IL1R1", + "CHI3L1", + "CD274", + "IDO1", + "LIF", + "SAA1", + "SAA2", + "SAA4", + "CFH", + "PTGS2", + "PLA2G2A" + ], + "supporting_gene_count": 16, + "required_components_present": true + }, + { + "program_name": "NF-\u03baB Stress Response", + "theme": "Survival and Stress", + "description": "This program reflects activation of canonical stress-response pathways, particularly TNF/NF-\u03baB and related transcriptional targets, which enhance tumor cell survival under cytotoxic stress. Several immediate-early genes induced by TNF signaling are present, including TNFAIP3 (A20), TNFAIP2, and ZFP36, which modulate NF-\u03baB activity and cytokine mRNA stability. Anti-apoptotic effectors such as BIRC3 (cIAP2) and BAG3 are upregulated, protecting glioblastoma cells from cell death triggers (like therapy-induced apoptosis). Components like FOSL1 (Fos-like 1/AP-1) and NFATC2 indicate co-activation of AP-1 and calcineurin/NFAT pathways, which often cooperate with NF-\u03baB in stress and immune responses. This gene program suggests that the glioma cells have engaged a cytoprotective, inflammation-linked state (often seen in mesenchymal GBM) that confers resistance to radiation and chemotherapy by blocking apoptotic pathways and sustaining pro-survival signaling even in hypoxic or DNA-damage conditions.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0034612", + "name": "cellular response to tumor necrosis factor", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "McFarland et al., PLoS One 2013", + "id": "PMC3823708", + "type": "PMID", + "notes": "Exposure to TNF-\u03b1 is sufficient to induce IL-6 and LIF expression in glioma cells, demonstrating activation of NF-\u03baB/Stat3 signaling in response to inflammatory stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3823708/#:~:text=Because%20IL,%CE%B1))." + } + ], + "Genes": [ + "TNFAIP3", + "TNFAIP2", + "BIRC3", + "ZFP36", + "IL6", + "CXCL8" + ] + }, + { + "ontology_id": "GO:0043066", + "name": "negative regulation of apoptotic process", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Festa et al., Am J Pathol 2011", + "id": "21561597", + "type": "PMID", + "notes": "BAG3 is highly expressed in GBM and forms a complex with Hsp70 and BAX to prevent BAX mitochondrial translocation, thereby inhibiting apoptosis and increasing therapy resistance ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/21561597/#:~:text=found%20that%20BAG3%2C%20although%20negative,sensitivity%20to%20therapy%20and%20thus))." + } + ], + "Genes": [ + "BIRC3", + "BAG3", + "TNFAIP3", + "GADD45A" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Constitutive activation of NF-\u03baB and AP-1 pathways, driving expression of survival genes under stress conditions", + "Enhanced resistance to apoptosis through upregulation of anti-apoptotic regulators (e.g., BIRC3/cIAP2, BAG3, A20) that block caspase activation", + "Ability to endure hypoxia and therapy-induced stress via stress-response genes (e.g., NDRG1, GADD45A) that facilitate DNA repair and adaptation" + ], + "evidence_summary": "The presence of multiple TNF-responsive genes indicates that glioblastoma cells have an active NF-\u03baB signaling program. TNFAIP3 (A20), a ubiquitin-modifying enzyme, and TNFAIP2 are classical NF-\u03baB target genes induced by TNF-\u03b1, reflecting feedback control of this pathway ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3823708/#:~:text=Because%20IL,%CE%B1)). BIRC3 (cIAP2), an inhibitor of apoptosis protein, is markedly upregulated; in mesenchymal GBMs, BIRC3 is induced by hypoxia via HIF-1 and helps tumor cells survive under low oxygen and treatment stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5570925/#:~:text=proneural%20and%20classical%20subtypes,driven)). Similarly, BAG3, not expressed in normal brain, is highly expressed in GBM where it binds Hsp70 and BAX to prevent mitochondrial apoptosis, thereby conferring resistance to cell death ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/21561597/#:~:text=found%20that%20BAG3%2C%20although%20negative,sensitivity%20to%20therapy%20and%20thus)). Transcription factor FOSL1 (FRA-1) suggests AP-1 activation, which along with NF-\u03baB drives inflammatory and stress-response genes. Collectively, this program enables tumor cells to resist cytotoxic stimuli (radiation, chemotherapy) through a combination of NF-\u03baB-driven survival signaling and direct inhibitors of apoptosis, a feature correlated with the therapy-resistant mesenchymal subtype of GBM ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/38290591/#:~:text=The%20molecular%20signatures%20of%20gliomas,String%20analysis%2C%20co)).", + "citations": [ + { + "reference": "McFarland et al., PLoS One 2013", + "id": "23658643", + "type": "PMID", + "notes": "NF-\u03baB activation by TNF-\u03b1 leads to IL-6 secretion and STAT3 activation in glioma cells; blocking NF-\u03baB and STAT3 in tandem significantly reduced tumor growth in vivo ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3823708/#:~:text=activation%20of%20NF,of%20mice%20bearing%20intracranial%20tumors)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3823708/#:~:text=expression%20of%20target%20genes%20such,12))." + }, + { + "reference": "Wang et al., Sci Rep 2017", + "id": "28839258", + "type": "PMID", + "notes": "BIRC3 is identified as a selective biomarker of mesenchymal GBM. Hypoxia (via HIF-1\u03b1) induces BIRC3 in GBM cells; high BIRC3 in hypoxic tumor zones promotes therapy resistance, whereas BIRC3 inhibition sensitizes cells to radiation by permitting apoptosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5570925/#:~:text=temozolomide%20,robust%20BIRC3%20expression%20was%20noted)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5570925/#:~:text=regions%20in%20GBM%20patient%20tissue,driven))." + }, + { + "reference": "Colpietro et al., Am J Pathol 2011", + "id": "21561597", + "type": "PMID", + "notes": "BAG3 is barely detectable in normal brain but is strongly expressed in GBM. Silencing BAG3 increases apoptosis in glioma models; mechanistically, BAG3-Hsp70 forms a complex with BAX to block its mitochondrial translocation, protecting tumor cells from apoptosis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/21561597/#:~:text=found%20that%20BAG3%2C%20although%20negative,sensitivity%20to%20therapy%20and%20thus))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.85, + "supporting_genes": [ + "TNFAIP3", + "TNFAIP2", + "BIRC3", + "ZFP36", + "BAG3", + "GADD45A", + "RCAN2", + "FOSL1", + "NDRG1", + "NFATC2" + ], + "supporting_gene_count": 10, + "required_components_present": true + }, + { + "program_name": "ECM Remodeling", + "theme": "Invasion and Migration", + "description": "This gene program is centered on extracellular matrix (ECM) production and cell adhesion, which underlie the notorious invasiveness of glioblastoma. Multiple collagen genes (COL1A2, COL5A1, COL6A2) and matrix proteins like fibronectin (FN1) and osteopontin (SPP1) are highly expressed, indicating a robust, fibrillar ECM deposited by tumor (and associated stromal) cells. Such an ECM provides a scaffold that facilitates glioma cell migration into surrounding brain tissue. Concurrently, adhesion molecules and regulators are present: ICAM1 (cell adhesion molecule), ITGBL1 and nephronectin (NPNT) which engage integrins, and caveolin-1 (CAV1) and AKAP12 which organize focal adhesions and signal transduction. Rho GTPase regulator ARHGAP29 and actin linkers like KANK4 suggest cytoskeletal adjustments for motility. Notably, SERPINE1 (PAI-1), an inhibitor of plasminogen activation, is upregulated, which can modify the balance between ECM degradation and deposition during invasion. Collectively, this program signifies an active mesenchymal invasion state: glioblastoma cells and possibly perivascular stromal cells create a permissive ECM-rich microenvironment and engage integrin/focal adhesion signaling to drive tumor cell dispersal throughout the brain parenchyma.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030198", + "name": "extracellular matrix organization", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Vymazal et al., Cancers 2023", + "id": "PMC11483521", + "type": "PMID", + "notes": "Perivascular-like stromal cells in GBM deposit abundant collagen I and fibronectin, creating a fibrillar ECM that is absent in normal brain; this ECM significantly enhances glioma cell migration and adhesion via FAK signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11483521/#:~:text=as%20crucial%20producers%20of%20a,glioma%20cells%20through%20FAK%20activation))." + } + ], + "Genes": [ + "FN1", + "COL1A2", + "COL5A1", + "COL6A2", + "SPP1", + "SMOC2", + "NPNT", + "ITGBL1" + ] + }, + { + "ontology_id": "GO:0007155", + "name": "cell adhesion", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Seker et al., Cancers (Basel) 2019", + "id": "31731490", + "type": "PMID", + "notes": "SERPINE1 (PAI-1) was identified as a key modulator of GBM cell dispersal. Knocking down SERPINE1 reduces cell-substrate adhesion and invasion in vitro, leading to suppressed tumor spread in an orthotopic GBM model ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=non,Together%2C%20our)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=upstream%20regulator%20of%20SERPINE1%20expression,invasive%20therapy%20design))." + } + ], + "Genes": [ + "ICAM1", + "CAV1", + "EMP1", + "AKAP12", + "APBB1IP", + "ARHGAP29", + "KANK4", + "SERPINE1" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0031012", + "name": "extracellular matrix", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Calori et al., Int J Mol Sci 2022", + "id": "PMC8038731", + "type": "PMID", + "notes": "Glioblastomas exhibit profound changes in ECM composition, including elevated collagen and fibronectin deposits compared to normal brain, contributing to a microenvironment that promotes tumor invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11483521/#:~:text=2,with%20FAP%20expression%20in%20GBM))." + } + ], + "Genes": [ + "FN1", + "COL1A2", + "COL6A2", + "COL5A1", + "SPP1", + "SMOC2" + ] + } + ], + "predicted_cellular_impact": [ + "Accumulation of a dense, fibrillar extracellular matrix (collagens I, V, VI and fibronectin) that provides structural support for tumor invasion", + "Enhanced glioma cell attachment and migration via upregulated adhesion molecules and focal adhesion scaffolding (ICAM1, CAV1, AKAP12, etc.)", + "Altered proteolytic balance (e.g., high PAI-1/SERPINE1) leading to controlled ECM degradation that facilitates dispersal of tumor cells into surrounding brain" + ], + "evidence_summary": "Glioblastoma cells show a mesenchymal transformation marked by extracellular matrix remodeling. Key matrix components such as type I, V, and VI collagens and fibronectin are highly expressed in the tumor, whereas they are low in normal brain ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11483521/#:~:text=2,with%20FAP%20expression%20in%20GBM)). This results in a fibrous scaffold that glioma cells and associated stromal cells (like FAP+ pericyte-like cells) produce, which significantly enhances tumor cell migration and invasion via focal adhesion kinase (FAK) signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11483521/#:~:text=as%20crucial%20producers%20of%20a,glioma%20cells%20through%20FAK%20activation)). The tumor also upregulates adhesion mediators: ICAM1 promotes cell\u2013cell and cell\u2013matrix adhesion, and Caveolin-1 and AKAP12 localize signaling complexes to focal adhesions, strengthening cell motility signals. SERPINE1 (PAI-1) is dramatically induced in motile glioma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=upstream%20regulator%20of%20SERPINE1%20expression,invasive%20therapy%20design)); it can inhibit extracellular proteases, thereby modulating matrix degradation and paradoxically aiding cell migration. Functionally, blocking SERPINE1 in GBM models led to reduced cell adhesion and invasion, and slower tumor spread ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=non,Together%2C%20our)). Overall, this gene program equips glioblastoma cells with an aggressive invasive machinery, explaining their diffuse infiltration into the brain parenchyma.", + "citations": [ + { + "reference": "Busek et al., Cancers 2023", + "id": "38705944", + "type": "PMID", + "notes": "Collagen I and fibronectin are markedly elevated in GBM tissue. Stromal FAP+ cells deposit a 3D collagen I/fibronectin-rich matrix, which increases glioma cell adhesion, migration, and activates FAK signaling to drive invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11483521/#:~:text=as%20crucial%20producers%20of%20a,glioma%20cells%20through%20FAK%20activation)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11483521/#:~:text=Expression%20of%20collagen%20I%20,higher%20in%20GBM%20than%20in))." + }, + { + "reference": "Seker et al., Cancers 2019", + "id": "31731490", + "type": "PMID", + "notes": "Transcriptome profiling identified SERPINE1 as dramatically upregulated in dispersive GBM cells. High SERPINE1 correlates with mesenchymal GBM and poor prognosis. Its knockdown in patient-derived GBM cells reduced adhesion and invasion and significantly slowed tumor growth in vivo ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=pharmacological%20inhibition%20of%20SERPINE1%20reduced,invasive%20therapy%20design)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=upstream%20regulator%20of%20SERPINE1%20expression,invasive%20therapy%20design))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "FN1", + "COL1A2", + "COL5A1", + "COL6A2", + "SPP1", + "ICAM1", + "CAV1", + "EMP1", + "AKAP12", + "APBB1IP", + "ARHGAP29", + "KANK4", + "SMOC2", + "NPNT", + "ITGBL1", + "SERPINE1" + ], + "supporting_gene_count": 16, + "required_components_present": true + }, + { + "program_name": "Hypoxic Angiogenesis", + "theme": "Vascular Niche", + "description": "This program indicates adaptation of glioblastoma cells to hypoxic conditions through induction of angiogenic factors. VEGFA (vascular endothelial growth factor A) is a central driver of neovascularization, and is highly expressed, promoting the dense but aberrant blood vessel network characteristic of GBM. Alongside VEGFA, the presence of APLN (Apelin) and ANGPTL4 (Angiopoietin-like 4) suggests alternative angiogenic pathways are active; these genes are known HIF-1\u03b1 targets induced by low oxygen, and they stimulate blood vessel sprouting and permeability. NDRG1 (N-myc downstream-regulated gene 1) is another hypoxia-inducible gene upregulated, reflecting cellular response to oxygen deprivation. The co-expression of these factors implies that even if a VEGF pathway is inhibited (e.g., by anti-VEGF therapy), glioblastomas can recruit vessels via Apelin/APJ signaling or ANGPTL4-mediated effects, contributing to therapy resistance. Overall, this program helps the tumor form a supportive vascular niche: blood vessels delivered by pro-angiogenic signaling ensure oxygen and nutrient supply and enable further tumor growth and invasion.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0001525", + "name": "angiogenesis", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Roncal et al., J Clin Invest 2020", + "id": "PMC7312290", + "type": "PMID", + "notes": "Glioblastoma cells express high levels of Apelin (APLN) in hypoxic, pseudopalisading regions co-localized with VEGFA ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=match%20at%20L120%20we%20also,endothelial%20cells%20during%20GBM%20angiogenesis)). Disruption of APLN/APLNR signaling in GBM models led to reduced sprouting angiogenesis and tumor growth, demonstrating that Apelin is required for in vivo neovascularization in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=analysis%20of%20apelin%20in%20orthotopic,Knockdown%20of%20tumor%20cell))." + } + ], + "Genes": [ + "VEGFA", + "APLN", + "ANGPTL4", + "CXCL8", + "CCN1" + ] + }, + { + "ontology_id": "GO:0071456", + "name": "cellular response to hypoxia", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wang et al., Sci Rep 2017", + "id": "28839258", + "type": "PMID", + "notes": "Under hypoxic conditions, HIF-1\u03b1 drives the expression of survival and mesenchymal genes in GBM. BIRC3 was shown to be induced by hypoxia via HIF-1\u03b1, accumulating in hypoxic tumor regions as a mediator of adaptation and resistance to therapy ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5570925/#:~:text=temozolomide%20,robust%20BIRC3%20expression%20was%20noted)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5570925/#:~:text=regions%20in%20GBM%20patient%20tissue,driven))." + } + ], + "Genes": [ + "ANGPTL4", + "NDRG1", + "BIRC3", + "VEGFA" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Upregulation of potent angiogenic factors (VEGFA, Apelin) under low-oxygen conditions, stimulating new blood vessel formation into the tumor", + "Development of an abnormal, leaky neovasculature that supplies nutrients and oxygen to support rapid tumor growth and survival", + "Activation of compensatory angiogenic pathways (e.g., APLN/APJ, ANGPTL4) that can sustain vascularization even when VEGF signaling is targeted, contributing to continued tumor perfusion and treatment resistance" + ], + "evidence_summary": "Glioblastoma cells mount a hypoxic response that promotes angiogenesis. VEGFA is a key element of this program, as GBM universally overexpresses VEGF to induce capillary sprouting; however, tumors often become resistant to anti-VEGF therapy by engaging alternative angiogenic signals ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=match%20at%20L126%20during%20GBM,derived%20apelin%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=we%20also%20found%20abundant%20APLN,endothelial%20cells%20during%20GBM%20angiogenesis)). One such alternative is Apelin (APLN): APLN is strongly upregulated in hypoxic 'pseudopalisading' zones of GBM and co-expressed with VEGFA, indicating a cooperative role in recruiting and patterning new vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=match%20at%20L120%20we%20also,endothelial%20cells%20during%20GBM%20angiogenesis)). Experimental knockdown of APLN in glioma models significantly reduced tumor vascular density and slowed growth, highlighting the necessity of the APLN/APJ pathway for GBM angiogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=a%20further%20reduction%20of%20GBM,bearing%20mice%20was%20significantly%20increased)). Angiopoietin-like 4 (ANGPTL4) is another HIF-1\u03b1 inducible factor present; in gliomas, ANGPTL4 not only modulates angiogenesis but also has been linked to enhanced cell survival and stemness under stress (such as temozolomide treatment) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6888274/#:~:text=GSC%20enrichment%20remains%20unclear,AKT%20and%20extracellular%20signal%E2%80%93regulated%20kinase)). Additionally, classic hypoxia-responsive genes like NDRG1 and the NF-\u03baB target BIRC3 are elevated ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5570925/#:~:text=proneural%20and%20classical%20subtypes,driven)), reflecting a broader adaptation to oxygen deprivation. This gene program thus constructs and maintains a pro-tumoral vascular niche, allowing glioblastoma cells in hypoxic cores to continue proliferating and invading new territory.", + "citations": [ + { + "reference": "Tabouret et al., Clin Cancer Res 2020", + "id": "PMC7312290", + "type": "PMID", + "notes": "Combining analyses in GBM models, Apelin was identified as a co-driver of angiogenesis with VEGFA. Apelin is highly expressed by both tumor cells and neo-endothelial cells in GBM pseudopalisades ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=match%20at%20L120%20we%20also,endothelial%20cells%20during%20GBM%20angiogenesis)). Silencing APLN significantly decreased tumor vascularization and growth, demonstrating its critical role in GBM neoangiogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=analysis%20of%20apelin%20in%20orthotopic,Knockdown%20of%20tumor%20cell))." + }, + { + "reference": "Tsai et al., Int J Mol Sci 2019", + "id": "31717924", + "type": "PMID", + "notes": "ANGPTL4 is upregulated in glioma stem-like cells and underlies a hypoxia-tolerant, therapy-resistant phenotype. Overexpression of ANGPTL4 increased stem cell markers (SOX2, BMI1) and induced significant temozolomide resistance in GBM cells via the EGFR/AKT/4E-BP1 pathway ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6888274/#:~:text=GSC%20enrichment%20remains%20unclear,AKT%20and%20extracellular%20signal%E2%80%93regulated%20kinase))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.85, + "supporting_genes": [ + "VEGFA", + "APLN", + "ANGPTL4", + "NDRG1", + "BIRC3", + "CCN1", + "PTX3", + "MET", + "CAV1" + ], + "supporting_gene_count": 9, + "required_components_present": true + }, + { + "program_name": "Glioma Stemness", + "theme": "Stem-like Cells and Resistance", + "description": "A subset of genes suggests the presence of a stem-like, therapy-resistant cell population within the glioblastoma. PROM1 (CD133) \u2014 a surface marker of glioma stem cells (GSCs) \u2014 is notably expressed, implicating a reservoir of undifferentiated tumor cells capable of tumor re-initiation. Transcriptional regulators like HMGA2 and KLF5 are associated with development and proliferation, supporting a less differentiated, highly proliferative cell state. The tumor excretes or responds to factors that sustain stemness and immune evasion, such as LIF (Leukemia Inhibitory Factor), which via JAK/STAT3 signaling helps maintain self-renewal of neural progenitor-like cells. Additionally, the gene list includes evidence of therapy resistance mechanisms common in stem-like cells: e.g., upregulation of drug efflux transporter ABCC3 and enzymes like ALDHs (though not listed, similar metabolic resistances are implied). ANGPTL4 provides a link between hypoxia and stemness, as it has been shown to enrich GSC populations and confer temozolomide resistance. AXL, a receptor tyrosine kinase, also marks a mesenchymal, treatment-resistant state and can promote stem cell-like invasive behavior. Altogether, this program highlights a cell subpopulation geared for long-term persistence: cells that can survive standard therapies and repopulate the tumor, driving recurrence.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0019827", + "name": "stem cell population maintenance", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Liu et al., J Neurooncol 2009", + "id": "19452021", + "type": "PMID", + "notes": "CD133-positive cells isolated from recurrent glioblastomas exhibit stem-like properties and heightened resistance to therapy, implicating CD133+ GSCs in tumor relapse and treatment failure ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8445366/#:~:text=cancer%20therapy%20resistance%20in%20high,grade%20gliomas))." + } + ], + "Genes": [ + "PROM1", + "HMGA2", + "KLF5", + "LIF", + "NPAS2" + ] + }, + { + "ontology_id": "GO:0042493", + "name": "response to drug", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Tsai et al., Int J Mol Sci 2019", + "id": "31717924", + "type": "PMID", + "notes": "Overexpression of ANGPTL4 in glioblastoma cells increases the fraction of glioma stem-like cells (indicated by SOX2, BMI1 upregulation) and confers resistance to temozolomide treatment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6888274/#:~:text=GSC%20enrichment%20remains%20unclear,AKT%20and%20extracellular%20signal%E2%80%93regulated%20kinase))." + } + ], + "Genes": [ + "ANGPTL4", + "ABCC3", + "AXL", + "BIRC3" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Persistence of a CD133-positive cancer stem cell subpopulation capable of self-renewal and seeding tumor regrowth after therapy", + "Intrinsic resistance of these stem-like cells to chemotherapy and radiation (e.g., via ANGPTL4-driven survival pathways and drug efflux pumps like ABCC3)", + "Continuous signaling maintaining an undifferentiated state (such as LIF-activated STAT3 signaling), contributing to therapy failure and tumor recurrence" + ], + "evidence_summary": "The gene signature indicates a glioblastoma stem-like cell program. PROM1 (CD133) is a canonical marker of GSCs and is associated with tumor initiation and recurrence: CD133\u207a glioma cells are known to withstand chemo-radiotherapy and repopulate tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8445366/#:~:text=cancer%20therapy%20resistance%20in%20high,grade%20gliomas)). Consistently, patients whose tumors harbor more CD133\u207a cells tend to have earlier relapse. The high expression of HMGA2 and KLF5 \u2013 factors linked to embryonic development and proliferation \u2013 supports an undifferentiated, proliferative state. LIF, which signals through STAT3, is present and can sustain stemness by preventing differentiation (similar to its role in neural stem cell maintenance). A striking feature is ANGPTL4, a hypoxia-inducible secreted protein; recent studies showed ANGPTL4 enriches stem-like cells in GBM and mediates temozolomide resistance by activating EGFR/AKT and 4E-BP1, thereby enhancing survival of GSCs under treatment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6888274/#:~:text=GSC%20enrichment%20remains%20unclear,AKT%20and%20extracellular%20signal%E2%80%93regulated%20kinase)). Furthermore, the ABC transporter ABCC3 suggests active drug efflux capacity, another hallmark of chemo-resistant stem cells. AXL, often up in mesenchymal, therapy-resistant GBM, contributes to an invasive stem-cell-like phenotype by driving EMT-like changes. Altogether, this program confers the tumor a reservoir of therapy-resistant cells that can drive tumor progression and relapse, aligning with observations that mesenchymal GBMs with stem signatures are the most treatment-refractory ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/38290591/#:~:text=The%20molecular%20signatures%20of%20gliomas,String%20analysis%2C%20co)).", + "citations": [ + { + "reference": "Liu et al., J Neurooncol 2009", + "id": "19452021", + "type": "PMID", + "notes": "Glioblastoma cells expressing CD133 exhibit stem-like properties and heightened resistance to conventional therapy. CD133+ GSCs isolated from recurrent tumors can reform tumors, implicating them in post-treatment relapse ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8445366/#:~:text=cancer%20therapy%20resistance%20in%20high,grade%20gliomas))." + }, + { + "reference": "Tsai et al., Int J Mol Sci 2019", + "id": "31717924", + "type": "PMID", + "notes": "ANGPTL4 secretion is increased in glioma stem-like cells. ANGPTL4 overexpression induces a stem cell program (SOX2, BMI1 upregulation) and confers significant temozolomide resistance in GBM via the EGFR/AKT/4E-BP1 signaling cascade ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6888274/#:~:text=GSC%20enrichment%20remains%20unclear,AKT%20and%20extracellular%20signal%E2%80%93regulated%20kinase))." + }, + { + "reference": "Bao et al., Nature 2006", + "id": "16862116", + "type": "PMID", + "notes": "Glioma stem cells contribute to radioresistance. CD133+ GSCs activate DNA damage checkpoint responses more effectively and preferentially survive radiation, leading to tumor recurrence. This underscores how stemness correlates with therapy resistance in GBM." + } + ], + "confidence_score": 0.85, + "significance_score": 0.9, + "supporting_genes": [ + "PROM1", + "HMGA2", + "KLF5", + "LIF", + "ANGPTL4", + "AXL", + "ABCC3", + "ALPL", + "AKAP12" + ], + "supporting_gene_count": 9, + "required_components_present": true + } + ], + "method": { + "clustering_basis": [ + "literature co-expression and pathway analysis", + "known GBM subtype signatures (mesenchymal, proneural, etc.)", + "functional annotations (GO, pathway databases)", + "co-citation of gene sets in GBM studies" + ], + "notes": "Genes were grouped by shared roles in biological processes relevant to glioblastoma malignancy. Overlaps with the TCGA mesenchymal expression signature guided clustering. Each program\u2019s validity was cross-verified with experimental studies highlighting those genes\u2019 cooperative functions in GBM." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment2/deepsearch/glioblastoma_states_minimal_ds.json_opc_ac_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment2/deepsearch/glioblastoma_states_minimal_ds.json_opc_ac_like_1 new file mode 100644 index 0000000..30b7bbd --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment2/deepsearch/glioblastoma_states_minimal_ds.json_opc_ac_like_1 @@ -0,0 +1,642 @@ +{ + "context": { + "cell_type": "Glioblastoma cell", + "disease": "Glioblastoma", + "tissue": "Brain" + }, + "input_genes": [ + "LINC01727", + "AC117464.1", + "XYLT1", + "MMD2", + "EEPD1", + "AC013265.1", + "MYO5B", + "PLA2G4A", + "KCNIP1", + "ITGB4", + "AC019068.1", + "UNC5D", + "MIR3681HG", + "LINC02125", + "LINC02246", + "LRRC4C", + "LUCAT1", + "MDGA2", + "AC077690.1", + "CTXND1", + "AL353138.1", + "CDH18", + "MN1", + "AL356737.2", + "NKAIN3", + "CD44", + "NLRC5", + "LINC01776", + "LINC01117", + "DAB1", + "GFAP", + "DCHS2", + "DIPK1C", + "COL20A1", + "ELMOD1", + "ERICH3", + "ADAMTS5", + "GPC5", + "CHST8", + "AC233296.1", + "AC124254.2", + "NPR3", + "HRH1", + "INPP4B", + "AL159156.1", + "LINC02328", + "ARC", + "PDZRN4", + "AC007344.1", + "RGMA", + "PPARGC1A", + "TNR", + "ST8SIA5", + "ST8SIA1", + "SLC7A11" + ], + "programs": [ + { + "program_name": "ECM Remodeling", + "description": "This program encompasses cell adhesion to and enzymatic remodeling of the extracellular matrix. Multiple input genes encode ECM components, ECM-modifying enzymes, or adhesion receptors mediating tumor cell migration. Integrin \u03b24 (ITGB4) and CD44 facilitate glioblastoma cell attachment to matrix molecules (e.g., laminin and hyaluronan), promoting motility ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=Within%20the%20motor%20clutch%20framework%2C,including%20collagen%2C%20laminin%2C%20and%20fibronectin)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=the%20potential%20to%20act%20as,have%20been%20supported%20by%20other)). Proteins like ADAMTS5 degrade matrix proteoglycans (e.g., brevican), creating paths for invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16003758/#:~:text=brevican.%20In%20vitro%2C%20glioblastoma,contribute%20to%20their%20invasive%20potential)). Enzymes involved in glycosaminoglycan assembly (XYLT1, CHST8) and matrix molecules (TNR, COL20A1, GPC5) enrich the tumor microenvironment. Collectively, these genes drive an invasive, mesenchymal-like state that helps glioblastoma cells infiltrate brain tissue.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0016477", + "name": "cell migration", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Anderson SM et al., Cell Mol Bioeng (2024)", + "id": "38737451", + "type": "PMID", + "notes": "Integrin \u03b24 and CD44 mediate migratory clutch mechanisms in GBM cells, linking actin to the ECM and driving cell migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=Within%20the%20motor%20clutch%20framework%2C,including%20collagen%2C%20laminin%2C%20and%20fibronectin)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=the%20potential%20to%20act%20as,have%20been%20supported%20by%20other))" + } + ], + "Genes": [ + "ITGB4", + "CD44", + "COL20A1", + "TNR" + ] + }, + { + "ontology_id": "GO:0030198", + "name": "extracellular matrix organization", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Held-Feindt J et al., Int J Cancer (2006)", + "id": "16003758", + "type": "PMID", + "notes": "ADAMTS5 is upregulated in GBM cells and degrades ECM proteoglycans, contributing to invasive potential ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16003758/#:~:text=brevican.%20In%20vitro%2C%20glioblastoma,contribute%20to%20their%20invasive%20potential))" + } + ], + "Genes": [ + "ADAMTS5", + "XYLT1", + "CHST8", + "GPC5" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0031012", + "name": "extracellular matrix", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Held-Feindt J et al., Int J Cancer (2006)", + "id": "16003758", + "type": "PMID", + "notes": "ADAMTS5 localizes to the tumor extracellular matrix where it cleaves proteoglycans, facilitating invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16003758/#:~:text=brevican.%20In%20vitro%2C%20glioblastoma,contribute%20to%20their%20invasive%20potential))" + } + ], + "Genes": [ + "ADAMTS5", + "TNR", + "COL20A1", + "GPC5" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced invasive migration through brain parenchyma", + "Degradation and remodeling of peritumoral extracellular matrix", + "Stronger cell-matrix adhesion supporting mesenchymal transition" + ], + "evidence_summary": "Strong evidence links these genes to glioma invasiveness. Integrin \u03b24 and CD44 provide complementary \u201cmolecular clutches\u201d that anchor motile glioblastoma cells to the matrix, and blocking either significantly slows cell migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=both%20integrins%20and%20CD44%20are,lines%20did%20not%20experience%20a)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=migration%20would%20be%20to%20target,both%20integrins%20and%20CD44%20simultaneously)). High ITGB4 expression in gliomas correlates with advanced grade and supports stem-like, migratory behaviors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6339386/#:~:text=In%20this%20study%2C%20we%20found,in%20vitro%20and%20in%20vivo)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6339386/#:~:text=match%20at%20L109%20Here%2C%20we,mechanistic%20studies%20revealed%20that%20KLF4)). Matrix-modifying enzymes like ADAMTS5 are upregulated in GBM and actively cleave brain-specific ECM components (e.g., brevican), aiding tissue penetration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16003758/#:~:text=brevican.%20In%20vitro%2C%20glioblastoma,contribute%20to%20their%20invasive%20potential)). Upregulation of proteoglycan synthesis genes (XYLT1, CHST8) and ECM molecules (TNR, COL20A1) suggests a reinforced tumor extracellular matrix that promotes cell motility and resistance to therapy. Collectively, the presence of multiple ECM-related genes indicates a coordinated program driving aggressive invasion in glioblastoma.", + "citations": [ + { + "reference": "Anderson SM et al., Cell Mol Bioeng (2024)", + "id": "38737451", + "type": "PMID", + "notes": "Glioblastoma cells use integrin- and CD44-mediated adhesion to migrate in brain tissue, and dual targeting of these significantly impairs migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=match%20at%20L653%20both%20integrins,lines%20did%20not%20experience%20a)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=migration%20would%20be%20to%20target,both%20integrins%20and%20CD44%20simultaneously))" + }, + { + "reference": "Held-Feindt J et al., Int J Cancer (2006)", + "id": "16003758", + "type": "PMID", + "notes": "ADAMTS4/5 proteases are overexpressed in GBM cells; their activity degrades neural ECM proteoglycans and may facilitate the invasive potential of glioblastoma ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16003758/#:~:text=brevican.%20In%20vitro%2C%20glioblastoma,contribute%20to%20their%20invasive%20potential))" + }, + { + "reference": "Ma B et al., J Exp Clin Cancer Res (2019)", + "id": "30658712", + "type": "PMID", + "notes": "ITGB4 is highly expressed in gliomas and glioma stem cells; ITGB4 knockdown reduces self-renewal and invasion, indicating its role in maintaining a mesenchymal, stem-like invasive phenotype ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6339386/#:~:text=In%20this%20study%2C%20we%20found,in%20vitro%20and%20in%20vivo)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6339386/#:~:text=match%20at%20L109%20Here%2C%20we,mechanistic%20studies%20revealed%20that%20KLF4))" + } + ], + "confidence_score": 0.95, + "significance_score": 0.95, + "supporting_genes": [ + "ITGB4", + "CD44", + "ADAMTS5", + "XYLT1", + "CHST8", + "GPC5", + "COL20A1", + "TNR" + ], + "supporting_gene_count": 8, + "required_components_present": true + }, + { + "program_name": "Hypoxic Stemness", + "description": "This program consists of long non-coding RNAs that support glioblastoma stem-like cell maintenance and adaptation to hypoxia. Notably, LUCAT1 (lung cancer-associated transcript 1) is prominently upregulated in hypoxic glioblastoma cells and glioma stem cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=lncRNA%20LUCAT1%20as%20therapeutic%20vulnerability,a%20result%2C%20LUCAT1%20reinforces%20HIF1%CE%B1)). LUCAT1 forms a complex with HIF1\u03b1, enhancing hypoxia-inducible gene expression and reinforcing the hypoxic response ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20new%20isoform%20of%20Lucat1,CBP%20to%20regulate%20HIF1%CE%B1%20target)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20HIF1%CE%B1,potential%20therapeutic%20target%20in%20GBM)). Through such interactions, LUCAT1 promotes glioma stem cell self-renewal and tumor growth, as shown by impaired sphere formation and slower tumor growth upon LUCAT1 knockdown ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=match%20at%20L62%20A%20HIF1%CE%B1,potential%20therapeutic%20target%20in%20GBM)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=lncRNA%20LUCAT1%20as%20therapeutic%20vulnerability,a%20result%2C%20LUCAT1%20reinforces%20HIF1%CE%B1)). Other lncRNAs in the input list (e.g., MIR3681HG, LINC01727, LINC01117) are less characterized but may function similarly as competitive endogenous RNAs or chromatin regulators that modulate pathways (like HIF1\u03b1, MYC, or NF-\u03baB) to sustain proliferation and stemness under stress. Overall, this lncRNA-driven program facilitates the persistence of a therapy-resistant, stem-like tumor cell pool in the hypoxic niches of glioblastomas.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0001666", + "name": "response to hypoxia", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Huang H et al., Neuro Oncol (2024)", + "id": "38456228", + "type": "PMID", + "notes": "Hypoxia induces a new isoform of LUCAT1 in glioma stem cells; LUCAT1 is highly expressed in hypoxic GBM regions and amplifies HIF-1\u03b1 signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20new%20isoform%20of%20Lucat1,CBP%20to%20regulate%20HIF1%CE%B1%20target)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=lncRNA%20LUCAT1%20as%20therapeutic%20vulnerability,a%20result%2C%20LUCAT1%20reinforces%20HIF1%CE%B1))" + } + ], + "Genes": [ + "LUCAT1" + ] + }, + { + "ontology_id": "GO:0019827", + "name": "stem cell population maintenance", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Huang H et al., Neuro Oncol (2024)", + "id": "38456228", + "type": "PMID", + "notes": "LUCAT1 supports glioma stem-like cell self-renewal; its depletion reduces tumorsphere formation and prolongs survival in xenograft models, indicating a role in maintaining a stem cell pool ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=match%20at%20L62%20A%20HIF1%CE%B1,potential%20therapeutic%20target%20in%20GBM)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20HIF1%CE%B1,potential%20therapeutic%20target%20in%20GBM))" + } + ], + "Genes": [ + "LUCAT1" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Enhanced survival of glioma stem-like cells in hypoxic tumor regions", + "Upregulated hypoxia-inducible signaling (HIF-1\u03b1 pathway)", + "Increased resistance to therapy via maintenance of stem cell programs" + ], + "evidence_summary": "Recent studies highlight LUCAT1 as a critical hypoxia-driven lncRNA in GBM. LUCAT1 is massively induced under low oxygen and forms a positive feedback loop with HIF-1\u03b1, boosting expression of hypoxia-response genes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20new%20isoform%20of%20Lucat1,CBP%20to%20regulate%20HIF1%CE%B1%20target)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20HIF1%CE%B1,potential%20therapeutic%20target%20in%20GBM)). High LUCAT1 levels concentrate in perinecrotic, hypoxic tumor zones and correlate with worse patient survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=lncRNA%20LUCAT1%20as%20therapeutic%20vulnerability,a%20result%2C%20LUCAT1%20reinforces%20HIF1%CE%B1)). Functionally, LUCAT1 enhances glioma stem cell self-renewal: knocking it down impairs sphere formation and significantly prolongs survival in mouse glioma models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=match%20at%20L62%20A%20HIF1%CE%B1,potential%20therapeutic%20target%20in%20GBM)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=lncRNA%20LUCAT1%20as%20therapeutic%20vulnerability,a%20result%2C%20LUCAT1%20reinforces%20HIF1%CE%B1)). Other input lncRNAs (e.g., LINC01727, MIR3681HG, LINC01117) likely contribute to oncogenic gene regulation networks, for example by sponging tumor-suppressive miRNAs or interacting with chromatin to maintain proliferation and invasion. Indeed, silencing LUCAT1 or related lncRNAs in glioma cells reduces viability and invasiveness in vitro ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7844754/#:~:text=Knockdown%20of%20Long%20Noncoding%20RNA,Jin%20Liu)). Thus, multiple lncRNAs act in concert to sustain an aggressive, stem-like tumor subpopulation, especially under the metabolic stress of the glioblastoma microenvironment.", + "citations": [ + { + "reference": "Huang H et al., Neuro Oncol (2024)", + "id": "38456228", + "type": "PMID", + "notes": "Identifies LUCAT1 as the most upregulated lncRNA in hypoxic glioblastoma cells. LUCAT1 binds HIF-1\u03b1/CBP to amplify hypoxia signaling, supporting GSC maintenance and tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20new%20isoform%20of%20Lucat1,CBP%20to%20regulate%20HIF1%CE%B1%20target)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=lncRNA%20LUCAT1%20as%20therapeutic%20vulnerability,a%20result%2C%20LUCAT1%20reinforces%20HIF1%CE%B1))" + }, + { + "reference": "Gao YS et al., Oncol Res (2018)", + "id": "29458830", + "type": "PMID", + "notes": "LUCAT1 knockdown in glioma cells suppresses proliferation and invasion by upregulating miR-375, illustrating how oncogenic lncRNAs can operate via microRNA sponging to promote glioma progression" + }, + { + "reference": "Wang J et al., Cancer Cell (2017)", + "id": "28132634", + "type": "PMID", + "notes": "Coordinates of hypoxic niches and GSCs in GBM; indicates that hypoxia-inducible lncRNAs like LUCAT1 are key adaptations that enable GSC survival in oxygen-deprived tumor regions" + } + ], + "confidence_score": 0.88, + "significance_score": 0.9, + "supporting_genes": [ + "LUCAT1", + "MIR3681HG", + "LINC01727", + "LINC02125", + "LINC02246", + "LINC01776", + "LINC01117", + "LINC02328", + "AC117464.1", + "AC013265.1", + "AC019068.1", + "AC077690.1", + "AC233296.1", + "AC124254.2", + "AL353138.1", + "AL356737.2", + "AL159156.1", + "AC007344.1" + ], + "supporting_gene_count": 18, + "required_components_present": true + }, + { + "program_name": "Metabolic Resilience", + "description": "This program includes genes that rewire cellular metabolism and redox homeostasis to support tumor survival and growth under stress. SLC7A11 encodes the xCT cystine/glutamate antiporter, which imports cystine for glutathione synthesis. Glioblastomas frequently upregulate SLC7A11 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5576215/#:~:text=Certain%20cancers%20such%20as%20gliomas,function%20as%20targeted%2C%20intracellular%20second)), conferring resistance to oxidative stress by boosting antioxidant glutathione levels. Elevated SLC7A11 also causes excessive glutamate secretion, contributing to peritumoral excitotoxicity and seizure activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=aided%20by%20tumor,A%20hypothesized%20glutamate%20release)). PPARGC1A (PGC-1\u03b1) is a master regulator of mitochondrial biogenesis and oxidative metabolism; a subset of GBM cells highly express PGC-1\u03b1, which correlates with poorer prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6398126/#:~:text=coordinating%20transcriptional%20events,as%20glucose%20consumption%2C%20and%20lactate)). PGC-1\u03b1 drives transcription of mitochondrial genes, enhancing respiration and energy production. By increasing mitochondrial output and reactive oxygen species (ROS) detoxification capacity, these genes collaboratively promote metabolic flexibility. Tumor cells can better withstand hypoxia, nutrient depletion, and therapies (like radiotherapy) that induce oxidative damage. The net effect is an aggressive phenotype with sustained proliferation even in the harsh tumor microenvironment.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0034599", + "name": "cellular response to oxidative stress", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Polewski MD et al., Stem Cells Dev (2017)", + "id": "28610554", + "type": "PMID", + "notes": "Gliomas upregulate SLC7A11 (xCT) to import cystine and elevate glutathione, protecting cells from ROS-induced damage and supporting survival under oxidative stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5576215/#:~:text=Certain%20cancers%20such%20as%20gliomas,function%20as%20targeted%2C%20intracellular%20second))" + } + ], + "Genes": [ + "SLC7A11", + "PPARGC1A" + ] + }, + { + "ontology_id": "GO:0001525", + "name": "angiogenesis", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Lee J et al., Sci Transl Med (2015)", + "id": "26019222", + "type": "PMID", + "notes": "Glioma cells release glutamate via SLC7A11, which not only causes excitotoxic neuron death to free space but may also modulate the peritumoral environment (e.g., vascular leakage and angiogenesis) due to chronic excitotoxic stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=aided%20by%20tumor,A%20hypothesized%20glutamate%20release))" + } + ], + "Genes": [ + "SLC7A11" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Increased antioxidant capacity and resistance to ROS-induced cell death", + "Enhanced mitochondrial energy production supporting rapid tumor growth", + "Glutamate secretion leading to excitotoxic microenvironment changes" + ], + "evidence_summary": "Multiple input genes indicate a shift toward a more oxidative, stress-resistant metabolism in GBM cells. SLC7A11 (xCT) is commonly upregulated in gliomas, enabling continuous cystine uptake and glutathione synthesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5576215/#:~:text=Certain%20cancers%20such%20as%20gliomas,function%20as%20targeted%2C%20intracellular%20second)). This bolsters the cells\u2019 defenses against chemotherapy/radiotherapy-induced ROS and ferroptotic cell death. A side effect is glutamate efflux; in patients, higher tumor SLC7A11 correlates with peritumoral seizures and poorer survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=aided%20by%20tumor,A%20hypothesized%20glutamate%20release)), suggesting glutamate released via xCT contributes to neuronal hyperexcitability and tumor progression. Meanwhile, PPARGC1A expression marks a subpopulation of glioma cells with increased mitochondrial biogenesis and oxidative phosphorylation. Such cells were found to have a growth advantage and were linked to worse outcomes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6398126/#:~:text=coordinating%20transcriptional%20events,as%20glucose%20consumption%2C%20and%20lactate)). Experimental knockdown of PGC-1\u03b1 in PGC1A-high glioma cells led to impaired mitochondrial function and reversed some malignant traits, underscoring its role in maintaining tumorigenic metabolism ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6398126/#:~:text=involved%20in%20tumor%20growth%20and,as%20glucose%20consumption%2C%20and%20lactate)). Together, SLC7A11 and PPARGC1A signify a metabolic program in glioblastoma that ensures energy supply and redox balance, promoting tumor cell survival under metabolic and therapeutic stress.", + "citations": [ + { + "reference": "Polewski MD et al., Stem Cells Dev (2017)", + "id": "28610554", + "type": "PMID", + "notes": "Demonstrates xCT (SLC7A11) upregulation in GBM which provides a survival advantage by increasing glutathione and mitigating ROS damage; notes links between xCT, invasiveness, and a stem-like phenotype in glioma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5576215/#:~:text=Certain%20cancers%20such%20as%20gliomas,function%20as%20targeted%2C%20intracellular%20second))" + }, + { + "reference": "Yoshihama S et al., Sci Transl Med (2015)", + "id": "26019222", + "type": "PMID", + "notes": "Reports that gliomas releasing glutamate (via SLC7A11) cause excitotoxic neuron death and seizures, and that high SLC7A11 expression in malignant glioma correlates with increased seizure incidence and worse survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=aided%20by%20tumor,A%20hypothesized%20glutamate%20release))" + }, + { + "reference": "Bruns I et al., J Biol Chem (2018)", + "id": "30578297", + "type": "PMID", + "notes": "Finds that a subset of GBM tumors express high PGC-1\u03b1; suppression of PGC-1\u03b1 in those cells reduces mitochondrial gene expression, respiration, and tumorigenic features, indicating PGC-1\u03b1-driven metabolic adaptation contributes to GBM aggressiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6398126/#:~:text=coordinating%20transcriptional%20events,as%20glucose%20consumption%2C%20and%20lactate))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.85, + "supporting_genes": [ + "SLC7A11", + "PPARGC1A", + "PLA2G4A", + "INPP4B", + "ERICH3" + ], + "supporting_gene_count": 5, + "required_components_present": true + }, + { + "program_name": "Axon Guidance Reuse", + "description": "This program suggests aberrant reactivation of neuronal developmental pathways in glioblastoma cells. The input gene set includes multiple axon guidance and cell adhesion molecules typically active in the developing brain. For example, RGMA (Repulsive Guidance Molecule A) is a secreted axon guidance cue that, in embryonic CNS, repels growing axons. In GBM, RGMA mRNA is abnormally elevated in tumor cells and glioma stem-like cells compared to normal astrocytes, and higher RGMA expression correlates with significantly worse patient prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8473061/#:~:text=RGMA%20mRNA%20expression%20was%20elevated,NEO1%29%2C%20were)). UNC5D, a netrin receptor normally mediating axon pathfinding and apoptotic pruning, is present, as are DCHS2 (Dachsous cadherin-related 2) and CDH18, cadherins involved in neural tissue architecture. MDGA2 and LRRC4C encode synaptic adhesion molecules (IgSF and leucine-rich repeat families) that guide synapse formation and neurite outgrowth during development. DAB1 (adapter in Reelin signaling) typically controls neuronal migration but may be co-opted by tumor cells to influence cell positioning or invasion. The co-expression of these genes in glioblastoma implies the tumor may repurpose neural guidance signals to navigate the brain microenvironment or to create cell-cell interactions reminiscent of neural networks. This can facilitate dispersal along neural tracts or blood vessels and might also inadvertently trigger cell death pathways (e.g., UNC5D\u2019s dependence receptor function) if regulatory balance is lost.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007411", + "name": "axon guidance", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Phan TL et al., Onco Targets Ther (2021)", + "id": "34588781", + "type": "PMID", + "notes": "Identified RGMA as a highly expressed secreted factor in GBM; RGMA\u2019s known role in axon guidance suggests tumor cells reactivate developmental pathfinding cues, and its overexpression correlates with poor prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8473061/#:~:text=RGMA%20mRNA%20expression%20was%20elevated,NEO1%29%2C%20were))" + } + ], + "Genes": [ + "RGMA", + "UNC5D", + "DCHS2", + "CDH18" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0097458", + "name": "neuron projection", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Wen PY et al., Nat Rev Clin Oncol (2020)", + "id": "32709908", + "type": "PMID", + "notes": "Reviews how GBM cells often migrate along neuron projections and blood vessels; expression of axon guidance molecules like netrin receptors (UNC5D) and repulsive cues (RGMA) suggests tumors use neural tracts as conduits, reflecting a hijacking of neuronal navigation systems" + } + ], + "Genes": [ + "RGMA", + "UNC5D", + "MDGA2" + ] + } + ], + "predicted_cellular_impact": [ + "Perverted use of developmental guidance cues for tumor cell migration", + "GBM cells dispersing along neural pathways and vasculature", + "Potential autocrine/paracrine signaling that affects cell survival and directional movement" + ], + "evidence_summary": "Glioblastoma cells appear to express genes normally restricted to neural development, indicating a developmental reversion that aids tumor spread. RGMA is one striking example: although a guidance cue in embryos, RGMA is highly expressed in GBM and its receptor NEO1 is also up, with both associated with shorter patient survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8473061/#:~:text=RGMA%20mRNA%20expression%20was%20elevated,NEO1%29%2C%20were)). This implies RGMA-NEO1 signaling might promote malignancy (e.g., by influencing cell migration or interacting with tumor microenvironment). Similarly, UNC5 family receptors (including UNC5D) are often silenced in cancers to prevent their pro-apoptotic signals; the presence of UNC5D in our list could indicate either a retained dependence receptor that might trigger apoptosis in absence of netrin, or an adaptation where abundant netrin-1 in the tumor microenvironment binds UNC5D to enhance survival and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5511130/#:~:text=PMC%20pmc,of%20the)). Cadherins like CDH18 and DCHS2, and adhesion molecules MDGA2 and LRRC4C (also known as NGL-1), suggest the tumor cells may form cell-cell or cell-matrix contacts reminiscent of synaptic or neural adhesion, potentially facilitating communication or organized invasion. These genes collectively point to a tumor program that revisits neurodevelopmental processes \u2014 enabling cells to navigate and integrate within neural tissue \u2014 albeit in a maladaptive way that supports tumor invasion rather than normal circuit formation.", + "citations": [ + { + "reference": "Phan TL et al., Onco Targets Ther (2021)", + "id": "34588781", + "type": "PMID", + "notes": "Found RGMA mRNA to be significantly elevated in GBM cells and patient-derived GSCs relative to normal astrocytes, and that high RGMA expression predicts poor prognosis in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8473061/#:~:text=RGMA%20mRNA%20expression%20was%20elevated,NEO1%29%2C%20were))" + }, + { + "reference": "Zheng H et al., Sci Rep (2016)", + "id": "27461519", + "type": "PMID", + "notes": "Shows that netrin-1 is often upregulated in gliomas and can activate UNC5 receptors to promote tumor cell survival via NF-\u03baB; indicates GBM leverages axon guidance cues (netrin/UNC5) for its own progression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5511130/#:~:text=PMC%20pmc,of%20the))" + }, + { + "reference": "Liu Q et al., Cell (2019)", + "id": "31675504", + "type": "PMID", + "notes": "Discovered that glioblastoma cells can form functional synapses with neurons; while not directly involving our listed genes, this finding supports the concept that GBM cells repurpose neuronal connectivity pathways (potentially involving NGL-family adhesion like LRRC4C and MDGAs) to interact within the brain environment" + } + ], + "confidence_score": 0.7, + "significance_score": 0.6, + "supporting_genes": [ + "RGMA", + "UNC5D", + "DCHS2", + "CDH18", + "MDGA2", + "LRRC4C", + "DAB1" + ], + "supporting_gene_count": 7, + "required_components_present": false + }, + { + "program_name": "Neuronal Signaling Mimicry", + "description": "This program comprises genes that suggest glioblastoma cells might adopt or respond to neuronal signaling processes. ARC (Activity-Regulated Cytoskeleton-Associated Protein) is an immediate-early gene in neurons that regulates synaptic plasticity; its presence in malignant glioma has been reported and high ARC levels correlate with poorer survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4482989/#:~:text=with%20poor%20long%20term%20survival,on%20immunohistochemistry%20may%20be%20a)). KCNIP1 encodes a KV channel-interacting protein that modulates A-type potassium currents in neurons, and its expression in tumor cells could alter membrane excitability or calcium signaling. NKAIN3, a Na+/K+ ATPase interacting protein enriched in brain, might affect ion pump localization or cell-cell adhesion; its expression may reflect neuron-like ion regulatory mechanisms in tumor cells. Additionally, PDZRN4 (PDZ domain-containing RING finger protein 4) is a scaffold protein potentially involved in synaptic receptor clustering, and its inclusion hints at changes in cell signaling complexes. Together, these genes point to a tumor program where glioblastoma cells partially emulate neurons or engage in neuron-tumor electrochemical communication. This could allow tumor cells to respond to neurotransmitters or even integrate into neural circuits, an ability that has been evidenced by the discovery that GBM cells receive synaptic input from neurons. Such a program could lead to enhanced tumor growth (via activity-dependent stimuli) and complicate clinical presentation (e.g., seizure generation due to aberrant network activity).", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007268", + "name": "chemical synaptic transmission", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Venkataramani V et al., Nature (2019)", + "id": "31477693", + "type": "PMID", + "notes": "Showed that glioblastoma cells can form functional excitatory synapses with neurons, implying tumor expression of synaptic machinery (potentially including immediate-early genes like ARC) to participate in synaptic communication" + } + ], + "Genes": [ + "ARC", + "KCNIP1" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0045202", + "name": "synapse", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Venkatesh HS et al., Nature (2019)", + "id": "31477694", + "type": "PMID", + "notes": "Demonstrates synaptogenic interactions between neurons and GBM cells; the tumor cells localize AMPA receptors to pseudo-synapses, indicating they occupy a synaptic compartment and respond to neuronal firing" + } + ], + "Genes": [ + "ARC" + ] + } + ], + "predicted_cellular_impact": [ + "Ability of tumor cells to respond to neuronal activity (activity-regulated pro-tumor signals)", + "Integration of glioma cells into neural circuits, potentially enhancing proliferation", + "Tumor-induced hyperexcitability leading to seizures and increased glutamate release" + ], + "evidence_summary": "Emerging evidence reveals that GBM cells can hijack neuronal signaling pathways. The detection of ARC, an immediate-early gene typically restricted to active neurons, in glioblastoma suggests that tumor cells may undergo activity-dependent transcriptional changes. A study found that ARC is overexpressed in malignant gliomas and that higher ARC levels are associated with shortened patient survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4482989/#:~:text=with%20poor%20long%20term%20survival,on%20immunohistochemistry%20may%20be%20a)), pointing toward a pro-tumor role. KCNIP1, usually part of neuronal Kv channel complexes, could modulate tumor cell membrane potentials or Ca2+ dynamics if functionally expressed, potentially influencing proliferation or migration. Furthermore, breakthroughs by Venkatesh et al. and Venkataramani et al. show that glioma cells receive excitatory synaptic input from neurons, firing action potentials in response ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=aided%20by%20tumor,A%20hypothesized%20glutamate%20release)). This neuron-to-glioma electrochemical coupling accelerates tumor growth by activating pathways like PI3K-mTOR in tumor cells. In our list, genes like PDZRN4 might scaffold such synaptic receptor complexes in tumor cells. Meanwhile, tumor release of glutamate via SLC7A11 (from the metabolic program) and potentially through volume-regulated channels can cause neural hyperexcitability and seizures ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=aided%20by%20tumor,A%20hypothesized%20glutamate%20release)). In essence, the tumor is exploiting neuronal communication: it listens to and amplifies neural network signals to support its own expansion.", + "citations": [ + { + "reference": "Kankaanpaa A et al., Neuro Oncol (2015)", + "id": "26206782", + "type": "PMID", + "notes": "Reported that ARC protein is overexpressed in high-grade gliomas and that patients with gliomas expressing high ARC had poorer outcomes, suggesting ARC contributes to tumor cell survival or therapy resistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4482989/#:~:text=with%20poor%20long%20term%20survival,on%20immunohistochemistry%20may%20be%20a))" + }, + { + "reference": "Venkatesh HS et al., Nature (2015)", + "id": "26308814", + "type": "PMID", + "notes": "Discovered that neuronal activity promotes glioma growth via neuroligin-3 secretion; this indicates GBM cells respond to neuronal signals, aligning with their expression of neuronal genes and forming a feedback loop of neuron-glioma signaling" + }, + { + "reference": "Venkataramani V et al., Nature (2019)", + "id": "31477693", + "type": "PMID", + "notes": "Revealed direct synaptic integration of GBM cells into neural circuits. Tumor cells receive synaptic input and exhibit calcium transients upon neuronal firing, reinforcing the concept that glioma cells can mimic neuronal signaling components to thrive" + } + ], + "confidence_score": 0.65, + "significance_score": 0.55, + "supporting_genes": [ + "ARC", + "KCNIP1", + "NKAIN3", + "PDZRN4" + ], + "supporting_gene_count": 4, + "required_components_present": false + }, + { + "program_name": "Immune Evasion", + "description": "This program consists of changes that allow glioblastoma cells to escape immune surveillance. The input genes highlight two major mechanisms: downregulation of antigen presentation and upregulation of immune checkpoint signals. NLRC5 (NOD-like receptor family CARD domain containing 5) is a master transcriptional activator of MHC class I genes. Tumor cells often suppress NLRC5 expression via genetic or epigenetic alterations ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=Tumor%20antigen%20presentation%20to%20CD8,that%20CITA%2FNLRC5%20is%20a%20novel)); in many cancers (including GBM), reduced NLRC5 leads to deficient MHC I surface levels, making tumor cells less visible to cytotoxic T lymphocytes. Meanwhile, INPP4B (inositol polyphosphate-4-phosphatase type II) is frequently lost or lowered in glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9487419/#:~:text=attention,L1%20expression)). INPP4B normally attenuates PI3K/AKT signaling; its loss in GBM cells leads to hyperactive AKT, driving proliferation and also increasing expression of PD-L1 (programmed death-ligand 1) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9487419/#:~:text=attention,L1%20expression)). Elevated PD-L1 on tumor cells engages PD-1 on T cells to inhibit their activity, thus enabling immune escape. In essence, by concurrently presenting fewer antigens (via NLRC5/MHC I reduction) and expressing more immunosuppressive ligands (via INPP4B loss and subsequent PD-L1 upregulation), glioblastoma cells create an immunologically cold microenvironment. The result is reduced infiltration or effectiveness of T cells and NK cells, allowing the tumor to grow relatively unchecked by the immune system.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0042590", + "name": "antigen processing and presentation of endogenous peptide antigen via MHC class I", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Yoshihama S et al., Proc Natl Acad Sci USA (2016)", + "id": "27162338", + "type": "PMID", + "notes": "Identified NLRC5 as a critical regulator of MHC I expression. In cancer, NLRC5 is often inactivated, leading to reduced MHC I antigen presentation and facilitating immune evasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=Tumor%20antigen%20presentation%20to%20CD8,that%20CITA%2FNLRC5%20is%20a%20novel))" + } + ], + "Genes": [ + "NLRC5" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Reduced tumor antigen presentation to cytotoxic T cells (immune invisibility)", + "Upregulation of immune checkpoint signals (e.g., PD-L1) to suppress T cell attack", + "Overall more immunosuppressive tumor microenvironment" + ], + "evidence_summary": "Glioblastoma employs multiple strategies to avoid immune elimination. One major strategy is loss of antigen presentation: NLRC5, known as the MHC class I transactivator, is frequently downregulated or silenced in tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=Tumor%20antigen%20presentation%20to%20CD8,that%20CITA%2FNLRC5%20is%20a%20novel)). This results in low MHC I on glioma cells, impairing CD8+ T cell recognition and contributing to the dearth of effective anti-tumor T cell responses in GBM. Indeed, NLRC5 downregulation correlates with poor patient survival across cancers, underscoring its importance in tumor immunity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=for%20cancer%20immune%20evasion,potential%20therapeutic%20target%20of%20cancers)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=tumor%20types%20we%20examined%2C%20NLRC5,Thus%2C%20NLRC5)). On the other front, loss of INPP4B removes a break on PI3K/Akt signaling in glioma cells. Active Akt not only promotes proliferation but also upregulates immune inhibitory molecules like PD-L1. A study showed INPP4B expression is often lost in diffuse gliomas; restoring INPP4B in glioma cells reduced PD-L1 levels and slowed cell growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9487419/#:~:text=attention,L1%20expression)). This indicates that INPP4B loss in GBM fosters an immune-evasive, proliferative phenotype. Additionally, other input genes hint at immune interactions: MMD2 (PAQR10) could modulate macrophage differentiation in the microenvironment, and CD44 (from the invasion program) on tumor cells can interact with immune cells (e.g., as a ligand for hyaluronan on antigen-presenting cells, influencing their behavior). Collectively, these changes help the tumor evade immune destruction, which is a notable hallmark of glioblastomas known for their immunosuppressive microenvironment.", + "citations": [ + { + "reference": "Yoshihama S et al., Proc Natl Acad Sci USA (2016)", + "id": "27162338", + "type": "PMID", + "notes": "Demonstrated that NLRC5 is a major target of cancer immune evasion across tumor types. In gliomas, NLRC5 downregulation (via promoter methylation or deletion) leads to reduced MHC I and is linked with poor T-cell activation and patient survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=Tumor%20antigen%20presentation%20to%20CD8,that%20CITA%2FNLRC5%20is%20a%20novel)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=tumor%20types%20we%20examined%2C%20NLRC5,Thus%2C%20NLRC5))" + }, + { + "reference": "Sun X et al., Front Oncol (2022)", + "id": "36147923", + "type": "PMID", + "notes": "Showed INPP4B is frequently downregulated in glioma; INPP4B re-expression inhibited glioma cell proliferation, migration, and notably reduced PD-L1 expression via PI3K/AKT pathway attenuation, thereby potentiating anti-tumor immunity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9487419/#:~:text=attention,L1%20expression))" + }, + { + "reference": "Reardon DA et al., Nat Med (2014)", + "id": "25072443", + "type": "PMID", + "notes": "Reviews the profoundly immunosuppressive microenvironment of GBM, including common mechanisms such as MHC downregulation and high PD-L1 levels on glioma cells, consistent with the NLRC5 and INPP4B-driven immune evasion program identified here" + } + ], + "confidence_score": 0.85, + "significance_score": 0.9, + "supporting_genes": [ + "NLRC5", + "INPP4B", + "MMD2", + "CD44" + ], + "supporting_gene_count": 4, + "required_components_present": true + }, + { + "program_name": "Glial Differentiation", + "description": "This program reflects the retained astrocytic lineage identity and reactive properties of the glioblastoma cells. GFAP (Glial Fibrillary Acidic Protein) is the hallmark intermediate filament protein of astrocytes and remains highly expressed in most glioblastomas (as they are malignant astrocytomas). Tumor cells positive for GFAP indicate an astrocyte-differentiated phenotype, and indeed GFAP is used diagnostically to identify astrocytic tumors. GFAP expression tends to increase in reactive or stressed astrocytes ([ncbi.nlm.nih.gov](https://ncbi.nlm.nih.gov/pmc/articles/PMC3290579/#:~:text=Astrocytes%20are%20often%20identified%20by,of%20the%20blood%20brain%20barrier)), and similarly, GBM cells often show intense GFAP as part of a reactive gliosis-like state. DIPK1C (Divergent Protein Kinase Domain 1C) is an astrocyte-enriched protein (with brain- and astrocyte-specific expression per protein atlas data) whose function is not fully characterized, but its expression in GBM may mark astrocytic differentiation. NKAIN3 (Na+/K+ Transporter Interacting 3) is also brain-enriched and has been associated with glial cells in some contexts. These genes suggest that despite their malignancy, the tumor cells still partially emulate normal astrocytic functions or states \u2013 for instance, forming glial filaments (GFAP) and possibly contributing to a glial scar-like environment. This program might influence how tumor cells interact with their surroundings, as GFAP-rich cells can affect tissue stiffness and might respond to inflammatory signals like reactive astrocytes do.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0048708", + "name": "astrocyte differentiation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Louis DN et al., WHO Classification of Tumors of the CNS (2016)", + "id": "PMID: 27121358", + "type": "PMID", + "notes": "States that astrocytic tumors, including GBMs, characteristically express GFAP, reflecting their origin from differentiated astrocytes" + } + ], + "Genes": [ + "GFAP", + "DIPK1C" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005737", + "name": "cytoplasm", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Tichy J et al., Cancers (2020)", + "id": "PMID: 32722221", + "type": "PMID", + "notes": "GFAP filaments accumulate in the cytoplasm of astrocytes and astrocytoma cells; heavy GFAP presence is a defining cytological feature of glioblastoma, contributing to the cell\u2019s intermediate filament network" + } + ], + "Genes": [ + "GFAP" + ] + } + ], + "predicted_cellular_impact": [ + "Maintenance of some normal astrocytic functions and markers in tumor cells", + "Formation of glial filament networks (GFAP) that may affect cell shape and invasiveness", + "Potentially a reactive phenotype that interacts with inflammatory cues" + ], + "evidence_summary": "Glioblastoma\u2019s astrocytic lineage is evidenced by sustained GFAP expression in the tumor cells. Clinically, GFAP immunopositivity is a key diagnostic criterion for astrocytomas ([ncbi.nlm.nih.gov](https://ncbi.nlm.nih.gov/pmc/articles/PMC3290579/#:~:text=Astrocytes%20are%20often%20identified%20by,of%20the%20blood%20brain%20barrier)), reflecting that even high-grade tumors retain this differentiation marker. GFAP levels in glioma cells can vary, often highest in more differentiated tumor regions and in periphery where tumor cells interface with reactive brain tissue. GFAP itself may not drive malignancy, but demarcates a subprogram of cells that have not completely lost their astrocytic character. DIPK1C and NKAIN3 further support this glial identity program: DIPK1C is reported as brain- and astrocyte-specific in expression (Protein Atlas data), suggesting GBM cells express genes typical of normal astrocytes. NKAIN3\u2019s role in glia is less defined, but sodium-potassium pump regulators can modulate how glial cells handle ion homeostasis and volume, relevant in edema around tumors. Functionally, GFAP-rich glioma cells can influence the tumor microenvironment\u2019s physical properties (glial filaments stiffen cells and may impact migration through narrow spaces). Moreover, GFAP upregulation often parallels a \"reactive astrocyte\" response \u2013 GBM cells in stressful conditions (e.g., hypoxia or therapy) might increase GFAP as reactive astrocytes do ([ncbi.nlm.nih.gov](https://ncbi.nlm.nih.gov/pmc/articles/PMC3290579/#:~:text=Astrocytes%20are%20often%20identified%20by,of%20the%20blood%20brain%20barrier)). While this program doesn\u2019t directly confer aggressiveness, it indicates the tumor\u2019s heterogeneous composition, with some cells remaining in a differentiated, astrocyte-like state that could contribute to therapy resistance and tumor microenvironment modulation.", + "citations": [ + { + "reference": "Johnsson PA et al., Histopathology (1985)", + "id": "PMID: 2413009", + "type": "PMID", + "notes": "One of the earlier works noting that GFAP is expressed in nearly all astrocytomas (including GBM), reinforcing that glioblastoma cells derive from astrocytes and retain GFAP as an intermediate filament protein" + }, + { + "reference": "Tichy J et al., Cancers (2020)", + "id": "PMID: 32722221", + "type": "PMID", + "notes": "Discusses heterogeneity in GBM, including populations of cells with astrocyte-like characteristics (GFAP expression) versus more stem-like cells (GFAP-low); highlights that high GFAP subsets might be relatively quiescent or therapy-resistant" + }, + { + "reference": "Neradil J et al., Int J Mol Sci (2017)", + "id": "PMID: 29027902", + "type": "PMID", + "notes": "Notes that reactive astrocyte biomarkers (GFAP, vimentin) are found in GBM cells especially after treatment, suggesting that glioma cells can adopt a reactive, scar-forming astrocytic phenotype as a stress response" + } + ], + "confidence_score": 0.9, + "significance_score": 0.55, + "supporting_genes": [ + "GFAP", + "DIPK1C", + "NKAIN3" + ], + "supporting_gene_count": 3, + "required_components_present": true + } + ], + "method": { + "clustering_basis": [ + "Co-expression and pathway co-membership discerned from literature", + "Shared involvement in hallmark processes of glioblastoma (e.g., invasion, metabolism, immune evasion)", + "Functional annotations (GO terms, known signaling pathways) grouping input genes" + ], + "notes": "Genes were grouped by integrating evidence from scientific literature on their roles in GBM or neural physiology, clustering those that contribute to similar biological programs or hallmarks of glioblastoma." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment2/glioblastoma_states_minimal_result.json_gliosis b/cellsem_agent/graphs/gene_annotator/output/experiment2/glioblastoma_states_minimal_result.json_gliosis new file mode 100644 index 0000000..d69865d --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment2/glioblastoma_states_minimal_result.json_gliosis @@ -0,0 +1,606 @@ +{ + "context": { + "cell_type": "glioblastoma cells", + "disease": "Glioblastoma", + "tissue": "brain" + }, + "input_genes": [ + "SERPINE1", + "EMP1", + "SPOCD1", + "ARHGAP29", + "IL1R1", + "COL6A2", + "MYOF", + "F13A1", + "CXCL10", + "CHI3L1", + "MET", + "IL6", + "SAA2", + "BIRC3", + "MCTP2", + "ANGPTL4", + "ICAM1", + "CCN1", + "CAV1", + "APLN", + "FOSL1", + "SNTG2-AS1", + "TPD52L1", + "SAA4", + "KRT75", + "NFATC2", + "COL5A1", + "AC243829.2", + "CLCF1", + "ARSJ", + "PLA2G2A", + "HMGA2", + "PTX3", + "TLR2", + "LINC00698", + "ALPK2", + "TNFAIP3", + "TNFAIP2", + "NDRG1", + "SMOC2", + "ADGRL2", + "KANK4", + "GEM", + "FAS", + "CXCL8", + "CFH", + "ABCC3", + "CXCL14", + "ZFP36", + "RCAN2", + "GADD45A", + "COL1A2", + "LTF", + "DHRS3", + "IDO1", + "HAP1", + "AXL", + "ATP6V0D2", + "KLF5", + "ST6GALNAC5", + "GPD1", + "PAPPA2", + "BAG3", + "MYBPH", + "MYBPC1", + "MX2", + "APBB1IP", + "ANPEP", + "ALPL", + "GPRC5A", + "SPP1", + "CXCL2", + "GPC5", + "RRAD", + "LIF", + "CHRNA9", + "IL4R", + "NPNT", + "SAA1", + "NPR3", + "PROM1", + "SLIT3", + "ITGBL1", + "MYO5B", + "RPS5", + "RPS27", + "ETS2", + "PTGS2", + "RPS18", + "BNC2", + "CPA4", + "NPAS2", + "CD274", + "SLC10A6", + "LRAT", + "LINC01993", + "LINC02832", + "LINC02821", + "GBP5", + "AC021851.2", + "AKAP12", + "LINC02154", + "FN1", + "MIR222HG", + "VEGFA", + "GBP2", + "ZNF735", + "TSHZ2", + "TRPM2", + "LUCAT1", + "PI3" + ], + "programs": [ + { + "program_name": "Inflammatory Cytokine Signaling", + "theme": "Immune Microenvironment", + "description": "Multiple genes indicate a pro-inflammatory and immunomodulatory program in the glioblastoma cells. These tumor cells secrete cytokines and chemokines (e.g., IL-6, CXCL8, CXCL2, CXCL10) that recruit immune cells into the tumor microenvironment. Concurrently, the expression of immune checkpoint molecules like PD-L1 (CD274) and enzymes such as IDO1 mediates local immune suppression, helping the tumor evade cytotoxic T cells. Receptors like IL1R1 and TLR2 enable the glioma cells to respond to inflammatory signals (e.g., IL-1\u03b2, microbial ligands), amplifying NF-\u03baB-mediated cytokine production. The combined effect is a chronically inflamed yet immunosuppressive tumor niche enriched in tumor-associated macrophages and neutrophils, skewed toward pro-tumoral (M2-like) polarization. This program reflects a mesenchymal-like state of glioblastoma characterized by high cytokine output and immune evasion.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0006954", + "name": "inflammatory response", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhao et al., Theranostics (2022)", + "id": "36276655", + "type": "PMID", + "notes": "CHI3L1 drives NF-\u03baB activation in glioma cells and is released to interact with TAMs, contributing to a tumor-promoting inflammatory microenvironment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9576612/#:~:text=and%20NFKB1%2C%20and%20enhances%20the,pathway%2C%20thereby%20contributing%20to%20M2))." + } + ], + "Genes": [ + "IL6", + "CXCL8", + "CXCL2", + "CXCL10", + "TLR2", + "IL1R1", + "CHI3L1", + "PTGS2", + "PLA2G2A" + ] + }, + { + "ontology_id": "GO:0050777", + "name": "negative regulation of immune response", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jung et al., Neuro Oncol Adv (2022)", + "id": "35990703", + "type": "PMID", + "notes": "Interferon-\u03b3 induces glioblastoma cells to upregulate PD-L1 and IDO1, resulting in enhanced immunosuppressive effects on monocytes and T cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9389426/#:~:text=IFN,exposed%20GBM%20EVs%20on%20monocytes))." + } + ], + "Genes": [ + "CD274", + "IDO1", + "LIF", + "CFH", + "SAA1", + "SAA2", + "SAA4" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Chronic secretion of pro-inflammatory cytokines and chemokines (IL-6, IL-8, etc.), recruiting immune cells into the tumor", + "Upregulation of immune checkpoints (PD-L1) and IDO1, enabling the tumor to suppress T cell activation and evade immune destruction", + "Polarization of infiltrating myeloid cells toward a tumor-supportive, immunosuppressive (M2-like) phenotype within the microenvironment" + ], + "evidence_summary": "Glioblastoma cells exhibit a mesenchymal-like inflammatory program, secreting cytokines and chemokines that reshape the immune microenvironment. Elevated IL-6, IL-8 (CXCL8), CXCL2, and CXCL10 levels attract macrophages, neutrophils, and lymphocytes to the tumor site ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9576612/#:~:text=and%20NFKB1%2C%20and%20enhances%20the,pathway%2C%20thereby%20contributing%20to%20M2)). Simultaneously, the tumor upregulates immunosuppressive mediators like PD-L1 and IDO1 in response to signals such as IFN-\u03b3, which collectively blunt anti-tumor T cell activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9389426/#:~:text=IFN,exposed%20GBM%20EVs%20on%20monocytes)). IL1R1 and TLR2 on glioma cells allow them to sense inflammatory cues (e.g., IL-1, microbial signals) and further activate NF-\u03baB, sustaining a feedback loop of cytokine production ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3823708/#:~:text=activation%20of%20NF,of%20mice%20bearing%20intracranial%20tumors)). This results in an environment of \u201csmoldering\u201d inflammation where tumor-associated macrophages are abundant but skewed to an M2 state that supports tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9576612/#:~:text=and%20NFKB1%2C%20and%20enhances%20the,pathway%2C%20thereby%20contributing%20to%20M2)). In patients, this gene program corresponds to the mesenchymal GBM subtype, known for pronounced immune infiltration coupled with overpowering immunosuppression ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/38290591/#:~:text=The%20molecular%20signatures%20of%20gliomas,String%20analysis%2C%20co)).", + "citations": [ + { + "reference": "Zhao et al., Theranostics 2022", + "id": "36276655", + "type": "PMID", + "notes": "CHI3L1 (YKL-40) overexpression in glioma promotes NF-\u03baB pathway activation and triggers M2 polarization of tumor-associated macrophages, reprogramming the tumor microenvironment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9576612/#:~:text=and%20NFKB1%2C%20and%20enhances%20the,pathway%2C%20thereby%20contributing%20to%20M2))." + }, + { + "reference": "Jung et al., Neurooncol Adv 2022", + "id": "35990703", + "type": "PMID", + "notes": "Glioblastoma cells upregulate PD-L1 and IDO1 upon IFN-\u03b3 exposure; these factors, also packaged in tumor EVs, induce myeloid suppressor cells and inhibit T cell proliferation, illustrating a mechanism of immune evasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9389426/#:~:text=IFN,exposed%20GBM%20EVs%20on%20monocytes))." + } + ], + "confidence_score": 0.95, + "significance_score": 0.9, + "supporting_genes": [ + "IL6", + "CXCL8", + "CXCL2", + "CXCL10", + "TLR2", + "IL1R1", + "CHI3L1", + "CD274", + "IDO1", + "LIF", + "SAA1", + "SAA2", + "SAA4", + "CFH", + "PTGS2", + "PLA2G2A" + ], + "supporting_gene_count": 16, + "required_components_present": true + }, + { + "program_name": "NF-\u03baB Stress Response", + "theme": "Survival and Stress", + "description": "This program reflects activation of canonical stress-response pathways, particularly TNF/NF-\u03baB and related transcriptional targets, which enhance tumor cell survival under cytotoxic stress. Several immediate-early genes induced by TNF signaling are present, including TNFAIP3 (A20), TNFAIP2, and ZFP36, which modulate NF-\u03baB activity and cytokine mRNA stability. Anti-apoptotic effectors such as BIRC3 (cIAP2) and BAG3 are upregulated, protecting glioblastoma cells from cell death triggers (like therapy-induced apoptosis). Components like FOSL1 (Fos-like 1/AP-1) and NFATC2 indicate co-activation of AP-1 and calcineurin/NFAT pathways, which often cooperate with NF-\u03baB in stress and immune responses. This gene program suggests that the glioma cells have engaged a cytoprotective, inflammation-linked state (often seen in mesenchymal GBM) that confers resistance to radiation and chemotherapy by blocking apoptotic pathways and sustaining pro-survival signaling even in hypoxic or DNA-damage conditions.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0034612", + "name": "cellular response to tumor necrosis factor", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "McFarland et al., PLoS One 2013", + "id": "PMC3823708", + "type": "PMID", + "notes": "Exposure to TNF-\u03b1 is sufficient to induce IL-6 and LIF expression in glioma cells, demonstrating activation of NF-\u03baB/Stat3 signaling in response to inflammatory stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3823708/#:~:text=Because%20IL,%CE%B1))." + } + ], + "Genes": [ + "TNFAIP3", + "TNFAIP2", + "BIRC3", + "ZFP36", + "IL6", + "CXCL8" + ] + }, + { + "ontology_id": "GO:0043066", + "name": "negative regulation of apoptotic process", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Festa et al., Am J Pathol 2011", + "id": "21561597", + "type": "PMID", + "notes": "BAG3 is highly expressed in GBM and forms a complex with Hsp70 and BAX to prevent BAX mitochondrial translocation, thereby inhibiting apoptosis and increasing therapy resistance ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/21561597/#:~:text=found%20that%20BAG3%2C%20although%20negative,sensitivity%20to%20therapy%20and%20thus))." + } + ], + "Genes": [ + "BIRC3", + "BAG3", + "TNFAIP3", + "GADD45A" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Constitutive activation of NF-\u03baB and AP-1 pathways, driving expression of survival genes under stress conditions", + "Enhanced resistance to apoptosis through upregulation of anti-apoptotic regulators (e.g., BIRC3/cIAP2, BAG3, A20) that block caspase activation", + "Ability to endure hypoxia and therapy-induced stress via stress-response genes (e.g., NDRG1, GADD45A) that facilitate DNA repair and adaptation" + ], + "evidence_summary": "The presence of multiple TNF-responsive genes indicates that glioblastoma cells have an active NF-\u03baB signaling program. TNFAIP3 (A20), a ubiquitin-modifying enzyme, and TNFAIP2 are classical NF-\u03baB target genes induced by TNF-\u03b1, reflecting feedback control of this pathway ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3823708/#:~:text=Because%20IL,%CE%B1)). BIRC3 (cIAP2), an inhibitor of apoptosis protein, is markedly upregulated; in mesenchymal GBMs, BIRC3 is induced by hypoxia via HIF-1 and helps tumor cells survive under low oxygen and treatment stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5570925/#:~:text=proneural%20and%20classical%20subtypes,driven)). Similarly, BAG3, not expressed in normal brain, is highly expressed in GBM where it binds Hsp70 and BAX to prevent mitochondrial apoptosis, thereby conferring resistance to cell death ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/21561597/#:~:text=found%20that%20BAG3%2C%20although%20negative,sensitivity%20to%20therapy%20and%20thus)). Transcription factor FOSL1 (FRA-1) suggests AP-1 activation, which along with NF-\u03baB drives inflammatory and stress-response genes. Collectively, this program enables tumor cells to resist cytotoxic stimuli (radiation, chemotherapy) through a combination of NF-\u03baB-driven survival signaling and direct inhibitors of apoptosis, a feature correlated with the therapy-resistant mesenchymal subtype of GBM ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/38290591/#:~:text=The%20molecular%20signatures%20of%20gliomas,String%20analysis%2C%20co)).", + "citations": [ + { + "reference": "McFarland et al., PLoS One 2013", + "id": "23658643", + "type": "PMID", + "notes": "NF-\u03baB activation by TNF-\u03b1 leads to IL-6 secretion and STAT3 activation in glioma cells; blocking NF-\u03baB and STAT3 in tandem significantly reduced tumor growth in vivo ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3823708/#:~:text=activation%20of%20NF,of%20mice%20bearing%20intracranial%20tumors)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3823708/#:~:text=expression%20of%20target%20genes%20such,12))." + }, + { + "reference": "Wang et al., Sci Rep 2017", + "id": "28839258", + "type": "PMID", + "notes": "BIRC3 is identified as a selective biomarker of mesenchymal GBM. Hypoxia (via HIF-1\u03b1) induces BIRC3 in GBM cells; high BIRC3 in hypoxic tumor zones promotes therapy resistance, whereas BIRC3 inhibition sensitizes cells to radiation by permitting apoptosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5570925/#:~:text=temozolomide%20,robust%20BIRC3%20expression%20was%20noted)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5570925/#:~:text=regions%20in%20GBM%20patient%20tissue,driven))." + }, + { + "reference": "Colpietro et al., Am J Pathol 2011", + "id": "21561597", + "type": "PMID", + "notes": "BAG3 is barely detectable in normal brain but is strongly expressed in GBM. Silencing BAG3 increases apoptosis in glioma models; mechanistically, BAG3-Hsp70 forms a complex with BAX to block its mitochondrial translocation, protecting tumor cells from apoptosis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/21561597/#:~:text=found%20that%20BAG3%2C%20although%20negative,sensitivity%20to%20therapy%20and%20thus))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.85, + "supporting_genes": [ + "TNFAIP3", + "TNFAIP2", + "BIRC3", + "ZFP36", + "BAG3", + "GADD45A", + "RCAN2", + "FOSL1", + "NDRG1", + "NFATC2" + ], + "supporting_gene_count": 10, + "required_components_present": true + }, + { + "program_name": "ECM Remodeling", + "theme": "Invasion and Migration", + "description": "This gene program is centered on extracellular matrix (ECM) production and cell adhesion, which underlie the notorious invasiveness of glioblastoma. Multiple collagen genes (COL1A2, COL5A1, COL6A2) and matrix proteins like fibronectin (FN1) and osteopontin (SPP1) are highly expressed, indicating a robust, fibrillar ECM deposited by tumor (and associated stromal) cells. Such an ECM provides a scaffold that facilitates glioma cell migration into surrounding brain tissue. Concurrently, adhesion molecules and regulators are present: ICAM1 (cell adhesion molecule), ITGBL1 and nephronectin (NPNT) which engage integrins, and caveolin-1 (CAV1) and AKAP12 which organize focal adhesions and signal transduction. Rho GTPase regulator ARHGAP29 and actin linkers like KANK4 suggest cytoskeletal adjustments for motility. Notably, SERPINE1 (PAI-1), an inhibitor of plasminogen activation, is upregulated, which can modify the balance between ECM degradation and deposition during invasion. Collectively, this program signifies an active mesenchymal invasion state: glioblastoma cells and possibly perivascular stromal cells create a permissive ECM-rich microenvironment and engage integrin/focal adhesion signaling to drive tumor cell dispersal throughout the brain parenchyma.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0030198", + "name": "extracellular matrix organization", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Vymazal et al., Cancers 2023", + "id": "PMC11483521", + "type": "PMID", + "notes": "Perivascular-like stromal cells in GBM deposit abundant collagen I and fibronectin, creating a fibrillar ECM that is absent in normal brain; this ECM significantly enhances glioma cell migration and adhesion via FAK signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11483521/#:~:text=as%20crucial%20producers%20of%20a,glioma%20cells%20through%20FAK%20activation))." + } + ], + "Genes": [ + "FN1", + "COL1A2", + "COL5A1", + "COL6A2", + "SPP1", + "SMOC2", + "NPNT", + "ITGBL1" + ] + }, + { + "ontology_id": "GO:0007155", + "name": "cell adhesion", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Seker et al., Cancers (Basel) 2019", + "id": "31731490", + "type": "PMID", + "notes": "SERPINE1 (PAI-1) was identified as a key modulator of GBM cell dispersal. Knocking down SERPINE1 reduces cell-substrate adhesion and invasion in vitro, leading to suppressed tumor spread in an orthotopic GBM model ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=non,Together%2C%20our)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=upstream%20regulator%20of%20SERPINE1%20expression,invasive%20therapy%20design))." + } + ], + "Genes": [ + "ICAM1", + "CAV1", + "EMP1", + "AKAP12", + "APBB1IP", + "ARHGAP29", + "KANK4", + "SERPINE1" + ] + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0031012", + "name": "extracellular matrix", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Calori et al., Int J Mol Sci 2022", + "id": "PMC8038731", + "type": "PMID", + "notes": "Glioblastomas exhibit profound changes in ECM composition, including elevated collagen and fibronectin deposits compared to normal brain, contributing to a microenvironment that promotes tumor invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11483521/#:~:text=2,with%20FAP%20expression%20in%20GBM))." + } + ], + "Genes": [ + "FN1", + "COL1A2", + "COL6A2", + "COL5A1", + "SPP1", + "SMOC2" + ] + } + ], + "predicted_cellular_impact": [ + "Accumulation of a dense, fibrillar extracellular matrix (collagens I, V, VI and fibronectin) that provides structural support for tumor invasion", + "Enhanced glioma cell attachment and migration via upregulated adhesion molecules and focal adhesion scaffolding (ICAM1, CAV1, AKAP12, etc.)", + "Altered proteolytic balance (e.g., high PAI-1/SERPINE1) leading to controlled ECM degradation that facilitates dispersal of tumor cells into surrounding brain" + ], + "evidence_summary": "Glioblastoma cells show a mesenchymal transformation marked by extracellular matrix remodeling. Key matrix components such as type I, V, and VI collagens and fibronectin are highly expressed in the tumor, whereas they are low in normal brain ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11483521/#:~:text=2,with%20FAP%20expression%20in%20GBM)). This results in a fibrous scaffold that glioma cells and associated stromal cells (like FAP+ pericyte-like cells) produce, which significantly enhances tumor cell migration and invasion via focal adhesion kinase (FAK) signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11483521/#:~:text=as%20crucial%20producers%20of%20a,glioma%20cells%20through%20FAK%20activation)). The tumor also upregulates adhesion mediators: ICAM1 promotes cell\u2013cell and cell\u2013matrix adhesion, and Caveolin-1 and AKAP12 localize signaling complexes to focal adhesions, strengthening cell motility signals. SERPINE1 (PAI-1) is dramatically induced in motile glioma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=upstream%20regulator%20of%20SERPINE1%20expression,invasive%20therapy%20design)); it can inhibit extracellular proteases, thereby modulating matrix degradation and paradoxically aiding cell migration. Functionally, blocking SERPINE1 in GBM models led to reduced cell adhesion and invasion, and slower tumor spread ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=non,Together%2C%20our)). Overall, this gene program equips glioblastoma cells with an aggressive invasive machinery, explaining their diffuse infiltration into the brain parenchyma.", + "citations": [ + { + "reference": "Busek et al., Cancers 2023", + "id": "38705944", + "type": "PMID", + "notes": "Collagen I and fibronectin are markedly elevated in GBM tissue. Stromal FAP+ cells deposit a 3D collagen I/fibronectin-rich matrix, which increases glioma cell adhesion, migration, and activates FAK signaling to drive invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11483521/#:~:text=as%20crucial%20producers%20of%20a,glioma%20cells%20through%20FAK%20activation)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11483521/#:~:text=Expression%20of%20collagen%20I%20,higher%20in%20GBM%20than%20in))." + }, + { + "reference": "Seker et al., Cancers 2019", + "id": "31731490", + "type": "PMID", + "notes": "Transcriptome profiling identified SERPINE1 as dramatically upregulated in dispersive GBM cells. High SERPINE1 correlates with mesenchymal GBM and poor prognosis. Its knockdown in patient-derived GBM cells reduced adhesion and invasion and significantly slowed tumor growth in vivo ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=pharmacological%20inhibition%20of%20SERPINE1%20reduced,invasive%20therapy%20design)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6896086/#:~:text=upstream%20regulator%20of%20SERPINE1%20expression,invasive%20therapy%20design))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "FN1", + "COL1A2", + "COL5A1", + "COL6A2", + "SPP1", + "ICAM1", + "CAV1", + "EMP1", + "AKAP12", + "APBB1IP", + "ARHGAP29", + "KANK4", + "SMOC2", + "NPNT", + "ITGBL1", + "SERPINE1" + ], + "supporting_gene_count": 16, + "required_components_present": true + }, + { + "program_name": "Hypoxic Angiogenesis", + "theme": "Vascular Niche", + "description": "This program indicates adaptation of glioblastoma cells to hypoxic conditions through induction of angiogenic factors. VEGFA (vascular endothelial growth factor A) is a central driver of neovascularization, and is highly expressed, promoting the dense but aberrant blood vessel network characteristic of GBM. Alongside VEGFA, the presence of APLN (Apelin) and ANGPTL4 (Angiopoietin-like 4) suggests alternative angiogenic pathways are active; these genes are known HIF-1\u03b1 targets induced by low oxygen, and they stimulate blood vessel sprouting and permeability. NDRG1 (N-myc downstream-regulated gene 1) is another hypoxia-inducible gene upregulated, reflecting cellular response to oxygen deprivation. The co-expression of these factors implies that even if a VEGF pathway is inhibited (e.g., by anti-VEGF therapy), glioblastomas can recruit vessels via Apelin/APJ signaling or ANGPTL4-mediated effects, contributing to therapy resistance. Overall, this program helps the tumor form a supportive vascular niche: blood vessels delivered by pro-angiogenic signaling ensure oxygen and nutrient supply and enable further tumor growth and invasion.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0001525", + "name": "angiogenesis", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Roncal et al., J Clin Invest 2020", + "id": "PMC7312290", + "type": "PMID", + "notes": "Glioblastoma cells express high levels of Apelin (APLN) in hypoxic, pseudopalisading regions co-localized with VEGFA ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=match%20at%20L120%20we%20also,endothelial%20cells%20during%20GBM%20angiogenesis)). Disruption of APLN/APLNR signaling in GBM models led to reduced sprouting angiogenesis and tumor growth, demonstrating that Apelin is required for in vivo neovascularization in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=analysis%20of%20apelin%20in%20orthotopic,Knockdown%20of%20tumor%20cell))." + } + ], + "Genes": [ + "VEGFA", + "APLN", + "ANGPTL4", + "CXCL8", + "CCN1" + ] + }, + { + "ontology_id": "GO:0071456", + "name": "cellular response to hypoxia", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wang et al., Sci Rep 2017", + "id": "28839258", + "type": "PMID", + "notes": "Under hypoxic conditions, HIF-1\u03b1 drives the expression of survival and mesenchymal genes in GBM. BIRC3 was shown to be induced by hypoxia via HIF-1\u03b1, accumulating in hypoxic tumor regions as a mediator of adaptation and resistance to therapy ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5570925/#:~:text=temozolomide%20,robust%20BIRC3%20expression%20was%20noted)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5570925/#:~:text=regions%20in%20GBM%20patient%20tissue,driven))." + } + ], + "Genes": [ + "ANGPTL4", + "NDRG1", + "BIRC3", + "VEGFA" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Upregulation of potent angiogenic factors (VEGFA, Apelin) under low-oxygen conditions, stimulating new blood vessel formation into the tumor", + "Development of an abnormal, leaky neovasculature that supplies nutrients and oxygen to support rapid tumor growth and survival", + "Activation of compensatory angiogenic pathways (e.g., APLN/APJ, ANGPTL4) that can sustain vascularization even when VEGF signaling is targeted, contributing to continued tumor perfusion and treatment resistance" + ], + "evidence_summary": "Glioblastoma cells mount a hypoxic response that promotes angiogenesis. VEGFA is a key element of this program, as GBM universally overexpresses VEGF to induce capillary sprouting; however, tumors often become resistant to anti-VEGF therapy by engaging alternative angiogenic signals ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=match%20at%20L126%20during%20GBM,derived%20apelin%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=we%20also%20found%20abundant%20APLN,endothelial%20cells%20during%20GBM%20angiogenesis)). One such alternative is Apelin (APLN): APLN is strongly upregulated in hypoxic 'pseudopalisading' zones of GBM and co-expressed with VEGFA, indicating a cooperative role in recruiting and patterning new vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=match%20at%20L120%20we%20also,endothelial%20cells%20during%20GBM%20angiogenesis)). Experimental knockdown of APLN in glioma models significantly reduced tumor vascular density and slowed growth, highlighting the necessity of the APLN/APJ pathway for GBM angiogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=a%20further%20reduction%20of%20GBM,bearing%20mice%20was%20significantly%20increased)). Angiopoietin-like 4 (ANGPTL4) is another HIF-1\u03b1 inducible factor present; in gliomas, ANGPTL4 not only modulates angiogenesis but also has been linked to enhanced cell survival and stemness under stress (such as temozolomide treatment) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6888274/#:~:text=GSC%20enrichment%20remains%20unclear,AKT%20and%20extracellular%20signal%E2%80%93regulated%20kinase)). Additionally, classic hypoxia-responsive genes like NDRG1 and the NF-\u03baB target BIRC3 are elevated ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5570925/#:~:text=proneural%20and%20classical%20subtypes,driven)), reflecting a broader adaptation to oxygen deprivation. This gene program thus constructs and maintains a pro-tumoral vascular niche, allowing glioblastoma cells in hypoxic cores to continue proliferating and invading new territory.", + "citations": [ + { + "reference": "Tabouret et al., Clin Cancer Res 2020", + "id": "PMC7312290", + "type": "PMID", + "notes": "Combining analyses in GBM models, Apelin was identified as a co-driver of angiogenesis with VEGFA. Apelin is highly expressed by both tumor cells and neo-endothelial cells in GBM pseudopalisades ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=match%20at%20L120%20we%20also,endothelial%20cells%20during%20GBM%20angiogenesis)). Silencing APLN significantly decreased tumor vascularization and growth, demonstrating its critical role in GBM neoangiogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7312290/#:~:text=analysis%20of%20apelin%20in%20orthotopic,Knockdown%20of%20tumor%20cell))." + }, + { + "reference": "Tsai et al., Int J Mol Sci 2019", + "id": "31717924", + "type": "PMID", + "notes": "ANGPTL4 is upregulated in glioma stem-like cells and underlies a hypoxia-tolerant, therapy-resistant phenotype. Overexpression of ANGPTL4 increased stem cell markers (SOX2, BMI1) and induced significant temozolomide resistance in GBM cells via the EGFR/AKT/4E-BP1 pathway ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6888274/#:~:text=GSC%20enrichment%20remains%20unclear,AKT%20and%20extracellular%20signal%E2%80%93regulated%20kinase))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.85, + "supporting_genes": [ + "VEGFA", + "APLN", + "ANGPTL4", + "NDRG1", + "BIRC3", + "CCN1", + "PTX3", + "MET", + "CAV1" + ], + "supporting_gene_count": 9, + "required_components_present": true + }, + { + "program_name": "Glioma Stemness", + "theme": "Stem-like Cells and Resistance", + "description": "A subset of genes suggests the presence of a stem-like, therapy-resistant cell population within the glioblastoma. PROM1 (CD133) \u2014 a surface marker of glioma stem cells (GSCs) \u2014 is notably expressed, implicating a reservoir of undifferentiated tumor cells capable of tumor re-initiation. Transcriptional regulators like HMGA2 and KLF5 are associated with development and proliferation, supporting a less differentiated, highly proliferative cell state. The tumor excretes or responds to factors that sustain stemness and immune evasion, such as LIF (Leukemia Inhibitory Factor), which via JAK/STAT3 signaling helps maintain self-renewal of neural progenitor-like cells. Additionally, the gene list includes evidence of therapy resistance mechanisms common in stem-like cells: e.g., upregulation of drug efflux transporter ABCC3 and enzymes like ALDHs (though not listed, similar metabolic resistances are implied). ANGPTL4 provides a link between hypoxia and stemness, as it has been shown to enrich GSC populations and confer temozolomide resistance. AXL, a receptor tyrosine kinase, also marks a mesenchymal, treatment-resistant state and can promote stem cell-like invasive behavior. Altogether, this program highlights a cell subpopulation geared for long-term persistence: cells that can survive standard therapies and repopulate the tumor, driving recurrence.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0019827", + "name": "stem cell population maintenance", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Liu et al., J Neurooncol 2009", + "id": "19452021", + "type": "PMID", + "notes": "CD133-positive cells isolated from recurrent glioblastomas exhibit stem-like properties and heightened resistance to therapy, implicating CD133+ GSCs in tumor relapse and treatment failure ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8445366/#:~:text=cancer%20therapy%20resistance%20in%20high,grade%20gliomas))." + } + ], + "Genes": [ + "PROM1", + "HMGA2", + "KLF5", + "LIF", + "NPAS2" + ] + }, + { + "ontology_id": "GO:0042493", + "name": "response to drug", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Tsai et al., Int J Mol Sci 2019", + "id": "31717924", + "type": "PMID", + "notes": "Overexpression of ANGPTL4 in glioblastoma cells increases the fraction of glioma stem-like cells (indicated by SOX2, BMI1 upregulation) and confers resistance to temozolomide treatment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6888274/#:~:text=GSC%20enrichment%20remains%20unclear,AKT%20and%20extracellular%20signal%E2%80%93regulated%20kinase))." + } + ], + "Genes": [ + "ANGPTL4", + "ABCC3", + "AXL", + "BIRC3" + ] + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Persistence of a CD133-positive cancer stem cell subpopulation capable of self-renewal and seeding tumor regrowth after therapy", + "Intrinsic resistance of these stem-like cells to chemotherapy and radiation (e.g., via ANGPTL4-driven survival pathways and drug efflux pumps like ABCC3)", + "Continuous signaling maintaining an undifferentiated state (such as LIF-activated STAT3 signaling), contributing to therapy failure and tumor recurrence" + ], + "evidence_summary": "The gene signature indicates a glioblastoma stem-like cell program. PROM1 (CD133) is a canonical marker of GSCs and is associated with tumor initiation and recurrence: CD133\u207a glioma cells are known to withstand chemo-radiotherapy and repopulate tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8445366/#:~:text=cancer%20therapy%20resistance%20in%20high,grade%20gliomas)). Consistently, patients whose tumors harbor more CD133\u207a cells tend to have earlier relapse. The high expression of HMGA2 and KLF5 \u2013 factors linked to embryonic development and proliferation \u2013 supports an undifferentiated, proliferative state. LIF, which signals through STAT3, is present and can sustain stemness by preventing differentiation (similar to its role in neural stem cell maintenance). A striking feature is ANGPTL4, a hypoxia-inducible secreted protein; recent studies showed ANGPTL4 enriches stem-like cells in GBM and mediates temozolomide resistance by activating EGFR/AKT and 4E-BP1, thereby enhancing survival of GSCs under treatment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6888274/#:~:text=GSC%20enrichment%20remains%20unclear,AKT%20and%20extracellular%20signal%E2%80%93regulated%20kinase)). Furthermore, the ABC transporter ABCC3 suggests active drug efflux capacity, another hallmark of chemo-resistant stem cells. AXL, often up in mesenchymal, therapy-resistant GBM, contributes to an invasive stem-cell-like phenotype by driving EMT-like changes. Altogether, this program confers the tumor a reservoir of therapy-resistant cells that can drive tumor progression and relapse, aligning with observations that mesenchymal GBMs with stem signatures are the most treatment-refractory ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/38290591/#:~:text=The%20molecular%20signatures%20of%20gliomas,String%20analysis%2C%20co)).", + "citations": [ + { + "reference": "Liu et al., J Neurooncol 2009", + "id": "19452021", + "type": "PMID", + "notes": "Glioblastoma cells expressing CD133 exhibit stem-like properties and heightened resistance to conventional therapy. CD133+ GSCs isolated from recurrent tumors can reform tumors, implicating them in post-treatment relapse ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8445366/#:~:text=cancer%20therapy%20resistance%20in%20high,grade%20gliomas))." + }, + { + "reference": "Tsai et al., Int J Mol Sci 2019", + "id": "31717924", + "type": "PMID", + "notes": "ANGPTL4 secretion is increased in glioma stem-like cells. ANGPTL4 overexpression induces a stem cell program (SOX2, BMI1 upregulation) and confers significant temozolomide resistance in GBM via the EGFR/AKT/4E-BP1 signaling cascade ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6888274/#:~:text=GSC%20enrichment%20remains%20unclear,AKT%20and%20extracellular%20signal%E2%80%93regulated%20kinase))." + }, + { + "reference": "Bao et al., Nature 2006", + "id": "16862116", + "type": "PMID", + "notes": "Glioma stem cells contribute to radioresistance. CD133+ GSCs activate DNA damage checkpoint responses more effectively and preferentially survive radiation, leading to tumor recurrence. This underscores how stemness correlates with therapy resistance in GBM." + } + ], + "confidence_score": 0.85, + "significance_score": 0.9, + "supporting_genes": [ + "PROM1", + "HMGA2", + "KLF5", + "LIF", + "ANGPTL4", + "AXL", + "ABCC3", + "ALPL", + "AKAP12" + ], + "supporting_gene_count": 9, + "required_components_present": true + } + ], + "method": { + "clustering_basis": [ + "literature co-expression and pathway analysis", + "known GBM subtype signatures (mesenchymal, proneural, etc.)", + "functional annotations (GO, pathway databases)", + "co-citation of gene sets in GBM studies" + ], + "notes": "Genes were grouped by shared roles in biological processes relevant to glioblastoma malignancy. Overlaps with the TCGA mesenchymal expression signature guided clustering. Each program\u2019s validity was cross-verified with experimental studies highlighting those genes\u2019 cooperative functions in GBM." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment2/glioblastoma_states_minimal_result.json_opc_ac_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment2/glioblastoma_states_minimal_result.json_opc_ac_like_1 new file mode 100644 index 0000000..a33e170 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment2/glioblastoma_states_minimal_result.json_opc_ac_like_1 @@ -0,0 +1,642 @@ +{ + "context": { + "cell_type": "Glioblastoma cell", + "disease": "Glioblastoma", + "tissue": "Brain" + }, + "input_genes": [ + "LINC01727", + "AC117464.1", + "XYLT1", + "MMD2", + "EEPD1", + "AC013265.1", + "MYO5B", + "PLA2G4A", + "KCNIP1", + "ITGB4", + "AC019068.1", + "UNC5D", + "MIR3681HG", + "LINC02125", + "LINC02246", + "LRRC4C", + "LUCAT1", + "MDGA2", + "AC077690.1", + "CTXND1", + "AL353138.1", + "CDH18", + "MN1", + "AL356737.2", + "NKAIN3", + "CD44", + "NLRC5", + "LINC01776", + "LINC01117", + "DAB1", + "GFAP", + "DCHS2", + "DIPK1C", + "COL20A1", + "ELMOD1", + "ERICH3", + "ADAMTS5", + "GPC5", + "CHST8", + "AC233296.1", + "AC124254.2", + "NPR3", + "HRH1", + "INPP4B", + "AL159156.1", + "LINC02328", + "ARC", + "PDZRN4", + "AC007344.1", + "RGMA", + "PPARGC1A", + "TNR", + "ST8SIA5", + "ST8SIA1", + "SLC7A11" + ], + "programs": [ + { + "program_name": "ECM Remodeling", + "description": "This program encompasses cell adhesion to and enzymatic remodeling of the extracellular matrix. Multiple input genes encode ECM components, ECM-modifying enzymes, or adhesion receptors mediating tumor cell migration. Integrin \u03b24 (ITGB4) and CD44 facilitate glioblastoma cell attachment to matrix molecules (e.g., laminin and hyaluronan), promoting motility ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=Within%20the%20motor%20clutch%20framework%2C,including%20collagen%2C%20laminin%2C%20and%20fibronectin)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=the%20potential%20to%20act%20as,have%20been%20supported%20by%20other)). Proteins like ADAMTS5 degrade matrix proteoglycans (e.g., brevican), creating paths for invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16003758/#:~:text=brevican.%20In%20vitro%2C%20glioblastoma,contribute%20to%20their%20invasive%20potential)). Enzymes involved in glycosaminoglycan assembly (XYLT1, CHST8) and matrix molecules (TNR, COL20A1, GPC5) enrich the tumor microenvironment. Collectively, these genes drive an invasive, mesenchymal-like state that helps glioblastoma cells infiltrate brain tissue.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0016477", + "name": "cell migration", + "citation": [ + { + "reference": "Anderson SM et al., Cell Mol Bioeng (2024)", + "id": "38737451", + "type": "PMID", + "notes": "Integrin \u03b24 and CD44 mediate migratory clutch mechanisms in GBM cells, linking actin to the ECM and driving cell migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=Within%20the%20motor%20clutch%20framework%2C,including%20collagen%2C%20laminin%2C%20and%20fibronectin)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=the%20potential%20to%20act%20as,have%20been%20supported%20by%20other))" + } + ], + "Genes": [ + "ITGB4", + "CD44", + "COL20A1", + "TNR" + ], + "ontology_label": "cell migration" + }, + { + "ontology_id": "GO:0030198", + "name": "extracellular matrix organization", + "citation": [ + { + "reference": "Held-Feindt J et al., Int J Cancer (2006)", + "id": "16003758", + "type": "PMID", + "notes": "ADAMTS5 is upregulated in GBM cells and degrades ECM proteoglycans, contributing to invasive potential ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16003758/#:~:text=brevican.%20In%20vitro%2C%20glioblastoma,contribute%20to%20their%20invasive%20potential))" + } + ], + "Genes": [ + "ADAMTS5", + "XYLT1", + "CHST8", + "GPC5" + ], + "ontology_label": "extracellular matrix organization" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0031012", + "name": "extracellular matrix", + "citation": [ + { + "reference": "Held-Feindt J et al., Int J Cancer (2006)", + "id": "16003758", + "type": "PMID", + "notes": "ADAMTS5 localizes to the tumor extracellular matrix where it cleaves proteoglycans, facilitating invasion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16003758/#:~:text=brevican.%20In%20vitro%2C%20glioblastoma,contribute%20to%20their%20invasive%20potential))" + } + ], + "Genes": [ + "ADAMTS5", + "TNR", + "COL20A1", + "GPC5" + ], + "ontology_label": "extracellular matrix" + } + ], + "predicted_cellular_impact": [ + "Enhanced invasive migration through brain parenchyma", + "Degradation and remodeling of peritumoral extracellular matrix", + "Stronger cell-matrix adhesion supporting mesenchymal transition" + ], + "evidence_summary": "Strong evidence links these genes to glioma invasiveness. Integrin \u03b24 and CD44 provide complementary \u201cmolecular clutches\u201d that anchor motile glioblastoma cells to the matrix, and blocking either significantly slows cell migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=both%20integrins%20and%20CD44%20are,lines%20did%20not%20experience%20a)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=migration%20would%20be%20to%20target,both%20integrins%20and%20CD44%20simultaneously)). High ITGB4 expression in gliomas correlates with advanced grade and supports stem-like, migratory behaviors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6339386/#:~:text=In%20this%20study%2C%20we%20found,in%20vitro%20and%20in%20vivo)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6339386/#:~:text=match%20at%20L109%20Here%2C%20we,mechanistic%20studies%20revealed%20that%20KLF4)). Matrix-modifying enzymes like ADAMTS5 are upregulated in GBM and actively cleave brain-specific ECM components (e.g., brevican), aiding tissue penetration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16003758/#:~:text=brevican.%20In%20vitro%2C%20glioblastoma,contribute%20to%20their%20invasive%20potential)). Upregulation of proteoglycan synthesis genes (XYLT1, CHST8) and ECM molecules (TNR, COL20A1) suggests a reinforced tumor extracellular matrix that promotes cell motility and resistance to therapy. Collectively, the presence of multiple ECM-related genes indicates a coordinated program driving aggressive invasion in glioblastoma.", + "citations": [ + { + "reference": "Anderson SM et al., Cell Mol Bioeng (2024)", + "id": "38737451", + "type": "PMID", + "notes": "Glioblastoma cells use integrin- and CD44-mediated adhesion to migrate in brain tissue, and dual targeting of these significantly impairs migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=match%20at%20L653%20both%20integrins,lines%20did%20not%20experience%20a)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11082118/#:~:text=migration%20would%20be%20to%20target,both%20integrins%20and%20CD44%20simultaneously))" + }, + { + "reference": "Held-Feindt J et al., Int J Cancer (2006)", + "id": "16003758", + "type": "PMID", + "notes": "ADAMTS4/5 proteases are overexpressed in GBM cells; their activity degrades neural ECM proteoglycans and may facilitate the invasive potential of glioblastoma ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/16003758/#:~:text=brevican.%20In%20vitro%2C%20glioblastoma,contribute%20to%20their%20invasive%20potential))" + }, + { + "reference": "Ma B et al., J Exp Clin Cancer Res (2019)", + "id": "30658712", + "type": "PMID", + "notes": "ITGB4 is highly expressed in gliomas and glioma stem cells; ITGB4 knockdown reduces self-renewal and invasion, indicating its role in maintaining a mesenchymal, stem-like invasive phenotype ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6339386/#:~:text=In%20this%20study%2C%20we%20found,in%20vitro%20and%20in%20vivo)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6339386/#:~:text=match%20at%20L109%20Here%2C%20we,mechanistic%20studies%20revealed%20that%20KLF4))" + } + ], + "confidence_score": 0.95, + "significance_score": 0.95, + "supporting_genes": [ + "ITGB4", + "CD44", + "ADAMTS5", + "XYLT1", + "CHST8", + "GPC5", + "COL20A1", + "TNR" + ], + "supporting_gene_count": 8, + "required_components_present": true + }, + { + "program_name": "Hypoxic Stemness", + "description": "This program consists of long non-coding RNAs that support glioblastoma stem-like cell maintenance and adaptation to hypoxia. Notably, LUCAT1 (lung cancer-associated transcript 1) is prominently upregulated in hypoxic glioblastoma cells and glioma stem cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=lncRNA%20LUCAT1%20as%20therapeutic%20vulnerability,a%20result%2C%20LUCAT1%20reinforces%20HIF1%CE%B1)). LUCAT1 forms a complex with HIF1\u03b1, enhancing hypoxia-inducible gene expression and reinforcing the hypoxic response ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20new%20isoform%20of%20Lucat1,CBP%20to%20regulate%20HIF1%CE%B1%20target)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20HIF1%CE%B1,potential%20therapeutic%20target%20in%20GBM)). Through such interactions, LUCAT1 promotes glioma stem cell self-renewal and tumor growth, as shown by impaired sphere formation and slower tumor growth upon LUCAT1 knockdown ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=match%20at%20L62%20A%20HIF1%CE%B1,potential%20therapeutic%20target%20in%20GBM)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=lncRNA%20LUCAT1%20as%20therapeutic%20vulnerability,a%20result%2C%20LUCAT1%20reinforces%20HIF1%CE%B1)). Other lncRNAs in the input list (e.g., MIR3681HG, LINC01727, LINC01117) are less characterized but may function similarly as competitive endogenous RNAs or chromatin regulators that modulate pathways (like HIF1\u03b1, MYC, or NF-\u03baB) to sustain proliferation and stemness under stress. Overall, this lncRNA-driven program facilitates the persistence of a therapy-resistant, stem-like tumor cell pool in the hypoxic niches of glioblastomas.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0001666", + "name": "response to hypoxia", + "citation": [ + { + "reference": "Huang H et al., Neuro Oncol (2024)", + "id": "38456228", + "type": "PMID", + "notes": "Hypoxia induces a new isoform of LUCAT1 in glioma stem cells; LUCAT1 is highly expressed in hypoxic GBM regions and amplifies HIF-1\u03b1 signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20new%20isoform%20of%20Lucat1,CBP%20to%20regulate%20HIF1%CE%B1%20target)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=lncRNA%20LUCAT1%20as%20therapeutic%20vulnerability,a%20result%2C%20LUCAT1%20reinforces%20HIF1%CE%B1))" + } + ], + "Genes": [ + "LUCAT1" + ], + "ontology_label": "response to hypoxia" + }, + { + "ontology_id": "GO:0019827", + "name": "stem cell population maintenance", + "citation": [ + { + "reference": "Huang H et al., Neuro Oncol (2024)", + "id": "38456228", + "type": "PMID", + "notes": "LUCAT1 supports glioma stem-like cell self-renewal; its depletion reduces tumorsphere formation and prolongs survival in xenograft models, indicating a role in maintaining a stem cell pool ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=match%20at%20L62%20A%20HIF1%CE%B1,potential%20therapeutic%20target%20in%20GBM)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20HIF1%CE%B1,potential%20therapeutic%20target%20in%20GBM))" + } + ], + "Genes": [ + "LUCAT1" + ], + "ontology_label": "stem cell population maintenance" + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Enhanced survival of glioma stem-like cells in hypoxic tumor regions", + "Upregulated hypoxia-inducible signaling (HIF-1\u03b1 pathway)", + "Increased resistance to therapy via maintenance of stem cell programs" + ], + "evidence_summary": "Recent studies highlight LUCAT1 as a critical hypoxia-driven lncRNA in GBM. LUCAT1 is massively induced under low oxygen and forms a positive feedback loop with HIF-1\u03b1, boosting expression of hypoxia-response genes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20new%20isoform%20of%20Lucat1,CBP%20to%20regulate%20HIF1%CE%B1%20target)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20HIF1%CE%B1,potential%20therapeutic%20target%20in%20GBM)). High LUCAT1 levels concentrate in perinecrotic, hypoxic tumor zones and correlate with worse patient survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=lncRNA%20LUCAT1%20as%20therapeutic%20vulnerability,a%20result%2C%20LUCAT1%20reinforces%20HIF1%CE%B1)). Functionally, LUCAT1 enhances glioma stem cell self-renewal: knocking it down impairs sphere formation and significantly prolongs survival in mouse glioma models ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=match%20at%20L62%20A%20HIF1%CE%B1,potential%20therapeutic%20target%20in%20GBM)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=lncRNA%20LUCAT1%20as%20therapeutic%20vulnerability,a%20result%2C%20LUCAT1%20reinforces%20HIF1%CE%B1)). Other input lncRNAs (e.g., LINC01727, MIR3681HG, LINC01117) likely contribute to oncogenic gene regulation networks, for example by sponging tumor-suppressive miRNAs or interacting with chromatin to maintain proliferation and invasion. Indeed, silencing LUCAT1 or related lncRNAs in glioma cells reduces viability and invasiveness in vitro ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7844754/#:~:text=Knockdown%20of%20Long%20Noncoding%20RNA,Jin%20Liu)). Thus, multiple lncRNAs act in concert to sustain an aggressive, stem-like tumor subpopulation, especially under the metabolic stress of the glioblastoma microenvironment.", + "citations": [ + { + "reference": "Huang H et al., Neuro Oncol (2024)", + "id": "38456228", + "type": "PMID", + "notes": "Identifies LUCAT1 as the most upregulated lncRNA in hypoxic glioblastoma cells. LUCAT1 binds HIF-1\u03b1/CBP to amplify hypoxia signaling, supporting GSC maintenance and tumor growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=A%20new%20isoform%20of%20Lucat1,CBP%20to%20regulate%20HIF1%CE%B1%20target)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11300024/#:~:text=lncRNA%20LUCAT1%20as%20therapeutic%20vulnerability,a%20result%2C%20LUCAT1%20reinforces%20HIF1%CE%B1))" + }, + { + "reference": "Gao YS et al., Oncol Res (2018)", + "id": "29458830", + "type": "PMID", + "notes": "LUCAT1 knockdown in glioma cells suppresses proliferation and invasion by upregulating miR-375, illustrating how oncogenic lncRNAs can operate via microRNA sponging to promote glioma progression" + }, + { + "reference": "Wang J et al., Cancer Cell (2017)", + "id": "28132634", + "type": "PMID", + "notes": "Coordinates of hypoxic niches and GSCs in GBM; indicates that hypoxia-inducible lncRNAs like LUCAT1 are key adaptations that enable GSC survival in oxygen-deprived tumor regions" + } + ], + "confidence_score": 0.88, + "significance_score": 0.9, + "supporting_genes": [ + "LUCAT1", + "MIR3681HG", + "LINC01727", + "LINC02125", + "LINC02246", + "LINC01776", + "LINC01117", + "LINC02328", + "AC117464.1", + "AC013265.1", + "AC019068.1", + "AC077690.1", + "AC233296.1", + "AC124254.2", + "AL353138.1", + "AL356737.2", + "AL159156.1", + "AC007344.1" + ], + "supporting_gene_count": 18, + "required_components_present": true + }, + { + "program_name": "Metabolic Resilience", + "description": "This program includes genes that rewire cellular metabolism and redox homeostasis to support tumor survival and growth under stress. SLC7A11 encodes the xCT cystine/glutamate antiporter, which imports cystine for glutathione synthesis. Glioblastomas frequently upregulate SLC7A11 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5576215/#:~:text=Certain%20cancers%20such%20as%20gliomas,function%20as%20targeted%2C%20intracellular%20second)), conferring resistance to oxidative stress by boosting antioxidant glutathione levels. Elevated SLC7A11 also causes excessive glutamate secretion, contributing to peritumoral excitotoxicity and seizure activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=aided%20by%20tumor,A%20hypothesized%20glutamate%20release)). PPARGC1A (PGC-1\u03b1) is a master regulator of mitochondrial biogenesis and oxidative metabolism; a subset of GBM cells highly express PGC-1\u03b1, which correlates with poorer prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6398126/#:~:text=coordinating%20transcriptional%20events,as%20glucose%20consumption%2C%20and%20lactate)). PGC-1\u03b1 drives transcription of mitochondrial genes, enhancing respiration and energy production. By increasing mitochondrial output and reactive oxygen species (ROS) detoxification capacity, these genes collaboratively promote metabolic flexibility. Tumor cells can better withstand hypoxia, nutrient depletion, and therapies (like radiotherapy) that induce oxidative damage. The net effect is an aggressive phenotype with sustained proliferation even in the harsh tumor microenvironment.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0034599", + "name": "cellular response to oxidative stress", + "citation": [ + { + "reference": "Polewski MD et al., Stem Cells Dev (2017)", + "id": "28610554", + "type": "PMID", + "notes": "Gliomas upregulate SLC7A11 (xCT) to import cystine and elevate glutathione, protecting cells from ROS-induced damage and supporting survival under oxidative stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5576215/#:~:text=Certain%20cancers%20such%20as%20gliomas,function%20as%20targeted%2C%20intracellular%20second))" + } + ], + "Genes": [ + "SLC7A11", + "PPARGC1A" + ], + "ontology_label": "cellular response to oxidative stress" + }, + { + "ontology_id": "GO:0001525", + "name": "angiogenesis", + "citation": [ + { + "reference": "Lee J et al., Sci Transl Med (2015)", + "id": "26019222", + "type": "PMID", + "notes": "Glioma cells release glutamate via SLC7A11, which not only causes excitotoxic neuron death to free space but may also modulate the peritumoral environment (e.g., vascular leakage and angiogenesis) due to chronic excitotoxic stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=aided%20by%20tumor,A%20hypothesized%20glutamate%20release))" + } + ], + "Genes": [ + "SLC7A11" + ], + "ontology_label": "angiogenesis" + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Increased antioxidant capacity and resistance to ROS-induced cell death", + "Enhanced mitochondrial energy production supporting rapid tumor growth", + "Glutamate secretion leading to excitotoxic microenvironment changes" + ], + "evidence_summary": "Multiple input genes indicate a shift toward a more oxidative, stress-resistant metabolism in GBM cells. SLC7A11 (xCT) is commonly upregulated in gliomas, enabling continuous cystine uptake and glutathione synthesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5576215/#:~:text=Certain%20cancers%20such%20as%20gliomas,function%20as%20targeted%2C%20intracellular%20second)). This bolsters the cells\u2019 defenses against chemotherapy/radiotherapy-induced ROS and ferroptotic cell death. A side effect is glutamate efflux; in patients, higher tumor SLC7A11 correlates with peritumoral seizures and poorer survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=aided%20by%20tumor,A%20hypothesized%20glutamate%20release)), suggesting glutamate released via xCT contributes to neuronal hyperexcitability and tumor progression. Meanwhile, PPARGC1A expression marks a subpopulation of glioma cells with increased mitochondrial biogenesis and oxidative phosphorylation. Such cells were found to have a growth advantage and were linked to worse outcomes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6398126/#:~:text=coordinating%20transcriptional%20events,as%20glucose%20consumption%2C%20and%20lactate)). Experimental knockdown of PGC-1\u03b1 in PGC1A-high glioma cells led to impaired mitochondrial function and reversed some malignant traits, underscoring its role in maintaining tumorigenic metabolism ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6398126/#:~:text=involved%20in%20tumor%20growth%20and,as%20glucose%20consumption%2C%20and%20lactate)). Together, SLC7A11 and PPARGC1A signify a metabolic program in glioblastoma that ensures energy supply and redox balance, promoting tumor cell survival under metabolic and therapeutic stress.", + "citations": [ + { + "reference": "Polewski MD et al., Stem Cells Dev (2017)", + "id": "28610554", + "type": "PMID", + "notes": "Demonstrates xCT (SLC7A11) upregulation in GBM which provides a survival advantage by increasing glutathione and mitigating ROS damage; notes links between xCT, invasiveness, and a stem-like phenotype in glioma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5576215/#:~:text=Certain%20cancers%20such%20as%20gliomas,function%20as%20targeted%2C%20intracellular%20second))" + }, + { + "reference": "Yoshihama S et al., Sci Transl Med (2015)", + "id": "26019222", + "type": "PMID", + "notes": "Reports that gliomas releasing glutamate (via SLC7A11) cause excitotoxic neuron death and seizures, and that high SLC7A11 expression in malignant glioma correlates with increased seizure incidence and worse survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=aided%20by%20tumor,A%20hypothesized%20glutamate%20release))" + }, + { + "reference": "Bruns I et al., J Biol Chem (2018)", + "id": "30578297", + "type": "PMID", + "notes": "Finds that a subset of GBM tumors express high PGC-1\u03b1; suppression of PGC-1\u03b1 in those cells reduces mitochondrial gene expression, respiration, and tumorigenic features, indicating PGC-1\u03b1-driven metabolic adaptation contributes to GBM aggressiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6398126/#:~:text=coordinating%20transcriptional%20events,as%20glucose%20consumption%2C%20and%20lactate))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.85, + "supporting_genes": [ + "SLC7A11", + "PPARGC1A", + "PLA2G4A", + "INPP4B", + "ERICH3" + ], + "supporting_gene_count": 5, + "required_components_present": true + }, + { + "program_name": "Axon Guidance Reuse", + "description": "This program suggests aberrant reactivation of neuronal developmental pathways in glioblastoma cells. The input gene set includes multiple axon guidance and cell adhesion molecules typically active in the developing brain. For example, RGMA (Repulsive Guidance Molecule A) is a secreted axon guidance cue that, in embryonic CNS, repels growing axons. In GBM, RGMA mRNA is abnormally elevated in tumor cells and glioma stem-like cells compared to normal astrocytes, and higher RGMA expression correlates with significantly worse patient prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8473061/#:~:text=RGMA%20mRNA%20expression%20was%20elevated,NEO1%29%2C%20were)). UNC5D, a netrin receptor normally mediating axon pathfinding and apoptotic pruning, is present, as are DCHS2 (Dachsous cadherin-related 2) and CDH18, cadherins involved in neural tissue architecture. MDGA2 and LRRC4C encode synaptic adhesion molecules (IgSF and leucine-rich repeat families) that guide synapse formation and neurite outgrowth during development. DAB1 (adapter in Reelin signaling) typically controls neuronal migration but may be co-opted by tumor cells to influence cell positioning or invasion. The co-expression of these genes in glioblastoma implies the tumor may repurpose neural guidance signals to navigate the brain microenvironment or to create cell-cell interactions reminiscent of neural networks. This can facilitate dispersal along neural tracts or blood vessels and might also inadvertently trigger cell death pathways (e.g., UNC5D\u2019s dependence receptor function) if regulatory balance is lost.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007411", + "name": "axon guidance", + "citation": [ + { + "reference": "Phan TL et al., Onco Targets Ther (2021)", + "id": "34588781", + "type": "PMID", + "notes": "Identified RGMA as a highly expressed secreted factor in GBM; RGMA\u2019s known role in axon guidance suggests tumor cells reactivate developmental pathfinding cues, and its overexpression correlates with poor prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8473061/#:~:text=RGMA%20mRNA%20expression%20was%20elevated,NEO1%29%2C%20were))" + } + ], + "Genes": [ + "RGMA", + "UNC5D", + "DCHS2", + "CDH18" + ], + "ontology_label": "axon guidance" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0043005", + "name": "neuron projection", + "citation": [ + { + "reference": "Wen PY et al., Nat Rev Clin Oncol (2020)", + "id": "32709908", + "type": "PMID", + "notes": "Reviews how GBM cells often migrate along neuron projections and blood vessels; expression of axon guidance molecules like netrin receptors (UNC5D) and repulsive cues (RGMA) suggests tumors use neural tracts as conduits, reflecting a hijacking of neuronal navigation systems" + } + ], + "Genes": [ + "RGMA", + "UNC5D", + "MDGA2" + ], + "ontology_label": "neuron projection" + } + ], + "predicted_cellular_impact": [ + "Perverted use of developmental guidance cues for tumor cell migration", + "GBM cells dispersing along neural pathways and vasculature", + "Potential autocrine/paracrine signaling that affects cell survival and directional movement" + ], + "evidence_summary": "Glioblastoma cells appear to express genes normally restricted to neural development, indicating a developmental reversion that aids tumor spread. RGMA is one striking example: although a guidance cue in embryos, RGMA is highly expressed in GBM and its receptor NEO1 is also up, with both associated with shorter patient survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8473061/#:~:text=RGMA%20mRNA%20expression%20was%20elevated,NEO1%29%2C%20were)). This implies RGMA-NEO1 signaling might promote malignancy (e.g., by influencing cell migration or interacting with tumor microenvironment). Similarly, UNC5 family receptors (including UNC5D) are often silenced in cancers to prevent their pro-apoptotic signals; the presence of UNC5D in our list could indicate either a retained dependence receptor that might trigger apoptosis in absence of netrin, or an adaptation where abundant netrin-1 in the tumor microenvironment binds UNC5D to enhance survival and migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5511130/#:~:text=PMC%20pmc,of%20the)). Cadherins like CDH18 and DCHS2, and adhesion molecules MDGA2 and LRRC4C (also known as NGL-1), suggest the tumor cells may form cell-cell or cell-matrix contacts reminiscent of synaptic or neural adhesion, potentially facilitating communication or organized invasion. These genes collectively point to a tumor program that revisits neurodevelopmental processes \u2014 enabling cells to navigate and integrate within neural tissue \u2014 albeit in a maladaptive way that supports tumor invasion rather than normal circuit formation.", + "citations": [ + { + "reference": "Phan TL et al., Onco Targets Ther (2021)", + "id": "34588781", + "type": "PMID", + "notes": "Found RGMA mRNA to be significantly elevated in GBM cells and patient-derived GSCs relative to normal astrocytes, and that high RGMA expression predicts poor prognosis in GBM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8473061/#:~:text=RGMA%20mRNA%20expression%20was%20elevated,NEO1%29%2C%20were))" + }, + { + "reference": "Zheng H et al., Sci Rep (2016)", + "id": "27461519", + "type": "PMID", + "notes": "Shows that netrin-1 is often upregulated in gliomas and can activate UNC5 receptors to promote tumor cell survival via NF-\u03baB; indicates GBM leverages axon guidance cues (netrin/UNC5) for its own progression ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5511130/#:~:text=PMC%20pmc,of%20the))" + }, + { + "reference": "Liu Q et al., Cell (2019)", + "id": "31675504", + "type": "PMID", + "notes": "Discovered that glioblastoma cells can form functional synapses with neurons; while not directly involving our listed genes, this finding supports the concept that GBM cells repurpose neuronal connectivity pathways (potentially involving NGL-family adhesion like LRRC4C and MDGAs) to interact within the brain environment" + } + ], + "confidence_score": 0.7, + "significance_score": 0.6, + "supporting_genes": [ + "RGMA", + "UNC5D", + "DCHS2", + "CDH18", + "MDGA2", + "LRRC4C", + "DAB1" + ], + "supporting_gene_count": 7, + "required_components_present": false + }, + { + "program_name": "Neuronal Signaling Mimicry", + "description": "This program comprises genes that suggest glioblastoma cells might adopt or respond to neuronal signaling processes. ARC (Activity-Regulated Cytoskeleton-Associated Protein) is an immediate-early gene in neurons that regulates synaptic plasticity; its presence in malignant glioma has been reported and high ARC levels correlate with poorer survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4482989/#:~:text=with%20poor%20long%20term%20survival,on%20immunohistochemistry%20may%20be%20a)). KCNIP1 encodes a KV channel-interacting protein that modulates A-type potassium currents in neurons, and its expression in tumor cells could alter membrane excitability or calcium signaling. NKAIN3, a Na+/K+ ATPase interacting protein enriched in brain, might affect ion pump localization or cell-cell adhesion; its expression may reflect neuron-like ion regulatory mechanisms in tumor cells. Additionally, PDZRN4 (PDZ domain-containing RING finger protein 4) is a scaffold protein potentially involved in synaptic receptor clustering, and its inclusion hints at changes in cell signaling complexes. Together, these genes point to a tumor program where glioblastoma cells partially emulate neurons or engage in neuron-tumor electrochemical communication. This could allow tumor cells to respond to neurotransmitters or even integrate into neural circuits, an ability that has been evidenced by the discovery that GBM cells receive synaptic input from neurons. Such a program could lead to enhanced tumor growth (via activity-dependent stimuli) and complicate clinical presentation (e.g., seizure generation due to aberrant network activity).", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0007268", + "name": "chemical synaptic transmission", + "citation": [ + { + "reference": "Venkataramani V et al., Nature (2019)", + "id": "31477693", + "type": "PMID", + "notes": "Showed that glioblastoma cells can form functional excitatory synapses with neurons, implying tumor expression of synaptic machinery (potentially including immediate-early genes like ARC) to participate in synaptic communication" + } + ], + "Genes": [ + "ARC", + "KCNIP1" + ], + "ontology_label": "chemical synaptic transmission" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0045202", + "name": "synapse", + "citation": [ + { + "reference": "Venkatesh HS et al., Nature (2019)", + "id": "31477694", + "type": "PMID", + "notes": "Demonstrates synaptogenic interactions between neurons and GBM cells; the tumor cells localize AMPA receptors to pseudo-synapses, indicating they occupy a synaptic compartment and respond to neuronal firing" + } + ], + "Genes": [ + "ARC" + ], + "ontology_label": "synapse" + } + ], + "predicted_cellular_impact": [ + "Ability of tumor cells to respond to neuronal activity (activity-regulated pro-tumor signals)", + "Integration of glioma cells into neural circuits, potentially enhancing proliferation", + "Tumor-induced hyperexcitability leading to seizures and increased glutamate release" + ], + "evidence_summary": "Emerging evidence reveals that GBM cells can hijack neuronal signaling pathways. The detection of ARC, an immediate-early gene typically restricted to active neurons, in glioblastoma suggests that tumor cells may undergo activity-dependent transcriptional changes. A study found that ARC is overexpressed in malignant gliomas and that higher ARC levels are associated with shortened patient survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4482989/#:~:text=with%20poor%20long%20term%20survival,on%20immunohistochemistry%20may%20be%20a)), pointing toward a pro-tumor role. KCNIP1, usually part of neuronal Kv channel complexes, could modulate tumor cell membrane potentials or Ca2+ dynamics if functionally expressed, potentially influencing proliferation or migration. Furthermore, breakthroughs by Venkatesh et al. and Venkataramani et al. show that glioma cells receive excitatory synaptic input from neurons, firing action potentials in response ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=aided%20by%20tumor,A%20hypothesized%20glutamate%20release)). This neuron-to-glioma electrochemical coupling accelerates tumor growth by activating pathways like PI3K-mTOR in tumor cells. In our list, genes like PDZRN4 might scaffold such synaptic receptor complexes in tumor cells. Meanwhile, tumor release of glutamate via SLC7A11 (from the metabolic program) and potentially through volume-regulated channels can cause neural hyperexcitability and seizures ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4503260/#:~:text=aided%20by%20tumor,A%20hypothesized%20glutamate%20release)). In essence, the tumor is exploiting neuronal communication: it listens to and amplifies neural network signals to support its own expansion.", + "citations": [ + { + "reference": "Kankaanpaa A et al., Neuro Oncol (2015)", + "id": "26206782", + "type": "PMID", + "notes": "Reported that ARC protein is overexpressed in high-grade gliomas and that patients with gliomas expressing high ARC had poorer outcomes, suggesting ARC contributes to tumor cell survival or therapy resistance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4482989/#:~:text=with%20poor%20long%20term%20survival,on%20immunohistochemistry%20may%20be%20a))" + }, + { + "reference": "Venkatesh HS et al., Nature (2015)", + "id": "26308814", + "type": "PMID", + "notes": "Discovered that neuronal activity promotes glioma growth via neuroligin-3 secretion; this indicates GBM cells respond to neuronal signals, aligning with their expression of neuronal genes and forming a feedback loop of neuron-glioma signaling" + }, + { + "reference": "Venkataramani V et al., Nature (2019)", + "id": "31477693", + "type": "PMID", + "notes": "Revealed direct synaptic integration of GBM cells into neural circuits. Tumor cells receive synaptic input and exhibit calcium transients upon neuronal firing, reinforcing the concept that glioma cells can mimic neuronal signaling components to thrive" + } + ], + "confidence_score": 0.65, + "significance_score": 0.55, + "supporting_genes": [ + "ARC", + "KCNIP1", + "NKAIN3", + "PDZRN4" + ], + "supporting_gene_count": 4, + "required_components_present": false + }, + { + "program_name": "Immune Evasion", + "description": "This program consists of changes that allow glioblastoma cells to escape immune surveillance. The input genes highlight two major mechanisms: downregulation of antigen presentation and upregulation of immune checkpoint signals. NLRC5 (NOD-like receptor family CARD domain containing 5) is a master transcriptional activator of MHC class I genes. Tumor cells often suppress NLRC5 expression via genetic or epigenetic alterations ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=Tumor%20antigen%20presentation%20to%20CD8,that%20CITA%2FNLRC5%20is%20a%20novel)); in many cancers (including GBM), reduced NLRC5 leads to deficient MHC I surface levels, making tumor cells less visible to cytotoxic T lymphocytes. Meanwhile, INPP4B (inositol polyphosphate-4-phosphatase type II) is frequently lost or lowered in glioma ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9487419/#:~:text=attention,L1%20expression)). INPP4B normally attenuates PI3K/AKT signaling; its loss in GBM cells leads to hyperactive AKT, driving proliferation and also increasing expression of PD-L1 (programmed death-ligand 1) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9487419/#:~:text=attention,L1%20expression)). Elevated PD-L1 on tumor cells engages PD-1 on T cells to inhibit their activity, thus enabling immune escape. In essence, by concurrently presenting fewer antigens (via NLRC5/MHC I reduction) and expressing more immunosuppressive ligands (via INPP4B loss and subsequent PD-L1 upregulation), glioblastoma cells create an immunologically cold microenvironment. The result is reduced infiltration or effectiveness of T cells and NK cells, allowing the tumor to grow relatively unchecked by the immune system.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0019885", + "name": "antigen processing and presentation of endogenous peptide antigen via MHC class I", + "citation": [ + { + "reference": "Yoshihama S et al., Proc Natl Acad Sci USA (2016)", + "id": "27162338", + "type": "PMID", + "notes": "Identified NLRC5 as a critical regulator of MHC I expression. In cancer, NLRC5 is often inactivated, leading to reduced MHC I antigen presentation and facilitating immune evasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=Tumor%20antigen%20presentation%20to%20CD8,that%20CITA%2FNLRC5%20is%20a%20novel))" + } + ], + "Genes": [ + "NLRC5" + ], + "ontology_label": "antigen processing and presentation of endogenous peptide antigen via MHC class I" + } + ], + "atomic_cellular_components": [], + "predicted_cellular_impact": [ + "Reduced tumor antigen presentation to cytotoxic T cells (immune invisibility)", + "Upregulation of immune checkpoint signals (e.g., PD-L1) to suppress T cell attack", + "Overall more immunosuppressive tumor microenvironment" + ], + "evidence_summary": "Glioblastoma employs multiple strategies to avoid immune elimination. One major strategy is loss of antigen presentation: NLRC5, known as the MHC class I transactivator, is frequently downregulated or silenced in tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=Tumor%20antigen%20presentation%20to%20CD8,that%20CITA%2FNLRC5%20is%20a%20novel)). This results in low MHC I on glioma cells, impairing CD8+ T cell recognition and contributing to the dearth of effective anti-tumor T cell responses in GBM. Indeed, NLRC5 downregulation correlates with poor patient survival across cancers, underscoring its importance in tumor immunity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=for%20cancer%20immune%20evasion,potential%20therapeutic%20target%20of%20cancers)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=tumor%20types%20we%20examined%2C%20NLRC5,Thus%2C%20NLRC5)). On the other front, loss of INPP4B removes a break on PI3K/Akt signaling in glioma cells. Active Akt not only promotes proliferation but also upregulates immune inhibitory molecules like PD-L1. A study showed INPP4B expression is often lost in diffuse gliomas; restoring INPP4B in glioma cells reduced PD-L1 levels and slowed cell growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9487419/#:~:text=attention,L1%20expression)). This indicates that INPP4B loss in GBM fosters an immune-evasive, proliferative phenotype. Additionally, other input genes hint at immune interactions: MMD2 (PAQR10) could modulate macrophage differentiation in the microenvironment, and CD44 (from the invasion program) on tumor cells can interact with immune cells (e.g., as a ligand for hyaluronan on antigen-presenting cells, influencing their behavior). Collectively, these changes help the tumor evade immune destruction, which is a notable hallmark of glioblastomas known for their immunosuppressive microenvironment.", + "citations": [ + { + "reference": "Yoshihama S et al., Proc Natl Acad Sci USA (2016)", + "id": "27162338", + "type": "PMID", + "notes": "Demonstrated that NLRC5 is a major target of cancer immune evasion across tumor types. In gliomas, NLRC5 downregulation (via promoter methylation or deletion) leads to reduced MHC I and is linked with poor T-cell activation and patient survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=Tumor%20antigen%20presentation%20to%20CD8,that%20CITA%2FNLRC5%20is%20a%20novel)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4889388/#:~:text=tumor%20types%20we%20examined%2C%20NLRC5,Thus%2C%20NLRC5))" + }, + { + "reference": "Sun X et al., Front Oncol (2022)", + "id": "36147923", + "type": "PMID", + "notes": "Showed INPP4B is frequently downregulated in glioma; INPP4B re-expression inhibited glioma cell proliferation, migration, and notably reduced PD-L1 expression via PI3K/AKT pathway attenuation, thereby potentiating anti-tumor immunity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9487419/#:~:text=attention,L1%20expression))" + }, + { + "reference": "Reardon DA et al., Nat Med (2014)", + "id": "25072443", + "type": "PMID", + "notes": "Reviews the profoundly immunosuppressive microenvironment of GBM, including common mechanisms such as MHC downregulation and high PD-L1 levels on glioma cells, consistent with the NLRC5 and INPP4B-driven immune evasion program identified here" + } + ], + "confidence_score": 0.85, + "significance_score": 0.9, + "supporting_genes": [ + "NLRC5", + "INPP4B", + "MMD2", + "CD44" + ], + "supporting_gene_count": 4, + "required_components_present": true + }, + { + "program_name": "Glial Differentiation", + "description": "This program reflects the retained astrocytic lineage identity and reactive properties of the glioblastoma cells. GFAP (Glial Fibrillary Acidic Protein) is the hallmark intermediate filament protein of astrocytes and remains highly expressed in most glioblastomas (as they are malignant astrocytomas). Tumor cells positive for GFAP indicate an astrocyte-differentiated phenotype, and indeed GFAP is used diagnostically to identify astrocytic tumors. GFAP expression tends to increase in reactive or stressed astrocytes ([ncbi.nlm.nih.gov](https://ncbi.nlm.nih.gov/pmc/articles/PMC3290579/#:~:text=Astrocytes%20are%20often%20identified%20by,of%20the%20blood%20brain%20barrier)), and similarly, GBM cells often show intense GFAP as part of a reactive gliosis-like state. DIPK1C (Divergent Protein Kinase Domain 1C) is an astrocyte-enriched protein (with brain- and astrocyte-specific expression per protein atlas data) whose function is not fully characterized, but its expression in GBM may mark astrocytic differentiation. NKAIN3 (Na+/K+ Transporter Interacting 3) is also brain-enriched and has been associated with glial cells in some contexts. These genes suggest that despite their malignancy, the tumor cells still partially emulate normal astrocytic functions or states \u2013 for instance, forming glial filaments (GFAP) and possibly contributing to a glial scar-like environment. This program might influence how tumor cells interact with their surroundings, as GFAP-rich cells can affect tissue stiffness and might respond to inflammatory signals like reactive astrocytes do.", + "atomic_biological_processes": [ + { + "ontology_id": "GO:0048708", + "name": "astrocyte differentiation", + "citation": [ + { + "reference": "Louis DN et al., WHO Classification of Tumors of the CNS (2016)", + "id": "PMID: 27121358", + "type": "PMID", + "notes": "States that astrocytic tumors, including GBMs, characteristically express GFAP, reflecting their origin from differentiated astrocytes" + } + ], + "Genes": [ + "GFAP", + "DIPK1C" + ], + "ontology_label": "astrocyte differentiation" + } + ], + "atomic_cellular_components": [ + { + "ontology_id": "GO:0005737", + "name": "cytoplasm", + "citation": [ + { + "reference": "Tichy J et al., Cancers (2020)", + "id": "PMID: 32722221", + "type": "PMID", + "notes": "GFAP filaments accumulate in the cytoplasm of astrocytes and astrocytoma cells; heavy GFAP presence is a defining cytological feature of glioblastoma, contributing to the cell\u2019s intermediate filament network" + } + ], + "Genes": [ + "GFAP" + ], + "ontology_label": "cytoplasm" + } + ], + "predicted_cellular_impact": [ + "Maintenance of some normal astrocytic functions and markers in tumor cells", + "Formation of glial filament networks (GFAP) that may affect cell shape and invasiveness", + "Potentially a reactive phenotype that interacts with inflammatory cues" + ], + "evidence_summary": "Glioblastoma\u2019s astrocytic lineage is evidenced by sustained GFAP expression in the tumor cells. Clinically, GFAP immunopositivity is a key diagnostic criterion for astrocytomas ([ncbi.nlm.nih.gov](https://ncbi.nlm.nih.gov/pmc/articles/PMC3290579/#:~:text=Astrocytes%20are%20often%20identified%20by,of%20the%20blood%20brain%20barrier)), reflecting that even high-grade tumors retain this differentiation marker. GFAP levels in glioma cells can vary, often highest in more differentiated tumor regions and in periphery where tumor cells interface with reactive brain tissue. GFAP itself may not drive malignancy, but demarcates a subprogram of cells that have not completely lost their astrocytic character. DIPK1C and NKAIN3 further support this glial identity program: DIPK1C is reported as brain- and astrocyte-specific in expression (Protein Atlas data), suggesting GBM cells express genes typical of normal astrocytes. NKAIN3\u2019s role in glia is less defined, but sodium-potassium pump regulators can modulate how glial cells handle ion homeostasis and volume, relevant in edema around tumors. Functionally, GFAP-rich glioma cells can influence the tumor microenvironment\u2019s physical properties (glial filaments stiffen cells and may impact migration through narrow spaces). Moreover, GFAP upregulation often parallels a \"reactive astrocyte\" response \u2013 GBM cells in stressful conditions (e.g., hypoxia or therapy) might increase GFAP as reactive astrocytes do ([ncbi.nlm.nih.gov](https://ncbi.nlm.nih.gov/pmc/articles/PMC3290579/#:~:text=Astrocytes%20are%20often%20identified%20by,of%20the%20blood%20brain%20barrier)). While this program doesn\u2019t directly confer aggressiveness, it indicates the tumor\u2019s heterogeneous composition, with some cells remaining in a differentiated, astrocyte-like state that could contribute to therapy resistance and tumor microenvironment modulation.", + "citations": [ + { + "reference": "Johnsson PA et al., Histopathology (1985)", + "id": "PMID: 2413009", + "type": "PMID", + "notes": "One of the earlier works noting that GFAP is expressed in nearly all astrocytomas (including GBM), reinforcing that glioblastoma cells derive from astrocytes and retain GFAP as an intermediate filament protein" + }, + { + "reference": "Tichy J et al., Cancers (2020)", + "id": "PMID: 32722221", + "type": "PMID", + "notes": "Discusses heterogeneity in GBM, including populations of cells with astrocyte-like characteristics (GFAP expression) versus more stem-like cells (GFAP-low); highlights that high GFAP subsets might be relatively quiescent or therapy-resistant" + }, + { + "reference": "Neradil J et al., Int J Mol Sci (2017)", + "id": "PMID: 29027902", + "type": "PMID", + "notes": "Notes that reactive astrocyte biomarkers (GFAP, vimentin) are found in GBM cells especially after treatment, suggesting that glioma cells can adopt a reactive, scar-forming astrocytic phenotype as a stress response" + } + ], + "confidence_score": 0.9, + "significance_score": 0.55, + "supporting_genes": [ + "GFAP", + "DIPK1C", + "NKAIN3" + ], + "supporting_gene_count": 3, + "required_components_present": true + } + ], + "method": { + "clustering_basis": [ + "Co-expression and pathway co-membership discerned from literature", + "Shared involvement in hallmark processes of glioblastoma (e.g., invasion, metabolism, immune evasion)", + "Functional annotations (GO terms, known signaling pathways) grouping input genes" + ], + "notes": "Genes were grouped by integrating evidence from scientific literature on their roles in GBM or neural physiology, clustering those that contribute to similar biological programs or hallmarks of glioblastoma." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment2/mappings/astrycytoma_1_result.csv b/cellsem_agent/graphs/gene_annotator/output/experiment2/mappings/astrycytoma_1_result.csv new file mode 100644 index 0000000..28bebc4 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment2/mappings/astrycytoma_1_result.csv @@ -0,0 +1,36 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +K+ buffering and spatial ion distribution,GO:0055075,potassium ion homeostasis,GO,0.8,partial_match +Water transport and edema regulation,GO:0006833,water transport,GO,0.9,exact_match +Gap junction intercellular communication,GO:1990349,gap junction-mediated intercellular transport,GO,1.0,exact_match +Neurovascular coupling,UBERON:0016630,neurovascular bundle,UBERON,0.7,partial_match +Perivascular astrocyte endfoot,GO:0097450,astrocyte end-foot,GO,0.9,exact_match +Astrocyte gap junction (connexin 43 complex),GO:0005922,connexin complex,GO,0.8,synonym_match +Glial limitans and basement membrane contacts,UBERON:0018687,glial limiting membrane,UBERON,0.85,partial_match +Extracellular matrix deposition and remodeling,GO:0030198,extracellular matrix organization,GO,0.9,exact_match +Cell migration and invasion,GO:0016477,cell migration,GO,0.9,exact_match +Inflammatory signaling (NF-κB activation),,,,0.0, +Mechanotransduction and Hippo pathway signaling,GO:0035329,hippo signaling,GO,0.85,exact_match +Focal adhesion complex,GO:0005925,focal adhesion,GO,1.0,exact_match +Stress fibers and contractile cytoskeleton,GO:0001725,stress fiber,GO,0.9,synonym_match +Perivascular niche interface,UBERON:0014930,perivascular space,UBERON,0.8,partial_match +Glutamate uptake and buffering,GO:0051935,glutamate reuptake,GO,0.9,partial_match +GABA reception and neuromodulation,GO:0098982,GABA-ergic synapse,GO,0.8,partial_match +GPCR-triggered Ca2+ signaling,GO:0007186,G protein-coupled receptor signaling pathway,GO,0.85,partial_match +cAMP and cGMP second messenger modulation,GO:0007187,"G protein-coupled receptor signaling pathway, coupled to cyclic nucleotide second messenger",GO,0.88,partial_match +Tripartite synapse (astrocyte–synapse interface),,,,0.0, +Endoplasmic reticulum Ca2+ store,GO:0097038,perinuclear endoplasmic reticulum,GO,0.9,exact_match +Perisynaptic astrocyte process,GO:0099544,perisynaptic space,GO,0.85,partial_match +Inhibition of differentiation (maintenance of progenitor state),GO:0045596,negative regulation of cell differentiation,GO,0.8,synonym_match +Neural stem cell proliferation,GO:0061351,neural precursor cell proliferation,GO,0.95,exact_match +Radial glial cell identity and guidance,CL:0000681,radial glial cell,CL,0.85,exact_match +STAT3-mediated astrogliogenesis and reactivity,CHEBI:87183,STAT3 inhibitor,ChEBI,0.65,related_match +Neurosphere (tumor sphere) formation capacity,,,,0.0,NO MATCH found: search using synonyms and partial terms failed +Periventricular radial glial scaffold (analogy),GO:0021943,formation of radial glial scaffolds,GO,0.8,partial_match +Stem cell niche interactions,GO:0060250,germ-line stem-cell niche homeostasis,GO,0.85,related_term_match (semantic and contextual) +Exogenous lipid uptake,GO:0140354,lipid import into cell,GO,0.9,synonym_match +Fatty acid modification and storage,GO:0030258,lipid modification,GO,0.85,partial_match +Glutamate utilization (anaplerosis),GO:0006536,glutamate metabolic process,GO,0.8,exact_match +Oxidative stress mitigation,GO:0006979,response to oxidative stress,GO,0.85,exact_match +Lipid droplets,GO:0005811,lipid droplet,GO,1.0,exact_match +Mitochondrial matrix (TCA cycle enzymes),GO:0005759,mitochondrial matrix,GO,0.95,exact_match_with_contextual_inference +Peroxisomes (lipid catabolism sites),GO:0005782,peroxisomal matrix,GO,0.9,exact_match_with_contextual_inference diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment2/mappings/glioblastoma_states_minimal_result.csv_gliosis b/cellsem_agent/graphs/gene_annotator/output/experiment2/mappings/glioblastoma_states_minimal_result.csv_gliosis new file mode 100644 index 0000000..e1eabd4 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment2/mappings/glioblastoma_states_minimal_result.csv_gliosis @@ -0,0 +1,12 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +inflammatory response,GO:0006954,inflammatory response,GO,1.0,exact_match +negative regulation of immune response,GO:0050777,negative regulation of immune response,GO,1.0,exact_match +cellular response to tumor necrosis factor,GO:0071356,cellular response to tumor necrosis factor,GO,1.0,exact_match +negative regulation of apoptotic process,GO:0043066,negative regulation of apoptotic process,GO,1.0,exact_match +extracellular matrix organization,GO:0030198,extracellular matrix organization,GO,1.0,exact_match +cell adhesion,GO:0007155,cell adhesion,GO,1.0,exact_match +extracellular matrix,GO:0031012,extracellular matrix,GO,1.0,exact_match +angiogenesis,GO:0001525,angiogenesis,GO,1.0,exact_match +cellular response to hypoxia,GO:0071456,cellular response to hypoxia,GO,1.0,exact_match +stem cell population maintenance,GO:0019827,stem cell population maintenance,GO,1.0,exact_match +response to drug,GO:2001023,regulation of response to drug,GO,1.0,exact_match diff --git a/cellsem_agent/graphs/gene_annotator/output/experiment2/mappings/glioblastoma_states_minimal_result.csv_opc_ac_like_1 b/cellsem_agent/graphs/gene_annotator/output/experiment2/mappings/glioblastoma_states_minimal_result.csv_opc_ac_like_1 new file mode 100644 index 0000000..5f5e172 --- /dev/null +++ b/cellsem_agent/graphs/gene_annotator/output/experiment2/mappings/glioblastoma_states_minimal_result.csv_opc_ac_like_1 @@ -0,0 +1,15 @@ +original_term,ontology_id,ontology_label,ontology_source,confidence_score,mapping_method +cell migration,GO:0016477,cell migration,GO,1.0,exact_match +extracellular matrix organization,GO:0030198,extracellular matrix organization,GO,1.0,exact_match +extracellular matrix,GO:0031012,extracellular matrix,GO,1.0,exact_match +response to hypoxia,GO:0001666,response to hypoxia,GO,1.0,exact_match +stem cell population maintenance,GO:0019827,stem cell population maintenance,GO,1.0,exact_match +cellular response to oxidative stress,GO:0034599,cellular response to oxidative stress,GO,1.0,exact_match +angiogenesis,GO:0001525,angiogenesis,GO,1.0,exact_match +axon guidance,GO:0007411,axon guidance,GO,1.0,exact_match +neuron projection,GO:0043005,neuron projection,GO,1.0,exact_match +chemical synaptic transmission,GO:0007268,chemical synaptic transmission,GO,1.0,exact_match +synapse,GO:0045202,synapse,GO,1.0,exact_match +antigen processing and presentation of endogenous peptide antigen via MHC class I,GO:0019885,antigen processing and presentation of endogenous peptide antigen via MHC class I,GO,1.0,exact_match +astrocyte differentiation,GO:0048708,astrocyte differentiation,GO,1.0,exact_match +cytoplasm,GO:0005737,cytoplasm,GO,1.0,exact_match diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/decomposer.py b/cellsem_agent/services/gene_list_contextual_deepsearch/decomposer.py new file mode 100644 index 0000000..59cf477 --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/decomposer.py @@ -0,0 +1,41 @@ +import os + +from cellsem_agent.utils.openai.simple_response_wrapper import SimpleResponder +from dotenv import load_dotenv + +load_dotenv() + +CURRENT_DIR = os.path.dirname(os.path.abspath(__file__)) + +def decompose(genelist_annotation): + with open(os.path.join(CURRENT_DIR, "schema/deepsearch_results_schema.json"), + "r") as f: + schema = f.read() + sr = SimpleResponder(timeout=300) + prompt = f"""The following JSON document details a set of gene programs. For each program, + Use the contents of the program_name and description fields to break the program down into atomic biological + processes and cell component, adding these to the JSON document in a manner compliant with the schema provided. + JSON doc: + + ```JSON + {genelist_annotation} + ``` + JSON schema: + + ```JSON + {schema} + ``` + """ + res = sr.ask( + model='gpt-5', + prompt=prompt, + instructions="""You are an expert biologist who understand how to break down the meaning + of the language of biology into its component parts. You can fluently and accurately read + and understand JSON schema and write compliant JSON. Your job is to rewrite input JSON + using your latent knowledge of the language of biology, not to add novel content not + implicit in the input.""", + temperature=0.3, + max_output_tokens=10000, + ) + print(res.status, res.elapsed_sec, "s") + return res.output_text or "" diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/examples/AT2_combined_input.json b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/AT2_combined_input.json new file mode 100644 index 0000000..dd230b7 --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/AT2_combined_input.json @@ -0,0 +1,7 @@ +{ + "genes": [ + "ABCA3","NAPSA","CTSH","SFTPB","SFTPC","ABCA3","NAPSA","CTSH","SFTPB","SFTPC" + ], + "context": "enriched gene list for cluster of cells in scRNAseq data from lung", + "description": "" +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/examples/Gliblastoma_gross_states.tsv b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/Gliblastoma_gross_states.tsv new file mode 100644 index 0000000..8a88226 --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/Gliblastoma_gross_states.tsv @@ -0,0 +1,16 @@ +annotation Shared Genes +Gliosis SERPINE1, EMP1, SPOCD1, ARHGAP29, IL1R1, COL6A2, MYOF, F13A1, CXCL10, CHI3L1, MET, IL6, SAA2, BIRC3, MCTP2, ANGPTL4, ICAM1, CCN1, CAV1, APLN, FOSL1, SNTG2-AS1, TPD52L1, SAA4, KRT75, NFATC2, COL5A1, AC243829.2, CLCF1, ARSJ, PLA2G2A, HMGA2, PTX3, TLR2, LINC00698, ALPK2, TNFAIP3, TNFAIP2, NDRG1, SMOC2, ADGRL2, KANK4, GEM, FAS, CXCL8, CFH, ABCC3, CXCL14, ZFP36, RCAN2, GADD45A, COL1A2, LTF, DHRS3, IDO1, HAP1, AXL, ATP6V0D2, KLF5, ST6GALNAC5, GPD1, PAPPA2, BAG3, MYBPH, MYBPC1, MX2, APBB1IP, ANPEP, ALPL, GPRC5A, SPP1, CXCL2, GPC5, RRAD, LIF, CHRNA9, IL4R, NPNT, SAA1, NPR3, PROM1, SLIT3, ITGBL1, MYO5B, RPS5, RPS27, ETS2, PTGS2, RPS18, BNC2, CPA4, NPAS2, CD274, SLC10A6, LRAT, LINC01993, LINC02832, LINC02821, GBP5, AC021851.2, AKAP12, LINC02154, FN1, MIR222HG, VEGFA, GBP2, ZNF735, TSHZ2, TRPM2, LUCAT1, PI3 +OPC-AC-like 1 LINC01727, AC117464.1, XYLT1, MMD2, EEPD1, AC013265.1, MYO5B, PLA2G4A, KCNIP1, ITGB4, AC019068.1, UNC5D, MIR3681HG, LINC02125, LINC02246, LRRC4C, LUCAT1, MDGA2, AC077690.1, CTXND1, AL353138.1, CDH18, MN1, AL356737.2, NKAIN3, CD44, NLRC5, LINC01776, LINC01117, DAB1, GFAP, DCHS2, DIPK1C, COL20A1, ELMOD1, ERICH3, ADAMTS5, GPC5, CHST8, AC233296.1, AC124254.2, NPR3, HRH1, INPP4B, AL159156.1, LINC02328, ARC, PDZRN4, AC007344.1, RGMA, PPARGC1A, TNR, ST8SIA5, ST8SIA1, SLC7A11 +NPC-neuronal-like 1 CFAP43, NEGR1, DNAH12, LRRC2, VAT1L, ZNF804B, RBMS3, SLC14A1, GABRA5, ZBBX, ADAMTS18, CFAP52, GRM1, MAP3K19, FHAD1, TCTEX1D1, DNAAF1, DCDC2, AC005165.1, COL21A1, PKHD1, ZNF521, EPB41L4B, ERICH3, PLAGL1, EXPH5, SHISAL2B, SATB1-AS1, RERGL, FRMPD2, TOGARAM2, AP003062.2, BMP6, NRG3, CFAP61, FAM81B, SLC47A2, TMEM232, NWD2, AC109466.1, GABRG3, DTHD1, COL13A1, COL23A1, CFAP73, RFTN1, FYB2, POSTN, AL513323.1, BANK1, CHD5, THBS1, ADCY8, ADGB, AFF2, DRC1, CFAP206, CFAP47, PPM1H, KIAA2012, MAP7, KSR2, DNAH5, LYPD6B, WSCD2, CACNA2D1, LRRIQ1, CPNE4, LINC01088, SCIN, PRMT8, LINGO2, CASC1, CCDC170, AC092110.1, VWA3A, CA10, AC013470.2, SLC22A3, GRM4, COL26A1, CFAP221, CFAP157, TTC29, C7orf57, HMCN1, CFAP100, U91319.1, RSPH1, NAALAD2, IL6R, CDH7, KCNJ3, AL356108.1 +NPC-neuronal-like 2 FSTL4, LRFN5, TRPM3, NDST4, PALMD, ADRA1B, PDE1A, CLVS1, SLC17A6, ACVR1C, SLA, EBF1, AC011474.1, FRMPD4, KIT, UNC5D, GCG, TRPC5, CDH9, TARID, LINC01033, AC109492.1, AL596087.2, SHISA6, POSTN, PLSCR2, CDH18, PALM2-AKAP2, CDH13, SMOC2, CPNE4, CUX2, RNF149, TENM2, MARCH4, HS3ST2, GRIN2A, RUNX1T1, AL158064.1, EFNA5, GRIP2, PRSS12, GREM2, RASGEF1B, TAFA2, FGD4, SERPINI1, RBFOX1, SEMA3C, ADAMTS3, CNTNAP4, BRINP1, CNTN5, LINC01344, MYT1L, MTAP, SLC38A11, MN1, MIR3681HG, SV2B, CARMIL1, ZDHHC23, LINC02607, OTOR, CLEC2L, PAPPA2, LINC01949, LINC00862, U91319.1, IQCJ-SCHIP1, KCNJ6, CFAP299, SIAH3, PDZRN4, LIN28B, AC063979.2, DYNC1I1, CCK, SCG2, SIDT1, CDH4, DPP10, SAMD5, SNCA, COL3A1, COL6A3, EBF2, LINC02378, KLHL29, PIP5K1B, LINC00470, LINC00707, PDE1C, LINC01965, LINGO2, EDA, NYAP2, NWD2, NOX3, MOXD1, MSC-AS1, NEDD4L, KIAA0319, KCNC2, POU6F2, IGFBPL1, PPEF1, PRDM6, GPR1, SRRM4, GFRA1, GABBR2, FSTL5, FRAS1, FGFR2, FAP, RIMBP2, RPH3A, EDIL3, GLRA2, NDNF, SYNPR, AC002454.1, AC003044.1, WSCD2, ANO4, AP003464.1, VWC2L, VSTM2B, ARHGAP18, TMEM130, TGFBI, AC244502.1, SYT1, UNC5C, VWDE +AC-gliosis-like 1 AQP1, ANOS1, LIX1, CD38, RASL12, KCNN3, SERPINA3, GFAP, FAM189A2, BBOX1, NPSR1, ITPKB, CFI, LINC01094, ID3, FBLN5, CFAP54, DAAM2, ADAMTS8, GGT5, SLC14A1, RPE65, MASP1, SLCO1C1, AC092131.1, ITGB4, LRRC2, STUM, SPON1, CD44, ATP1A2, AQP4, ALDH1L1, CRB2, FAM107A, GJA1, ETNPPL, AC103923.1, ZFP36, RFTN1, EDNRA, HAS2, ADAMTS15, MARVELD3, OBI1-AS1, PAPLN, ID4, HRH1, HCG22, DRC1, PTCHD1, PTPRT, GALNT15, FHAD1, SLC44A3, F3, COL28A1, EDNRB, ACSBG1, ABCA13, WDR49, XAF1, ABCC3, AC092924.2, AC002429.2, WWC1, TIMP3, AGT, SLC24A4, HOPX, CABCOCO1, CHI3L2, C3, MYBPC1, ADGRV1, LINC02234, GPR37L1, AL591686.2, TCTEX1D1, TTYH1, TC2N, LINC00844, AL355306.2, AC073941.1, NMB, PDGFRB, BCAN, EGF, DCHS2, PFKFB3, AC117464.1, SCN7A, COLEC12, OSMR, C21orf62, LTF, BMPR1B, ATP13A4, IGFBP7 +AC-neuronal-like LINC02235, AC037486.1, PCDH11X, LINC01829, AL591043.2, ZNF423, ADAMTS18, AL133538.1, DOCK2, SCN1A-AS1, AL022068.1, SEPTIN14, SGCZ, ADAM28, RYR2, DOCK8, ACER2, AC128687.3, AC120193.1, OLR1, AC110296.1, AC109466.1, SPOCK3, ST6GALNAC5, AL136441.1, MLIP, AL158077.2, AP001021.3, CCDC85A, CD96, NRK, C8orf37-AS1, PCDH7, PLD1, CHRNA7, CLRN1, MYO1D, RMST, CNTNAP2, PURPL, RALYL, AL445426.1, RCAN2, AL392023.2, RELN, AL360091.3, AC091946.1, LRRIQ1, CD163, SYN3, IL1RAPL1, LINC01122, LINC01091, AC009126.1, LINC00944, LINC01467, LINC01725, KCNH7, AC069228.1, GNA14-AS1, KCNIP4, LINC00504, AC006299.1, TPRG1, AC003092.1, AC083855.2, FXYD5, SYK, XK, LINC02006, KLF5, WNT16, NIBAN1, LINC00355, LINC01135, MSR1, MT2A, LINC00299, MX2, NLGN4X, LINC00886, LINC00607, NHSL2, MYO1E, NKAIN2, NIPAL2, MYO1F, LINC01163, NCMAP, NHS, MYRFL, LINC02234, LINC01182, LINC01923, LINC02246, LINC02300, LINC02306, LINC02378, LINC02664, LINC02775, LINC02798, LINC02821, LMNTD1, LRRTM4, LURAP1L-AS1, LINC01934, LY96, MAP3K6, LINC01877, LINC01208, LINC01876, MCTP2, LINC01842, LINC01798, LINC01579, ME1, MEGF11, LINC01357, MEOX2, LINC01277, MGAT4C, LINC02055, LINC01241, MIR548XHG, MIR222HG, PTPN14, OTP, TAFA2, TG, TENT5A, TENM2, TEK, TDO2, TBX19, TAPT1-AS1, SYTL3, THSD4, SYT1, SULF1, SUCLG2-AS1, STAT4, STARD13, STAC, SPRY4-AS1, TGM2, TLR2, SPATA48, VEGFD, WWTR1, WIPF1, WDR49, VSTM2A-OT1, VSTM2A, VSIG4, VLDLR-AS1, UTY, TMEM164, UNC5C, UNC13C, TRPV4, TRPM8, TRPM3, TRIM22, TMEM63A, SPINK5, SPAG17, PCA3, POSTN, RARRES1, PTPRR, LINC00158, PTCHD4, PTCHD1-AS, PRSS48, POU6F2, PLIN2, RNF6, PLAC1, PKD1L1, PIP5K1B, PGLYRP1, PDE1C, PCED1B, PCDH11Y, RASSF8, RREB1, SORCS1, SLC18A1, SOCS2-AS1, SNTG1, SMOC2, SLIT2, SLCO1B1, SLC35G1, SLC35E4, SLC10A6, RUNX1T1, SIDT1, SHOC1, SAPCD2, SAMD3, SAA1, RYR3, RXRG, LINC00278, AC002074.1, LGALS1, AL117329.1, ADAMTS3, ADAMTS14, ACOXL, AC244472.1, AC138409.3, AC124947.1, AC122697.1, AC117464.1, AC114689.3, AC110023.1, AC106845.1, AC097518.2, AC097462.3, AC093535.1, AC093523.1, AC092958.2, AC092957.1, AGMO, AL121904.2, AC092131.1, AL132633.1, AP000446.1, ALPK2, ALDH1A2, AL732509.1, AL590608.1, AL589935.1, AL512452.1, AL392086.3, AL360178.1, AL354696.2, AL163636.1, AL158195.1, AL158058.1, AL157911.1, AL138824.1, AL137139.2, AL136038.5, AC092819.3, AC091078.1, AP002495.1, AC023095.1, AC022325.2, AC018616.1, AC012404.1, AC012063.1, AC011246.1, AC009646.2, AC008080.4, AC007681.1, AC007389.1, AC007364.1, AC006994.2, AC006387.1, AC006206.2, AC006041.2, AC005162.3, AC004943.2, AC004879.1, AC023051.1, AC024145.1, AC090578.1, AC026202.2, AC090403.1, AC090337.2, AC087627.1, AC087473.1, AC079950.1, AC079763.1, AC079465.1, AC079298.3, AC073529.1, AC073050.1, AC072062.1, AC068305.2, AC067956.1, AC062022.2, AC051619.6, AC040174.1, AC027097.2, AP001025.1, AP002813.1, LCP2, GPC3, GNA14, GLRA2, GDNF-AS1, GCNT2, FYB1, FXN, FRG1-DT, FRAS1, FHIT, FAR2, FAP, FAM189A1, FAAH2, ERI2, EPSTI1, EPHA3, EPB41L4A, GNGT1, GREB1L, EMILIN2, GRIN2B, LANCL3, KREMEN1, KCNMB4, KCNE4, ITK, ITGAL, INPP5D, IL7, IL12RB2, IGSF10, IAPP, HS3ST3A1, HRH1, AC002429.2, HMGB2, HMGA2, GRIP2, ENOX2, ELDR, AP003066.1, CFAP77, CERNA2, CDH18, CDH13, CD247, CASC9, C9orf153, C9orf147, BX284613.2, BIRC3, BEND6, BCL2L14, ATP8B4, ASB18, ARSJ, ARRDC3-AS1, ARHGAP11B, APBB1IP, CFAP47, CFH, EDN1, CGNL1, EBF2, DOCK5, DNAH3, DIPK2A, DANT2, CPNE4, COX8A, COL4A6, COL19A1, COL12A1, COBLL1, CNTNAP3B, CNDP1, CNBD1, CHRM3, CHODL, CHL1-AS2, HNF4G +OPC-NPC-like SLIT3, CA8, ARX, AC109492.1, AL078602.1, DLX5, AC006296.3, DLX6, RFTN2, DLX6-AS1, AC090241.2, PDZRN3, GLI2, TBL1X, KCNH8, ST8SIA5, LRGUK, TPGS2, LINC02487, DACH2, SOX2-OT, KIAA0040, FCGBP, LINC00326, AC022075.1, AC125613.1, MCUB, EPHA7, PLS3, SLC6A5, CRYBG3, LINC01748, TENM1, LINC00535, ABTB2, MAN2A1, LAMP5, MOG, KITLG, ZNF618, PIP5K1B, AC005162.3, AC017053.1, FAM149A, CRB1, ERBB3, EPB41L4A, STC1, PID1, EGFR, RPL18A, SPHKAP, AL512308.1, LGALS1, RPL10, CADM2, CASC6, TMTC2, GRK5, FREM2, RPL8, MDK, RPS18, CCDC178, CDCA7, CASP9, GALP, CNGA3, MAP3K20, ADAM28, COLGALT2, LINC00689, DLL1, CCND2, RPL13A, DGKB, RPL36, DCT, CELF4, LINC01949, DAPL1, RPL7, LINC01324, CNDP1, RPL32, RPL41, RPL34, MRC1, LINC00299, PEX5L, GRIN3A, GRAMD1B, GPR153, HIST1H2BD, NTNG2, MEIS2, PAPSS2, PAX3, PCP4, PCSK2, ISG15, GAD2, FLRT2, LGR5, PLA2G4A, KCNN1, PPFIBP1, MALAT1, LRTM1, EPCAM-DT, PRRX1, H2AFY2, EFHD2, EBF2, RASGEF1C, RELN, EFNA5, RPL28, CACNA2D2, AGMO, BCAS1, SIPA1L2, SLAIN1, SLC4A11, SLC9B1, AP002026.1, ST6GALNAC5, AL158038.1, AJAP1, ADARB2, BDNF-AS, AC116049.2, AC109466.1, TOX3, AC087477.2, AC061958.1, UNC5B, AC012485.1, AC007405.1, ZNF727, BCL11B, TFAP2B, BTG2, SAT1, C15orf41 +Proliferative DLGAP5, CKAP2L, CDCA2, CDC25C, TTK, BUB1, HMMR, CDCA8, TOP2A, GTSE1, KIF23, BUB1B, ASPM, AURKA, KIF14, CEP55, KIF18A, CDK1, TROAP, DEPDC1, CENPE, TPX2, KIF2C, KNL1, KIF20A, AURKB, NEIL3, CCNB1, ESPL1, APOLD1, HJURP, PIMREG, KIF11, PIF1, UBE2C, NDC80, CDC20, PBK, ARHGAP11A, NUSAP1, PRR11, ESCO2, PTTG1, MELK, KIF4A, CDKN3, NMU, BORA, KIF18B, KIFC1, CCNF, BIRC5, MKI67, ARHGAP11B, IQGAP3, NCAPG, SGO1, SKA3, GAS2L3, SGO2, RRM2, DIAPH3, CDCA3, CENPF, FAM83D, NUF2, POLQ, RACGAP1, KPNA2, MIR924HG, FBXO43, TACC3, WDR62, E2F7, PCLAF, ASF1B, ECT2, SHCBP1, PLK1, FAM111B, DEPDC1B, MXD3, NCAPH, PRC1, EXO1, KIF15, FOXM1, CCNB2, RTKN2, NOSTRIN, AC010173.1, SPC25, FOXN4, HMGB2, CKS2, CENPI, BRIP1, MYBL2, LMO7, KIF24, AC073529.1, STIL, AC090159.1, PLK4 +Gliosis-hypoxia ADAM28, LINC02615, POT1-AS1, MET, HILPDA, LUCAT1, PTGS2, RUNX2, SPNS2, PHLDB2, LINC01705, FAM160A1, ERRFI1, FAT4, TNNI3K, TRIB3, NDRG1, AC051619.5, AC083837.1, PRKCH, PPP1R3C, MGAM, ANGPTL4, COL13A1, CHSY3, AP001528.1, CDON, CAV1, SHISA6, SLC39A14, C21orf62-AS1, HMOX1, BNIP3L, LINC01376, ABI3BP, VLDLR-AS1, OLFM1, LTBP2, AHNAK2, NOX4, AC092944.1, COL5A1, PLAG1, GCNT1, AC099681.1, CFAP61, RPL34-AS1, OSMR-AS1, AMPD3, EHHADH, COL24A1, RNF217-AS1, AP006545.3, EPHA1-AS1, EPHA3, ZNF385B, LINC02340, LVRN, PDE4C, GPC5, RCAN2, EPSTI1, AC008014.1, LINC00240, AL158064.1, AL390957.1, MX2, C4orf47, ABLIM3, ITGB3, SCN9A, C9orf153, SLC6A6, NECTIN3-AS1, CALN1, GRK5, CPEB1, CPA4, UNC5C +Proliferative 2 FAM111B, MYBL2, EXO1, ZNF367, BRIP1, CLSPN, CHAF1A, DTL, PCLAF, CHEK1, CDC45, FANCA, MCM6, RRM2, MCM10, ASF1B, CENPU, FANCD2, POLA2, MIR924HG, CCNE2, WDR76, ESCO2, FBLN7, CENPK, NXPH2, MELK, CHAF1B, GRM8, HELLS, POLE2, E2F1, E2F7, DHFR, ABHD3, CDCA7, ASPN, FANCI, RAD18, XRCC2, AC008543.1, GINS1, AL034348.1, BRCA1, BRCA2, SPC24, KIF15, AC011447.3, VRK1, WDHD1, KIF24, XYLB, SKA3, RAB39A, LRRC63, RAD54L, DIAPH3, CGAS, CENPP, SPC25, CENPI, PRIM2, POLQ, KBTBD12, RAD51AP1, AMPH, LIG1, AC007681.1, MCM5, AC130324.2, TNFAIP8, AURKB, DDX11-AS1, SIMC1, MMS22L, MCM4, ATAD2, FANCB, DNA2, AC006115.2, TRPC3, PLD5, PLK4, LIMK2, ESPL1, TP73, ARNTL2, ZNF90, MBNL3, AC004943.2, KIAA0319, COL9A1, MYBL1, NEIL3, WDR62, SDK1, LAMA1, CLN6, PER3, PCNA, CCDC138, ECM2, CAMK4, EFNA5, CD83, REXO5, DDB2, MCM8, KIFC1, CEP152, IQGAP3, AC104073.4, DAPK2, KNTC1, ZGRF1, RFC2, MND1, UHRF1, MBOAT1, SFMBT1, RFC3, CKAP2L, POLA1, KCTD16, ARHGAP11B, BICC1, SVEP1, AP002495.1, FAM189A1, SYK, ORC6, GHR, FOXM1, HMGN2, ZNF730, GLYATL2, ARHGAP19, HMGB2, HESX1, AC009630.1, STAC, PBK, TCF19, MASTL +AC-gliosis-like 2 POSTN, KIAA1211L, CPNE4, HMGA2, TRPM8, CYTOR, RGS6, RPH3A, CCN4, ADAMTS9-AS1, SPRY1, LEF1, VAT1L, COL22A1, MIR4435-2HG, AC000065.1, CPED1, ARHGAP6, TRPM3, ANGPT1, ALK, CA2, SERPINE1, CHRM3-AS2, ITGA3, KIRREL3, RUBCNL, SLA, CCDC175, SHISA6, AC064875.1, SNED1, SPRY4, RBPMS, EMP1, LINC02832, LINC02742, HOPX, IQGAP2, GDF15, IRAK2, ST8SIA5, HIVEP3, TMEM154, COL19A1, TFCP2L1, GRM7, PLAT, GLRA2, FHL2, TENT5A, ANXA2, FSIP1, SYNJ2, SYT6, CLMN, PDGFD, CHST8, CHL1, PCSK5, GALR1, GABBR2, CNTNAP5, ARHGAP26, CA10, SLC18A1, SHISA9, SLC24A2, COL23A1, COL25A1, COL27A1, RHOJ, CAMK2B, CAMK2A, SLC4A4, RGS20, RCAN1, ESR2, C6orf141, CDH4, SLCO2B1, BNC2, AL050403.2, DNAH9, SOX1-OT, EGR1, SPRY2, EPHA3, PPP1R1C, AL121917.1, SCG2, AC090791.1, WNT16, IL27RA, MBNL3, ADAM19, IL1RAP, AC004828.2, AC011287.1, WIPF3, LINC01776, HS3ST5, INSYN2A, JAG1, NPR3, AC124254.2, NPY1R, TRIB3, UNC13C, METTL7B, AC002454.1, VAV3, NTSR1, TSPAN18, TPRG1, KLHL29, VSNL1, LINC01949 +OPC-like 1 AFAP1L2, COL4A3, FERMT1, VIPR2, AL512308.1, CALCRL, REPS2, FGF12, CCDC26, OTOGL, ELMO1, PCDH15, COL4A4, THSD4, FA2H, LRRC7, PLPP4, PLA2G4A, AR, LINC00689, TNS3, BCAS1, DLL3, KCNIP3, MIR503HG, ANO3, PLAAT1, MEGF11, GSG1L, UGT8, COL20A1, ALCAM, C2orf27A, LHFPL3-AS1, CA10, SLC5A4, ADAMTS17, DCT, CHST9, NRSN1, AC110285.1, CCND1, TRPC4, TACR1, TNR, SOX6, PDE4A, GPR17, ARPP21, MYRF, PRKG2, LINC01268, LINC01322, AC023282.1, EYA1, ERBB3, LRRC3B, DISC1, BRINP1, SLC8A3, SLIT1, ATP13A5, LINC00320, SMOC1, LIN28B, CACNA1E, OMG, LAMB4, SLC26A7, GFPT2, PDE7B, FRG1-DT, PODN, PCSK2, FAM160A1, PRSS12, HS6ST2, PAPPA, DOCK10, ITGA9, DLL1, DGKB, OR4N2, CSMD3, CRYBG3, MDGA2, SEMA3E, CLDN11, KIF21B, NKD1, AQP4, GHR, AGMO, AC068308.1, MOG, TMPRSS9, USP43, MIR217HG, LRFN5, UGDH, AL139231.1, AL136114.1, AC005909.2, MYRIP, ANO4, TMEM132C, AC077690.1, AL031293.1, AC104051.2 +NPC-neuronal-like 3 GRIN3A, CUX2, LINC02144, LINC00639, CACNA2D3, DLX6-AS1, SYT1, OLFM3, TOX, THRB, SLAIN1, GABRB2, PLCB1, HRK, NYAP2, LINC00581, AL009178.3, MAML3, SLC17A6, LYPD6B, LRTM1, CARMIL1, CNTN2, EBF3, INSYN2B, NSG2, GRK5, FRAS1, KITLG, B3GAT2, MEIS2, SYNPR, ZNF618, CDH12, SPOCK1, SRRM4, SVEP1, AC006296.3, PCP4, LEMD1, CEMIP2, NXPH1, KLHL35, UNCX, ABTB2, MDGA2, AP003464.1, ROBO3, CNTNAP5, ERBB4, AC017053.1, SOX1-OT, AC022075.1, EPHA3, CRIM1, CRABP1, ARX, RBFOX3, RMST, ARHGAP18, FLRT2, AL392023.2, GLYCTK-AS1, BEND7, LINC02488, HS3ST5, CDH4, LINC02133, EPHA7, FGFR2, ANTXR2, AL353138.1, LAMP5, DACH1, ARL4D, CELF4, DLX6, CDH18, PRKCA, PROX1-AS1, SSTR2, OTP, STMN2, AC115282.1, SV2B, SYT4, TMEM196, NRP1, PCSK2, NFIA-AS2, MYT1L, MYCBP2-AS1, MIAT, SLCO4C1, DUOX1, ENC1, SLC4A10, EPHA5, SLC18A1, SLIT1, EBF1, SDS, DYNC1I1, SPHKAP, MCUB, STARD4-AS1, ST18, DACH2, ST6GAL1, FGD5, TENM2, CNDP1, CLMP, TP73, UNC5D, VWC2L, WNK2, CDH22, SCML4, GABRA1, RXRG, RND3, MIR548XHG, LINC01550, LINC01122, LINC01102, NDST4, NRN1, KLRD1, NRSN1, OSBPL10, KLHL29, KLHDC8A, KCNQ3, KCNK2, KCNH8, IGF1, PBX3, HSD11B2, PIP5K1B, HMCN1, PKNOX2, POU6F2, GRIP2, PRDM8, PTCHD4, LINC02428, RBFOX1, RIPOR2, ABCB5, LINC00707, AC068722.1, B3GLCT, AL445623.2, ADCY8, BPIFC, CASC15, ADAMTS9-AS2, AC090403.1 +OPC-like 2 PPP1R16B, BCAS1, AC008080.4, MOG, GLRA3, ENPP6, ADAM33, GPC3, CLDN11, PLD1, SEMA4D, MYRF, MBP, GPR17, KCNS3, TNS3, RASGEF1B, AC069209.2, ADRA1A, CD22, FA2H, CDK18, ST18, FERMT1, NOS1, TMEM235, AC110285.1, ACAN, MAG, PRICKLE1, AL512308.1, FAM83D, BMP2, BMPER, COL18A1, LINC01447, P2RX7, ZNF536, ATP6V0A4, AMPD3, SLC7A14, ANO3, LCNL1, PTGDS, SOX10, SPNS2, FLACC1, NFASC, ERBB3, TNS2, TUBB4A, DNAH10, DCT, UGT8, SLC1A1, PRSS12, AC107223.1, RASGEF1C, PKD1L1, SEMA3D, ADAMTSL1, AFAP1L2, TMEFF2, TMTC4, PKP4-AS1, PLAAT1, DOCK6, SGCD, TLL1, CPM, COL20A1, PLP1, CNDP1, VSTM2B, CHST15, PPFIBP2, CDH8, CDH19, TMCC3, FGF12, TF, SH3RF3, SHROOM4, SIRT2, NPAS1, OPCML, OTOGL, P2RX4, MACROD2, LINC01170, LIMS2, CCDC148, PARD3B, SLC7A14-AS1, ITPR2, PCDH11Y, SRCIN1, GALNT13, FRMD4B, KIF21B, AATK, C10orf90, ARPP21, CA10, CABLES1, MMP17, REPS2, ATP8A2, SYT6, SYT7, MYRFL, MYT1L, PIK3R6, TFEB, FAM13C, THBS1, EYS, AC009227.1, PTGER3, TMTC1, EFCAB5, EBF2, AC012636.1, LSAMP-AS1, RNF122, BRINP2, KTN1-AS1, SEMA3E, APCDD1, SERINC5, SERPINB9, LIN28B, SAMHD1, ITGB5, AC079209.1, SHANK2, AC079148.3, LINC00906, ABCA2, AC044781.1, SLC8A3, SMOC1, RNF152, AL161910.1, RAPGEF1, TRG-AS1, PRDM16, AC004852.2, PPFIBP1, UST, AFMID, COL12A1, VEPH1, AF121898.1, VWC2L, ADAMTS14, PDE1C, ZNF365, ZNF469, CCDC26, CADM1, PKP4, DAPL1, AP003464.1, DIPK1C, TRIM67, DLL3, DIO2, DGKB, DLX6-AS1, PRDM8 +OPC-AC-like 2 AC007402.1, LINC02397, DLL3, PRR5L, MYO5C, UNC13C, EGFR, AL359546.1, SLC24A3, INKA2, AC003991.1, ZNF804B, LINC01902, AC087854.1, DUSP10, SWAP70, LUZP2, RAB27B, AC117464.1, DLL1, AC013265.1, NKD1, KLRC2, SLC22A3, BX284613.2, CREM, AC002069.2, HES6, HIP1, GRM5, DPF3, MIR4300HG, CNTN6, HRH2, COL20A1, ANKFN1, MCTP1, GLYCTK-AS1, CHST9, CASZ1, OLFML2B, SKOR2, NTN4, SEZ6L, ELMO1, ATP10B, CCDC178, GRIK1, CCND2, MYT1, TMEM196, CEP126, STEAP4, AOAH, COL4A4, OR4N2, AGMO, VCAN-AS1, COLGALT2, VSTM4, AC062021.1, DACH2, LINC02199, LINC01965, AC016042.1, ZFHX4-AS1, ZFP36L1, LEPR, LINC00299, AC007344.1, LINC00689, AC004852.2, AC004158.1, AC069228.1, VIPR2, KCNIP3, AC098868.1, BTG2, ADAMTS19, ADAMTS17, TMPRSS9, MALAT1, TNFRSF11B, CSMD1, USP43, AC092819.3, AC092958.1 \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/examples/astrycytoma_1.json b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/astrycytoma_1.json new file mode 100644 index 0000000..6ffd597 --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/astrycytoma_1.json @@ -0,0 +1,206 @@ +{ + "genes": [ + "FAM189A2", + "OGFRL1", + "MAP3K5", + "ITPR2", + "ETNPPL", + "NRG3", + "CD38", + "FMN2", + "LINC01088", + "KCNN3", + "DAAM2", + "AC002429.2", + "OBI1-AS1", + "NTRK2", + "SYTL4", + "WDR49", + "ADGRV1", + "LIFR", + "AQP4", + "ID3", + "OSBPL11", + "DPP10", + "SERPINI2", + "TLR4", + "NAA11", + "MGAT4C", + "AC026316.5", + "EEPD1", + "RASSF4", + "AL392086.3", + "SLC4A4", + "EDNRB", + "SLC39A11", + "ATP1A2", + "SLCO1C1", + "AHCYL2", + "SPON1", + "SLC1A3", + "GRAMD2B", + "DTNA", + "AC012405.1", + "NKAIN3", + "NTM", + "SLC14A1", + "DCLK2", + "DCLK1", + "ID4", + "AC124854.1", + "LINC01094", + "PCDH9", + "GABBR2", + "PARD3B", + "PDE8A", + "LRIG1", + "C5ORF64", + "RNF19A", + "SPARCL1", + "AC093535.1", + "FADS2", + "PLEKHA5", + "ASTN2", + "ADAMTS9", + "AC073941.1", + "SLC24A4", + "PAPPA", + "AC068587.4", + "FARP1", + "SORL1", + "ARHGAP26", + "CADPS", + "ST3GAL6", + "ITPKB", + "GABRB1", + "FAM107A", + "MIR99AHG", + "ANK2", + "AC107223.1", + "PPP2R2B", + "LPL", + "AL589935.1", + "MRVI1", + "TNIK", + "AL160272.1", + "AC016766.1", + "RANBP3L", + "ARHGEF4", + "ADCY2", + "NPL", + "KCNQ5", + "AC079352.1", + "LIX1", + "APOE", + "SLC25A48", + "ADCYAP1R1", + "AHCYL1", + "RASL12", + "GINS3", + "PTPRG", + "AL096709.1", + "BMP2K", + "MCF2L2", + "RBMS3", + "SLCO3A1", + "AL445426.1", + "CARMIL1", + "CACNA2D3", + "CDHR3", + "NAV3", + "UTRN", + "NRP2", + "DNAH7", + "KIAA1671", + "HPSE2", + "COL4A5", + "AC083864.5", + "L3MBTL4", + "AC092131.1", + "PCSK6", + "AC097450.1", + "ANOS1", + "SYNPO2", + "LINC00836", + "MAPK4", + "AL365259.1", + "WNK2", + "LMO3", + "SSBP2", + "SLC1A4", + "PPP2R5A", + "LINC00299", + "SLC15A2", + "CNTN1", + "FKBP5", + "GREB1L", + "LUZP2", + "MAP7", + "AC023095.1", + "IGFBP7", + "ALDH1A1", + "GRAMD1C", + "RHBDL3", + "DAPK1", + "LINC02058", + "TENM4", + "RTN1", + "LINC01138", + "GLUD1", + "NEBL", + "LINC01117", + "AC092691.1", + "TJP2", + "PCDH9-AS2", + "YAP1", + "ABCC9", + "LAMA1", + "AL137024.1", + "ERBB4", + "ADRA1A", + "MYBPC1", + "NT5DC3", + "AQP1", + "NKAIN4", + "ARAP2", + "RHOB", + "AQP4-AS1", + "CDH20", + "RGMA", + "OSGIN2", + "PRKG1", + "MROH7", + "PRRX1", + "MAST4", + "CHL1", + "PAPLN", + "OSBPL3", + "RFX4", + "CD44", + "ATP13A4", + "COL5A3", + "ITGA6", + "DOCK7", + "CPE", + "DPF3", + "ZNF521", + "DHRS3", + "AC006148.1", + "LMNTD1", + "AC092924.2", + "LHFPL6", + "AC024145.1", + "LIMCH1", + "SRPX2", + "AL590999.1", + "ADCY8", + "AC008957.2", + "TTYH2", + "GJA1", + "SHROOM3", + "USH1C", + "AC007262.2" + ], + "context": "The following gene set represents a gene program found in some subset of malignant cells isolated from an IDH-mutant astrocytoma. As well as astrocytoma, include results relevant to normal astrocytes and astrocyte development.\n", + "description": "" +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/examples/glioblastoma_states_extended.json b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/glioblastoma_states_extended.json new file mode 100644 index 0000000..3858ba0 --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/glioblastoma_states_extended.json @@ -0,0 +1,94 @@ +{ + "examples": [ + { + "id": "gliosis", + "genes": ["SERPINE1", "EMP1", "SPOCD1", "ARHGAP29", "IL1R1", "COL6A2", "MYOF", "F13A1", "CXCL10", "CHI3L1", "MET", "IL6", "SAA2", "BIRC3", "MCTP2", "ANGPTL4", "ICAM1", "CCN1", "CAV1", "APLN", "FOSL1", "SNTG2-AS1", "TPD52L1", "SAA4", "KRT75", "NFATC2", "COL5A1", "AC243829.2", "CLCF1", "ARSJ", "PLA2G2A", "HMGA2", "PTX3", "TLR2", "LINC00698", "ALPK2", "TNFAIP3", "TNFAIP2", "NDRG1", "SMOC2", "ADGRL2", "KANK4", "GEM", "FAS", "CXCL8", "CFH", "ABCC3", "CXCL14", "ZFP36", "RCAN2", "GADD45A", "COL1A2", "LTF", "DHRS3", "IDO1", "HAP1", "AXL", "ATP6V0D2", "KLF5", "ST6GALNAC5", "GPD1", "PAPPA2", "BAG3", "MYBPH", "MYBPC1", "MX2", "APBB1IP", "ANPEP", "ALPL", "GPRC5A", "SPP1", "CXCL2", "GPC5", "RRAD", "LIF", "CHRNA9", "IL4R", "NPNT", "SAA1", "NPR3", "PROM1", "SLIT3", "ITGBL1", "MYO5B", "RPS5", "RPS27", "ETS2", "PTGS2", "RPS18", "BNC2", "CPA4", "NPAS2", "CD274", "SLC10A6", "LRAT", "LINC01993", "LINC02832", "LINC02821", "GBP5", "AC021851.2", "AKAP12", "LINC02154", "FN1", "MIR222HG", "VEGFA", "GBP2", "ZNF735", "TSHZ2", "TRPM2", "LUCAT1", "PI3"], + "context": "Reactive gliosis state in malignant glioblastoma cells within brain tumor microenvironment, characterized by inflammatory responses, extracellular matrix remodeling, and tissue repair mechanisms typical of astrocytic activation during tumor progression and invasion", + "description": "Gliosis state representing reactive astrocytic activation in malignant glioblastoma cells. This state is characterized by inflammatory cytokine production (IL6, CXCL10, CXCL8), extracellular matrix remodeling (COL5A1, COL1A2, FN1), and stress response pathways (SERPINE1, HMGA2, PTX3). The state reflects the tumor's activation of wound healing and inflammatory programs that promote invasion and angiogenesis. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "opc_ac_like_1", + "genes": ["LINC01727", "AC117464.1", "XYLT1", "MMD2", "EEPD1", "AC013265.1", "MYO5B", "PLA2G4A", "KCNIP1", "ITGB4", "AC019068.1", "UNC5D", "MIR3681HG", "LINC02125", "LINC02246", "LRRC4C", "LUCAT1", "MDGA2", "AC077690.1", "CTXND1", "AL353138.1", "CDH18", "MN1", "AL356737.2", "NKAIN3", "CD44", "NLRC5", "LINC01776", "LINC01117", "DAB1", "GFAP", "DCHS2", "DIPK1C", "COL20A1", "ELMOD1", "ERICH3", "ADAMTS5", "GPC5", "CHST8", "AC233296.1", "AC124254.2", "NPR3", "HRH1", "INPP4B", "AL159156.1", "LINC02328", "ARC", "PDZRN4", "AC007344.1", "RGMA", "PPARGC1A", "TNR", "ST8SIA5", "ST8SIA1", "SLC7A11"], + "context": "Oligodendrocyte Progenitor Cell-Astrocyte hybrid state in malignant glioblastoma cells expressing markers of both glial lineages, with enhanced proliferative capacity and dedifferentiation potential characteristic of glioma stem-like cells within brain tumor tissue", + "description": "Oligodendrocyte Progenitor Cell-Astrocyte-like state 1 representing a hybrid cellular phenotype in malignant glioblastoma cells. This state combines features of oligodendrocyte progenitor cells (OPCs) and astrocytes, expressing GFAP (astrocytic marker) alongside developmental regulators and extracellular matrix components (COL20A1, ADAMTS5). The state includes neural development genes (DAB1, ARC) and may represent dedifferentiated tumor cells with enhanced plasticity and stem-like properties. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "npc_neuronal_like_1", + "genes": ["CFAP43", "NEGR1", "DNAH12", "LRRC2", "VAT1L", "ZNF804B", "RBMS3", "SLC14A1", "GABRA5", "ZBBX", "ADAMTS18", "CFAP52", "GRM1", "MAP3K19", "FHAD1", "TCTEX1D1", "DNAAF1", "DCDC2", "AC005165.1", "COL21A1", "PKHD1", "ZNF521", "EPB41L4B", "ERICH3", "PLAGL1", "EXPH5", "SHISAL2B", "SATB1-AS1", "RERGL", "FRMPD2", "TOGARAM2", "AP003062.2", "BMP6", "NRG3", "CFAP61", "FAM81B", "SLC47A2", "TMEM232", "NWD2", "AC109466.1", "GABRG3", "DTHD1", "COL13A1", "COL23A1", "CFAP73", "RFTN1", "FYB2", "POSTN", "AL513323.1", "BANK1", "CHD5", "THBS1", "ADCY8", "ADGB", "AFF2", "DRC1", "CFAP206", "CFAP47", "PPM1H", "KIAA2012", "MAP7", "KSR2", "DNAH5", "LYPD6B", "WSCD2", "CACNA2D1", "LRRIQ1", "CPNE4", "LINC01088", "SCIN", "PRMT8", "LINGO2", "CASC1", "CCDC170", "AC092110.1", "VWA3A", "CA10", "AC013470.2", "SLC22A3", "GRM4", "COL26A1", "CFAP221", "CFAP157", "TTC29", "C7orf57", "HMCN1", "CFAP100", "U91319.1", "RSPH1", "NAALAD2", "IL6R", "CDH7", "KCNJ3", "AL356108.1"], + "context": "Neural Progenitor Cell-neuronal hybrid state in malignant glioblastoma cells expressing neuronal differentiation markers and cilia-related genes, suggesting aberrant neural development programs and potential for neuronal-like differentiation within brain tumor tissue", + "description": "Neural Progenitor Cell-neuronal-like state 1 characterized by extensive expression of cilia and flagella-associated proteins (CFAP43, CFAP52, CFAP61, CFAP73, CFAP206, CFAP47, DNAH12, DNAH5), suggesting dysregulated ciliary function in tumor cells. This state also expresses neuronal markers (GABRA5, GABRG3, GRM1, GRM4) and neural development factors (NRG3, CHD5), indicating a neural progenitor-like phenotype with neuronal differentiation potential. The abundance of ciliary genes may reflect tumor cell attempts at neural tube-like organization or aberrant developmental programs. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "npc_neuronal_like_2", + "genes": ["FSTL4", "LRFN5", "TRPM3", "NDST4", "PALMD", "ADRA1B", "PDE1A", "CLVS1", "SLC17A6", "ACVR1C", "SLA", "EBF1", "AC011474.1", "FRMPD4", "KIT", "UNC5D", "GCG", "TRPC5", "CDH9", "TARID", "LINC01033", "AC109492.1", "AL596087.2", "SHISA6", "POSTN", "PLSCR2", "CDH18", "PALM2-AKAP2", "CDH13", "SMOC2", "CPNE4", "CUX2", "RNF149", "TENM2", "MARCH4", "HS3ST2", "GRIN2A", "RUNX1T1", "AL158064.1", "EFNA5", "GRIP2", "PRSS12", "GREM2", "RASGEF1B", "TAFA2", "FGD4", "SERPINI1", "RBFOX1", "SEMA3C", "ADAMTS3", "CNTNAP4", "BRINP1", "CNTN5", "LINC01344", "MYT1L", "MTAP", "SLC38A11", "MN1", "MIR3681HG", "SV2B", "CARMIL1", "ZDHHC23", "LINC02607", "OTOR", "CLEC2L", "PAPPA2", "LINC01949", "LINC00862", "U91319.1", "IQCJ-SCHIP1", "KCNJ6", "CFAP299", "SIAH3", "PDZRN4", "LIN28B", "AC063979.2", "DYNC1I1", "CCK", "SCG2", "SIDT1", "CDH4", "DPP10", "SAMD5", "SNCA", "COL3A1", "COL6A3", "EBF2", "LINC02378", "KLHL29", "PIP5K1B", "LINC00470", "LINC00707", "PDE1C", "LINC01965", "LINGO2", "EDA", "NYAP2", "NWD2", "NOX3", "MOXD1", "MSC-AS1", "NEDD4L", "KIAA0319", "KCNC2", "POU6F2", "IGFBPL1", "PPEF1", "PRDM6", "GPR1", "SRRM4", "GFRA1", "GABBR2", "FSTL5", "FRAS1", "FGFR2", "FAP", "RIMBP2", "RPH3A", "EDIL3", "GLRA2", "NDNF", "SYNPR", "AC002454.1", "AC003044.1", "WSCD2", "ANO4", "AP003464.1", "VWC2L", "VSTM2B", "ARHGAP18", "TMEM130", "TGFBI", "AC244502.1", "SYT1", "UNC5C", "VWDE"], + "context": "Neural Progenitor Cell-neuronal hybrid state in malignant glioblastoma cells with enhanced synaptic and neurotransmitter signaling capabilities, cell adhesion molecules, and guidance cues characteristic of mature neuronal differentiation within brain tumor microenvironment", + "description": "Neural Progenitor Cell-neuronal-like state 2 exhibiting advanced neuronal differentiation features including synaptic vesicle proteins (SV2B, SYT1), neurotransmitter transporters (SLC17A6), ion channels (GRIN2A, TRPM3, TRPC5), and neuronal adhesion molecules (CDH9, CDH13, CDH18, CNTN5, CNTNAP4). This state expresses transcription factors crucial for neuronal development (EBF1, EBF2, MYT1L, CUX2) and guidance molecules (SEMA3C, EFNA5, UNC5C, UNC5D). The comprehensive neuronal gene expression pattern suggests these tumor cells have acquired mature neuronal-like properties while maintaining malignant characteristics. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "ac_gliosis_like_1", + "genes": ["AQP1", "ANOS1", "LIX1", "CD38", "RASL12", "KCNN3", "SERPINA3", "GFAP", "FAM189A2", "BBOX1", "NPSR1", "ITPKB", "CFI", "LINC01094", "ID3", "FBLN5", "CFAP54", "DAAM2", "ADAMTS8", "GGT5", "SLC14A1", "RPE65", "MASP1", "SLCO1C1", "AC092131.1", "ITGB4", "LRRC2", "STUM", "SPON1", "CD44", "ATP1A2", "AQP4", "ALDH1L1", "CRB2", "FAM107A", "GJA1", "ETNPPL", "AC103923.1", "ZFP36", "RFTN1", "EDNRA", "HAS2", "ADAMTS15", "MARVELD3", "OBI1-AS1", "PAPLN", "ID4", "HRH1", "HCG22", "DRC1", "PTCHD1", "PTPRT", "GALNT15", "FHAD1", "SLC44A3", "F3", "COL28A1", "EDNRB", "ACSBG1", "ABCA13", "WDR49", "XAF1", "ABCC3", "AC092924.2", "AC002429.2", "WWC1", "TIMP3", "AGT", "SLC24A4", "HOPX", "CABCOCO1", "CHI3L2", "C3", "MYBPC1", "ADGRV1", "LINC02234", "GPR37L1", "AL591686.2", "TCTEX1D1", "TTYH1", "TC2N", "LINC00844", "AL355306.2", "AC073941.1", "NMB", "PDGFRB", "BCAN", "EGF", "DCHS2", "PFKFB3", "AC117464.1", "SCN7A", "COLEC12", "OSMR", "C21orf62", "LTF", "BMPR1B", "ATP13A4", "IGFBP7"], + "context": "Astrocyte-gliosis hybrid state in malignant glioblastoma cells combining classic astrocytic markers with reactive gliosis features, enhanced water transport systems, and blood-brain barrier-related functions characteristic of astrocytic activation in brain tumor pathology", + "description": "Astrocyte-gliosis-like state 1 representing classic astrocytic phenotype with strong expression of astrocyte markers (GFAP, AQP1, AQP4, ALDH1L1, GJA1) and water transport systems crucial for brain homeostasis. This state shows enhanced complement system activation (C3, CFI, MASP1), extracellular matrix remodeling (ADAMTS8, ADAMTS15, TIMP3), and blood-brain barrier-related functions. The expression of reactive astrocyte markers (SERPINA3, CHI3L2) alongside homeostatic astrocyte genes suggests a hybrid state maintaining some normal astrocytic functions while exhibiting pathological activation. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "proliferative", + "genes": ["DLGAP5", "CKAP2L", "CDCA2", "CDC25C", "TTK", "BUB1", "HMMR", "CDCA8", "TOP2A", "GTSE1", "KIF23", "BUB1B", "ASPM", "AURKA", "KIF14", "CEP55", "KIF18A", "CDK1", "TROAP", "DEPDC1", "CENPE", "TPX2", "KIF2C", "KNL1", "KIF20A", "AURKB", "NEIL3", "CCNB1", "ESPL1", "APOLD1", "HJURP", "PIMREG", "KIF11", "PIF1", "UBE2C", "NDC80", "CDC20", "PBK", "ARHGAP11A", "NUSAP1", "PRR11", "ESCO2", "PTTG1", "MELK", "KIF4A", "CDKN3", "NMU", "BORA", "KIF18B", "KIFC1", "CCNF", "BIRC5", "MKI67", "ARHGAP11B", "IQGAP3", "NCAPG", "SGO1", "SKA3", "GAS2L3", "SGO2", "RRM2", "DIAPH3", "CDCA3", "CENPF", "FAM83D", "NUF2", "POLQ", "RACGAP1", "KPNA2", "MIR924HG", "FBXO43", "TACC3", "WDR62", "E2F7", "PCLAF", "ASF1B", "ECT2", "SHCBP1", "PLK1", "FAM111B", "DEPDC1B", "MXD3", "NCAPH", "PRC1", "EXO1", "KIF15", "FOXM1", "CCNB2", "RTKN2", "NOSTRIN", "AC010173.1", "SPC25", "FOXN4", "HMGB2", "CKS2", "CENPI", "BRIP1", "MYBL2", "LMO7", "KIF24", "AC073529.1", "STIL", "AC090159.1", "PLK4"], + "context": "Highly proliferative state in malignant glioblastoma cells characterized by active cell cycle progression, mitotic spindle assembly, chromosome segregation, and DNA replication machinery typical of rapidly dividing cancer cells within brain tumor tissue", + "description": "Proliferative state representing highly active cell division in malignant glioblastoma cells. This state is dominated by cell cycle regulators (CDK1, CCNB1, CCNB2), mitotic checkpoint proteins (BUB1, BUB1B, TTK), kinetochore components (CENPE, CENPF, CENPI), and spindle assembly factors (AURKA, AURKB, PLK1, PLK4). The extensive expression of kinesin motor proteins (KIF11, KIF14, KIF15, KIF18A, KIF20A, KIF23) and DNA replication machinery (TOP2A, RRM2, PCLAF) indicates rapid cell cycle progression and chromosomal instability characteristic of aggressive glioblastoma growth. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "gliosis_hypoxia", + "genes": ["ADAM28", "LINC02615", "POT1-AS1", "MET", "HILPDA", "LUCAT1", "PTGS2", "RUNX2", "SPNS2", "PHLDB2", "LINC01705", "FAM160A1", "ERRFI1", "FAT4", "TNNI3K", "TRIB3", "NDRG1", "AC051619.5", "AC083837.1", "PRKCH", "PPP1R3C", "MGAM", "ANGPTL4", "COL13A1", "CHSY3", "AP001528.1", "CDON", "CAV1", "SHISA6", "SLC39A14", "C21orf62-AS1", "HMOX1", "BNIP3L", "LINC01376", "ABI3BP", "VLDLR-AS1", "OLFM1", "LTBP2", "AHNAK2", "NOX4", "AC092944.1", "COL5A1", "PLAG1", "GCNT1", "AC099681.1", "CFAP61", "RPL34-AS1", "OSMR-AS1", "AMPD3", "EHHADH", "COL24A1", "RNF217-AS1", "AP006545.3", "EPHA1-AS1", "EPHA3", "ZNF385B", "LINC02340", "LVRN", "PDE4C", "GPC5", "RCAN2", "EPSTI1", "AC008014.1", "LINC00240", "AL158064.1", "AL390957.1", "MX2", "C4orf47", "ABLIM3", "ITGB3", "SCN9A", "C9orf153", "SLC6A6", "NECTIN3-AS1", "CALN1", "GRK5", "CPEB1", "CPA4", "UNC5C"], + "context": "Hypoxic gliosis state in malignant glioblastoma cells responding to low oxygen conditions within brain tumor microenvironment, characterized by hypoxia-inducible factor activation, metabolic reprogramming, and angiogenic signaling pathways", + "description": "Gliosis-hypoxia state representing the cellular response to oxygen deprivation in malignant glioblastoma cells. This state is characterized by classic hypoxia response genes (HILPDA, NDRG1, BNIP3L, HMOX1) indicating activation of hypoxia-inducible factor (HIF) pathways. The state includes angiogenic factors (ANGPTL4), metabolic enzymes (EHHADH, AMPD3), and stress response proteins (TRIB3, ERRFI1). Expression of inflammatory mediators (PTGS2) and matrix metalloproteinases (ADAM28) suggests enhanced invasion potential under hypoxic conditions, a hallmark of aggressive glioblastoma behavior in poorly vascularized tumor regions. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "ac_neuronal_like", + "genes": ["LINC02235", "AC037486.1", "PCDH11X", "LINC01829", "AL591043.2", "ZNF423", "ADAMTS18", "AL133538.1", "DOCK2", "SCN1A-AS1", "AL022068.1", "SEPTIN14", "SGCZ", "ADAM28", "RYR2", "DOCK8", "ACER2", "AC128687.3", "AC120193.1", "OLR1", "AC110296.1", "AC109466.1", "SPOCK3", "ST6GALNAC5", "AL136441.1", "MLIP"], + "context": "Astrocyte-neuronal hybrid state in malignant glioblastoma cells expressing both astrocytic and neuronal markers, with enhanced cell-cell adhesion, calcium signaling, and synaptic-like functions within brain tumor tissue", + "description": "Astrocyte-neuronal-like state representing a hybrid cellular phenotype combining astrocytic and neuronal characteristics in malignant glioblastoma cells. This state expresses protocadherins (PCDH11X, PCDH7) for cell adhesion, calcium release channels (RYR2), and neuronal-specific markers. The presence of acetylcholine receptors (CHRNA7) and synaptic proteins (SYN3) suggests acquisition of neuronal-like signaling capabilities. This hybrid state may represent tumor cell plasticity and dedifferentiation, allowing cells to exploit both astrocytic and neuronal functional programs for survival and growth. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "opc_npc_like", + "genes": ["SLIT3", "CA8", "ARX", "AC109492.1", "AL078602.1", "DLX5", "AC006296.3", "DLX6", "RFTN2", "DLX6-AS1", "AC090241.2", "PDZRN3", "GLI2", "TBL1X", "KCNH8", "ST8SIA5", "LRGUK", "TPGS2", "LINC02487", "DACH2", "SOX2-OT", "KIAA0040", "FCGBP", "LINC00326", "AC022075.1", "AC125613.1", "MCUB", "EPHA7", "PLS3", "SLC6A5", "CRYBG3", "LINC01748", "TENM1", "LINC00535", "ABTB2", "MAN2A1", "LAMP5", "MOG", "KITLG", "ZNF618"], + "context": "Oligodendrocyte Progenitor Cell-Neural Progenitor Cell hybrid state in malignant glioblastoma cells with active developmental transcription factors, stem cell markers, and neural patterning genes characteristic of early brain development within tumor tissue", + "description": "Oligodendrocyte Progenitor Cell-Neural Progenitor Cell-like state representing early neural development programs in malignant glioblastoma cells. This state is characterized by key developmental transcription factors (DLX5, DLX6, ARX, GLI2) essential for brain patterning and neural progenitor specification. Expression of EGFR, SOX2-OT, and ribosomal proteins (RPL18A, RPL10, RPL8) indicates active proliferation and stem cell-like properties. The state includes guidance molecules (SLIT3, EPHA7) and oligodendrocyte markers (MOG), suggesting cells poised for glial differentiation while maintaining progenitor characteristics. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "proliferative_2", + "genes": ["FAM111B", "MYBL2", "EXO1", "ZNF367", "BRIP1", "CLSPN", "CHAF1A", "DTL", "PCLAF", "CHEK1", "CDC45", "FANCA", "MCM6", "RRM2", "MCM10", "ASF1B", "CENPU", "FANCD2", "POLA2", "MIR924HG", "CCNE2", "WDR76", "ESCO2", "FBLN7", "CENPK", "NXPH2", "MELK", "CHAF1B", "GRM8", "HELLS", "POLE2", "E2F1", "E2F7", "DHFR", "ABHD3", "CDCA7", "ASPN", "FANCI", "RAD18", "XRCC2"], + "context": "Highly proliferative state with enhanced DNA repair mechanisms in malignant glioblastoma cells, characterized by active homologous recombination, replication fork protection, and cell cycle checkpoint signaling within rapidly dividing tumor tissue", + "description": "Proliferative state 2 representing enhanced DNA replication and repair in malignant glioblastoma cells. This state is distinguished by extensive DNA repair machinery including Fanconi anemia pathway components (FANCA, FANCD2, FANCI), homologous recombination factors (BRCA1, BRCA2, RAD18, XRCC2), and replication licensing proteins (MCM4, MCM5, MCM6, MCM8, MCM10). The expression of chromatin assembly factors (CHAF1A, CHAF1B, ASF1B) and DNA polymerases (POLA1, POLA2, POLE2) indicates active DNA synthesis. This repair-focused proliferative state may confer resistance to DNA-damaging therapies commonly used in glioblastoma treatment. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "ac_gliosis_like_2", + "genes": ["POSTN", "KIAA1211L", "CPNE4", "HMGA2", "TRPM8", "CYTOR", "RGS6", "RPH3A", "CCN4", "ADAMTS9-AS1", "SPRY1", "LEF1", "VAT1L", "COL22A1", "MIR4435-2HG", "AC000065.1", "CPED1", "ARHGAP6", "TRPM3", "ANGPT1", "ALK", "CA2", "SERPINE1", "CHRM3-AS2", "ITGA3", "KIRREL3", "RUBCNL", "SLA", "CCDC175", "SHISA6"], + "context": "Advanced astrocyte-gliosis state in malignant glioblastoma cells with enhanced extracellular matrix production, angiogenic signaling, and calcium channel activity characteristic of reactive astrocytes in brain tumor progression", + "description": "Astrocyte-gliosis-like state 2 representing an advanced reactive astrocytic phenotype in malignant glioblastoma cells. This state is characterized by extensive extracellular matrix remodeling (POSTN, COL22A1, ADAMTS9-AS1), angiogenic signaling (ANGPT1), and calcium channel activity (TRPM3, TRPM8, CA2). The expression of transcription factor LEF1 and growth factors (GDF15) indicates active cellular reprogramming and paracrine signaling. The state includes GABA receptors (GABBR2) and synaptic proteins (SYT6), suggesting retention of some neuronal communication capabilities alongside reactive astrocytic functions. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "opc_like_1", + "genes": ["AFAP1L2", "COL4A3", "FERMT1", "VIPR2", "AL512308.1", "CALCRL", "REPS2", "FGF12", "CCDC26", "OTOGL", "ELMO1", "PCDH15", "COL4A4", "THSD4", "FA2H", "LRRC7", "PLPP4", "PLA2G4A", "AR", "LINC00689", "TNS3", "BCAS1", "DLL3", "KCNIP3", "MIR503HG", "ANO3", "PLAAT1", "MEGF11", "GSG1L", "UGT8"], + "context": "Oligodendrocyte Progenitor Cell state in malignant glioblastoma cells with active myelination programs, lipid biosynthesis, and neural development signaling characteristic of oligodendrocyte lineage within brain tumor tissue", + "description": "Oligodendrocyte Progenitor Cell-like state 1 representing cells committed to oligodendrocyte lineage in malignant glioblastoma. This state expresses key oligodendrocyte markers including myelin regulatory factor (MYRF), fatty acid 2-hydroxylase (FA2H) for sphingolipid synthesis, and UDP galactosyltransferase (UGT8) for galactosylceramide production. The expression of G-protein coupled receptor 17 (GPR17) and proteolipid protein 1 (PLP1) indicates active myelination programs. Notch signaling components (DLL1, DLL3) and transcription factors (SOX6, SOX10) suggest maintained progenitor properties with capacity for oligodendrocyte differentiation. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "npc_neuronal_like_3", + "genes": ["GRIN3A", "CUX2", "LINC02144", "LINC00639", "CACNA2D3", "DLX6-AS1", "SYT1", "OLFM3", "TOX", "THRB", "SLAIN1", "GABRB2", "PLCB1", "HRK", "NYAP2", "LINC00581", "AL009178.3", "MAML3", "SLC17A6", "LYPD6B", "LRTM1", "CARMIL1", "CNTN2", "EBF3", "INSYN2B", "NSG2", "GRK5", "FRAS1", "KITLG", "B3GAT2"], + "context": "Advanced Neural Progenitor Cell-neuronal state in malignant glioblastoma cells with mature synaptic organization, neurotransmitter signaling, and axon guidance systems characteristic of differentiated neurons within brain tumor microenvironment", + "description": "Neural Progenitor Cell-neuronal-like state 3 representing the most advanced neuronal differentiation in malignant glioblastoma cells. This state expresses sophisticated neuronal machinery including NMDA receptors (GRIN3A), voltage-gated calcium channels (CACNA2D3), vesicular glutamate transporters (SLC17A6), and synaptotagmin (SYT1) for neurotransmitter release. The expression of early B-cell factors (EBF1, EBF3) and homeobox transcription factors (DLX6) indicates active neuronal specification programs. Guidance molecules (FRAS1) and cell adhesion proteins (CNTN2) suggest formation of neural circuits. This state represents tumor cells that have acquired complex neuronal functions while maintaining malignant properties. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "opc_like_2", + "genes": ["PPP1R16B", "BCAS1", "AC008080.4", "MOG", "GLRA3", "ENPP6", "ADAM33", "GPC3", "CLDN11", "PLD1", "SEMA4D", "MYRF", "MBP", "GPR17", "KCNS3", "TNS3", "RASGEF1B", "AC069209.2", "ADRA1A", "CD22", "FA2H", "CDK18", "ST18", "FERMT1", "NOS1", "TMEM235", "AC110285.1", "ACAN", "MAG", "PRICKLE1"], + "context": "Mature Oligodendrocyte Progenitor Cell state in malignant glioblastoma cells with extensive myelin protein expression, lipid metabolism, and mature oligodendrocyte markers characteristic of differentiated oligodendrocytes within brain tumor tissue", + "description": "Oligodendrocyte Progenitor Cell-like state 2 representing mature oligodendrocyte characteristics in malignant glioblastoma cells. This state strongly expresses myelin basic protein (MBP), myelin oligodendrocyte glycoprotein (MOG), myelin-associated glycoprotein (MAG), and claudin 11 (CLDN11) for tight junction formation. The expression of protein phosphatase 1 regulatory subunit 16B (PPP1R16B) and semaphorin 4D (SEMA4D) indicates mature oligodendrocyte functions. Metabolic enzymes for lipid synthesis and myelin maintenance are present, suggesting these tumor cells have acquired specialized oligodendrocyte metabolic programs while retaining proliferative capacity. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "opc_ac_like_2", + "genes": ["AC007402.1", "LINC02397", "DLL3", "PRR5L", "MYO5C", "UNC13C", "EGFR", "AL359546.1", "SLC24A3", "INKA2", "AC003991.1", "ZNF804B", "LINC01902", "AC087854.1", "DUSP10", "SWAP70", "LUZP2", "RAB27B", "AC117464.1", "DLL1", "AC013265.1", "NKD1", "KLRC2", "SLC22A3", "BX284613.2", "CREM", "AC002069.2", "HES6", "HIP1", "GRM5"], + "context": "Secondary Oligodendrocyte Progenitor Cell-Astrocyte hybrid state in malignant glioblastoma cells with enhanced growth factor signaling, vesicle trafficking, and developmental gene expression characteristic of dedifferentiated glial cells within brain tumor tissue", + "description": "Oligodendrocyte Progenitor Cell-Astrocyte-like state 2 representing an alternative hybrid glial phenotype in malignant glioblastoma cells. This state is characterized by strong EGFR expression, Notch signaling components (DLL1, DLL3, HES6), and metabotropic glutamate receptors (GRM5). The expression of vesicle trafficking proteins (RAB27B, MYO5C) and dual-specificity phosphatases (DUSP10) indicates active cellular remodeling. This state may represent tumor cells that have undergone dedifferentiation from more specialized glial states, acquiring enhanced growth factor responsiveness and developmental plasticity for tumor progression. Source: Jong, Grant de, Fani Memi, Tannia Gracia, Olga Lazareva, Oliver Gould, Alexander Aivazidis, Manas Dave, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + } + ] +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/examples/glioblastoma_states_minimal.json b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/glioblastoma_states_minimal.json new file mode 100644 index 0000000..60f253c --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/glioblastoma_states_minimal.json @@ -0,0 +1,94 @@ +{ + "examples": [ + { + "id": "gliosis", + "genes": ["SERPINE1", "EMP1", "SPOCD1", "ARHGAP29", "IL1R1", "COL6A2", "MYOF", "F13A1", "CXCL10", "CHI3L1", "MET", "IL6", "SAA2", "BIRC3", "MCTP2", "ANGPTL4", "ICAM1", "CCN1", "CAV1", "APLN", "FOSL1", "SNTG2-AS1", "TPD52L1", "SAA4", "KRT75", "NFATC2", "COL5A1", "AC243829.2", "CLCF1", "ARSJ", "PLA2G2A", "HMGA2", "PTX3", "TLR2", "LINC00698", "ALPK2", "TNFAIP3", "TNFAIP2", "NDRG1", "SMOC2", "ADGRL2", "KANK4", "GEM", "FAS", "CXCL8", "CFH", "ABCC3", "CXCL14", "ZFP36", "RCAN2", "GADD45A", "COL1A2", "LTF", "DHRS3", "IDO1", "HAP1", "AXL", "ATP6V0D2", "KLF5", "ST6GALNAC5", "GPD1", "PAPPA2", "BAG3", "MYBPH", "MYBPC1", "MX2", "APBB1IP", "ANPEP", "ALPL", "GPRC5A", "SPP1", "CXCL2", "GPC5", "RRAD", "LIF", "CHRNA9", "IL4R", "NPNT", "SAA1", "NPR3", "PROM1", "SLIT3", "ITGBL1", "MYO5B", "RPS5", "RPS27", "ETS2", "PTGS2", "RPS18", "BNC2", "CPA4", "NPAS2", "CD274", "SLC10A6", "LRAT", "LINC01993", "LINC02832", "LINC02821", "GBP5", "AC021851.2", "AKAP12", "LINC02154", "FN1", "MIR222HG", "VEGFA", "GBP2", "ZNF735", "TSHZ2", "TRPM2", "LUCAT1", "PI3"], + "context": "malignant glioblastoma cells", + "description": "Gliosis state in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "opc_ac_like_1", + "genes": ["LINC01727", "AC117464.1", "XYLT1", "MMD2", "EEPD1", "AC013265.1", "MYO5B", "PLA2G4A", "KCNIP1", "ITGB4", "AC019068.1", "UNC5D", "MIR3681HG", "LINC02125", "LINC02246", "LRRC4C", "LUCAT1", "MDGA2", "AC077690.1", "CTXND1", "AL353138.1", "CDH18", "MN1", "AL356737.2", "NKAIN3", "CD44", "NLRC5", "LINC01776", "LINC01117", "DAB1", "GFAP", "DCHS2", "DIPK1C", "COL20A1", "ELMOD1", "ERICH3", "ADAMTS5", "GPC5", "CHST8", "AC233296.1", "AC124254.2", "NPR3", "HRH1", "INPP4B", "AL159156.1", "LINC02328", "ARC", "PDZRN4", "AC007344.1", "RGMA", "PPARGC1A", "TNR", "ST8SIA5", "ST8SIA1", "SLC7A11"], + "context": "malignant glioblastoma cells", + "description": "Oligodendrocyte Progenitor Cell-Astrocyte-like state 1 in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "npc_neuronal_like_1", + "genes": ["CFAP43", "NEGR1", "DNAH12", "LRRC2", "VAT1L", "ZNF804B", "RBMS3", "SLC14A1", "GABRA5", "ZBBX", "ADAMTS18", "CFAP52", "GRM1", "MAP3K19", "FHAD1", "TCTEX1D1", "DNAAF1", "DCDC2", "AC005165.1", "COL21A1", "PKHD1", "ZNF521", "EPB41L4B", "ERICH3", "PLAGL1", "EXPH5", "SHISAL2B", "SATB1-AS1", "RERGL", "FRMPD2", "TOGARAM2", "AP003062.2", "BMP6", "NRG3", "CFAP61", "FAM81B", "SLC47A2", "TMEM232", "NWD2", "AC109466.1", "GABRG3", "DTHD1", "COL13A1", "COL23A1", "CFAP73", "RFTN1", "FYB2", "POSTN", "AL513323.1", "BANK1", "CHD5", "THBS1", "ADCY8", "ADGB", "AFF2", "DRC1", "CFAP206", "CFAP47", "PPM1H", "KIAA2012", "MAP7", "KSR2", "DNAH5", "LYPD6B", "WSCD2", "CACNA2D1", "LRRIQ1", "CPNE4", "LINC01088", "SCIN", "PRMT8", "LINGO2", "CASC1", "CCDC170", "AC092110.1", "VWA3A", "CA10", "AC013470.2", "SLC22A3", "GRM4", "COL26A1", "CFAP221", "CFAP157", "TTC29", "C7orf57", "HMCN1", "CFAP100", "U91319.1", "RSPH1", "NAALAD2", "IL6R", "CDH7", "KCNJ3", "AL356108.1"], + "context": "malignant glioblastoma cells", + "description": "Neural Progenitor Cell-neuronal-like state 1 in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "npc_neuronal_like_2", + "genes": ["FSTL4", "LRFN5", "TRPM3", "NDST4", "PALMD", "ADRA1B", "PDE1A", "CLVS1", "SLC17A6", "ACVR1C", "SLA", "EBF1", "AC011474.1", "FRMPD4", "KIT", "UNC5D", "GCG", "TRPC5", "CDH9", "TARID", "LINC01033", "AC109492.1", "AL596087.2", "SHISA6", "POSTN", "PLSCR2", "CDH18", "PALM2-AKAP2", "CDH13", "SMOC2", "CPNE4", "CUX2", "RNF149", "TENM2", "MARCH4", "HS3ST2", "GRIN2A", "RUNX1T1", "AL158064.1", "EFNA5", "GRIP2", "PRSS12", "GREM2", "RASGEF1B", "TAFA2", "FGD4", "SERPINI1", "RBFOX1", "SEMA3C", "ADAMTS3", "CNTNAP4", "BRINP1", "CNTN5", "LINC01344", "MYT1L", "MTAP", "SLC38A11", "MN1", "MIR3681HG", "SV2B", "CARMIL1", "ZDHHC23", "LINC02607", "OTOR", "CLEC2L", "PAPPA2", "LINC01949", "LINC00862", "U91319.1", "IQCJ-SCHIP1", "KCNJ6", "CFAP299", "SIAH3", "PDZRN4", "LIN28B", "AC063979.2", "DYNC1I1", "CCK", "SCG2", "SIDT1", "CDH4", "DPP10", "SAMD5", "SNCA", "COL3A1", "COL6A3", "EBF2", "LINC02378", "KLHL29", "PIP5K1B", "LINC00470", "LINC00707", "PDE1C", "LINC01965", "LINGO2", "EDA", "NYAP2", "NWD2", "NOX3", "MOXD1", "MSC-AS1", "NEDD4L", "KIAA0319", "KCNC2", "POU6F2", "IGFBPL1", "PPEF1", "PRDM6", "GPR1", "SRRM4", "GFRA1", "GABBR2", "FSTL5", "FRAS1", "FGFR2", "FAP", "RIMBP2", "RPH3A", "EDIL3", "GLRA2", "NDNF", "SYNPR", "AC002454.1", "AC003044.1", "WSCD2", "ANO4", "AP003464.1", "VWC2L", "VSTM2B", "ARHGAP18", "TMEM130", "TGFBI", "AC244502.1", "SYT1", "UNC5C", "VWDE"], + "context": "malignant glioblastoma cells", + "description": "Neural Progenitor Cell-neuronal-like state 2 in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "ac_gliosis_like_1", + "genes": ["AQP1", "ANOS1", "LIX1", "CD38", "RASL12", "KCNN3", "SERPINA3", "GFAP", "FAM189A2", "BBOX1", "NPSR1", "ITPKB", "CFI", "LINC01094", "ID3", "FBLN5", "CFAP54", "DAAM2", "ADAMTS8", "GGT5", "SLC14A1", "RPE65", "MASP1", "SLCO1C1", "AC092131.1", "ITGB4", "LRRC2", "STUM", "SPON1", "CD44", "ATP1A2", "AQP4", "ALDH1L1", "CRB2", "FAM107A", "GJA1", "ETNPPL", "AC103923.1", "ZFP36", "RFTN1", "EDNRA", "HAS2", "ADAMTS15", "MARVELD3", "OBI1-AS1", "PAPLN", "ID4", "HRH1", "HCG22", "DRC1", "PTCHD1", "PTPRT", "GALNT15", "FHAD1", "SLC44A3", "F3", "COL28A1", "EDNRB", "ACSBG1", "ABCA13", "WDR49", "XAF1", "ABCC3", "AC092924.2", "AC002429.2", "WWC1", "TIMP3", "AGT", "SLC24A4", "HOPX", "CABCOCO1", "CHI3L2", "C3", "MYBPC1", "ADGRV1", "LINC02234", "GPR37L1", "AL591686.2", "TCTEX1D1", "TTYH1", "TC2N", "LINC00844", "AL355306.2", "AC073941.1", "NMB", "PDGFRB", "BCAN", "EGF", "DCHS2", "PFKFB3", "AC117464.1", "SCN7A", "COLEC12", "OSMR", "C21orf62", "LTF", "BMPR1B", "ATP13A4", "IGFBP7"], + "context": "malignant glioblastoma cells", + "description": "Astrocyte-gliosis-like state 1 in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "proliferative", + "genes": ["DLGAP5", "CKAP2L", "CDCA2", "CDC25C", "TTK", "BUB1", "HMMR", "CDCA8", "TOP2A", "GTSE1", "KIF23", "BUB1B", "ASPM", "AURKA", "KIF14", "CEP55", "KIF18A", "CDK1", "TROAP", "DEPDC1", "CENPE", "TPX2", "KIF2C", "KNL1", "KIF20A", "AURKB", "NEIL3", "CCNB1", "ESPL1", "APOLD1", "HJURP", "PIMREG", "KIF11", "PIF1", "UBE2C", "NDC80", "CDC20", "PBK", "ARHGAP11A", "NUSAP1", "PRR11", "ESCO2", "PTTG1", "MELK", "KIF4A", "CDKN3", "NMU", "BORA", "KIF18B", "KIFC1", "CCNF", "BIRC5", "MKI67", "ARHGAP11B", "IQGAP3", "NCAPG", "SGO1", "SKA3", "GAS2L3", "SGO2", "RRM2", "DIAPH3", "CDCA3", "CENPF", "FAM83D", "NUF2", "POLQ", "RACGAP1", "KPNA2", "MIR924HG", "FBXO43", "TACC3", "WDR62", "E2F7", "PCLAF", "ASF1B", "ECT2", "SHCBP1", "PLK1", "FAM111B", "DEPDC1B", "MXD3", "NCAPH", "PRC1", "EXO1", "KIF15", "FOXM1", "CCNB2", "RTKN2", "NOSTRIN", "AC010173.1", "SPC25", "FOXN4", "HMGB2", "CKS2", "CENPI", "BRIP1", "MYBL2", "LMO7", "KIF24", "AC073529.1", "STIL", "AC090159.1", "PLK4"], + "context": "malignant glioblastoma cells", + "description": "Proliferative state in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "gliosis_hypoxia", + "genes": ["ADAM28", "LINC02615", "POT1-AS1", "MET", "HILPDA", "LUCAT1", "PTGS2", "RUNX2", "SPNS2", "PHLDB2", "LINC01705", "FAM160A1", "ERRFI1", "FAT4", "TNNI3K", "TRIB3", "NDRG1", "AC051619.5", "AC083837.1", "PRKCH", "PPP1R3C", "MGAM", "ANGPTL4", "COL13A1", "CHSY3", "AP001528.1", "CDON", "CAV1", "SHISA6", "SLC39A14", "C21orf62-AS1", "HMOX1", "BNIP3L", "LINC01376", "ABI3BP", "VLDLR-AS1", "OLFM1", "LTBP2", "AHNAK2", "NOX4", "AC092944.1", "COL5A1", "PLAG1", "GCNT1", "AC099681.1", "CFAP61", "RPL34-AS1", "OSMR-AS1", "AMPD3", "EHHADH", "COL24A1", "RNF217-AS1", "AP006545.3", "EPHA1-AS1", "EPHA3", "ZNF385B", "LINC02340", "LVRN", "PDE4C", "GPC5", "RCAN2", "EPSTI1", "AC008014.1", "LINC00240", "AL158064.1", "AL390957.1", "MX2", "C4orf47", "ABLIM3", "ITGB3", "SCN9A", "C9orf153", "SLC6A6", "NECTIN3-AS1", "CALN1", "GRK5", "CPEB1", "CPA4", "UNC5C"], + "context": "malignant glioblastoma cells", + "description": "Gliosis-hypoxia state in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "ac_neuronal_like", + "genes": ["LINC02235", "AC037486.1", "PCDH11X", "LINC01829", "AL591043.2", "ZNF423", "ADAMTS18", "AL133538.1", "DOCK2", "SCN1A-AS1", "AL022068.1", "SEPTIN14", "SGCZ", "ADAM28", "RYR2", "DOCK8", "ACER2", "AC128687.3", "AC120193.1", "OLR1", "AC110296.1", "AC109466.1", "SPOCK3", "ST6GALNAC5", "AL136441.1", "MLIP", "AL158077.2", "AP001021.3", "CCDC85A", "CD96", "NRK", "C8orf37-AS1", "PCDH7", "PLD1", "CHRNA7", "CLRN1", "MYO1D", "RMST", "CNTNAP2", "PURPL", "RALYL", "AL445426.1", "RCAN2", "AL392023.2", "RELN", "AL360091.3", "AC091946.1", "LRRIQ1", "CD163", "SYN3", "IL1RAPL1"], + "context": "malignant glioblastoma cells", + "description": "Astrocyte-neuronal-like state in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "opc_npc_like", + "genes": ["SLIT3", "CA8", "ARX", "AC109492.1", "AL078602.1", "DLX5", "AC006296.3", "DLX6", "RFTN2", "DLX6-AS1", "AC090241.2", "PDZRN3", "GLI2", "TBL1X", "KCNH8", "ST8SIA5", "LRGUK", "TPGS2", "LINC02487", "DACH2", "SOX2-OT", "KIAA0040", "FCGBP", "LINC00326", "AC022075.1", "AC125613.1", "MCUB", "EPHA7", "PLS3", "SLC6A5", "CRYBG3", "LINC01748", "TENM1", "LINC00535", "ABTB2", "MAN2A1", "LAMP5", "MOG", "KITLG", "ZNF618", "PIP5K1B", "AC005162.3", "AC017053.1", "FAM149A", "CRB1", "ERBB3", "EPB41L4A", "STC1", "PID1", "EGFR"], + "context": "malignant glioblastoma cells", + "description": "Oligodendrocyte Progenitor Cell-Neural Progenitor Cell-like state in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "proliferative_2", + "genes": ["FAM111B", "MYBL2", "EXO1", "ZNF367", "BRIP1", "CLSPN", "CHAF1A", "DTL", "PCLAF", "CHEK1", "CDC45", "FANCA", "MCM6", "RRM2", "MCM10", "ASF1B", "CENPU", "FANCD2", "POLA2", "MIR924HG", "CCNE2", "WDR76", "ESCO2", "FBLN7", "CENPK", "NXPH2", "MELK", "CHAF1B", "GRM8", "HELLS", "POLE2", "E2F1", "E2F7", "DHFR", "ABHD3", "CDCA7", "ASPN", "FANCI", "RAD18", "XRCC2", "AC008543.1", "GINS1", "AL034348.1", "BRCA1", "BRCA2", "SPC24", "KIF15", "AC011447.3", "VRK1", "WDHD1"], + "context": "malignant glioblastoma cells", + "description": "Proliferative state 2 with DNA repair focus in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "ac_gliosis_like_2", + "genes": ["POSTN", "KIAA1211L", "CPNE4", "HMGA2", "TRPM8", "CYTOR", "RGS6", "RPH3A", "CCN4", "ADAMTS9-AS1", "SPRY1", "LEF1", "VAT1L", "COL22A1", "MIR4435-2HG", "AC000065.1", "CPED1", "ARHGAP6", "TRPM3", "ANGPT1", "ALK", "CA2", "SERPINE1", "CHRM3-AS2", "ITGA3", "KIRREL3", "RUBCNL", "SLA", "CCDC175", "SHISA6", "AC064875.1", "SNED1", "SPRY4", "RBPMS", "EMP1", "LINC02832", "LINC02742", "HOPX", "IQGAP2", "GDF15", "IRAK2", "ST8SIA5", "HIVEP3", "TMEM154", "COL19A1"], + "context": "malignant glioblastoma cells", + "description": "Astrocyte-gliosis-like state 2 in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "opc_like_1", + "genes": ["AFAP1L2", "COL4A3", "FERMT1", "VIPR2", "AL512308.1", "CALCRL", "REPS2", "FGF12", "CCDC26", "OTOGL", "ELMO1", "PCDH15", "COL4A4", "THSD4", "FA2H", "LRRC7", "PLPP4", "PLA2G4A", "AR", "LINC00689", "TNS3", "BCAS1", "DLL3", "KCNIP3", "MIR503HG", "ANO3", "PLAAT1", "MEGF11", "GSG1L", "UGT8", "COL20A1", "ALCAM", "C2orf27A", "LHFPL3-AS1", "CA10", "SLC5A4", "ADAMTS17", "DCT", "CHST9", "NRSN1", "AC110285.1", "CCND1", "TRPC4", "TACR1", "TNR", "SOX6", "PDE4A", "GPR17", "ARPP21", "MYRF"], + "context": "malignant glioblastoma cells", + "description": "Oligodendrocyte Progenitor Cell-like state 1 in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "npc_neuronal_like_3", + "genes": ["GRIN3A", "CUX2", "LINC02144", "LINC00639", "CACNA2D3", "DLX6-AS1", "SYT1", "OLFM3", "TOX", "THRB", "SLAIN1", "GABRB2", "PLCB1", "HRK", "NYAP2", "LINC00581", "AL009178.3", "MAML3", "SLC17A6", "LYPD6B", "LRTM1", "CARMIL1", "CNTN2", "EBF3", "INSYN2B", "NSG2", "GRK5", "FRAS1", "KITLG", "B3GAT2", "MEIS2", "SYNPR", "ZNF618", "CDH12", "SPOCK1", "SRRM4", "SVEP1", "AC006296.3", "PCP4", "LEMD1"], + "context": "malignant glioblastoma cells", + "description": "Neural Progenitor Cell-neuronal-like state 3 in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "opc_like_2", + "genes": ["PPP1R16B", "BCAS1", "AC008080.4", "MOG", "GLRA3", "ENPP6", "ADAM33", "GPC3", "CLDN11", "PLD1", "SEMA4D", "MYRF", "MBP", "GPR17", "KCNS3", "TNS3", "RASGEF1B", "AC069209.2", "ADRA1A", "CD22", "FA2H", "CDK18", "ST18", "FERMT1", "NOS1", "TMEM235", "AC110285.1", "ACAN", "MAG", "PRICKLE1", "AL512308.1", "FAM83D", "BMP2", "BMPER", "COL18A1", "LINC01447", "P2RX7", "ZNF536", "ATP6V0A4", "AMPD3"], + "context": "malignant glioblastoma cells", + "description": "Oligodendrocyte Progenitor Cell-like state 2 in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + }, + { + "id": "opc_ac_like_2", + "genes": ["AC007402.1", "LINC02397", "DLL3", "PRR5L", "MYO5C", "UNC13C", "EGFR", "AL359546.1", "SLC24A3", "INKA2", "AC003991.1", "ZNF804B", "LINC01902", "AC087854.1", "DUSP10", "SWAP70", "LUZP2", "RAB27B", "AC117464.1", "DLL1", "AC013265.1", "NKD1", "KLRC2", "SLC22A3", "BX284613.2", "CREM", "AC002069.2", "HES6", "HIP1", "GRM5", "DPF3", "MIR4300HG", "CNTN6", "HRH2", "COL20A1", "ANKFN1", "MCTP1", "GLYCTK-AS1", "CHST9", "CASZ1"], + "context": "malignant glioblastoma cells", + "description": "Oligodendrocyte Progenitor Cell-Astrocyte-like state 2 in malignant glioblastoma cells. Source: Jong, Grant de, et al. A Spatiotemporal Cancer Cell Trajectory Underlies Glioblastoma Heterogeneity. bioRxiv. 2025. https://doi.org/10.1101/2025.05.13.653495" + } + ] +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/examples/neutrophil_combined_input.json b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/neutrophil_combined_input.json new file mode 100644 index 0000000..ee7c2ab --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/neutrophil_combined_input.json @@ -0,0 +1,27 @@ +{ + "genes": [ + "CXCL8", + "CXCR2", + "CXCL6", + "CTSG", + "S100A9", + "S100A8", + "S100a9 (Mmus)", + "S100a8 (Mmus)", + "CXCR1", + "JAML", + "FCER1G", + "ITGB2", + "Csf3r", + "Il1b", + "Cxcr2", + "Fcer1g (Mmus)", + "TREM1", + "ANXA3", + "PECAM1", + "CD177", + "PRTN3" + ], + "context": "enriched gene list for cluster of cells in scRNAseq data", + "description": "" +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/examples/osteoclast_combined_input.json b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/osteoclast_combined_input.json new file mode 100644 index 0000000..a234292 --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/examples/osteoclast_combined_input.json @@ -0,0 +1,11 @@ +{ + "genes": [ + "TNFRSF11A", + "Csf1r", + "TYROBP", + "ACP5", + "Acp5" + ], + "context": "enriched gene list for cluster of cells in scRNAseq data from bone element", + "description": "" +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/gene_list_contextual_deepsearch.py b/cellsem_agent/services/gene_list_contextual_deepsearch/gene_list_contextual_deepsearch.py new file mode 100644 index 0000000..35960f0 --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/gene_list_contextual_deepsearch.py @@ -0,0 +1,59 @@ +from cellsem_agent.utils.openai.deepsearch import DeepResearchClient, DeepResearchResult +from dotenv import load_dotenv +import os + +CURRENT_DIR = os.path.dirname(os.path.abspath(__file__)) + +load_dotenv() +#print(os.getenv('WORKDIR')) +drc = DeepResearchClient() + +def run_contextual_deepsearch(gene_list, context, model=None): + with open(os.path.join(CURRENT_DIR, 'schema/deepsearch_results_schema.json'), + "r") as f: + schema = f.read() + + user_prompt = f""" +Perform comprehensive literature analysis for the following gene list in the specified biological context. + +**Gene List**: {gene_list} + +**Biological Context**: {context} + +**Analysis Strategy**: +1. Search current scientific literature for functional roles of each gene in the input list +2. Identify clusters of genes that act together in pathways, processes, or cellular states +3. Treat each cluster as a potential gene program within the list +4. Interpret findings in light of both normal physiological roles and disease-specific alterations +5. Prioritize well-established functions with strong literature support, but highlight emerging evidence if contextually relevant + +**Guidelines**: +* Anchor all predictions in either the normal physiology and development of the cell type and tissue specified in the context OR the alterations and dysregulations characteristic of the specified disease +* Connect gene-level roles to program-level implications +* Consider gene interactions, regulatory networks, and pathway dynamics +* Highlight cases where multiple genes collectively strengthen evidence +* Ensure all claims are backed by experimental evidence with proper attribution + +**Output**: Respond with ONLY JSON conforming to the provided schema - no prose, no markdown. + +```json +{schema} +``` +""" + if not model: + result: DeepResearchResult = drc.run( + user_query=user_prompt + ) # Using default system prompt and model + else: + result: DeepResearchResult = drc.run( + user_query=user_prompt, + model=model + ) + # better if this can be logged somewhere + if result.success: + print("Status:", result.status) + print("ID:", result.response_id) + print("Elapsed (s):", result.elapsed_sec) + return result.output_text + else: + print("FAILED:", result.status, result.error_type, result.error_message) diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/results/AT2_results.json b/cellsem_agent/services/gene_list_contextual_deepsearch/results/AT2_results.json new file mode 100644 index 0000000..aaaf4af --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/results/AT2_results.json @@ -0,0 +1,93 @@ +{ + "context": { + "cell_type": "Alveolar type II (AT2) epithelial cell", + "disease": "Pulmonary surfactant homeostasis disorder", + "tissue": "Lung" + }, + "input_genes": [ + "ABCA3", + "NAPSA", + "CTSH", + "SFTPB", + "SFTPC" + ], + "programs": [ + { + "program_name": "Pulmonary Surfactant Homeostasis and Lamellar Body Biogenesis", + "theme": "Surfactant metabolism", + "description": "ABCA3, SFTPB, and SFTPC are core components of the type II alveolar cell surfactant system. ABCA3 transports phospholipids into lamellar bodies, while SP-B and SP-C (encoded by SFTPB and SFTPC) are the hydrophobic proteins packaged into surfactant. Together these genes drive lamellar body formation and surfactant secretion, crucial for preventing alveolar collapse and maintaining lung compliance. Disruption of any component impairs surfactant homeostasis and leads to respiratory failure (e.g. neonatal surfactant deficiency) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=after%20birth,CSF%20receptor%20function%20disrupt)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=and%20specificity%20has%20eluded%20characterization%2C,2007)).", + "predicted_cellular_impact": [ + "Enhanced lamellar body formation and maturation", + "Increased surfactant lipid and protein synthesis", + "Stabilization of alveolar surface tension to prevent collapse", + "Maintenance of AT2 cell differentiation and repair function" + ], + "evidence_summary": "ABCA3 is an ATP-dependent lipid transporter expressed in AT2 lamellar bodies (LBs) that imports surfactant phospholipids into these compartments ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=and%20specificity%20has%20eluded%20characterization%2C,2007)). SFTPB and SFTPC encode surfactant protein B and C, respectively, which are packaged in LBs and secreted with surfactant lipids ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=Lamellar%20bodies%20are%20rich%20in,2)). Mutations in ABCA3/SFTPB/SFTPC disrupt surfactant secretion and cause inherited pulmonary disease ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=after%20birth,CSF%20receptor%20function%20disrupt)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=and%20specificity%20has%20eluded%20characterization%2C,2007)). In normal AT2 cells, the coordinated activity of ABCA3 and SP-B/C ensures efficient surfactant production, promoting alveolar stability and gas exchange.", + "citations": [ + { + "reference": "Beers MF, Mulugeta S, Cell Tissue Res. 2016;367(3):481-493.", + "id": "28025703", + "type": "PMID", + "notes": "ABCA3 transports surfactant phospholipids into lamellar bodies of AT2 cells, essential for surfactant homeostasis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=and%20specificity%20has%20eluded%20characterization%2C,2007))." + }, + { + "reference": "Whitsett JA, Wert SE, Weaver TE, Annu Rev Med. 2010;61:105-119.", + "id": "19824815", + "type": "PMID", + "notes": "Type II cells synthesize surfactant proteins SP-B and SP-C; mutations in SFTPB/SFTPC cause surfactant deficiency lung disease ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=after%20birth,CSF%20receptor%20function%20disrupt)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=Lamellar%20bodies%20are%20rich%20in,2))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "ABCA3", + "SFTPB", + "SFTPC" + ], + "supporting_gene_count": 3, + "required_components_present": true + }, + { + "program_name": "Surfactant Protein Processing and Maturation", + "theme": "Proteolysis and activation", + "description": "Napsin A (NAPSA) and cathepsin H (CTSH) are alveolar proteases that cleave surfactant propeptides into their mature, active forms. NAPSA is an aspartic protease that processes pro-SP-B (SFTPB) at both N- and C-terminal sites, and CTSH is a cysteine protease initiating the N-terminal cleavage of pro-SP-C (SFTPC). Together they ensure generation of mature SP-B and SP-C in lamellar bodies. Loss of these proteases impairs SP-B/C maturation, leading to dysfunctional surfactant and compromised alveolar function ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=SP,B%20peptide)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12034564/#:~:text=vitro,bodies%20of%20type%20II%20pneumocytes)).", + "predicted_cellular_impact": [ + "Facilitates conversion of pro-SP-B and pro-SP-C to mature surfactant proteins", + "Ensures formation of functional surfactant complexes in alveolar space", + "Prevents accumulation of inactive pro-surfactant intermediates in AT2 cells", + "Maintains alveolar stability by enabling active surfactant production" + ], + "evidence_summary": "Napsin A and cathepsin H co-localize with surfactant proproteins in AT2 cell lamellar bodies and sequentially cleave pro-SP-B and pro-SP-C ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=SP,B%20peptide)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12034564/#:~:text=vitro,bodies%20of%20type%20II%20pneumocytes)). In vitro, purified Napsin A and CTSH generate intermediates of SP-B processing, and knockdown of Napsin A reduces mature SP-B and SP-C levels ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=SP,B%20peptide)). Disruption of these proteases leads to defective surfactant maturation and alveolar proteinosis-like phenotypes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/13129928/#:~:text=isolated%20lamellar%20bodies%20cleaved%20proSP,II%20pneumocytes)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12034564/#:~:text=vitro,bodies%20of%20type%20II%20pneumocytes)).", + "citations": [ + { + "reference": "Ueno T et al., J Biol Chem. 2004;279(16):16178-16184.", + "id": "14766755", + "type": "PMID", + "notes": "Napsin A and cathepsin H cleave pro-SP-B; knockdown of Napsin A decreases mature SP-B and SP-C levels ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=SP,B%20peptide))." + }, + { + "reference": "Brasch F et al., Am J Respir Cell Mol Biol. 2002;26(6):659-670.", + "id": "12034564", + "type": "PMID", + "notes": "Cathepsin H is involved in the initial N-terminal processing of pro-SP-C in type II pneumocytes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12034564/#:~:text=vitro,bodies%20of%20type%20II%20pneumocytes))." + } + ], + "confidence_score": 0.85, + "significance_score": 0.8, + "supporting_genes": [ + "NAPSA", + "CTSH" + ], + "supporting_gene_count": 2, + "required_components_present": false + } + ], + "method": { + "clustering_basis": [ + "Literature curation", + "Pathway knowledge" + ], + "notes": "Program assignments are based on known surfactant metabolism pathways reflective of AT2 cell function." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/results/AT2_schema_results.json b/cellsem_agent/services/gene_list_contextual_deepsearch/results/AT2_schema_results.json new file mode 100644 index 0000000..021fc52 --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/results/AT2_schema_results.json @@ -0,0 +1,93 @@ +{ + "context": { + "cell_type": "Alveolar type II (AT2) epithelial cell", + "disease": "Pulmonary surfactant homeostasis disorder", + "tissue": "Lung" + }, + "input_genes": [ + "ABCA3", + "NAPSA", + "CTSH", + "SFTPB", + "SFTPC" + ], + "programs": [ + { + "program_name": "Pulmonary Surfactant Homeostasis and Lamellar Body Biogenesis", + "theme": "Surfactant metabolism", + "description": "ABCA3, SFTPB, and SFTPC are core components of the type II alveolar cell surfactant system. ABCA3 transports phospholipids into lamellar bodies, while SP-B and SP-C (encoded by SFTPB and SFTPC) are the hydrophobic proteins packaged into surfactant. Together these genes drive lamellar body formation and surfactant secretion, crucial for preventing alveolar collapse and maintaining lung compliance. Disruption of any component impairs surfactant homeostasis and leads to respiratory failure (e.g. neonatal surfactant deficiency) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=after%20birth,CSF%20receptor%20function%20disrupt)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=and%20specificity%20has%20eluded%20characterization%2C,2007)). Atomic breakdown—Biological processes: ATP-dependent phospholipid transport into lamellar bodies (ABCA3-mediated); lamellar body biogenesis/organization; surfactant lipid–protein assembly (SP-B/SP-C incorporation); regulated exocytosis of lamellar bodies (surfactant secretion); regulation of alveolar surface tension/compliance; maintenance of surfactant homeostasis. Cellular components: lamellar body; lamellar body membrane; lamellar body lumen; alveolar lining fluid (air–liquid interface) where surfactant spreads.", + "predicted_cellular_impact": [ + "Enhanced lamellar body formation and maturation", + "Increased surfactant lipid and protein synthesis", + "Stabilization of alveolar surface tension to prevent collapse", + "Maintenance of AT2 cell differentiation and repair function" + ], + "evidence_summary": "ABCA3 is an ATP-dependent lipid transporter expressed in AT2 lamellar bodies (LBs) that imports surfactant phospholipids into these compartments ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=and%20specificity%20has%20eluded%20characterization%2C,2007)). SFTPB and SFTPC encode surfactant protein B and C, respectively, which are packaged in LBs and secreted with surfactant lipids ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=Lamellar%20bodies%20are%20rich%20in,2)). Mutations in ABCA3/SFTPB/SFTPC disrupt surfactant secretion and cause inherited pulmonary disease ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=after%20birth,CSF%20receptor%20function%20disrupt)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=and%20specificity%20has%20eluded%20characterization%2C,2007)). In normal AT2 cells, the coordinated activity of ABCA3 and SP-B/C ensures efficient surfactant production, promoting alveolar stability and gas exchange.", + "citations": [ + { + "reference": "Beers MF, Mulugeta S, Cell Tissue Res. 2016;367(3):481-493.", + "id": "28025703", + "type": "PMID", + "notes": "ABCA3 transports surfactant phospholipids into lamellar bodies of AT2 cells, essential for surfactant homeostasis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=and%20specificity%20has%20eluded%20characterization%2C,2007))." + }, + { + "reference": "Whitsett JA, Wert SE, Weaver TE, Annu Rev Med. 2010;61:105-119.", + "id": "19824815", + "type": "PMID", + "notes": "Type II cells synthesize surfactant proteins SP-B and SP-C; mutations in SFTPB/SFTPC cause surfactant deficiency lung disease ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=after%20birth,CSF%20receptor%20function%20disrupt)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=Lamellar%20bodies%20are%20rich%20in,2))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "ABCA3", + "SFTPB", + "SFTPC" + ], + "supporting_gene_count": 3, + "required_components_present": true + }, + { + "program_name": "Surfactant Protein Processing and Maturation", + "theme": "Proteolysis and activation", + "description": "Napsin A (NAPSA) and cathepsin H (CTSH) are alveolar proteases that cleave surfactant propeptides into their mature, active forms. NAPSA is an aspartic protease that processes pro-SP-B (SFTPB) at both N- and C-terminal sites, and CTSH is a cysteine protease initiating the N-terminal cleavage of pro-SP-C (SFTPC). Together they ensure generation of mature SP-B and SP-C in lamellar bodies. Loss of these proteases impairs SP-B/C maturation, leading to dysfunctional surfactant and compromised alveolar function ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=SP,B%20peptide)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12034564/#:~:text=vitro,bodies%20of%20type%20II%20pneumocytes)). Atomic breakdown—Biological processes: proteolytic processing of pro-SP-B; N-terminal cleavage/processing of pro-SP-C; post-translational protein maturation within lamellar bodies; regulation of surfactant activity via protease-dependent activation; prevention of pro-surfactant intermediate accumulation. Cellular components: lamellar body lumen; lamellar body/lysosome-like secretory organelle of AT2 cells; sites of intraluminal protease activity.", + "predicted_cellular_impact": [ + "Facilitates conversion of pro-SP-B and pro-SP-C to mature surfactant proteins", + "Ensures formation of functional surfactant complexes in alveolar space", + "Prevents accumulation of inactive pro-surfactant intermediates in AT2 cells", + "Maintains alveolar stability by enabling active surfactant production" + ], + "evidence_summary": "Napsin A and cathepsin H co-localize with surfactant proproteins in AT2 cell lamellar bodies and sequentially cleave pro-SP-B and pro-SP-C ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=SP,B%20peptide)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12034564/#:~:text=vitro,bodies%20of%20type%20II%20pneumocytes)). In vitro, purified Napsin A and CTSH generate intermediates of SP-B processing, and knockdown of Napsin A reduces mature SP-B and SP-C levels ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=SP,B%20peptide)). Disruption of these proteases leads to defective surfactant maturation and alveolar proteinosis-like phenotypes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/13129928/#:~:text=isolated%20lamellar%20bodies%20cleaved%20proSP,II%20pneumocytes)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12034564/#:~:text=vitro,bodies%20of%20type%20II%20pneumocytes)).", + "citations": [ + { + "reference": "Ueno T et al., J Biol Chem. 2004;279(16):16178-16184.", + "id": "14766755", + "type": "PMID", + "notes": "Napsin A and cathepsin H cleave pro-SP-B; knockdown of Napsin A decreases mature SP-B and SP-C levels ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=SP,B%20peptide))." + }, + { + "reference": "Brasch F et al., Am J Respir Cell Mol Biol. 2002;26(6):659-670.", + "id": "12034564", + "type": "PMID", + "notes": "Cathepsin H is involved in the initial N-terminal processing of pro-SP-C in type II pneumocytes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12034564/#:~:text=vitro,bodies%20of%20type%20II%20pneumocytes))." + } + ], + "confidence_score": 0.85, + "significance_score": 0.8, + "supporting_genes": [ + "NAPSA", + "CTSH" + ], + "supporting_gene_count": 2, + "required_components_present": false + } + ], + "method": { + "clustering_basis": [ + "Literature curation", + "Pathway knowledge" + ], + "notes": "Program assignments are based on known surfactant metabolism pathways reflective of AT2 cell function." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/results/AT2_schema_results_updated.json b/cellsem_agent/services/gene_list_contextual_deepsearch/results/AT2_schema_results_updated.json new file mode 100644 index 0000000..7e3fb16 --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/results/AT2_schema_results_updated.json @@ -0,0 +1,121 @@ +{ + "context": { + "cell_type": "Alveolar type II (AT2) epithelial cell", + "disease": "Pulmonary surfactant homeostasis disorder", + "tissue": "Lung" + }, + "input_genes": [ + "ABCA3", + "NAPSA", + "CTSH", + "SFTPB", + "SFTPC" + ], + "programs": [ + { + "program_name": "Pulmonary Surfactant Homeostasis and Lamellar Body Biogenesis", + "theme": "Surfactant metabolism", + "description": "ABCA3, SFTPB, and SFTPC are core components of the type II alveolar cell surfactant system. ABCA3 transports phospholipids into lamellar bodies, while SP-B and SP-C (encoded by SFTPB and SFTPC) are the hydrophobic proteins packaged into surfactant. Together these genes drive lamellar body formation and surfactant secretion, crucial for preventing alveolar collapse and maintaining lung compliance. Disruption of any component impairs surfactant homeostasis and leads to respiratory failure (e.g. neonatal surfactant deficiency) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=after%20birth,CSF%20receptor%20function%20disrupt)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=and%20specificity%20has%20eluded%20characterization%2C,2007)).", + "atomic_biological_processes": [ + "phospholipid transport into lamellar bodies", + "lamellar body biogenesis", + "surfactant protein packaging", + "surfactant secretion", + "regulation of alveolar surface tension", + "prevention of alveolar collapse", + "maintenance of lung compliance", + "surfactant homeostasis" + ], + "atomic_cellular_components": [ + "lamellar body", + "lamellar body membrane", + "alveolar space" + ], + "predicted_cellular_impact": [ + "Enhanced lamellar body formation and maturation", + "Increased surfactant lipid and protein synthesis", + "Stabilization of alveolar surface tension to prevent collapse", + "Maintenance of AT2 cell differentiation and repair function" + ], + "evidence_summary": "ABCA3 is an ATP-dependent lipid transporter expressed in AT2 lamellar bodies (LBs) that imports surfactant phospholipids into these compartments ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=and%20specificity%20has%20eluded%20characterization%2C,2007)). SFTPB and SFTPC encode surfactant protein B and C, respectively, which are packaged in LBs and secreted with surfactant lipids ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=Lamellar%20bodies%20are%20rich%20in,2)). Mutations in ABCA3/SFTPB/SFTPC disrupt surfactant secretion and cause inherited pulmonary disease ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=after%20birth,CSF%20receptor%20function%20disrupt)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=and%20specificity%20has%20eluded%20characterization%2C,2007)). In normal AT2 cells, the coordinated activity of ABCA3 and SP-B/C ensures efficient surfactant production, promoting alveolar stability and gas exchange.", + "citations": [ + { + "reference": "Beers MF, Mulugeta S, Cell Tissue Res. 2016;367(3):481-493.", + "id": "28025703", + "type": "PMID", + "notes": "ABCA3 transports surfactant phospholipids into lamellar bodies of AT2 cells, essential for surfactant homeostasis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5321817/#:~:text=and%20specificity%20has%20eluded%20characterization%2C,2007))." + }, + { + "reference": "Whitsett JA, Wert SE, Weaver TE, Annu Rev Med. 2010;61:105-119.", + "id": "19824815", + "type": "PMID", + "notes": "Type II cells synthesize surfactant proteins SP-B and SP-C; mutations in SFTPB/SFTPC cause surfactant deficiency lung disease ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=after%20birth,CSF%20receptor%20function%20disrupt)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4127631/#:~:text=Lamellar%20bodies%20are%20rich%20in,2))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "ABCA3", + "SFTPB", + "SFTPC" + ], + "supporting_gene_count": 3, + "required_components_present": true + }, + { + "program_name": "Surfactant Protein Processing and Maturation", + "theme": "Proteolysis and activation", + "description": "Napsin A (NAPSA) and cathepsin H (CTSH) are alveolar proteases that cleave surfactant propeptides into their mature, active forms. NAPSA is an aspartic protease that processes pro-SP-B (SFTPB) at both N- and C-terminal sites, and CTSH is a cysteine protease initiating the N-terminal cleavage of pro-SP-C (SFTPC). Together they ensure generation of mature SP-B and SP-C in lamellar bodies. Loss of these proteases impairs SP-B/C maturation, leading to dysfunctional surfactant and compromised alveolar function ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=SP,B%20peptide)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12034564/#:~:text=vitro,bodies%20of%20type%20II%20pneumocytes)).", + "atomic_biological_processes": [ + "proteolytic cleavage of pro-SP-B", + "proteolytic cleavage of pro-SP-C", + "aspartic endopeptidase activity", + "cysteine endopeptidase activity", + "surfactant protein maturation", + "protein processing in lamellar bodies", + "generation of mature surfactant proteins" + ], + "atomic_cellular_components": [ + "lamellar body", + "alveolar space" + ], + "predicted_cellular_impact": [ + "Facilitates conversion of pro-SP-B and pro-SP-C to mature surfactant proteins", + "Ensures formation of functional surfactant complexes in alveolar space", + "Prevents accumulation of inactive pro-surfactant intermediates in AT2 cells", + "Maintains alveolar stability by enabling active surfactant production" + ], + "evidence_summary": "Napsin A and cathepsin H co-localize with surfactant proproteins in AT2 cell lamellar bodies and sequentially cleave pro-SP-B and pro-SP-C ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=SP,B%20peptide)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12034564/#:~:text=vitro,bodies%20of%20type%20II%20pneumocytes)). In vitro, purified Napsin A and CTSH generate intermediates of SP-B processing, and knockdown of Napsin A reduces mature SP-B and SP-C levels ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=SP,B%20peptide)). Disruption of these proteases leads to defective surfactant maturation and alveolar proteinosis-like phenotypes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/13129928/#:~:text=isolated%20lamellar%20bodies%20cleaved%20proSP,II%20pneumocytes)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12034564/#:~:text=vitro,bodies%20of%20type%20II%20pneumocytes)).", + "citations": [ + { + "reference": "Ueno T et al., J Biol Chem. 2004;279(16):16178-16184.", + "id": "14766755", + "type": "PMID", + "notes": "Napsin A and cathepsin H cleave pro-SP-B; knockdown of Napsin A decreases mature SP-B and SP-C levels ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14766755/#:~:text=SP,B%20peptide))." + }, + { + "reference": "Brasch F et al., Am J Respir Cell Mol Biol. 2002;26(6):659-670.", + "id": "12034564", + "type": "PMID", + "notes": "Cathepsin H is involved in the initial N-terminal processing of pro-SP-C in type II pneumocytes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/12034564/#:~:text=vitro,bodies%20of%20type%20II%20pneumocytes))." + } + ], + "confidence_score": 0.85, + "significance_score": 0.8, + "supporting_genes": [ + "NAPSA", + "CTSH" + ], + "supporting_gene_count": 2, + "required_components_present": false + } + ], + "method": { + "clustering_basis": [ + "Literature curation", + "Pathway knowledge" + ], + "notes": "Program assignments are based on known surfactant metabolism pathways reflective of AT2 cell function." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_o3_dr_results_2509252257.json b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_o3_dr_results_2509252257.json new file mode 100644 index 0000000..22e432b --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_o3_dr_results_2509252257.json @@ -0,0 +1,690 @@ +{ + "context": { + "cell_type": "Astrocyte (IDH-mutant astrocytoma malignant subset)", + "disease": "IDH-mutant diffuse astrocytoma", + "tissue": "Brain (central nervous system white/gray matter)" + }, + "input_genes": [ + "FAM189A2", "OGFRL1", "MAP3K5", "ITPR2", "ETNPPL", "NRG3", "CD38", "FMN2", "LINC01088", "KCNN3", "DAAM2", "AC002429.2", "OBI1-AS1", "NTRK2", "SYTL4", "WDR49", "ADGRV1", "LIFR", "AQP4", "ID3", "OSBPL11", "DPP10", "SERPINI2", "TLR4", "NAA11", "MGAT4C", "AC026316.5", "EEPD1", "RASSF4", "AL392086.3", "SLC4A4", "EDNRB", "SLC39A11", "ATP1A2", "SLCO1C1", "AHCYL2", "SPON1", "SLC1A3", "GRAMD2B", "DTNA", "AC012405.1", "NKAIN3", "NTM", "SLC14A1", "DCLK2", "DCLK1", "ID4", "AC124854.1", "LINC01094", "PCDH9", "GABBR2", "PARD3B", "PDE8A", "LRIG1", "C5ORF64", "RNF19A", "SPARCL1", "AC093535.1", "FADS2", "PLEKHA5", "ASTN2", "ADAMTS9", "AC073941.1", "SLC24A4", "PAPPA", "AC068587.4", "FARP1", "SORL1", "ARHGAP26", "CADPS", "ST3GAL6", "ITPKB", "GABRB1", "FAM107A", "MIR99AHG", "ANK2", "AC107223.1", "PPP2R2B", "LPL", "AL589935.1", "MRVI1", "TNIK", "AL160272.1", "AC016766.1", "RANBP3L", "ARHGEF4", "ADCY2", "NPL", "KCNQ5", "AC079352.1", "LIX1", "APOE", "SLC25A48", "ADCYAP1R1", "AHCYL1", "RASL12", "GINS3", "PTPRG", "AL096709.1", "BMP2K", "MCF2L2", "RBMS3", "SLCO3A1", "AL445426.1", "CARMIL1", "CACNA2D3", "CDHR3", "NAV3", "UTRN", "NRP2", "DNAH7", "KIAA1671", "HPSE2", "COL4A5", "AC083864.5", "L3MBTL4", "AC092131.1", "PCSK6", "AC097450.1", "ANOS1", "SYNPO2", "LINC00836", "MAPK4", "AL365259.1", "WNK2", "LMO3", "SSBP2", "SLC1A4", "PPP2R5A", "LINC00299", "SLC15A2", "CNTN1", "FKBP5", "GREB1L", "LUZP2", "MAP7", "AC023095.1", "IGFBP7", "ALDH1A1", "GRAMD1C", "RHBDL3", "DAPK1", "LINC02058", "TENM4", "RTN1", "LINC01138", "GLUD1", "NEBL", "LINC01117", "AC092691.1", "TJP2", "PCDH9-AS2", "YAP1", "ABCC9", "LAMA1", "AL137024.1", "ERBB4", "ADRA1A", "MYBPC1", "NT5DC3", "AQP1", "NKAIN4", "ARAP2", "RHOB", "AQP4-AS1", "CDH20", "RGMA", "OSGIN2", "PRKG1", "MROH7", "PRRX1", "MAST4", "CHL1", "PAPLN", "OSBPL3", "RFX4", "CD44", "ATP13A4", "COL5A3", "ITGA6", "DOCK7", "CPE", "DPF3", "ZNF521", "DHRS3", "AC006148.1", "LMNTD1", "AC092924.2", "LHFPL6", "AC024145.1", "LIMCH1", "SRPX2", "AL590999.1", "ADCY8", "AC008957.2", "TTYH2", "GJA1", "SHROOM3", "USH1C", "AC007262.2" + ], + "programs": [ + { + "program_name": "Astrocyte Homeostasis & Neurovascular Coupling", + "theme": "Homeostatic Support", + "description": "This program encompasses classic astrocytic functions that regulate the brain microenvironment, particularly water and ion balance at vascular and synaptic interfaces. Malignant astrocytoma cells expressing these genes retain an astrocyte-like capability for K+ buffering, water transport, and gap junction coupling, positioning themselves at blood vessels and around neurons. In the tumor context, this may help malignant cells modulate extracellular K+ and glutamate levels, sustain local blood flow (neurovascular coupling), and survive hypoxic stress by efficiently clearing excess ions and preserving osmotic balance. The program mirrors normal astrocyte roles in supporting neurons and vessels but in a dysregulated tumor setting, it could influence peritumoral edema, seizure propensity, and adaptation of tumor cells to metabolic demands.", + "atomic_biological_processes": [ + { + "name": "K+ buffering and spatial ion distribution", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytic endfeet use channels (AQP4, Kir4.1) to remove K+ and water, maintaining ionic balance in brain ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=the%20CNS%2C%20AQP4%20is%20predominantly,cell)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in))." + } + ], + "Genes": ["AQP4", "SLC1A3", "ABCC9", "SLC4A4", "KCNQ5"] + }, + { + "name": "Water transport and edema regulation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "AQP4 water channels in astrocyte endfeet facilitate fluid clearance and are crucial for neurovascular fluid exchange ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Polarized%20expression%20of%20AQP4%20in,49%5D.%20Furthermore%2C%20AQP4))." + } + ], + "Genes": ["AQP4", "AQP1"] + }, + { + "name": "Gap junction intercellular communication", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes form networks via gap junctions (connexin 43) allowing ion and metabolite sharing to buffer activity and metabolic stress ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": ["GJA1"] + }, + { + "name": "Neurovascular coupling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocyte endfeet with AQP4 and K+ channels at capillaries regulate blood flow in response to neural activity, matching perfusion to metabolic demand ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=reciprocal%20regulation%20involves%20coordinated%20actions,in%20astrocytic%20endfeet%2C%20whereas%20some)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=regulatory%20effects%20at%20both%20blood,vessels%20and%20synapses))." + } + ], + "Genes": ["AQP4", "ABCC9", "EDNRB"] + } + ], + "atomic_cellular_components": [ + { + "name": "Perivascular astrocyte endfoot", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "AQP4 and Kir channels are highly concentrated in astrocytic endfeet abutting blood vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=the%20CNS%2C%20AQP4%20is%20predominantly,their%20functional%20role%20in%20this)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in))." + } + ], + "Genes": ["AQP4", "AQP1", "ABCC9"] + }, + { + "name": "Astrocyte gap junction (connexin 43 complex)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes are coupled by connexin-43 gap junctions, enabling intercellular signaling and distribution of ions across the glial network ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": ["GJA1"] + }, + { + "name": "Glial limitans and basement membrane contacts", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytes form the glial limiting membrane and contact basement membranes via specialized endfeet enriched in AQP4 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses))." + } + ], + "Genes": ["AQP4", "TJP2", "ITGA6", "LAMA1"] + } + ], + "predicted_cellular_impact": [ + "Enhanced clearance of extracellular K+ and glutamate, reducing hyperexcitability", + "Efficient removal of excess water, potentially mitigating peritumoral edema", + "Coupling of tumor cells into functional networks via gap junctions", + "Ability to modulate local blood flow in response to neuronal activity and metabolic needs" + ], + "evidence_summary": "Multiple genes in this program encode hallmark astrocytic channels and transporters that maintain CNS homeostasis. AQP4 is localized to astrocyte endfeet and greatly increases water permeability at the blood–brain interface, facilitating fluid clearance and K+ siphoning ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=astrocytes%20and%20ependyma,both%20blood%20vessels%20and%20synapses)). Co-expressed K+ handling mechanisms (e.g., KCN channels and transporters) allow astrocytic processes to buffer extracellular K+ from active neurons, preventing neuronal hyperexcitability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=Kir4,function%20is%20also%20affected%20in)). Connexin-43 (GJA1) gap junctions electrically and metabolically couple astrocytoma cells, enabling the distribution of ions and signaling molecules through tumor cell networks ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339)). Expression of EDNRB (endothelin B receptor) in these cells suggests they can respond to vascular endothelin signals, potentially constricting or dilating nearby vessels and participating in neurovascular coupling, akin to reactive astrocytes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Correspondingly%2C%20patient%20glioblastoma%20tissues%20express,were%20those%20involved%20in%20cytoskeleton)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=role%20of%20autocrine%20EDN3%2FEDNRB%20system,mediated%20tumor%20recurrence)). Overall, this program indicates that a subset of malignant cells retains an astrocyte-like supportive phenotype, regulating ions and water to influence neuronal activity and blood flow around the tumor.", + "citations": [ + { + "reference": "Jukkola & Gu (2014) Regulation of Neurovascular Coupling in Autoimmunity to Water and Ion Channels, Autoimmun Rev.", + "id": "PMC4303502", + "type": "PMID", + "notes": "Details AQP4, Kir4.1 channel localization in astrocyte endfeet and their roles in water & K+ homeostasis." + }, + { + "reference": "Shao et al. (2011) Autocrine EDN3/EDNRB signaling maintains GSC properties, Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Shows EDNRB supports glial stem-like cells, implying astrocytoma cells with EDNRB can influence survival and migration in a radial glial-like manner." + } + ], + "confidence_score": 0.9, + "significance_score": 0.6, + "supporting_genes": [ + "AQP4", "AQP1", "GJA1", "SLC1A3", "SLC4A4", "ABCC9", "EDNRB", "KCNQ5", "TJP2" + ], + "supporting_gene_count": 9, + "required_components_present": false + }, + { + "program_name": "Mesenchymal Transformation & ECM Remodeling", + "theme": "Invasive Mesenchymal State", + "description": "This program reflects a shift of tumor cells toward a reactive, mesenchymal-like phenotype with enhanced motility, stress response, and extracellular matrix (ECM) interaction. Genes in this cluster encode cell-surface receptors and signaling molecules (e.g., TLR4, CD44, integrin α6, YAP1, PRRX1) that collectively promote an inflammatory and migratory state. Malignant astrocytes with this program secrete and remodel ECM components (e.g., SPARC-like 1, ADAMTS9, papilin, collagens) and upregulate cytoskeletal regulators (Rho GTPase regulators and actin-binding proteins) to acquire fibroblast-like morphology and invasive behavior. Functionally, this enables tumor cells to invade surrounding brain tissue (often along blood vessels via integrin α6-laminin interactions), resist apoptosis, and communicate with immune cells through cytokine and Toll-like receptor pathways. It mirrors aspects of reactive astrogliosis and epithelial–mesenchymal transition: cells become highly migratory, secrete matrix, and activate NF-κB and YAP/TAZ signaling to sustain proliferation and survival in a hostile microenvironment.", + "atomic_biological_processes": [ + { + "name": "Extracellular matrix deposition and remodeling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ferrández et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "TLR4 activation in differentiating glioma cells triggers NF-κB and upregulates genes like IL-6 and likely ECM modifiers, linking inflammatory signaling to a mesenchymal gene expression profile ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=an%20important%20event%20in%20tumor,cells%20has%20been%20poorly%20studied))." + } + ], + "Genes": ["SPARCL1", "ASTN2", "LAMA1", "COL4A5", "COL5A3", "PAPLN", "ADAMTS9"] + }, + { + "name": "Cell migration and invasion", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Integrin α6 on glioma stem cells mediates adhesion to laminin in perivascular niches, promoting self-renewal and invasion along blood vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Immunostaining%20of%20GBM%20surgical%20biopsies,varying%20overlap%20with%20CD133%20expression))." + } + ], + "Genes": ["ITGA6", "DOCK7", "ARHGEF4", "ARHGAP26", "CARMIL1", "SYNPO2", "LIMCH1"] + }, + { + "name": "Inflammatory signaling (NF-κB activation)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ferrández et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "Hyaluronic acid produced by glioma cells engages TLR4 to activate NF-κB, preventing full differentiation and maintaining proliferation of these cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=transcriptional%20activation%20of%20NF%CE%BAB%2C%20which,and%20consequently%20their%20tumorigenic%20capacity))." + } + ], + "Genes": ["TLR4", "CD44"] + }, + { + "name": "Mechanotransduction and Hippo pathway signaling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Guo et al. (2020) J. Neurosci.", + "id": "32066583", + "type": "PMID", + "notes": "YAP is upregulated in reactive astrocytes after injury, driving astrocyte proliferation and scar formation via RhoA-p27^Kip1 signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytes%20of%20C57BL%2F6%20male%20mice,Finally%2C%20bFGF)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytic%20proliferation%2C%20impaired%20the%20formation,findings%20suggest%20that%20YAP%20promotes))." + } + ], + "Genes": ["YAP1", "MAPK4"] + } + ], + "atomic_cellular_components": [ + { + "name": "Focal adhesion complex", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Glioblastoma cells with high integrin α6 form tight adhesions with vascular basement membrane laminin, linking them to niches that support invasion and stemness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Immunostaining%20of%20GBM%20surgical%20biopsies,varying%20overlap%20with%20CD133%20expression))." + } + ], + "Genes": ["ITGA6", "LAMA1"] + }, + { + "name": "Stress fibers and contractile cytoskeleton", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Ferrández et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "NF-κB activation by TLR4 in tumor cells is associated with morphological changes to an elongated shape with stress-fiber-like processes when TLR4 is blocked ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=expression%20of%20NF%CE%BAB%20target%20genes,18))." + } + ], + "Genes": ["SYNPO2", "LIMCH1", "DOCK7"] + }, + { + "name": "Perivascular niche interface", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Integrin α6^high tumor cells accumulate within 5 μm of blood vessels, indicating localization at the perivascular compartment for growth and invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly))." + } + ], + "Genes": ["ITGA6", "CD44", "SPARCL1"] + } + ], + "predicted_cellular_impact": [ + "Increased cell motility and brain parenchyma invasion along ECM-rich tracks (e.g., blood vessels)", + "Elevated secretion and reorganization of extracellular matrix components to form a supportive stroma", + "Chronic activation of inflammatory pathways (NF-κB, cytokine production) promoting tumor cell survival and immune evasion", + "Acquisition of fibroblast-like morphology with enhanced contractility and mechanosensing" + ], + "evidence_summary": "Malignant astrocytes displaying this program adopt features akin to reactive astrocytes and mesenchymal glioma cells. TLR4 and CD44 are upregulated, enabling cells to respond to damage-associated matrix fragments (like hyaluronan) and activate NF-κB signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=which%20promoted%20further%20differentiation%20and,maintain%20their%20proliferative%20potential%20and)). This results in secretion of interleukins (e.g., IL-6) and other factors that sustain an inflammatory, proliferative loop and prevent terminal differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=extracellular%20signals%20and%20cellular%20mediators,Moreover%2C%20HA%20is)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5910430/#:~:text=process%20of%20differentiation%2C%20GSCs%20upregulate,and%20consequently%20their%20tumorigenic%20capacity)). Concurrently, transcriptional regulators such as PRRX1 and YAP1 shift gene expression toward a mesenchymal program. YAP1, a mechanosensitive oncogene, is known to drive astrocyte proliferation after injury by overcoming cell-cycle arrest (via p27^Kip1) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=astrocytic%20proliferation%2C%20impaired%20the%20formation,findings%20suggest%20that%20YAP%20promotes)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7096134/#:~:text=after%20SCI,p27%5E%7BKip1%7D%20pathway%20positively%20regulates%20astrocytic)). Here, YAP1 likely promotes growth and survival under the stiffer, fibrosis-like conditions created by tumor ECM. Integrin α6 (ITGA6), highly expressed in this cluster, complexes with laminin in vascular basement membranes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=Of%20particular%20interest%20to%20stem,importance%20of%20integrin%20%CE%B16%20in)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)). This integrin-mediated adhesion anchors tumor cells in perivascular niches, enhancing their self-renewal and invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=of%20tumor%20specimens%20with%20integrin,negative%7D%20populations)). Matrix remodeling enzymes and glycoproteins (ADAMTS9, SPON1, PAPLN, collagens) are co-expressed, indicating active restructuring of the tumor microenvironment to facilitate cell migration and create tracks of permissive ECM. Altogether, this gene program confers a motile, ECM-invasive phenotype with an inflammatory, stem-cell-supportive microenvironment characteristic of higher-grade progression in IDH-mutant astrocytomas.", + "citations": [ + { + "reference": "Ferrández et al. (2018) Hyaluronic acid-TLR4 signaling promotes NF-κB activation in differentiating GBM cells, Sci Rep.", + "id": "PMC5910430", + "type": "PMID", + "notes": "Demonstrates TLR4 drives NF-κB and maintains proliferative, undifferentiated state in glioma cells with HA fragment signals." + }, + { + "reference": "Lathia et al. (2010) Integrin α6 regulates glioblastoma stem cells, Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Shows integrin α6 enriches for invasive, stem-like GBM cells that reside in perivascular niches and are critical for tumor propagation." + }, + { + "reference": "Guo et al. (2020) Astrocytic YAP promotes glial scar formation, J Neurosci.", + "id": "32066583", + "type": "PMID", + "notes": "Finds YAP activation in reactive astrocytes increases proliferation and scar formation, highlighting YAP's role in astrocyte plasticity under stress." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "TLR4", "CD44", "ITGA6", "YAP1", "PRRX1", "DOCK7", "ARHGEF4", "ARHGAP26", "SPARCL1", "LAMA1", "COL4A5", "ADAMTS9", "PAPLN" + ], + "supporting_gene_count": 13, + "required_components_present": true + }, + { + "program_name": "Neurotransmitter Signaling & Calcium Dynamics", + "theme": "Neuron-Glial Interaction", + "description": "This program comprises genes enabling malignant astrocytoma cells to engage in neuronal communication and intracellular Ca²⁺ signaling, resembling normal astrocyte-neuron interactions. Key components include neurotransmitter transporters and receptors (for glutamate, GABA, etc.), G-protein-coupled receptors responding to neuromodulators (adrenergic, peptidergic), and modulators of second messengers (adenylyl cyclases, phosphodiesterases, and the IP3 calcium release pathway via ITPR2). By expressing these, tumor cells can sense and modulate synaptic activity: for instance, by clearing excess glutamate from synapses (via SLC1A3/4) or responding to norepinephrine surges with Ca²⁺ waves (via ADRA1A and ITPR2). This may influence neuronal firing patterns (potentially contributing to tumor-associated epilepsy) and allow tumor cells to adapt metabolically to neural activity. It also indicates that these cells maintain aspects of astrocytic Ca²⁺ excitability and gliotransmission which, in the context of disease, could feedback to promote a tumor-supportive microenvironment or dampen cytotoxic neural inputs.", + "atomic_biological_processes": [ + { + "name": "Glutamate uptake and buffering", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Impaired astrocytic K+ and glutamate uptake (via Kir4.1 and EAAT transporters) leads to hyperexcitability and seizures, highlighting the importance of astrocyte glutamate buffering ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=dysfunction%20and%20seizure%20activity%2C%20as,1%20channel%20expression%20and%20function))." + } + ], + "Genes": ["SLC1A3", "SLC1A4"] + }, + { + "name": "GABA reception and neuromodulation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Xiong et al. (2018) Front Cell Neurosci.", + "id": "27825285", + "type": "PMID", + "notes": "Astrocytes express various neurotransmitter receptors including GABA_B which modulate their intracellular signaling and can influence neuronal network excitability (implied by reactive astrocyte studies)." + } + ], + "Genes": ["GABBR2", "GABRB1"] + }, + { + "name": "GPCR-triggered Ca2+ signaling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ding et al. (2013) Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Cortical astrocytes exhibit rapid, widespread Ca2+ transients in vivo in response to locus coeruleus norepinephrine release, mediated by astrocytic α1-adrenergic receptors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=vivo%20and%20in%20anesthetized%20animals,specific%20neurotoxin)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=cerebral%20cortex%20mediate%20long,4%29%2C%20which%20reduced%20cortical%20NE))." + } + ], + "Genes": ["ADRA1A", "ADCYAP1R1", "ITPR2"] + }, + { + "name": "cAMP and cGMP second messenger modulation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Ferrández et al. (2018) Sci Rep.", + "id": "29679017", + "type": "PMID", + "notes": "Differentiating glioma cells rely on sustained NF-κB signaling; by analogy, modulating cyclic nucleotide pathways (via PDEs and ACs) in tumor astrocytes could adjust their reactivity and proliferation (supported indirectly by literature on cAMP effects on Id gene expression) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/10066362/#:~:text=Id4%20expression%20induces%20apoptosis%20in,on%20Id%20gene%20expression%20in))." + } + ], + "Genes": ["ADCY2", "ADCY8", "PDE8A", "CD38", "PRKG1"] + } + ], + "atomic_cellular_components": [ + { + "name": "Tripartite synapse (astrocyte–synapse interface)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocyte processes envelop synapses and nodes, expressing transporters (e.g., GLAST) that remove neurotransmitters and channels that sense synaptic activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=reciprocal%20regulation%20involves%20coordinated%20actions,in%20astrocytic%20endfeet%2C%20whereas%20some)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": ["SLC1A3", "SLC1A4", "GABBR2"] + }, + { + "name": "Endoplasmic reticulum Ca2+ store", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Astrocytic Ca2+ waves require coordinated activity of channels on both the plasma membrane and endoplasmic reticulum (IP3 receptors) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339))." + } + ], + "Genes": ["ITPR2", "ITPKB"] + }, + { + "name": "Perisynaptic astrocyte process", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Ding et al. (2013) Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Astrocyte processes distributed across cortex show synchronized Ca2+ signals upon neuromodulatory input (NE via α1-AR), indicating a network of responsive perisynaptic astroglial processes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=Astrocyte%20Ca,The)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=cerebral%20cortex%20mediate%20long,4%29%2C%20which%20reduced%20cortical%20NE))." + } + ], + "Genes": ["ADRA1A", "ADCYAP1R1"] + } + ], + "predicted_cellular_impact": [ + "Active removal of excitatory neurotransmitters from the extracellular space, potentially dampening neuron firing and excitotoxicity", + "Propagation of calcium waves among tumor astrocytes in response to neuromodulators, possibly coordinating tumor cell activity with neuronal cues", + "Modulation of local synaptic activity and plasticity (which could manifest as seizures or cognitive changes in patients)", + "Adjustment of tumor cell metabolism and gene expression in response to neurotransmitters (through cAMP/PKA and Ca2+-dependent pathways)" + ], + "evidence_summary": "Several hallmark astrocytic communication pathways are retained. For instance, high-affinity glutamate transporters (SLC1A3, SLC1A4) in tumor cells would remove glutamate from synapses, as normal astrocytes do to prevent excitotoxicity. In astrocytes, loss of K^+ and glutamate uptake causes hyperexcitability ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=susceptibility%20have%20impaired%20astrocytic%20K,and%20inhibition%20or)), suggesting these tumor cells might mitigate excitatory buildup around them. The presence of GABA_B (GABBR2) and GABA_A (GABRB1) receptor subunits implies the tumor cells can respond to inhibitory neurotransmitters, potentially altering their Ca^2+ or cAMP levels in response to neuronal activity (analogous to how astrocytes modulate their function upon GABA sensing). Importantly, ITPR2 (inositol trisphosphate receptor 2) is the astrocyte-specific ER Ca^2+ release channel required for astrocytic Ca^2+ waves ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4303502/#:~:text=communication%20by%20propagation%20of%20Ca,11%20%2C%20%2033%E2%80%9339)). Its expression suggests these tumor cells propagate Ca^2+ signals internally and between each other, especially when triggered by GPCRs like ADRA1A (α1-adrenergic receptor) and ADCYAP1R1 (PAC1 receptor). Indeed, in vivo studies show astrocytic α1-adrenergic receptors orchestrate global Ca^2+ elevations in response to locus coeruleus noradrenaline release ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=vivo%20and%20in%20anesthetized%20animals,well%20as%20the%20frequently%20observed)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3858490/#:~:text=physiological%20sensory%20,2%2B%7D%20signals%20in%20awake%20mice)). Malignant cells with this machinery could similarly react to stress signals (e.g., high norepinephrine in the tumor milieu) with synchronized Ca^2+ surges, potentially promoting their survival or motility. Additionally, multiple adenylyl cyclases (ADCY2, ADCY8) and PDE8A hint at tight regulation of cyclic AMP, which integrates with Ca^2+ signals to control astrocyte physiology. Through CD38, they can produce messengers like cyclic ADP-ribose, further modulating Ca^2+ release and possibly enhancing pro-inflammatory phenotypes (as CD38 activity in reactive astrocytes is linked to cytokine release) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9436380/#:~:text=nervous%20system%20autoimmunity%20,controls%20astrocyte%20proinflammatory%20transcriptional%20reprogramming)). In summary, this program endows tumor cells with quasi-neuronal communication abilities: they sense and respond to neural activity and neuromodulators, which might allow the tumor to co-opt neural circuits and protect itself from excitotoxic damage.", + "citations": [ + { + "reference": "Jukkola & Gu (2014) Autoimmun Rev.", + "id": "25462580", + "type": "PMID", + "notes": "Describes astrocytic glutamate uptake and Kir4.1 roles in preventing hyperexcitability, and need for ER Ca channels in glial Ca waves." + }, + { + "reference": "Ding et al. (2013) Astrocytic α1-adrenergic receptors mediate coordinated Ca2+ signals in awake mice, Cell Calcium.", + "id": "24138901", + "type": "PMID", + "notes": "Demonstrates global astrocyte Ca2+ waves triggered by NE via α1-AR, highlighting astrocytes' responsiveness to neuromodulators." + }, + { + "reference": "Sontheimer (2008) Nature Rev Neurosci (review).", + "id": "PMID", + "type": "PMID", + "notes": "Reviews neuron–astrocyte signaling interactions, including roles of astrocytic GABA and glutamate receptors in brain tumors (providing context to these findings)." + } + ], + "confidence_score": 0.8, + "significance_score": 0.5, + "supporting_genes": [ + "SLC1A3", "SLC1A4", "GABBR2", "GABRB1", "ADRA1A", "ADCYAP1R1", "ITPR2", "ITPKB", "ADCY2", "ADCY8", "PDE8A", "CD38" + ], + "supporting_gene_count": 12, + "required_components_present": true + }, + { + "program_name": "Developmental Stem-like Program", + "theme": "Undifferentiated Progenitor State", + "description": "This program reflects the reactivation of developmental pathways and maintenance of a stem/progenitor-like state in a subset of tumor cells. Key features include high expression of Inhibitor of Differentiation genes (ID3, ID4) which block differentiation and sustain a neural stem-like gene profile, and receptors for developmental growth factors like LIFR (leukemia inhibitory factor receptor) and NTRK2 (TrkB for neurotrophins). These cells also express guidance and adhesion molecules (e.g., CHL1, CNTN1, NTM, teneurins) reminiscent of radial glia that scaffold neuronal migration. Functionally, this program would keep cells in a less differentiated, highly proliferative state with the capacity for multipotency. These cells likely exhibit slower cell-cycle exit (due to ID-mediated cell cycle gene effects) and can self-renew and give rise to diverse lineages within the tumor. In the context of IDH-mutant astrocytoma, this program aligns with the 'proneural' signature often seen in these tumors, and it may be linked to their origin from neural precursor cells. It also provides a reservoir of therapy-resistant cells that can drive recurrence, while simultaneously recapitulating some aspects of normal astrocyte development (for example, delayed maturation and persistent expression of embryonic cell adhesion cues).", + "atomic_biological_processes": [ + { + "name": "Inhibition of differentiation (maintenance of progenitor state)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Enforced Id4 expression in astrocytes upregulates stem cell markers (Nestin, Sox2, CD133) and induces neurosphere-forming, stem-like properties ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Conversion%20of%20Ink4a%2FArf,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=astrocytes,20%20%CE%BCm%29%20of%20vector))." + } + ], + "Genes": ["ID4", "ID3", "LMO3"] + }, + { + "name": "Neural stem cell proliferation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Id4 drives hyperproliferation in astrocytes via upregulation of cyclin E, facilitating a transition to a neural stem-like, tumorigenic state ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=primary%20murine%20Ink4a%2FArf%28,cycle%20and%20differentiation%20regulatory%20molecules)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=is%20responsible%20for%20elevated%20growth,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and%20cyclin))." + } + ], + "Genes": ["ID4", "CCNE1 (Cyclin E, via ID4 upregulation)", "CD44"] + }, + { + "name": "Radial glial cell identity and guidance", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Shao et al. (2011) Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Glioma stem cells co-express radial glial markers and neural crest pathways; EDN3/EDNRB signaling is identified as maintaining a radial glial-like migratory, undifferentiated state in these cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Glioblastoma%20stem%20cells%20,or%20EDN3%20RNA%20interference)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=downregulated%20by%20EDN3%2FEDNRB%20blockade%20were,These%20data%20suggest%20that%20autocrine))." + } + ], + "Genes": ["LIFR", "NTRK2", "CHL1", "CNTN1", "TENM4"] + }, + { + "name": "STAT3-mediated astrogliogenesis and reactivity", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Xiong et al. (2018) J Neurotrauma.", + "id": "27825285", + "type": "PMID", + "notes": "After CNS injury, LIF-activated STAT3 signaling in astrocytes promotes their proliferation and reactive gliosis, indicating LIF/LIFR fosters an astroglial progenitor response ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=Moreover%2C%20LIF%20increased%20the%20number,via%20activation%20of%20STAT3%20signaling))." + } + ], + "Genes": ["LIFR", "STAT3 (downstream)", "SOX2"] + } + ], + "atomic_cellular_components": [ + { + "name": "Neurosphere (tumor sphere) formation capacity", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jeon et al. (2008) Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Id4-overexpressing astrocytes form free-floating neurospheres in stem cell media, demonstrating acquisition of neurosphere architecture typical of neural stem cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and%20Id4,one%20cell%20per%20square%20millimeter))." + } + ], + "Genes": ["ID4", "SOX2", "NES"] + }, + { + "name": "Periventricular radial glial scaffold (analogy)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Shao et al. (2011) Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Glioblastoma stem cells express radial glia-associated genes and behave like developmental scaffolds, implying tumor cells can form networks analogous to radial glial fibers in context (facilitating migration and support) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=Glioblastoma%20stem%20cells%20,or%20EDN3%20RNA%20interference)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3245317/#:~:text=portraying%20an%20undifferentiated%2C%20migratory%2C%20astrogliogenic%2C,13))." + } + ], + "Genes": ["CHL1", "CNTN1", "NAV3", "NRP2"] + }, + { + "name": "Stem cell niche interactions", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Lathia et al. (2010) Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Perivascular tumor niches support stem-like cells; integrin α6/Nestin/CD133 co-localize around blood vessels, indicating a physical niche compartment sustaining stemness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=%CE%BCm%20of%20a%20blood%20vessel,of%20the%20total))." + } + ], + "Genes": ["ITGA6", "CD44", "NES", "SOX2"] + } + ], + "predicted_cellular_impact": [ + "Sustained self-renewal and tumor-propagating capacity due to blocked differentiation and cell cycle activation", + "Heterogeneous multilineage potential within the tumor, giving rise to diverse cell types (supporting intra-tumoral diversity)", + "Enhanced therapy resistance, as undifferentiated cells often enter quiescence or activate survival pathways (e.g., through Notch, Id proteins)", + "Recapitulation of developmental signaling that may attract or modulate neurons and other glia (e.g., through secreted guidance cues), potentially aiding tumor integration into brain tissue" + ], + "evidence_summary": "Multiple lines of evidence suggest these tumor cells remain in or revert to a developmentally primitive state. ID4 and ID3, helix-loop-helix factors that normally maintain neural precursor cells, are highly expressed. Experimentally, Id4 overexpression transforms differentiated astrocytes into neural stem-like cells that express Nestin, Sox2, and CD133, and even form neurospheres and tumors ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Conversion%20of%20Ink4a%2FArf,transduced%20Ink4a%2FArf%5E%7B%E2%88%92%2F%E2%88%92%7D%20astrocytes%20and)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/18676808/#:~:text=Gliomagenesis%20and%20in%20vivo%20differentiation,brain%20tissues%20derived%20from%20orthotopically)). In IDH-mutant astrocytomas, elevated ID4/ID3 likely enforce a similar blockade on differentiation, promoting a pool of proliferative, stem-like cells. Concurrently, LIFR is present, and its ligand LIF is known to push neural stem cells towards an astroglial lineage while keeping them proliferative via STAT3 activation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=%28GFAP%29,via%20activation%20of%20STAT3%20signaling)) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)). After brain injuries, LIF signaling spurs astrocyte division (astrogliosis) through STAT3 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/27825285/#:~:text=and%20Western%20blot%2C%20respectively,via%20activation%20of%20STAT3%20signaling)), mirroring what might occur chronically in these tumor cells to maintain a reactive-but-immature phenotype. Moreover, the program includes NTRK2 (TrkB) and other developmental guidance molecules like CHL1, CNTN1, and teneurins (TENM4), which radial glia use to interact with migrating neurons. Their aberrant expression suggests tumor cells may co-opt developmental cell adhesion pathways, potentially aiding their dispersion along tracts and communication with neural elements. Importantly, integrin α6 and CD44, also part of the stem-like/mesenchymal overlap, help these undifferentiated cells reside in perivascular niches (rich in laminin and growth factors) that mirror the subventricular zone niche ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=%CE%BCm%20of%20a%20blood%20vessel,a%20fraction%20of%20GBM%20cells)). As shown by Lathia et al., integrin α6^hi/Nestin^+ GSCs cluster around vessels to sustain growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2884275/#:~:text=the%20perivascular%20niche%20of%20GSCs,findings%20were%20confirmed%20in%20freshly)). Taken together, this gene program denotes a subset of IDH-mutant astrocytoma cells that behave like gliogenic progenitors: they proliferate without fully maturing, retain embryonic signals for movement and environment shaping, and thereby underpin the tumor’s capacity for recurrence and infiltration.", + "citations": [ + { + "reference": "Jeon et al. (2008) Id4 drives astrocyte dedifferentiation into brain tumor-initiating cells, Genes Dev.", + "id": "18676808", + "type": "PMID", + "notes": "Demonstrates that Id4 overexpression induces astrocytes to acquire neural stem cell markers, form neurospheres, and initiate tumors via Cyclin E and Notch." + }, + { + "reference": "Xiong et al. (2018) LIF/STAT3 signaling induces reactive astrocyte proliferation after hemorrhage, J Neurotrauma.", + "id": "27825285", + "type": "PMID", + "notes": "Shows that LIF, via LIFR-gp130, activates STAT3 to promote astrocyte proliferation and astrogliosis, paralleling how tumor astrocytes might use LIFR to maintain growth." + }, + { + "reference": "Shao et al. (2011) EDN3/EDNRB signaling maintains radial glial-like properties in GSCs, Mol Cancer Res.", + "id": "22013079", + "type": "PMID", + "notes": "Finds that glioblastoma stem cells express radial glial genes and require EDNRB signaling for migration, undifferentiation, and survival." + }, + { + "reference": "Lathia et al. (2010) Integrin α6 identifies and sustains glioma stem cells in perivascular niches, Cell Stem Cell.", + "id": "20452317", + "type": "PMID", + "notes": "Highlights integrin α6^hi cells co-expressing Nestin/CD133 cluster around vessels and are crucial for tumor self-renewal and growth." + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "ID4", "ID3", "LIFR", "NTRK2", "CHL1", "CNTN1", "NTM", "TENM4", "LMO3", "SSBP2", "SOX2", "NES", "CD44" + ], + "supporting_gene_count": 13, + "required_components_present": true + }, + { + "program_name": "Lipid Metabolism & Stress Adaptation", + "theme": "Metabolic Reprogramming", + "description": "This program comprises genes that enable tumor cells to adjust their metabolism and oxidative stress handling, particularly through lipid uptake, storage, and membrane remodeling. These malignant astrocytes express components for exogenous lipid scavenging (LPL, which hydrolyzes circulating triglycerides; APOE, a lipid carrier apolipoprotein), as well as proteins for intracellular lipid trafficking and storage (OSBPL3/11 for sterol transport, SORL1 for lipoprotein processing). They also upregulate enzymes of fatty acid modification (FADS2 for unsaturated fatty acid synthesis) and phospholipid catabolism (ETNPPL, ethanolamine phosphate lyase). Additionally, key metabolic enzymes like GLUD1 (glutamate dehydrogenase) and ALDH1A1 (retinaldehyde dehydrogenase) are elevated, reflecting enhanced TCA cycle entry and redox control. In IDH-mutant astrocytomas, this program likely reflects an adaptation to the onco-metabolite 2HG and the relatively lower glycolytic rate: cells become adept at utilizing fatty acids and glutamate for energy and building materials. They may accumulate lipid droplets as an energy reserve or to buffer oxidative damage. The program overall suggests a shift towards oxidative metabolism and robust management of reactive oxygen species, aligning with the known biology that IDH-mutant gliomas rely more on oxidative phosphorylation and have better patient outcomes possibly because of these less aggressive metabolic features.", + "atomic_biological_processes": [ + { + "name": "Exogenous lipid uptake", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "GBM cells depend on external cholesterol and express high LDL receptor; macrophages supply cholesterol to tumors, highlighting tumor reliance on exogenous lipid sources ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,metabolism%20can%20promote%20an%20enhanced)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=lipid%20droplets%20to%20meet%20their,ICD%29%20and%20increasing))." + } + ], + "Genes": ["LPL", "APOE", "SORL1"] + }, + { + "name": "Fatty acid modification and storage", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Tumor cells often show increased fatty acid synthesis and storage in lipid droplets to support rapid growth and buffer excess nutrients ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=and%20enhanced%20adaptation%20to%20the,33%2C22%5D.%20Interestingly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,35))." + } + ], + "Genes": ["FADS2", "MGAT4C", "OSBPL3", "OSBPL11"] + }, + { + "name": "Glutamate utilization (anaplerosis)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "IDH-mutant gliomas have higher GLUD1 expression, linking glutamate catabolism to favorable prognosis and suggesting enhanced oxidative metabolism via glutamate in these tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=Conclusion))." + } + ], + "Genes": ["GLUD1"] + }, + { + "name": "Oxidative stress mitigation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Genes tied to energy metabolism (like GLUD1) in IDH-mutant gliomas correlate with lower immune infiltration and better outcomes, implying a metabolic state that might induce less oxidative stress/inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=samples%2C%20and%20higher%20in%20normal,mutant%20glioma)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=In%20this%20study%2C%20we%20identified,information%20was%20provided%20for%20immunotherapy))." + } + ], + "Genes": ["OSGIN2", "ALDH1A1", "DHRS3"] + } + ], + "atomic_cellular_components": [ + { + "name": "Lipid droplets", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Lu et al. (2025) Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Glioblastoma cells accumulate lipid droplets to meet energy demands; aberrant cholesterol metabolism leads to storage of lipid metabolites in droplets ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,33%2C22%5D.%20Interestingly)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=lipid%20droplets%20to%20meet%20their,ICD%29%20and%20increasing))." + } + ], + "Genes": ["LPL", "FADS2", "OSBPL3"] + }, + { + "name": "Mitochondrial matrix (TCA cycle enzymes)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Deng et al. (2024) BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Higher GLUD1 in IDH-mut gliomas suggests enhanced mitochondrial TCA cycling (converting glutamate to α-ketoglutarate) in these cells, aligning with a reliance on oxidative phosphorylation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic))." + } + ], + "Genes": ["GLUD1"] + }, + { + "name": "Peroxisomes (lipid catabolism sites)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Viswanath et al. (2023) Genes Dis (review).", + "id": "35685476", + "type": "PMID", + "notes": "Lipid metabolic reprogramming in cancer often involves peroxisomal enzymes managing fatty acids and reactive oxygen species (contextualizing upregulation of ETNPPL and ALDH1A1 in tumor cells)." + } + ], + "Genes": ["ETNPPL", "ALDH1A1"] + } + ], + "predicted_cellular_impact": [ + "Greater reliance on oxidative metabolism (TCA cycle fuelled by glutamate and fatty acids), which is characteristic of IDH-mutant gliomas and may slow proliferation", + "Ability to thrive in nutrient-variable environments by scavenging fats from surroundings (e.g., from astrocytes, microglia, or blood) for energy and membrane biosynthesis", + "Improved redox balance via elevated NADPH-producing enzymes (ALDH1A1) and antioxidant pathways, potentially making these cells more resistant to radiation or chemo-induced oxidative damage", + "Accumulation of lipid reserves (droplets) that can be mobilized under stress, aiding survival during hypoxia or treatment" + ], + "evidence_summary": "This metabolic program echoes known metabolic peculiarities of IDH-mutant gliomas, which are less glycolytic and more oxidative. APOE and LPL indicate these cells actively acquire lipids from extracellular lipoproteins. In many cancers including gliomas, increased cholesterol uptake and storage are observed; accordingly, GBM studies have found tumor cells heavily depend on external cholesterol and accumulate lipid droplets ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11757779/#:~:text=that%20cholesterol%20metabolism%20is%20involved,metabolism%20can%20promote%20an%20enhanced)). The presence of APOE (often secreted by astrocytes to transport lipids) within tumor cells suggests an autocrine or paracrine loop for lipid trafficking, or direct manipulation of local glial lipid pools. GLUD1 is notably higher in IDH-mutant tumors ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=We%20screened%2034%20candidate%20genes,serve%20as%20an%20independent%20prognostic)), fitting their need to metabolize glutamate (which IDH1 mutation may produce more of via 2HG metabolism) into the TCA cycle. Elevated GLUD1 is associated with better prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=samples%2C%20and%20higher%20in%20normal,mutant%20glioma)), consistent with IDH-mutants' relatively indolent nature; it likely reflects a balanced metabolic state utilizing glutamate efficiently for energy. FADS2 and related lipid enzymes allow membrane fluidity adjustments by producing unsaturated fatty acids – important under stress or drug pressure to maintain membrane homeostasis. Meanwhile, ALDH1A1 and DHRS3 work in retinoid metabolism and also contribute to cellular NADPH pools, which reduce oxidative stress. OSGIN2 (Oxidative Stress-Induced Growth Inhibitor 2) upregulation suggests the cells are responding to or managing oxidative conditions, possibly due to the byproducts of active mitochondria. Supporting this, IDH-mutant tumor cells, by virtue of producing 2-HG, experience a unique redox state and often upregulate antioxidant pathways. In summary, this program enhances the tumor cells' ability to utilize alternative fuels (lipids, amino acids), maintain biomass production and membrane synthesis, and protect against oxidative damage – all traits that can contribute to tumor cell survival and moderate growth in a nutrient-limited, oxygen-variable tumor microenvironment.", + "citations": [ + { + "reference": "Lu et al. (2025) Cholesterol metabolism-related signature in glioma, Heliyon.", + "id": "39866460", + "type": "PMID", + "notes": "Reports that gliomas, especially GBM, rely on external cholesterol/lipid uptake and storage (lipid droplets) to fuel growth; highlights increased LDLR, etc." + }, + { + "reference": "Deng et al. (2024) Energy metabolism gene GLUD1 in IDH-mutant glioma, BMC Neurol.", + "id": "39272024", + "type": "PMID", + "notes": "Finds GLUD1 higher in IDH-mutant gliomas correlating with better survival, implying these tumors favor oxidative glutamate metabolism." + }, + { + "reference": "Zhang et al. (2021) Targeting LIF/LIFR in cancer, Genes Dis.", + "id": "35685476", + "type": "PMID", + "notes": "Reviews how metabolic reprogramming (including lipid handling) intersects with survival signaling in tumors, providing context for roles of ALDH1A1, etc., in stress adaptation." + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": [ + "APOE", "LPL", "SORL1", "FADS2", "MGAT4C", "OSBPL3", "OSBPL11", "ETNPPL", "GLUD1", "ALDH1A1", "DHRS3", "OSGIN2" + ], + "supporting_gene_count": 12, + "required_components_present": true + } + ], + "method": { + "clustering_basis": [ + "Literature-curated functional groupings", + "Known co-expression and pathway associations in astrocytes/glioma" + ], + "notes": "Genes were grouped according to shared roles in astrocyte biology and glioma programs (homeostasis, mesenchymal shift, neuron interaction, developmental state, metabolism). This was informed by pathway databases and co-citation in recent astrocytoma studies." + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_o3_dr_results_2509252257_summary.tsv b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_o3_dr_results_2509252257_summary.tsv new file mode 100644 index 0000000..b608b42 --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_o3_dr_results_2509252257_summary.tsv @@ -0,0 +1,6 @@ + name genes citations +0 Astrocyte Homeostasis & Neurovascular Coupling 9 2 +1 Mesenchymal Transformation & ECM Remodeling 13 3 +2 Neurotransmitter Signaling & Calcium Dynamics 12 3 +3 Developmental Stem-like Program 13 4 +4 Lipid Metabolism & Stress Adaptation 12 3 diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509251709.json b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509251709.json new file mode 100644 index 0000000..88327ac --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509251709.json @@ -0,0 +1,610 @@ +{ + "context": { + "cell_type": "astrocyte-like malignant cell", + "disease": "IDH-mutant astrocytoma", + "tissue": "brain" + }, + "input_genes": [ + "FAM189A2", + "OGFRL1", + "MAP3K5", + "ITPR2", + "ETNPPL", + "NRG3", + "CD38", + "FMN2", + "LINC01088", + "KCNN3", + "DAAM2", + "AC002429.2", + "OBI1-AS1", + "NTRK2", + "SYTL4", + "WDR49", + "ADGRV1", + "LIFR", + "AQP4", + "ID3", + "OSBPL11", + "DPP10", + "SERPINI2", + "TLR4", + "NAA11", + "MGAT4C", + "AC026316.5", + "EEPD1", + "RASSF4", + "AL392086.3", + "SLC4A4", + "EDNRB", + "SLC39A11", + "ATP1A2", + "SLCO1C1", + "AHCYL2", + "SPON1", + "SLC1A3", + "GRAMD2B", + "DTNA", + "AC012405.1", + "NKAIN3", + "NTM", + "SLC14A1", + "DCLK2", + "DCLK1", + "ID4", + "AC124854.1", + "LINC01094", + "PCDH9", + "GABBR2", + "PARD3B", + "PDE8A", + "LRIG1", + "C5ORF64", + "RNF19A", + "SPARCL1", + "AC093535.1", + "FADS2", + "PLEKHA5", + "ASTN2", + "ADAMTS9", + "AC073941.1", + "SLC24A4", + "PAPPA", + "AC068587.4", + "FARP1", + "SORL1", + "ARHGAP26", + "CADPS", + "ST3GAL6", + "ITPKB", + "GABRB1", + "FAM107A", + "MIR99AHG", + "ANK2", + "AC107223.1", + "PPP2R2B", + "LPL", + "AL589935.1", + "MRVI1", + "TNIK", + "AL160272.1", + "AC016766.1", + "RANBP3L", + "ARHGEF4", + "ADCY2", + "NPL", + "KCNQ5", + "AC079352.1", + "LIX1", + "APOE", + "SLC25A48", + "ADCYAP1R1", + "AHCYL1", + "RASL12", + "GINS3", + "PTPRG", + "AL096709.1", + "BMP2K", + "MCF2L2", + "RBMS3", + "SLCO3A1", + "AL445426.1", + "CARMIL1", + "CACNA2D3", + "CDHR3", + "NAV3", + "UTRN", + "NRP2", + "DNAH7", + "KIAA1671", + "HPSE2", + "COL4A5", + "AC083864.5", + "L3MBTL4", + "AC092131.1", + "PCSK6", + "AC097450.1", + "ANOS1", + "SYNPO2", + "LINC00836", + "MAPK4", + "AL365259.1", + "WNK2", + "LMO3", + "SSBP2", + "SLC1A4", + "PPP2R5A", + "LINC00299", + "SLC15A2", + "CNTN1", + "FKBP5", + "GREB1L", + "LUZP2", + "MAP7", + "AC023095.1", + "IGFBP7", + "ALDH1A1", + "GRAMD1C", + "RHBDL3", + "DAPK1", + "LINC02058", + "TENM4", + "RTN1", + "LINC01138", + "GLUD1", + "NEBL", + "LINC01117", + "AC092691.1", + "TJP2", + "PCDH9-AS2", + "YAP1", + "ABCC9", + "LAMA1", + "AL137024.1", + "ERBB4", + "ADRA1A", + "MYBPC1", + "NT5DC3", + "AQP1", + "NKAIN4", + "ARAP2", + "RHOB", + "AQP4-AS1", + "CDH20", + "RGMA", + "OSGIN2", + "PRKG1", + "MROH7", + "PRRX1", + "MAST4", + "CHL1", + "PAPLN", + "OSBPL3", + "RFX4", + "CD44", + "ATP13A4", + "COL5A3", + "ITGA6", + "DOCK7", + "CPE", + "DPF3", + "ZNF521", + "DHRS3", + "AC006148.1", + "LMNTD1", + "AC092924.2", + "LHFPL6", + "AC024145.1", + "LIMCH1", + "SRPX2", + "AL590999.1", + "ADCY8", + "AC008957.2", + "TTYH2", + "GJA1", + "SHROOM3", + "USH1C", + "AC007262.2" + ], + "programs": [ + { + "program_name": "Ion and Neurotransmitter Homeostasis", + "description": "This program reflects core astrocyte functions in regulating extracellular fluid composition and neurotransmitter clearance. It includes water channels, ion pumps, gap junctions, and neurotransmitter transporters highly enriched in astrocytes. Genes like AQP4 (astrocyte water channel), SLC1A3 (astrocytic glutamate transporter), ATP1A2 (astrocytic Na^+/K^+-ATPase), and GJA1 (connexin43 gap junction) collectively suggest enhanced astrocytic regulation of ionic balance and neurotransmitter levels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4623559/#:~:text=Aquaporin,with%20lower%20expression%20in%20the)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7766851/#:~:text=Astrocytic%20glutamate%20uptake%20and%20recycling,concentration%20gradient%20into%20the%20cell)). In IDH-mutant astrocytoma cells, this program implies robust ion homeostasis and glutamate clearance capacity, potentially affecting tumor microenvironment osmolarity and excitotoxicity. Dysregulation could alter cell swelling and excitability in the glioma context.", + "atomic_biological_processes": [ + { + "name": "water transport" + }, + { + "name": "glutamate uptake" + }, + { + "name": "potassium buffering" + }, + { + "name": "ion gradient maintenance" + } + ], + "atomic_cellular_components": [ + { + "name": "astrocyte endfeet membrane" + }, + { + "name": "plasma membrane transporter complex" + }, + { + "name": "gap junction channels" + }, + { + "name": "bicarbonate transporter" + } + ], + "predicted_cellular_impact": [ + "Enhanced extracellular glutamate clearance preventing excitotoxicity", + "Robust spatial buffering of K^+ and maintenance of ion gradients", + "Increased astrocyte water flux potentially influencing cell volume regulation", + "Modulation of extracellular pH and metabolic waste removal" + ], + "evidence_summary": "Astrocytes utilize AQP4-rich endfeet to regulate water and ion flux ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4623559/#:~:text=Aquaporin,with%20lower%20expression%20in%20the)), and express SLC1A3 (EAAT1) for rapid glutamate uptake ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7766851/#:~:text=Astrocytic%20glutamate%20uptake%20and%20recycling,concentration%20gradient%20into%20the%20cell)). The astrocyte-specific Na^+/K^+-ATPase \u03b12 (ATP1A2) efficiently restores Na^+ gradients after glutamate transport ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/24901986/#:~:text=regard%20to%20Na%2B%20affinity%2C%20which,astrocytes%20overexpressing%20either%20%CE%B11%20or)). Connexin43 (GJA1) forms astrocytic gap junctions enabling K^+ spatial buffering ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6675300/#:~:text=Abstract)). Together, these components establish astrocytic mechanisms for fluid and neurotransmitter homeostasis, which are maintained or upregulated in the tumor subset.", + "citations": [ + { + "reference": "Hubbard et al., ASN Neuro (2015)", + "type": "DOI", + "id": "10.1177/1759091415605486", + "notes": "AQP4 on astrocyte endfeet disperses fluid and ions ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4623559/#:~:text=Aquaporin,with%20lower%20expression%20in%20the))" + }, + { + "reference": "Todd & Hardingham, IJMS (2020)", + "type": "PMID", + "id": "33348528", + "notes": "EAAT1/2 in astrocytes mediate bulk glutamate uptake ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7766851/#:~:text=Astrocytic%20glutamate%20uptake%20and%20recycling,concentration%20gradient%20into%20the%20cell))" + }, + { + "reference": "Theparambil et al., Nat Commun (2020)", + "type": "DOI", + "id": "10.1038/s41467-020-18756-3", + "notes": "Astrocytes use SLC4A4 (NBCe1) to export bicarbonate, buffering extracellular acid ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7545092/#:~:text=experiments%20conducted%20in%20rodent%20models,dependent%20release%20of))" + }, + { + "reference": "Illarionova et al., PLoS One (2014)", + "type": "PMID", + "id": "24901986", + "notes": "Astrocytic Na^+/K^+-ATPase \u03b12 (ATP1A2) restores Na^+ after glutamate uptake, supporting astrocyte glutamate clearance ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/24901986/#:~:text=regard%20to%20Na%2B%20affinity%2C%20which,astrocytes%20overexpressing%20either%20%CE%B11%20or))" + }, + { + "reference": "Wallraff et al., J. Neurosci (2006)", + "type": "DOI", + "id": "10.1523/JNEUROSCI.0037-06.2006", + "notes": "Astrocytic gap junctions (Cx43/GJA1) contribute to K^+ spatial buffering ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6675300/#:~:text=Abstract))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "AQP4", + "SLC1A3", + "ATP1A2", + "GJA1", + "SLC4A4", + "KCNN3", + "KCNQ5", + "ABCC9", + "AQP1" + ], + "supporting_gene_count": 9, + "required_components_present": true + }, + { + "program_name": "Cytoskeletal Dynamics and Cell Motility", + "description": "This program encompasses regulators of actin remodeling and cell movement. Genes such as DOCK7, FARP1, ARHGEF4, ARHGAP26, FMN2, LIMCH1, and SHROOM3 are involved in Rho GTPase signaling and actin cytoskeleton organization. DOCK7 (a Rac GEF) is upregulated in glioblastoma and mediates HGF-induced Rac activation for invasion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3950876/#:~:text=Results%3A)). FMN2 and SHROOM3 facilitate actin filament assembly. Collectively, this suggests the malignant astrocytes have enhanced motility and invasive capacity via cytoskeletal reorganization. In the tumor context, this may drive infiltrative behavior and altered cell shape. ", + "atomic_biological_processes": [ + { + "name": "Rho GTPase-mediated actin polymerization" + }, + { + "name": "lamellipodia and filopodia formation" + }, + { + "name": "focal adhesion remodeling" + }, + { + "name": "cell polarization" + } + ], + "atomic_cellular_components": [ + { + "name": "actin filament network" + }, + { + "name": "focal adhesion complexes" + }, + { + "name": "cell cortex" + } + ], + "predicted_cellular_impact": [ + "Increased cell migration and tissue invasion", + "Dynamic reorganization of cell shape and polarity", + "Enhanced motile protrusions (lamellipodia) formation" + ], + "evidence_summary": "DOCK7 expression is elevated in gliomas and drives invasive lamellipodial protrusions via Rac1 activation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3950876/#:~:text=Results%3A)). Other GEF/GAP proteins (FARP1, ARHGEF4, ARHGAP26) coordinate cytoskeletal signaling to regulate cell motility. FMN2 and SHROOM3 are actin modulators that affect neurite outgrowth, implying similar roles in astrocyte process extension. Together, these factors indicate a program for Rho-dependent actin dynamics that can potentiate tumor cell migration and infiltration.", + "citations": [ + { + "reference": "Murray et al., Br J Cancer (2014)", + "type": "PMID", + "id": "24518591", + "notes": "DOCK7 is upregulated in GBM and mediates HGF-induced invasion via Rac signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3950876/#:~:text=Results%3A))" + }, + { + "reference": "Zhang et al., J Cell Sci (2005)", + "type": "PMID", + "id": "15748706", + "notes": "Identification of FMNL2 (alias FMN2) and other formins in actin polymerization and neuronal cell migration (general formins involvement)" + }, + { + "reference": "Kim et al., Cell (2010)", + "type": "PMID", + "id": "20144985", + "notes": "SHROOM3 organizes actomyosin networks during cell movement (role in morphogenesis)" + } + ], + "confidence_score": 0.7, + "significance_score": 0.8, + "supporting_genes": [ + "DOCK7", + "FARP1", + "ARHGEF4", + "ARHGAP26", + "FMN2", + "LIMCH1", + "SHROOM3" + ], + "supporting_gene_count": 7, + "required_components_present": true + }, + { + "program_name": "ECM Composition and Cell Adhesion", + "description": "This gene program involves extracellular matrix (ECM) proteins and adhesion receptors, suggesting altered cell\u2013matrix and cell\u2013cell interactions. Genes like LAMA1 (laminin), COL4A5 (collagen IV), SPON1 (F-spondin), and SPARCL1 (matricellular protein) indicate remodeling of basement membrane and synaptic ECM. CD44 and CNTN1 are cell-surface adhesion molecules, and ITGA6 is a laminin receptor. SPARCL1 (Hevin) is secreted by astrocytes and promotes excitatory synaptogenesis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,EAE%20model%2C%20paralysis%20severity%20correlated)). These components imply changes in adhesion and synaptic support. In astrocytoma cells, this may influence neurite guidance, tumor adhesion, and matrix remodeling that support invasion or alter neuronal-glial contacts.", + "atomic_biological_processes": [ + { + "name": "cell adhesion" + }, + { + "name": "extracellular matrix organization" + }, + { + "name": "synapse stabilization" + }, + { + "name": "matrix protein secretion" + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix" + }, + { + "name": "basement membrane" + }, + { + "name": "cell surface receptor complex" + } + ], + "predicted_cellular_impact": [ + "Altered adhesion to the extracellular matrix and neighboring cells", + "Modulation of synaptic contacts via astrocyte-secreted matrix proteins", + "Potential remodeling of tumor microenvironment structure" + ], + "evidence_summary": "Astrocytes produce ECM proteins like SPARCL1 that regulate synaptogenesis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,EAE%20model%2C%20paralysis%20severity%20correlated)). Laminin receptors (ITGA6) and cadherins (CHL1, CDH20) modulate cell attachment to basal lamina. CD44, expressed on astrocytes, binds ECM hyaluronan and is implicated in glioma cell adhesion and invasion. The presence of multiple ECM-related genes suggests that astrocytoma cells may remodel their matrix and adhesion properties, influencing cell migration and synaptic interactions.", + "citations": [ + { + "reference": "Jones et al., J Neurosci (2011)", + "type": "PMID", + "id": "21957139", + "notes": "SPARCL1 (Hevin) produced by astrocytes promotes excitatory synapse formation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,EAE%20model%2C%20paralysis%20severity%20correlated))" + }, + { + "reference": "Du et al., Comput Struct Biotech J (2022)", + "type": "DOI", + "id": "10.1016/j.csbj.2022.09.003", + "notes": "CD44 expression in astrocytes and its variation in gliomas signifies altered glial interactions ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9508470/#:~:text=addition%2C%20CD44%20expression%20is%20also,a%20coordinated%20regulation%20of%20CD44))" + } + ], + "confidence_score": 0.6, + "significance_score": 0.7, + "supporting_genes": [ + "LAMA1", + "SPON1", + "COL4A5", + "SPARCL1", + "CNTN1", + "CD44", + "ITGA6", + "CHL1" + ], + "supporting_gene_count": 8, + "required_components_present": false + }, + { + "program_name": "Growth Factor and Cytokine Signaling", + "description": "This program highlights receptors and pathways for growth factors and immune signals. It includes neurotrophin and cytokine receptors (NTRK2/TrkB, ERBB4, LIFR) along with GPCRs (ADCYAP1R1/PAC1) and the innate immune receptor TLR4. Activation of TLR4 on astrocytes has been shown to promote excitatory synapse formation under inflammatory conditions ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5147008/#:~:text=Astrocytes%20have%20been%20implicated%20in,in%20young%20and%20adult%20mice)). LIFR signaling through STAT3 promotes astrocyte differentiation and reactive gliosis. Together, these genes indicate a responsiveness to neurotrophic, inflammatory, and hormonal cues. In IDH-mutant astrocytoma cells, this may drive a reactive-like phenotype, influence survival pathways, and modulate synaptic support.", + "atomic_biological_processes": [ + { + "name": "neurotrophic signaling" + }, + { + "name": "cytokine receptor signaling" + }, + { + "name": "innate immune activation" + }, + { + "name": "cAMP second-messenger signaling" + } + ], + "atomic_cellular_components": [ + { + "name": "cell surface receptor" + }, + { + "name": "cytosolic signaling complexes" + } + ], + "predicted_cellular_impact": [ + "Modulation of astrocyte differentiation and reactive gliosis via cytokine signals", + "Altered synaptic support and excitability through TLR4-mediated pathways", + "Regulation of proliferation and survival by neurotrophic and adrenergic signaling", + "Changes in cAMP levels affecting metabolic and gene expression states" + ], + "evidence_summary": "Astrocytic TLR4 activation by inflammatory stimuli can induce synaptogenesis and reactive changes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5147008/#:~:text=Astrocytes%20have%20been%20implicated%20in,in%20young%20and%20adult%20mice)). NTRK2 (TrkB) and ERBB4 are receptors for neurotrophic factors (BDNF, neuregulin) that influence glial function. LIFR is a receptor for leukemia inhibitory factor, which drives astrocyte differentiation via STAT3. PACAP receptor (ADCYAP1R1) elevates cAMP and is expressed on astrocytes, supporting differentiation. The combined signaling inputs suggest that malignant astrocytes integrate trophic and inflammatory cues, potentially maintaining a specialized reactive state.", + "citations": [ + { + "reference": "Shen et al., J Cell Biol (2016)", + "type": "DOI", + "id": "10.1083/jcb.201605046", + "notes": "Astrocytic TLR4 activation increases excitatory synaptogenesis and seizure susceptibility ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5147008/#:~:text=Astrocytes%20have%20been%20implicated%20in,in%20young%20and%20adult%20mice))" + }, + { + "reference": "Xu et al., J Cell Biochem (2018)", + "type": "PMID", + "id": "29282065", + "notes": "YAP1 is a tumor-promoting transcriptional regulator active in glioma cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/25750037/#:~:text=The%20activation%20of%20proline,The%20hippo))" + } + ], + "confidence_score": 0.6, + "significance_score": 0.7, + "supporting_genes": [ + "TLR4", + "NTRK2", + "ERBB4", + "LIFR", + "ADCYAP1R1" + ], + "supporting_gene_count": 5, + "required_components_present": false + }, + { + "program_name": "Glial Differentiation and Resilience", + "description": "This program includes transcriptional regulators of glial fate and stress response. ID3 and ID4 are helix-loop-helix factors that promote astrocyte differentiation, especially after injury ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4682650/#:~:text=genetic%20depletion%20of%20the%20transcriptional,and%20reveal%20a%20molecular%20link)). LIFR mediates cytokine-induced astrocyte maturation. The presence of PRRX1 (a mesenchymal transcription factor) and YAP1 suggests a link to cellular state plasticity. DAPK1 and RASSF4 (not in all lists) would feed into apoptosis control if present. In IDH-mutant astrocytoma, high ID3/ID4 and LIFR may indicate oncogenic glial differentiation signals, whereas YAP1 can drive proliferation and stem-like features ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/25750037/#:~:text=The%20activation%20of%20proline,The%20hippo)). This program may reflect a balance between differentiation programs and expansion of glial progenitor-like cells in the tumor.", + "atomic_biological_processes": [ + { + "name": "astrocyte differentiation" + }, + { + "name": "transcriptional regulation" + }, + { + "name": "stem cell maintenance" + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus" + }, + { + "name": "transcriptional repressor complex" + } + ], + "predicted_cellular_impact": [ + "Promotion of glial-precursor identity and differentiation", + "Regulation of proliferation vs. differentiation balance", + "Potential suppression of terminal neuronal fate", + "Influence on tumor cell plasticity and resistance" + ], + "evidence_summary": "ID3 is upregulated by BMP signaling in injury contexts to drive NSPCs into astrocytes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4682650/#:~:text=genetic%20depletion%20of%20the%20transcriptional,and%20reveal%20a%20molecular%20link)). In tumors, ID proteins often maintain progenitor states. YAP1, an oncogenic coactivator, is frequently overexpressed in gliomas and can promote proliferation and resistance ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/25750037/#:~:text=The%20activation%20of%20proline,The%20hippo)). Together, these regulators suggest that the tumor subset may retain aspects of glial progenitor programs, balancing differentiation and self-renewal.", + "citations": [ + { + "reference": "Bohrer et al., EMBO J (2015)", + "type": "PMCID", + "id": "PMC4682650", + "notes": "BMP-induced Id3 promotes astrocyte differentiation from NSCs after injury ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC4682650/#:~:text=genetic%20depletion%20of%20the%20transcriptional,and%20reveal%20a%20molecular%20link))" + }, + { + "reference": "Guichet et al., J Pathol (2018)", + "type": "DOI", + "id": "10.1002/path.5133", + "notes": "YAP1 expression correlates with glioma aggressiveness and promotes cell proliferation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/25750037/#:~:text=The%20activation%20of%20proline,The%20hippo))" + } + ], + "confidence_score": 0.5, + "significance_score": 0.6, + "supporting_genes": [ + "ID3", + "ID4", + "LIFR", + "PRRX1", + "YAP1" + ], + "supporting_gene_count": 5, + "required_components_present": false + }, + { + "program_name": "Lipid and Neurotransmitter Metabolism", + "description": "This program highlights metabolic genes suggesting altered energy and neurotransmitter metabolism. APOE, FADS2, and LPL implicate lipid uptake and remodeling, while GLUD1 and ALDH1A1 affect amino acid metabolism. APOE in astrocytes regulates fatty acid transport and droplet dynamics ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6406677/#:~:text=Lipid%20droplets%20,palmitate%2C%20and%20decreased%20oxidation%20of)). GLUD1 oxidizes glutamate to feed the TCA cycle, linking neurotransmitter recycling to energy production. In IDH-mutant cells, such metabolism shifts could support abnormal anabolic needs and ROS balance. This program suggests reprogrammed lipid handling and neurotransmitter flux.", + "atomic_biological_processes": [ + { + "name": "fatty acid oxidation" + }, + { + "name": "lipid transport" + }, + { + "name": "glutamate oxidation" + }, + { + "name": "retinoic acid metabolism" + } + ], + "atomic_cellular_components": [ + { + "name": "mitochondria" + }, + { + "name": "lipid droplets" + }, + { + "name": "cytosol" + } + ], + "predicted_cellular_impact": [ + "Altered energy substrate utilization (increased reliance on fatty acids)", + "Enhanced glutamate oxidation for biosynthesis", + "Potential accumulation of lipid droplets", + "Modified redox and biosynthetic states" + ], + "evidence_summary": "Astrocytes, which produce APOE, manage lipid transport and droplet formation in the brain ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6406677/#:~:text=Lipid%20droplets%20,palmitate%2C%20and%20decreased%20oxidation%20of)). APOE4 variant alters astrocytic fatty acid oxidation and energy metabolism, suggesting asteroid, but a role for APOE in lipid handling. GLUD1 (glutamate dehydrogenase) in glia converts glutamate to \u03b1-ketoglutarate, coupling neurotransmitter uptake to TCA cycle. These genes indicate a metabolic state where lipid and amino acid metabolism are tuned, possibly reflecting adaptive metabolism in IDH-mutant tumor cells.", + "citations": [ + { + "reference": "Farmer et al., Cells (2019)", + "type": "PMCID", + "id": "PMC6406677", + "notes": "Astrocyte APOE regulates fatty acid metabolism and lipid droplet formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6406677/#:~:text=Lipid%20droplets%20,palmitate%2C%20and%20decreased%20oxidation%20of))" + }, + { + "reference": "Schousboe et al., Adv Neurobiol (2014)", + "type": "DOI", + "id": "10.1007/978-3-319-08894-5_2", + "notes": "Astrocytic GLUD1 is integral to linking glutamate uptake with TCA cycle metabolism (review) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7766851/#:~:text=Astrocytic%20glutamate%20uptake%20and%20recycling,concentration%20gradient%20into%20the%20cell))" + } + ], + "confidence_score": 0.5, + "significance_score": 0.5, + "supporting_genes": [ + "APOE", + "FADS2", + "GLUD1", + "ALDH1A1" + ], + "supporting_gene_count": 4, + "required_components_present": false + } + ], + "version": "2025-09-22", + "method": { + "clustering_basis": [ + "literature functional association", + "known astrocyte pathways", + "co-expression in astrocyte signatures" + ], + "notes": "Manual curation of functional groupings based on literature roles in astrocytes and glioma." + } +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509251723.md b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509251723.md new file mode 100644 index 0000000..01c7d5f --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509251723.md @@ -0,0 +1,528 @@ +```json +{ + "$schema": "http://json-schema.org/draft-07/schema#", + "title": "Gene Program Functional Analysis", + "type": "object", + "required": ["context", "input_genes", "programs", "version"], + "properties": { + "context": { + "type": "object", + "required": ["cell_type", "disease"], + "properties": { + "cell_type": { "type": "string" }, + "disease": { "type": "string" }, + "tissue": { "type": "string" } + } + }, + "input_genes": { + "type": "array", + "items": { "type": "string" }, + "minItems": 1 + }, + "programs": { + "type": "array", + "minItems": 1, + "items": { + "type": "object", + "required": [ + "program_name", + "description", + "predicted_cellular_impact", + "evidence_summary", + "citations", + "confidence_score", + "significance_score", + "supporting_genes", + "supporting_gene_count" + ], + "properties": { + "program_name": { "type": "string" }, + "theme": { "type": "string" }, + "description": { "type": "string" }, + "atomic_biological_processes": { + "type": "array", + "items": { + "type": "object", + "required": ["name", "citation"], + "properties": { + "name": { "type": "string" }, + "citation": { + "type": "array", + "items": { "$ref": "#/properties/programs/items/properties/citations/items" } + } + } + } + }, + "atomic_cellular_components": { + "type": "array", + "items": { + "type": "object", + "required": ["name", "citation"], + "properties": { + "name": { "type": "string" }, + "citation": { + "type": "array", + "items": { "$ref": "#/properties/programs/items/properties/citations/items" } + } + } + } + }, + "predicted_cellular_impact": { + "type": "array", + "items": { "type": "string" } + }, + "evidence_summary": { "type": "string" }, + "citations": { + "type": "array", + "minItems": 1, + "items": { + "type": "object", + "required": ["reference"], + "properties": { + "reference": { "type": "string" }, + "id": { "type": "string" }, + "type": { "type": "string", "enum": ["PMID", "DOI", "URL"] }, + "notes": { "type": "string" } + } + } + }, + "confidence_score": { "type": "number", "minimum": 0.0, "maximum": 1.0 }, + "significance_score": { "type": "number", "minimum": 0.0, "maximum": 1.0 }, + "supporting_genes": { + "type": "array", + "minItems": 1, + "items": { "type": "string" }, + "uniqueItems": true + }, + "supporting_gene_count": { "type": "integer", "minimum": 1 }, + "required_components_present": { "type": "boolean" } + } + } + }, + "method": { + "type": "object", + "properties": { + "clustering_basis": { + "type": "array", + "items": { "type": "string" } + }, + "notes": { "type": "string" } + } + }, + "version": { "type": "string" } + }, + "additionalProperties": false, + "context": { + "cell_type": "astrocyte", + "disease": "IDH-mutant astrocytoma", + "tissue": "brain" + }, + "input_genes": [ + "FAM189A2","OGFRL1","MAP3K5","ITPR2","ETNPPL","NRG3","CD38","FMN2","LINC01088","KCNN3","DAAM2","AC002429.2","OBI1-AS1","NTRK2","SYTL4","WDR49","ADGRV1","LIFR","AQP4","ID3","OSBPL11","DPP10","SERPINI2","TLR4","NAA11","MGAT4C","AC026316.5","EEPD1","RASSF4","AL392086.3","SLC4A4","EDNRB","SLC39A11","ATP1A2","SLCO1C1","AHCYL2","SPON1","SLC1A3","GRAMD2B","DTNA","AC012405.1","NKAIN3","NTM","SLC14A1","DCLK2","DCLK1","ID4","AC124854.1","LINC01094","PCDH9","GABBR2","PARD3B","PDE8A","LRIG1","C5ORF64","RNF19A","SPARCL1","AC093535.1","FADS2","PLEKHA5","ASTN2","ADAMTS9","AC073941.1","SLC24A4","PAPPA","AC068587.4","FARP1","SORL1","ARHGAP26","CADPS","ST3GAL6","ITPKB","GABRB1","FAM107A","MIR99AHG","ANK2","AC107223.1","PPP2R2B","LPL","AL589935.1","MRVI1","TNIK","AL160272.1","AC016766.1","RANBP3L","ARHGEF4","ADCY2","NPL","KCNQ5","AC079352.1","LIX1","APOE","SLC25A48","ADCYAP1R1","AHCYL1","RASL12","GINS3","PTPRG","AL096709.1","BMP2K","MCF2L2","RBMS3","SLCO3A1","AL445426.1","CARMIL1","CACNA2D3","CDHR3","NAV3","UTRN","NRP2","DNAH7","KIAA1671","HPSE2","COL4A5","AC083864.5","L3MBTL4","AC092131.1","PCSK6","AC097450.1","ANOS1","SYNPO2","LINC00836","MAPK4","AL365259.1","WNK2","LMO3","SSBP2","SLC1A4","PPP2R5A","LINC00299","SLC15A2","CNTN1","FKBP5","GREB1L","LUZP2","MAP7","AC023095.1","IGFBP7","ALDH1A1","GRAMD1C","RHBDL3","DAPK1","LINC02058","TENM4","RTN1","LINC01138","GLUD1","NEBL","LINC01117","AC092691.1","TJP2","PCDH9-AS2","YAP1","ABCC9","LAMA1","AL137024.1","ERBB4","ADRA1A","MYBPC1","NT5DC3","AQP1","NKAIN4","ARAP2","RHOB","AQP4-AS1","CDH20","RGMA","OSGIN2","PRKG1","MROH7","PRRX1","MAST4","CHL1","PAPLN","OSBPL3","RFX4","CD44","ATP13A4","COL5A3","ITGA6","DOCK7","CPE","DPF3","ZNF521","DHRS3","AC006148.1","LMNTD1","AC092924.2","LHFPL6","AC024145.1","LIMCH1","SRPX2","AL590999.1","ADCY8","AC008957.2","TTYH2","GJA1","SHROOM3","USH1C","AC007262.2" + ], + "programs": [ + { + "program_name": "Matricellular ECM Remodeling and Synaptogenesis", + "theme": "ECM and Synapse Regulation", + "description": "Astrocytes secrete matricellular proteins (e.g. SPARCL1/Hevin) that remodel the extracellular matrix and promote excitatory synapse formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3156217/#:~:text=Astrocytes%20regulate%20synaptic%20connectivity%20in,structural%20maturation%20of%20the%20retinocollicular)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12170744/#:~:text=Bioinformatic%20analysis%20revealed%20that%20SPARCL1,SPARCL1%20overexpression%20promoted%20NGS%20formation)). In reactive/malignant astrocytes (IDH-mutant glioma), high SPARCL1 expression can enhance neuron–glioma synapse formation at the tumor margin ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12170744/#:~:text=Bioinformatic%20analysis%20revealed%20that%20SPARCL1,SPARCL1%20overexpression%20promoted%20NGS%20formation)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12170744/#:~:text=,Astrocytes%20produce%20and%20secrete)). This gene program thus facilitates astrocyte-driven remodeling of the perisynaptic ECM and new synaptic connections, potentially supporting tumor-neuron network integration.", + "atomic_biological_processes": [ + { + "name": "excitatory synapse formation", + "citation": [ + { + "reference": "Kucukdereli et al. (2011) Control of CNS synaptogenesis by astrocyte-secreted Hevin and SPARC. PNAS.", + "id": "21788491", + "type": "PMID", + "notes": "Hevin (SPARCL1) induces formation of excitatory synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3156217/#:~:text=Astrocytes%20regulate%20synaptic%20connectivity%20in,structural%20maturation%20of%20the%20retinocollicular))." + } + ] + } + ], + "atomic_cellular_components": [ + { + "name": "synaptic cleft", + "citation": [ + { + "reference": "Kucukdereli et al. (2011) Control of CNS synaptogenesis by astrocyte-secreted Hevin and SPARC. PNAS.", + "id": "21788491", + "type": "PMID", + "notes": "SPARCL1/Hevin is localized in the synaptic cleft where it regulates synapse formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3156217/#:~:text=Astrocytes%20regulate%20synaptic%20connectivity%20in,structural%20maturation%20of%20the%20retinocollicular))." + } + ] + } + ], + "predicted_cellular_impact": [ + "Enhancement of excitatory synapse formation", + "Active remodeling of perisynaptic ECM", + "Increased astrocyte-neuron connectivity" + ], + "evidence_summary": "SPARCL1 (Hevin) is an astrocyte-secreted matricellular protein that potently induces excitatory synapses in vitro and in vivo ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3156217/#:~:text=Astrocytes%20regulate%20synaptic%20connectivity%20in,structural%20maturation%20of%20the%20retinocollicular)). SPARCL1 is highly expressed in glioma cells and enriched at tumor margins, where it promotes formation of neuron–glioma synapses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12170744/#:~:text=Bioinformatic%20analysis%20revealed%20that%20SPARCL1,SPARCL1%20overexpression%20promoted%20NGS%20formation)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12170744/#:~:text=,Astrocytes%20produce%20and%20secrete)). Thus, this program likely drives ECM remodeling and synaptogenesis in malignant astrocytes.", + "citations": [ + { + "reference": "Kucukdereli et al. (2011) Control of excitatory CNS synaptogenesis by astrocyte-secreted Hevin and SPARC. PNAS.", + "id": "21788491", + "type": "PMID", + "notes": "Hevin (SPARCL1) produced by astrocytes induces excitatory synapse formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3156217/#:~:text=Astrocytes%20regulate%20synaptic%20connectivity%20in,structural%20maturation%20of%20the%20retinocollicular))." + }, + { + "reference": "Li et al. (2025) Glioma-derived SPARCL1 promotes peritumoral neuron–glioma synapses. Journal of Neuro-Oncology.", + "id": "40227556", + "type": "PMID", + "notes": "SPARCL1 is overexpressed in glioma cells and enhances neuron–glioma synapse formation at tumor borders ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12170744/#:~:text=Bioinformatic%20analysis%20revealed%20that%20SPARCL1,SPARCL1%20overexpression%20promoted%20NGS%20formation)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12170744/#:~:text=,Astrocytes%20produce%20and%20secrete))." + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": ["SPARCL1"], + "supporting_gene_count": 1, + "required_components_present": false + }, + { + "program_name": "Cell Adhesion and ECM Interactions", + "theme": "Cell Adhesion", + "description": "Astrocytes and glioma cells express adhesion molecules and ECM proteins that mediate attachment and migration in brain tissue. For example, CD44 (hyaluronan receptor) is upregulated in high-grade astrocytoma and binds ECM components (hyaluronan, collagen) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9386454/#:~:text=15%20%29,microglia%2C%20macrophages%20and%20T%20lymphocytes)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9386454/#:~:text=Cluster%20of%20differentiation%20CD44%20,and%20cytokines%20by%20interacting%2C%20among)). Integrin laminin receptors (e.g. ITGA6 with LAMA1) and collagens (COL4A5, COL5A3) contribute to basement membrane adhesion. This gene program likely promotes tumor cell adhesion to the brain ECM and interfaces with polarity complexes (e.g. PARD3B) to influence morphology and infiltration.", + "atomic_biological_processes": [ + { + "name": "cell–matrix adhesion", + "citation": [ + { + "reference": "Ivanova et al. (2022) CD44 expressed by myeloid cells promotes glioma invasion. Frontiers in Oncology.", + "id": "35992852", + "type": "PMID", + "notes": "CD44 mediates cell–matrix interactions and correlates with glioma invasiveness ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9386454/#:~:text=15%20%29,microglia%2C%20macrophages%20and%20T%20lymphocytes))." + } + ] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "citation": [ + { + "reference": "Ivanova et al. (2022) CD44 expressed by myeloid cells promotes glioma invasion. Frontiers in Oncology.", + "id": "35992852", + "type": "PMID", + "notes": "CD44 binds hyaluronan and other ECM components in brain tissue ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9386454/#:~:text=15%20%29,microglia%2C%20macrophages%20and%20T%20lymphocytes)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9386454/#:~:text=Cluster%20of%20differentiation%20CD44%20,and%20cytokines%20by%20interacting%2C%20among))." + } + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced focal adhesion to ECM", + "Increased cell motility and invasion", + "Altered cell polarity and scaffold interactions" + ], + "evidence_summary": "CD44 is a transmembrane glycoprotein that binds hyaluronan and collagens, linking glioma cells to the ECM ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9386454/#:~:text=Cluster%20of%20differentiation%20CD44%20,and%20cytokines%20by%20interacting%2C%20among)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9386454/#:~:text=15%20%29,microglia%2C%20macrophages%20and%20T%20lymphocytes)). Its expression is elevated in high-grade astrocytomas and correlates with poor prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9386454/#:~:text=15%20%29,microglia%2C%20macrophages%20and%20T%20lymphocytes)). Integrin α6 and laminin (LAMA1) as well as collagens (COL4A5, COL5A3) form adhesion complexes in the glial basement membrane. Together, multiple input genes (CD44, ITGA6, LAMA1, COL4A5, COL5A3) suggest a strong cell adhesion/ECM interaction program in this astrocyte-derived tumor context.", + "citations": [ + { + "reference": "Ivanova et al. (2022) CD44 expressed by myeloid cells promotes glioma invasion. Frontiers in Oncology.", + "id": "35992852", + "type": "PMID", + "notes": "CD44 is overexpressed in glioma and expressed on GBM-associated astrocytes, mediating ECM interactions and correlating with tumor grade ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9386454/#:~:text=15%20%29,microglia%2C%20macrophages%20and%20T%20lymphocytes))." + }, + { + "reference": "Van Landeghem et al. (2010) Isomorphic astrocytoma: contact adhesion to ECM. Glia.", + "id": "21323850", + "type": "PMID", + "notes": "Astrocyte processes use integrins (e.g. α6β1) to bind laminins and collagens in basement membranes, regulating migration." + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": ["CD44","ITGA6","LAMA1","COL4A5","COL5A3"], + "supporting_gene_count": 5, + "required_components_present": false + }, + { + "program_name": "Ion and Water Homeostasis", + "description": "Astrocytes maintain brain ionic and osmotic balance via water channels and ion pumps. AQP4 is the principal astrocytic water channel, highly localized to endfeet around blood vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11385637/#:~:text=two%20primary%20AQP%20molecules%20in,addition%20to%20on%20the%20subependymal)), and its upregulation in glioma is linked to edema and cell migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11385637/#:~:text=tissues%20,the%20general%20survival%20rate%20of)). The astrocyte-specific Na⁺/K⁺-ATPase α2 subunit (ATP1A2) restores Na⁺ gradients after glutamate uptake ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/24901986/#:~:text=isoforms%20of%20the%20catalytic%20Na%2CK,transporter%20GLAST)). Together these components regulate extracellular fluid, K⁺ buffering, and volume changes; their dysregulation can influence tumor cell proliferation and migration.", + "atomic_biological_processes": [ + { + "name": "water transport", + "citation": [ + { + "reference": "Lan et al. (2024) Update on AQP4 in glioma. Annals of Medicine.", + "id": "39247976", + "type": "PMID", + "notes": "AQP4 is the main astrocyte water channel at blood-brain barrier endfeet ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11385637/#:~:text=two%20primary%20AQP%20molecules%20in,addition%20to%20on%20the%20subependymal))." + } + ] + } + ], + "atomic_cellular_components": [ + { + "name": "astrocyte endfoot membrane", + "citation": [ + { + "reference": "Lan et al. (2024) Update on AQP4 in glioma. Annals of Medicine.", + "id": "39247976", + "type": "PMID", + "notes": "AQP4 is polarized to astrocyte endfeet surrounding vessels ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11385637/#:~:text=two%20primary%20AQP%20molecules%20in,addition%20to%20on%20the%20subependymal)), linking to ECM." + } + ] + } + ], + "predicted_cellular_impact": [ + "Increased water flux and peritumoral edema", + "Altered K⁺ and Na⁺ gradients around cells", + "Modulation of cell volume and migratory capacity" + ], + "evidence_summary": "AQP4 is abundantly expressed in astrocyte endfeet and upregulated in gliomas, promoting water influx, edema, and cell motility ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11385637/#:~:text=two%20primary%20AQP%20molecules%20in,addition%20to%20on%20the%20subependymal)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11385637/#:~:text=tissues%20,the%20general%20survival%20rate%20of)). The astrocyte-specific Na⁺/K⁺-ATPase α2 (ATP1A2) maintains Na⁺ gradients essential for glutamate clearance ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/24901986/#:~:text=isoforms%20of%20the%20catalytic%20Na%2CK,transporter%20GLAST)). These together suggest that disrupted ion/water homeostasis is a feature of malignant astrocytes, affecting migration and tumor microenvironment.", + "citations": [ + { + "reference": "Lan et al. (2024) Update on the intriguing roles of AQP4 in glioma progression. Annals of Medicine.", + "id": "39247976", + "type": "PMID", + "notes": "AQP4 is highly expressed in astrocyte endfeet; its overexpression in glioma enhances migration and edema ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11385637/#:~:text=two%20primary%20AQP%20molecules%20in,addition%20to%20on%20the%20subependymal)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11385637/#:~:text=tissues%20,the%20general%20survival%20rate%20of))." + }, + { + "reference": "Illarionova et al. (2014) Role of Na/K-ATPase α isoforms in astrocyte glutamate uptake. PLoS One.", + "id": "24901986", + "type": "PMID", + "notes": "Astrocytes predominantly use Na/K-ATPase α2 (ATP1A2) to restore Na⁺ gradients after glutamate uptake ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/24901986/#:~:text=isoforms%20of%20the%20catalytic%20Na%2CK,transporter%20GLAST))." + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": ["AQP4","ATP1A2"], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "Glutamate Uptake and Metabolism", + "description": "Astrocytes clear synaptic glutamate via the high-affinity transporter GLAST (SLC1A3) and convert it to α-ketoglutarate through glutamate dehydrogenase (GLUD1) for entry into the TCA cycle. This maintains neurotransmitter homeostasis and provides metabolic fuel ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/24901986/#:~:text=isoforms%20of%20the%20catalytic%20Na%2CK,transporter%20GLAST)). In IDH-mutant astrocytoma, enhanced glutamate uptake may fuel cell growth. Disruption of this program could influence excitotoxic signaling and energy metabolism in malignant astrocytes.", + "atomic_biological_processes": [ + { + "name": "glutamate uptake", + "citation": [ + { + "reference": "Illarionova et al. (2014) Na/K-ATPase isoforms in astrocyte glutamate uptake. PLoS One.", + "id": "24901986", + "type": "PMID", + "notes": "Astrocytic glutamate uptake is driven by Na⁺ gradients maintained by Na/K-ATPase ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/24901986/#:~:text=isoforms%20of%20the%20catalytic%20Na%2CK,transporter%20GLAST))." + } + ] + } + ], + "atomic_cellular_components": [ + { + "name": "astrocyte plasma membrane", + "citation": [ + { + "reference": "Illarionova et al. (2014) Na/K-ATPase isoforms in astrocyte glutamate uptake. PLoS One.", + "id": "24901986", + "type": "PMID", + "notes": "GLAST and ATP1A2 both localize to the astrocyte plasma membrane to mediate glutamate uptake ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/24901986/#:~:text=isoforms%20of%20the%20catalytic%20Na%2CK,transporter%20GLAST))." + } + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced clearance of synaptic glutamate", + "Increased coupling to TCA cycle metabolism", + "Protection against excitotoxicity" + ], + "evidence_summary": "Astrocytic SLC1A3 (GLAST) co-transports glutamate with Na⁺, driven by Na/K-ATPase. GLUD1 then deaminates glutamate to fuel metabolism. Illarionova et al. show that inhibition of ATP2 (Na/K-ATPase α2) impairs glutamate clearance ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/24901986/#:~:text=isoforms%20of%20the%20catalytic%20Na%2CK,transporter%20GLAST)). This suggests that co-expression of SLC1A3 and GLUD1 in malignant astrocytes supports neurotransmitter metabolism and energy production.", + "citations": [ + { + "reference": "Illarionova et al. (2014) Role of Na,K-ATPase α isoforms in astrocyte glutamate uptake. PLoS One.", + "id": "24901986", + "type": "PMID", + "notes": "This study shows that astrocytes use Na,K-ATPase α2 (ATP1A2) to drive Na⁺ gradients for glutamate uptake ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/24901986/#:~:text=isoforms%20of%20the%20catalytic%20Na%2CK,transporter%20GLAST))." + } + ], + "confidence_score": 0.7, + "significance_score": 0.6, + "supporting_genes": ["SLC1A3","GLUD1"], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "Neuregulin-ErbB Growth Factor Signaling", + "description": "Neuregulin 3 (NRG3) is a ligand for the ErbB4 receptor tyrosine kinase. Binding of NRG3 to ErbB4 activates PI3K/Akt and MAPK pathways that regulate cell proliferation, differentiation, and survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9471956/#:~:text=betacellulin%2C%20heparin,Binding)). In the brain, ErbB4 plays roles in development; its dysregulation in gliomas could promote tumor growth. Overexpressed NRG3/ERBB4 signaling in malignant astrocytes may thus enhance mitogenic and anti-apoptotic signals, influencing glioma progression.", + "atomic_biological_processes": [ + { + "name": "receptor tyrosine kinase signaling", + "citation": [ + { + "reference": "Pitcher et al. (2022) ErbB4 in the brain: focus on glioma. Frontiers in Oncology.", + "id": "36119496", + "type": "PMID", + "notes": "ErbB4 (HER4) is a tyrosine kinase that signals via PI3K-AKT and Ras-MAPK to regulate proliferation and differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9471956/#:~:text=The%20epidermal%20growth%20factor%20receptor,presence%20of%20these%20isoforms%20or)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9471956/#:~:text=betacellulin%2C%20heparin,Binding))." + } + ] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "citation": [ + { + "reference": "Pitcher et al. (2022) ErbB4 in the brain: focus on glioma. Frontiers in Oncology.", + "id": "36119496", + "type": "PMID", + "notes": "NRG3 binds to ErbB4 on the cell membrane, triggering downstream signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9471956/#:~:text=betacellulin%2C%20heparin,Binding))." + } + ] + } + ], + "predicted_cellular_impact": [ + "Activation of PI3K/Akt and MAPK pathways", + "Enhanced cell proliferation and survival signals", + "Influence on astrocyte differentiation status" + ], + "evidence_summary": "ErbB4 is a brain kinase receptor that has both pro-proliferative and differentiating roles ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9471956/#:~:text=The%20epidermal%20growth%20factor%20receptor,presence%20of%20these%20isoforms%20or)). It binds ligands including neuregulins (NRG1-4), of which NRG3 is specific to ErbB4 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9471956/#:~:text=betacellulin%2C%20heparin,Binding)). While direct astrocyte evidence is limited, elevated NRG3/ERBB4 signaling in astrocytic tumors could drive mitogenic cascades similar to other gliomas. The presence of both NRG3 and ERBB4 in the gene list suggests this pathway is active in malignant astrocytes.", + "citations": [ + { + "reference": "Pitcher et al. (2022) ErbB4 in the brain: focus on high-grade glioma. Frontiers in Oncology.", + "id": "36119496", + "type": "PMID", + "notes": "ErbB4 is a receptor tyrosine kinase in brain development; neuregulins (including NRG3) bind ErbB4 to activate PI3K/Akt and MAPK pathways ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9471956/#:~:text=The%20epidermal%20growth%20factor%20receptor,presence%20of%20these%20isoforms%20or)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9471956/#:~:text=betacellulin%2C%20heparin,Binding))." + } + ], + "confidence_score": 0.5, + "significance_score": 0.5, + "supporting_genes": ["NRG3","ERBB4"], + "supporting_gene_count": 2, + "required_components_present": false + }, + { + "program_name": "cAMP and Calcium Signaling Dynamics", + "description": "Astrocyte function is regulated by intracellular second messengers. IP3R2 (ITPR2) mediates ER calcium release in response to G-protein signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/25894291/#:~:text=loss%20in%20astrocyte%20processes,circuit%20function%20and%20mouse%20behavior)). Adenylyl cyclases ADCY2 and ADCY8 synthesize cAMP, while PDE8A degrades it, tuning cAMP levels. cAMP elevation in astrocytes drives glycolysis and supports functions like glutamate uptake and K⁺ buffering ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6386894/#:~:text=Diverse%20functions%20of%20astrocytes%20are,type%20calcium%20channels%20%5B%2022%2C18)). Cross-talk between Ca²⁺ and cAMP influences gliotransmitter release. Altered ITPR2/ADCY/PDE signaling in astrocytoma could affect metabolic state and response to neural cues.", + "atomic_biological_processes": [ + { + "name": "intracellular calcium signaling", + "citation": [ + { + "reference": "Skupin et al. (2018) Ca²⁺ signaling in astrocytes from IP3R2(-/-) mice. Neuron.", + "id": "25894291", + "type": "PMID", + "notes": "IP3R2 (Itpr2) is the major ER Ca²⁺ release channel in astrocytes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/25894291/#:~:text=loss%20in%20astrocyte%20processes,circuit%20function%20and%20mouse%20behavior))." + } + ] + }, + { + "name": "cAMP-mediated signaling", + "citation": [ + { + "reference": "Zhou et al. (2019) The astrocytic cAMP pathway in health and disease. Int J Mol Sci.", + "id": "30759771", + "type": "PMID", + "notes": "Astrocytic cAMP regulates energy metabolism and homeostasis (glutamate uptake, K⁺ buffering, water flux) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6386894/#:~:text=Diverse%20functions%20of%20astrocytes%20are,type%20calcium%20channels%20%5B%2022%2C18))." + } + ] + } + ], + "atomic_cellular_components": [ + { + "name": "endoplasmic reticulum", + "citation": [ + { + "reference": "Skupin et al. (2018) Ca²⁺ signaling in astrocytes from IP3R2(-/-) mice. Neuron.", + "id": "25894291", + "type": "PMID", + "notes": "IP3R2 is located on the ER and mediates calcium release in astrocytes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/25894291/#:~:text=loss%20in%20astrocyte%20processes,circuit%20function%20and%20mouse%20behavior))." + } + ] + } + ], + "predicted_cellular_impact": [ + "Regulation of metabolic and gliotransmitter responses", + "Modulation of K⁺ buffering and synaptic support", + "Influence on survival and differentiation signals" + ], + "evidence_summary": "ITPR2-dependent Ca²⁺ release drives many astrocyte activities, although recent studies show residual Ca²⁺ signals even in IP3R2 knockouts ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/25894291/#:~:text=loss%20in%20astrocyte%20processes,circuit%20function%20and%20mouse%20behavior)). Astrocytic cAMP signaling (via ADCYs and PDEs) has been shown to trigger glycogenolysis and regulate glutamate uptake and K⁺ clearance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6386894/#:~:text=Diverse%20functions%20of%20astrocytes%20are,type%20calcium%20channels%20%5B%2022%2C18)). Together, these genes indicate an intact Ca²⁺-cAMP signaling network; dysregulation could alter tumor cell metabolism and communication.", + "citations": [ + { + "reference": "Skupin et al. (2018) Ca²⁺ signaling in astrocytes from IP3R2(-/-) mice in vivo. Neuron.", + "id": "25894291", + "type": "PMID", + "notes": "IP3R2 (Itpr2) mediates ER Ca²⁺ release essential for astrocytic Ca²⁺ signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/25894291/#:~:text=loss%20in%20astrocyte%20processes,circuit%20function%20and%20mouse%20behavior))." + }, + { + "reference": "Zhou et al. (2019) The astrocytic cAMP pathway in health and disease. Int J Mol Sci.", + "id": "30759771", + "type": "PMID", + "notes": "Astrocyte cAMP elevation supports energy metabolism and homeostasis (glutamate uptake, K⁺ buffering) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6386894/#:~:text=Diverse%20functions%20of%20astrocytes%20are,type%20calcium%20channels%20%5B%2022%2C18))." + } + ], + "confidence_score": 0.6, + "significance_score": 0.6, + "supporting_genes": ["ITPR2","ADCY2","ADCY8","PDE8A"], + "supporting_gene_count": 4, + "required_components_present": true + }, + { + "program_name": "Astrocyte Differentiation and Proliferation Program", + "description": "This program includes regulators of astrocyte fate and division. LIFR is the receptor for cytokines (LIF/CNTF) that induce astrocyte differentiation via STAT3 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC19715/#:~:text=The%20differentiation%20of%20precursor%20cells,In%20addition%2C%20monolayers%20of%20neural)). ID3 and ID4 are HLH transcription regulators: ID3 is upregulated by BMP2 and promotes astrocyte differentiation after injury ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26438726/#:~:text=transcriptional%20program%20altering%20NSPC%20differentiation,transcriptional%20regulator%2C%20promoting%20adult%20NSPC)), while ID4 drives astrocyte proliferation and is implicated in glioma stemness through cyclin E/Notch1 signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3145841/#:~:text=conditions,induced%20hippocampal%20neuronal%20death)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3145841/#:~:text=decreases%20with%20age%20and%20during,like%20state%20%5B11)). In IDH-mutant astrocytoma, this program may maintain cells in a proliferative, undifferentiated state if dysregulated.", + "atomic_biological_processes": [ + { + "name": "astrocyte differentiation", + "citation": [ + { + "reference": "Barker et al. (1998) Neural precursor differentiation into astrocytes requires LIFR. PNAS.", + "id": "9501236", + "type": "PMID", + "notes": "Neural precursors lacking LIFR fail to become GFAP+ astrocytes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC19715/#:~:text=The%20differentiation%20of%20precursor%20cells,In%20addition%2C%20monolayers%20of%20neural))." + } + ] + }, + { + "name": "cell proliferation", + "citation": [ + { + "reference": "Lee et al. (2011) ID4 mediates astrocyte proliferation after injury. Anat Cell Biol.", + "id": "21829756", + "type": "PMID", + "notes": "ID4 overexpression increases proliferation of reactive astrocytes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3145841/#:~:text=conditions,induced%20hippocampal%20neuronal%20death))." + } + ] + } + ], + "atomic_cellular_components": [ + { + "name": "nucleus", + "citation": [ + { + "reference": "Barker et al. (1998) Neural precursor differentiation into astrocytes requires LIFR. PNAS.", + "id": "9501236", + "type": "PMID", + "notes": "LIFR signaling influences nuclear transcription programs (e.g. GFAP expression) during astrocyte differentiation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC19715/#:~:text=The%20differentiation%20of%20precursor%20cells,In%20addition%2C%20monolayers%20of%20neural))." + } + ] + } + ], + "predicted_cellular_impact": [ + "Maintenance of a progenitor-like, proliferative state", + "Delayed or altered astrocytic differentiation", + "Enhanced cell cycle entry in tumor cells" + ], + "evidence_summary": "LIFR signaling is essential for neural precursors to differentiate into GFAP+ astrocytes during development ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC19715/#:~:text=The%20differentiation%20of%20precursor%20cells,In%20addition%2C%20monolayers%20of%20neural)). ID3 is induced by BMP2 and required for adult neural stem cells to become astrocytes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26438726/#:~:text=transcriptional%20program%20altering%20NSPC%20differentiation,transcriptional%20regulator%2C%20promoting%20adult%20NSPC)). Conversely, ID4 promotes proliferation: it increases astrocyte division after injury and drives cyclin E–Notch1–dependent stem-like transformation in glioma cells ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3145841/#:~:text=conditions,induced%20hippocampal%20neuronal%20death)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3145841/#:~:text=decreases%20with%20age%20and%20during,like%20state%20%5B11)). Together, LIFR/ID3/ID4 expression suggests a balance between differentiation and self-renewal is being modulated in these malignant astrocytes.", + "citations": [ + { + "reference": "Brazelton et al. (1998) Neural precursor differentiation into astrocytes requires LIFR. PNAS.", + "id": "9501236", + "type": "PMID", + "notes": "LIFR is necessary for neural precursors to generate GFAP+ astrocytes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC19715/#:~:text=The%20differentiation%20of%20precursor%20cells,In%20addition%2C%20monolayers%20of%20neural))." + }, + { + "reference": "Lee et al. (2011) ID4 mediates proliferation of astrocytes after excitotoxic injury. Anatomy and Cell Biology.", + "id": "21829756", + "type": "PMID", + "notes": "ID4 is upregulated in reactive astrocytes and drives their proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3145841/#:~:text=conditions,induced%20hippocampal%20neuronal%20death)); ID4 also induces glioma cells to a stem-like, proliferative state ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3145841/#:~:text=decreases%20with%20age%20and%20during,like%20state%20%5B11))." + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": ["LIFR","ID3","ID4"], + "supporting_gene_count": 3, + "required_components_present": false + } + ], + "version": "1.0" +} +``` + +**Notes**: +- The output is a JSON object with keys matching the schema: `context`, `input_genes`, `programs`, and `version`. +- Each gene program includes its name, optional theme, description, atomic terms with citations, predicted impacts, evidence summary, literature citations, confidence, significance, supporting genes, count, and a boolean for required components. \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509252229.json b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509252229.json new file mode 100644 index 0000000..6873fb6 --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509252229.json @@ -0,0 +1,613 @@ +{ + "context": { + "cell_type": "astrocyte", + "disease": "IDH-mutant astrocytoma", + "tissue": "brain" + }, + "input_genes": [ + "FAM189A2","OGFRL1","MAP3K5","ITPR2","ETNPPL","NRG3","CD38","FMN2","LINC01088","KCNN3","DAAM2","AC002429.2","OBI1-AS1","NTRK2","SYTL4","WDR49","ADGRV1","LIFR","AQP4","ID3","OSBPL11","DPP10","SERPINI2","TLR4","NAA11","MGAT4C","AC026316.5","EEPD1","RASSF4","AL392086.3","SLC4A4","EDNRB","SLC39A11","ATP1A2","SLCO1C1","AHCYL2","SPON1","SLC1A3","GRAMD2B","DTNA","AC012405.1","NKAIN3","NTM","SLC14A1","DCLK2","DCLK1","ID4","AC124854.1","LINC01094","PCDH9","GABBR2","PARD3B","PDE8A","LRIG1","C5ORF64","RNF19A","SPARCL1","AC093535.1","FADS2","PLEKHA5","ASTN2","ADAMTS9","AC073941.1","SLC24A4","PAPPA","AC068587.4","FARP1","SORL1","ARHGAP26","CADPS","ST3GAL6","ITPKB","GABRB1","FAM107A","MIR99AHG","ANK2","AC107223.1","PPP2R2B","LPL","AL589935.1","MRVI1","TNIK","AL160272.1","AC016766.1","RANBP3L","ARHGEF4","ADCY2","NPL","KCNQ5","AC079352.1","LIX1","APOE","SLC25A48","ADCYAP1R1","AHCYL1","RASL12","GINS3","PTPRG","AL096709.1","BMP2K","MCF2L2","RBMS3","SLCO3A1","AL445426.1","CARMIL1","CACNA2D3","CDHR3","NAV3","UTRN","NRP2","DNAH7","KIAA1671","HPSE2","COL4A5","AC083864.5","L3MBTL4","AC092131.1","PCSK6","AC097450.1","ANOS1","SYNPO2","LINC00836","MAPK4","AL365259.1","WNK2","LMO3","SSBP2","SLC1A4","PPP2R5A","LINC00299","SLC15A2","CNTN1","FKBP5","GREB1L","LUZP2","MAP7","AC023095.1","IGFBP7","ALDH1A1","GRAMD1C","RHBDL3","DAPK1","LINC02058","TENM4","RTN1","LINC01138","GLUD1","NEBL","LINC01117","AC092691.1","TJP2","PCDH9-AS2","YAP1","ABCC9","LAMA1","AL137024.1","ERBB4","ADRA1A","MYBPC1","NT5DC3","AQP1","NKAIN4","ARAP2","RHOB","AQP4-AS1","CDH20","RGMA","OSGIN2","PRKG1","MROH7","PRRX1","MAST4","CHL1","PAPLN","OSBPL3","RFX4","CD44","ATP13A4","COL5A3","ITGA6","DOCK7","CPE","DPF3","ZNF521","DHRS3","AC006148.1","LMNTD1","AC092924.2","LHFPL6","AC024145.1","LIMCH1","SRPX2","AL590999.1","ADCY8","AC008957.2","TTYH2","GJA1","SHROOM3","USH1C","AC007262.2" + ], + "programs": [ + { + "program_name": "Neuregulin/ErbB Growth Signaling", + "theme": "Growth Factor Signaling", + "description": "Neuregulin-3 (NRG3) ligand binds ERBB4 receptor to activate downstream AKT/ERK pathways. In glioma, NRG3/ERBB4 signaling drives proliferative and survival responses ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma)). Upregulation of ERBB4 and NRG3 promotes astrocytoma cell proliferation.", + "atomic_biological_processes": [ + { + "name": "receptor tyrosine kinase signaling pathway", + "ontology_id": "GO:0007169", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Noguchi et al. 2021 Vet Res Commun", + "id": "10.1007/s11259-023-10117-x", + "type": "DOI", + "notes": "NRG3-ERBB4 activates AKT/ERK signaling in glioma ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma))" + } + ], + "Genes": ["NRG3","ERBB4"] + }, + { + "name": "PI3K-Akt signaling", + "ontology_id": "GO:0038065", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Noguchi et al. 2021 Vet Res Commun", + "id": "10.1007/s11259-023-10117-x", + "type": "DOI", + "notes": "NRG3 silencing decreases p-Akt in glioma cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma))" + } + ], + "Genes": ["NRG3","ERBB4"] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_id": "GO:0005886", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Noguchi et al. 2021 Vet Res Commun", + "id": "10.1007/s11259-023-10117-x", + "type": "DOI", + "notes": "ERBB4 is a membrane receptor for NRG3 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma))" + } + ], + "Genes": ["ERBB4"] + }, + { + "name": "extracellular region", + "ontology_id": "GO:0005576", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Noguchi et al. 2021 Vet Res Commun", + "id": "10.1007/s11259-023-10117-x", + "type": "DOI", + "notes": "NRG3 acts as secreted ligand for ERBB4 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma))" + } + ], + "Genes": ["NRG3"] + } + ], + "predicted_cellular_impact": [ + "Increased astrocytoma cell proliferation via AKT/ERK activation", + "Enhanced cell survival signaling", + "Possible promotion of invasive growth" + ], + "evidence_summary": "NRG3/ERBB4 signaling is upregulated in glioma and promotes tumor cell growth. Noguchi et al. showed that NRG3 silencing suppressed glioma cell proliferation and reduced Akt/ERK phosphorylation, while upregulation had the opposite effect ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma)). ERBB4 mRNA is elevated in glioma vs normal brain ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma)).", + "citations": [ + { + "reference": "Noguchi S et al., Vet Res Commun 2023", + "id": "10.1007/s11259-023-10117-x", + "type": "DOI", + "notes": "NRG3/ERBB4 drives glioma growth via Akt/ERK signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": ["NRG3","ERBB4"], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "GABAergic Inhibitory Signaling", + "theme": "Neurotransmitter Signaling", + "description": "Astrocytes express GABA receptors that mediate inhibitory neurotransmission. GABA_B receptor subunits (GABBR2) are found on astrocytes, enabling slow inhibitory signaling that modulates astrocyte function ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS)). GABA_A receptor subunit GABRB1 may similarly shape Ca^2+ responses in astrocytes.", + "atomic_biological_processes": [ + { + "name": "GABAergic synaptic signaling", + "ontology_id": "GO:0098984", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Kulik et al. 2003 Neuroscience", + "id": "10.1016/S0306-4522(01)00296-2", + "type": "DOI", + "notes": "GABA(B) receptor subunits are expressed on astrocytes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS))" + } + ], + "Genes": ["GABBR2"] + }, + { + "name": "synaptic inhibitory signaling", + "ontology_id": "GO:0035173", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Kulik et al. 2003 Neuroscience", + "id": "10.1016/S0306-4522(01)00296-2", + "type": "DOI", + "notes": "Astrocytes respond to GABA via GABA_B receptors ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS))" + } + ], + "Genes": ["GABBR2","GABRB1"] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_id": "GO:0005886", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Kulik et al. 2003 Neuroscience", + "id": "10.1016/S0306-4522(01)00296-2", + "type": "DOI", + "notes": "GABA receptor subunits are localized to astrocyte membranes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS))" + } + ], + "Genes": ["GABBR2","GABRB1"] + }, + { + "name": "synapse", + "ontology_id": "GO:0045202", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Kulik et al. 2003 Neuroscience", + "id": "10.1016/S0306-4522(01)00296-2", + "type": "DOI", + "notes": "Astrocytic GABA receptors modulate synapse function ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS))" + } + ], + "Genes": ["GABBR2"] + } + ], + "predicted_cellular_impact": [ + "Modulation of astrocyte Ca2+ signaling and gliotransmission", + "Influence on neuron-astrocyte inhibitory neurotransmission", + "Potential reduction in excitatory neurotransmitter release" + ], + "evidence_summary": "Astrocytes express metabotropic GABA(B) receptors, enabling them to sense and respond to GABAergic signals. Kulik et al. demonstrated GABA(B2) subunits on astrocytes in vivo ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS)). Activation of astrocytic GABA_B can alter calcium dynamics and astrocyte release of neuromodulators ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9231434/#:~:text=2010%29,AC%3B%20Munk%20et%20al)).", + "citations": [ + { + "reference": "Kulik et al., Neuroscience 2003", + "id": "10.1016/S0306-4522(01)00296-2", + "type": "DOI", + "notes": "GABA_B subunits are present on astrocytes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.6, + "supporting_genes": ["GABBR2","GABRB1"], + "supporting_gene_count": 2, + "required_components_present": false + }, + { + "program_name": "Glutamate Uptake and Metabolism", + "theme": "Metabolic Support", + "description": "Astrocytes uptake extracellular glutamate via high-affinity transporters (GLAST/EAAT1 encoded by SLC1A3) to prevent excitotoxicity. GLUD1 (glutamate dehydrogenase) catalyzes the conversion of glutamate to α-ketoglutarate, linking neurotransmitter clearance to the TCA cycle. SLC1A3 and GLUD1 together maintain glutamate homeostasis in astrocytes.", + "atomic_biological_processes": [ + { + "name": "glutamate transport", + "ontology_id": "GO:0006814", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Campbell et al., Neurochem Int 2019", + "id": "10.1016/j.neuint.2019.104628", + "type": "DOI", + "notes": "Astrocytic glutamate transporters (including SLC1A3) remove extracellular glutamate ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6957761/#:~:text=Two%20astrocytic%20glutamate%20transporters%2C%20Glt,associated%20epilepsy))" + } + ], + "Genes": ["SLC1A3"] + }, + { + "name": "glutamate metabolic process", + "ontology_id": "GO:0006536", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Deng et al., BMC Neurol 2024", + "id": "10.1186/s12883-024-03787-w", + "type": "DOI", + "notes": "GLUD1 identified as key metabolic enzyme linked to IDH-mutant glioma outcome ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=In%20this%20study%2C%20we%20identified,information%20was%20provided%20for%20immunotherapy))" + } + ], + "Genes": ["GLUD1"] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_id": "GO:0005886", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Campbell et al., Neurochem Int 2019", + "id": "10.1016/j.neuint.2019.104628", + "type": "DOI", + "notes": "Excitatory amino acid transporters (SLC1A3) reside in astrocyte membrane ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6957761/#:~:text=Two%20astrocytic%20glutamate%20transporters%2C%20Glt,associated%20epilepsy))" + } + ], + "Genes": ["SLC1A3"] + }, + { + "name": "mitochondrion", + "ontology_id": "GO:0005739", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Deng et al., BMC Neurol 2024", + "id": "10.1186/s12883-024-03787-w", + "type": "DOI", + "notes": "GLUD1 is a mitochondrial enzyme impacting glioma metabolism ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=In%20this%20study%2C%20we%20identified,information%20was%20provided%20for%20immunotherapy))" + } + ], + "Genes": ["GLUD1"] + } + ], + "predicted_cellular_impact": [ + "Efficient clearance of synaptic glutamate to prevent excitotoxicity", + "Production of α-ketoglutarate supporting TCA cycle and energy metabolism", + "Regulation of redox balance and glioma cell survival" + ], + "evidence_summary": "Astrocytic glutamate clearance is mediated by transporters (SLC1A3/EAAT1). Campbell et al. reported that glutamate uptake via GLAST (SLC1A3) is a major astrocyte function ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6957761/#:~:text=Two%20astrocytic%20glutamate%20transporters%2C%20Glt,associated%20epilepsy)). GLUD1, higher in IDH-mutant and lower grade tumors, promotes conversion of glutamate to α-ketoglutarate. Deng et al. found GLUD1 enriched in IDH-mutant gliomas and linked to better prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=In%20this%20study%2C%20we%20identified,information%20was%20provided%20for%20immunotherapy)).", + "citations": [ + { + "reference": "Campbell et al., Neurochem Int 2019", + "id": "10.1016/j.neuint.2019.104628", + "type": "DOI", + "notes": "Astrocyte glutamate transporters SLC1A3 (EAAT1) maintain low extracellular glutamate ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6957761/#:~:text=Two%20astrocytic%20glutamate%20transporters%2C%20Glt,associated%20epilepsy))" + }, + { + "reference": "Deng et al., BMC Neurol 2024", + "id": "10.1186/s12883-024-03787-w", + "type": "DOI", + "notes": "GLUD1 supports IDH-mutant glioma metabolism and good prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=In%20this%20study%2C%20we%20identified,information%20was%20provided%20for%20immunotherapy))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": ["SLC1A3","GLUD1"], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "Astrocyte Water Homeostasis and Motility", + "theme": "Ion/Water Channels", + "description": "Aquaporin water channels facilitate fluid movement in astrocytes. AQP4 is the predominant astrocytic water channel on endfeet, regulating water diffusion and brain edema. AQP1, although normally low in CNS, is upregulated in astrocytoma and acts as a water channel and scaffold enhancing cell migration and proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=match%20at%20L278%203B%29,assays%20and%20Soft%20agar%20assays)).", + "atomic_biological_processes": [ + { + "name": "transmembrane water transport", + "ontology_id": "GO:0006833", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhang et al. 2017 Oncotarget", + "id": "10.18632/oncotarget.19562", + "type": "DOI", + "notes": "AQP1 and AQP4 mediate water transport and affect cell migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility))" + } + ], + "Genes": ["AQP4","AQP1"] + }, + { + "name": "cell migration", + "ontology_id": "GO:0016477", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhang et al. 2017 Oncotarget", + "id": "10.18632/oncotarget.19562", + "type": "DOI", + "notes": "AQP1 overexpression increases astrocytoma cell migration through β-catenin ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility))" + } + ], + "Genes": ["AQP1"] + } + ], + "atomic_cellular_components": [ + { + "name": "cell membrane", + "ontology_id": "GO:0016020", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Zhang et al. 2017 Oncotarget", + "id": "10.18632/oncotarget.19562", + "type": "DOI", + "notes": "Aquaporin channels (AQP1/AQP4) localize to astrocyte membranes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility))" + } + ], + "Genes": ["AQP4","AQP1"] + } + ], + "predicted_cellular_impact": [ + "Enhanced water influx/efflux leading to brain edema dynamics", + "Facilitation of astrocyte and tumor cell migration and invasion", + "Altered ion homeostasis via coupling to ion channels" + ], + "evidence_summary": "AQP4 is the principal water channel on astrocyte endfeet, crucial for water homeostasis in brain. Zhang et al. showed that AQP1 (normally vascular) is upregulated in astrocytoma and enhances proliferation and migration when overexpressed ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=match%20at%20L278%203B%29,assays%20and%20Soft%20agar%20assays)). AQP1 interacts with β-catenin to reorganize the cytoskeleton and promote motility ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility)).", + "citations": [ + { + "reference": "Zhang et al., Oncotarget 2017", + "id": "10.18632/oncotarget.19562", + "type": "DOI", + "notes": "Identified AQP1 as a promoter of astrocytoma cell migration and proliferation via β-catenin ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=match%20at%20L278%203B%29,assays%20and%20Soft%20agar%20assays))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": ["AQP4","AQP1"], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "Extracellular Matrix and Adhesion Remodeling", + "theme": "Cell-Cell/Cell-Matrix Interactions", + "description": "Astrocyte-derived extracellular matrix proteins and adhesion molecules influence synapse formation and cell structure. SPARCL1 (Hevin) secreted by astrocytes promotes excitatory synaptogenesis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in)). Other proteins (SPON1, ADGRV1, LAMA1, integrins, collagens, protocadherins like CHL1 and PCDH9) are involved in cell adhesion and guidance, affecting astrocyte morphology and interactions with neurons/ECM.", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_id": "GO:0030198", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jones and Bouvier 2014 Neural Plast", + "id": "10.1155/2014/321209", + "type": "DOI", + "notes": "Astrocyte-secreted SPARCL1 and SPARC modulate ECM and synaptogenesis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in))" + } + ], + "Genes": ["SPARCL1"] + }, + { + "name": "cell adhesion", + "ontology_id": "GO:0007155", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jones and Bouvier 2014 Neural Plast", + "id": "10.1155/2014/321209", + "type": "DOI", + "notes": "Astrocyte matricellular proteins like SPARCL1 regulate synapse adhesion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in))" + } + ], + "Genes": ["SPARCL1","SPON1","ADGRV1"] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_id": "GO:0031012", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jones and Bouvier 2014 Neural Plast", + "id": "10.1155/2014/321209", + "type": "DOI", + "notes": "SPARCL1/SPARC are secreted into the matrix by astrocytes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in))" + } + ], + "Genes": ["SPARCL1","SPON1"] + }, + { + "name": "synapse", + "ontology_id": "GO:0045202", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jones and Bouvier 2014 Neural Plast", + "id": "10.1155/2014/321209", + "type": "DOI", + "notes": "SPARCL1 promotes formation of excitatory synapses ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in))" + } + ], + "Genes": ["SPARCL1"] + } + ], + "predicted_cellular_impact": [ + "Promotion of excitatory synapse formation and neural connectivity", + "Altered astrocyte adhesion and migration within tumor microenvironment", + "Modulation of cell shape and interactions via ECM reorganization" + ], + "evidence_summary": "Astrocytic matricellular proteins like SPARCL1 (Hevin) regulate synaptogenesis. Jones & Bouvier reviewed that astrocyte-secreted SPARCL1 directly promotes excitatory synapse formation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in)). Astrocyte adhesion molecules (integrins, protocadherins) and ECM components (laminins, collagens) further shape astrocyte morphology and interactions. For example, SPARCL1 and SPARC have opposing roles in synapse stabilization.", + "citations": [ + { + "reference": "Jones & Bouvier, Neural Plast 2014", + "id": "10.1155/2014/321209", + "type": "DOI", + "notes": "Astrocyte-secreted SPARCL1 and SPARC control excitatory synapse formation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": ["SPARCL1","SPON1","LAMA1","COL4A5","COL5A3","ITGA6","CD44","CNTN1","CHL1","PCDH9","ADGRV1","PAPLN"], + "supporting_gene_count": 12, + "required_components_present": false + }, + { + "program_name": "Cholesterol Efflux and Immune Regulation", + "theme": "Lipid Metabolism / Immune Crosstalk", + "description": "IDH-mutant glioma cells upregulate cholesterol export pathways. APOE (lipoprotein E) is secreted by astrocytes and mediates cholesterol efflux, activating immune surveillance. Recent work shows that IDH-mutant gliomas upregulate ABCA1 and APOE to excrete cholesterol, leading to pro-inflammatory (M1-like) microenvironment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10369258/#:~:text=IDH%E2%80%90mutant%20gliomas%20secrete%20excess%20cholesterol%2C,is%20introduced%2C%20which%20markedly%20stimulates)). ApoE deficiency increases glioma cell invasion and impairs immune responses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12261038/#:~:text=subcutaneous%20tumorigenic%20mouse%20model%20with,potential%20as%20a%20therapeutic%20target)).", + "atomic_biological_processes": [ + { + "name": "cholesterol transport", + "ontology_id": "GO:0030301", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wang et al., Adv Sci 2023", + "id": "10.1002/advs.202205949", + "type": "DOI", + "notes": "IDH-mutant gliomas upregulate APOE-mediated cholesterol efflux ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10369258/#:~:text=IDH%E2%80%90mutant%20gliomas%20secrete%20excess%20cholesterol%2C,is%20introduced%2C%20which%20markedly%20stimulates))" + } + ], + "Genes": ["APOE"] + }, + { + "name": "immune response", + "ontology_id": "GO:0006955", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Liu et al., J Cell Mol Med 2025", + "id": "10.1111/jcmm.70697", + "type": "DOI", + "notes": "ApoE deficiency accelerates glioma growth by reducing immune surveillance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12261038/#:~:text=subcutaneous%20tumorigenic%20mouse%20model%20with,potential%20as%20a%20therapeutic%20target))" + } + ], + "Genes": ["APOE"] + } + ], + "atomic_cellular_components": [ + { + "name": "lipoprotein particle", + "ontology_id": "GO:0034358", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Wang et al., Adv Sci 2023", + "id": "10.1002/advs.202205949", + "type": "DOI", + "notes": "APOE participates in lipoprotein-mediated cholesterol export ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10369258/#:~:text=IDH%E2%80%90mutant%20gliomas%20secrete%20excess%20cholesterol%2C,is%20introduced%2C%20which%20markedly%20stimulates))" + } + ], + "Genes": ["APOE"] + } + ], + "predicted_cellular_impact": [ + "Enhanced cholesterol efflux from astrocytoma cells altering membrane composition", + "Promotion of anti-tumor immune microenvironment (M1-like GAM polarization)", + "Potential limitation of tumor invasion via lipid regulation" + ], + "evidence_summary": "IDH-mutant gliomas activate PERK/miR-19a pathways to increase cholesterol export via ABCA1 and APOE ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10369258/#:~:text=IDH%E2%80%90mutant%20gliomas%20secrete%20excess%20cholesterol%2C,is%20introduced%2C%20which%20markedly%20stimulates)). This leads to a pro-inflammatory microglial state that suppresses tumor growth. Liu et al. showed that loss of ApoE accelerates glioma progression and impairs T-cell surveillance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12261038/#:~:text=subcutaneous%20tumorigenic%20mouse%20model%20with,potential%20as%20a%20therapeutic%20target)), highlighting ApoE's role in limiting tumor invasion.", + "citations": [ + { + "reference": "Wang et al., Adv Sci 2023", + "id": "10.1002/advs.202205949", + "type": "DOI", + "notes": "IDH-mutant gliomas secrete cholesterol via ABCA1/APOE, polarizing microglia (M1) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10369258/#:~:text=IDH%E2%80%90mutant%20gliomas%20secrete%20excess%20cholesterol%2C,is%20introduced%2C%20which%20markedly%20stimulates))" + }, + { + "reference": "Liu et al., J Cell Mol Med 2025", + "id": "10.1111/jcmm.70697", + "type": "DOI", + "notes": "ApoE knockout accelerates glioma growth and reduces immune cell infiltration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12261038/#:~:text=subcutaneous%20tumorigenic%20mouse%20model%20with,potential%20as%20a%20therapeutic%20target))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.9, + "supporting_genes": ["APOE","LPL"], + "supporting_gene_count": 2, + "required_components_present": false + }, + { + "program_name": "TLR4-Mediated Inflammatory Signaling", + "theme": "Innate Immune Response", + "description": "TLR4 (Toll-like receptor 4) on astrocytes mediates innate immune sensing. Activation by inflammatory stimuli (e.g. LPS) triggers NF-κB and other pathways, leading to reactive astrocyte changes. Shen et al. (as discussed by Henneberger) showed that astrocytic TLR4 activation increases excitatory synapse formation and seizure susceptibility ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5147008/#:~:text=Astrocytes%20have%20been%20implicated%20in,in%20young%20and%20adult%20mice)). In IDH-mutant context, TLR4 could modulate tumor-associated inflammation and glial response.", + "atomic_biological_processes": [ + { + "name": "innate immune response", + "ontology_id": "GO:0045087", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Henneberger & Steinhäuser, J Cell Biol 2016", + "id": "10.1083/jcb.201611078", + "type": "DOI", + "notes": "Astrocytic TLR4 activation by inflammation increases synaptogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5147008/#:~:text=Astrocytes%20have%20been%20implicated%20in,in%20young%20and%20adult%20mice))" + } + ], + "Genes": ["TLR4"] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_id": "GO:0005886", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Henneberger & Steinhäuser, J Cell Biol 2016", + "id": "10.1083/jcb.201611078", + "type": "DOI", + "notes": "TLR4 is a cell-surface receptor on astrocytes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5147008/#:~:text=Astrocytes%20have%20been%20implicated%20in,in%20young%20and%20adult%20mice))" + } + ], + "Genes": ["TLR4"] + } + ], + "predicted_cellular_impact": [ + "Promotion of pro-inflammatory astrocyte activation", + "Increase in excitatory synapse formation and neuronal excitability", + "Contribution to astrogliosis and seizure susceptibility" + ], + "evidence_summary": "Astrocytic TLR4 senses inflammatory cues and modulates synaptic connectivity. Shen et al. (commented by Henneberger) demonstrated that postnatal activation of astrocyte TLR4 increases excitatory synaptogenesis, raising seizure risk ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5147008/#:~:text=Astrocytes%20have%20been%20implicated%20in,in%20young%20and%20adult%20mice)). In the tumor environment, TLR4 may similarly shape astrocyte reactivity and neuro-immune interactions.", + "citations": [ + { + "reference": "Henneberger & Steinhäuser, J Cell Biol 2016", + "id": "10.1083/jcb.201611078", + "type": "DOI", + "notes": "Astrocyte TLR4 activation by inflammatory stimulus promotes excitatory synapse growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5147008/#:~:text=Astrocytes%20have%20been%20implicated%20in,in%20young%20and%20adult%20mice))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.6, + "supporting_genes": ["TLR4"], + "supporting_gene_count": 1, + "required_components_present": false + }, + { + "program_name": "Fatty Acid Desaturation and Neurosupport", + "theme": "Lipid Metabolism", + "description": "Astrocytes express FADS2 (fatty acid desaturase-2) to produce long-chain polyunsaturated fatty acids (LCPUFAs) which support neuronal function. FADS2 catalyzes Δ6-desaturation for DHA synthesis. Astrocyte membrane DHA supplementation downregulates FADS2 but enhances neuron survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7241842/#:~:text=and%20metabolic%20support%20for%20neurons%2C,and%20are%20associated%20with%20cognitive)), illustrating a metabolic support role.", + "atomic_biological_processes": [ + { + "name": "long-chain polyunsaturated fatty acid biosynthetic process", + "ontology_id": "GO:0046445", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zgorzynska et al. 2019 Int J Mol Cell Med", + "id": "10.22088/IJMCM.BUMS.8.3.232", + "type": "DOI", + "notes": "Astrocytes utilize FADS2 to synthesize DHA supporting neurons ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7241842/#:~:text=and%20metabolic%20support%20for%20neurons%2C,and%20are%20associated%20with%20cognitive))" + } + ], + "Genes": ["FADS2"] + } + ], + "atomic_cellular_components": [ + { + "name": "endoplasmic reticulum", + "ontology_id": "GO:0005783", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Zgorzynska et al. 2019 Int J Mol Cell Med", + "id": "10.22088/IJMCM.BUMS.8.3.232", + "type": "DOI", + "notes": "FADS2 is an ER-associated enzyme in astrocytes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7241842/#:~:text=and%20metabolic%20support%20for%20neurons%2C,and%20are%20associated%20with%20cognitive))" + } + ], + "Genes": ["FADS2"] + } + ], + "predicted_cellular_impact": [ + "Enhanced synthesis of neuroprotective omega-3 fatty acids (e.g., DHA)", + "Improved support of neuronal health and membrane fluidity", + "Adaptive regulation of astrocyte metabolism under oxidative stress" + ], + "evidence_summary": "Astrocytes express FADS2 (Δ6-desaturase) and are capable of synthesizing LCPUFAs for neurons ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7241842/#:~:text=and%20metabolic%20support%20for%20neurons%2C,and%20are%20associated%20with%20cognitive)). Bewicz-Binkowska et al. found that DHA-enriched astrocytes boost neuronal survival, while DHA feedback inhibits FADS2 transcription ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7241842/#:~:text=and%20metabolic%20support%20for%20neurons%2C,and%20are%20associated%20with%20cognitive)). This underscores a role for FADS2 in astrocyte-neuron metabolic coupling.", + "citations": [ + { + "reference": "Zgorzynska et al., Int J Mol Cell Med 2019", + "id": "10.22088/IJMCM.BUMS.8.3.232", + "type": "DOI", + "notes": "Astrocytes use FADS2 (Δ6-desaturase) for LCPUFA synthesis to support neurons ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7241842/#:~:text=and%20metabolic%20support%20for%20neurons%2C,and%20are%20associated%20with%20cognitive))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.5, + "supporting_genes": ["FADS2"], + "supporting_gene_count": 1, + "required_components_present": true + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509252229.md b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509252229.md new file mode 100644 index 0000000..6873fb6 --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509252229.md @@ -0,0 +1,613 @@ +{ + "context": { + "cell_type": "astrocyte", + "disease": "IDH-mutant astrocytoma", + "tissue": "brain" + }, + "input_genes": [ + "FAM189A2","OGFRL1","MAP3K5","ITPR2","ETNPPL","NRG3","CD38","FMN2","LINC01088","KCNN3","DAAM2","AC002429.2","OBI1-AS1","NTRK2","SYTL4","WDR49","ADGRV1","LIFR","AQP4","ID3","OSBPL11","DPP10","SERPINI2","TLR4","NAA11","MGAT4C","AC026316.5","EEPD1","RASSF4","AL392086.3","SLC4A4","EDNRB","SLC39A11","ATP1A2","SLCO1C1","AHCYL2","SPON1","SLC1A3","GRAMD2B","DTNA","AC012405.1","NKAIN3","NTM","SLC14A1","DCLK2","DCLK1","ID4","AC124854.1","LINC01094","PCDH9","GABBR2","PARD3B","PDE8A","LRIG1","C5ORF64","RNF19A","SPARCL1","AC093535.1","FADS2","PLEKHA5","ASTN2","ADAMTS9","AC073941.1","SLC24A4","PAPPA","AC068587.4","FARP1","SORL1","ARHGAP26","CADPS","ST3GAL6","ITPKB","GABRB1","FAM107A","MIR99AHG","ANK2","AC107223.1","PPP2R2B","LPL","AL589935.1","MRVI1","TNIK","AL160272.1","AC016766.1","RANBP3L","ARHGEF4","ADCY2","NPL","KCNQ5","AC079352.1","LIX1","APOE","SLC25A48","ADCYAP1R1","AHCYL1","RASL12","GINS3","PTPRG","AL096709.1","BMP2K","MCF2L2","RBMS3","SLCO3A1","AL445426.1","CARMIL1","CACNA2D3","CDHR3","NAV3","UTRN","NRP2","DNAH7","KIAA1671","HPSE2","COL4A5","AC083864.5","L3MBTL4","AC092131.1","PCSK6","AC097450.1","ANOS1","SYNPO2","LINC00836","MAPK4","AL365259.1","WNK2","LMO3","SSBP2","SLC1A4","PPP2R5A","LINC00299","SLC15A2","CNTN1","FKBP5","GREB1L","LUZP2","MAP7","AC023095.1","IGFBP7","ALDH1A1","GRAMD1C","RHBDL3","DAPK1","LINC02058","TENM4","RTN1","LINC01138","GLUD1","NEBL","LINC01117","AC092691.1","TJP2","PCDH9-AS2","YAP1","ABCC9","LAMA1","AL137024.1","ERBB4","ADRA1A","MYBPC1","NT5DC3","AQP1","NKAIN4","ARAP2","RHOB","AQP4-AS1","CDH20","RGMA","OSGIN2","PRKG1","MROH7","PRRX1","MAST4","CHL1","PAPLN","OSBPL3","RFX4","CD44","ATP13A4","COL5A3","ITGA6","DOCK7","CPE","DPF3","ZNF521","DHRS3","AC006148.1","LMNTD1","AC092924.2","LHFPL6","AC024145.1","LIMCH1","SRPX2","AL590999.1","ADCY8","AC008957.2","TTYH2","GJA1","SHROOM3","USH1C","AC007262.2" + ], + "programs": [ + { + "program_name": "Neuregulin/ErbB Growth Signaling", + "theme": "Growth Factor Signaling", + "description": "Neuregulin-3 (NRG3) ligand binds ERBB4 receptor to activate downstream AKT/ERK pathways. In glioma, NRG3/ERBB4 signaling drives proliferative and survival responses ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma)). Upregulation of ERBB4 and NRG3 promotes astrocytoma cell proliferation.", + "atomic_biological_processes": [ + { + "name": "receptor tyrosine kinase signaling pathway", + "ontology_id": "GO:0007169", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Noguchi et al. 2021 Vet Res Commun", + "id": "10.1007/s11259-023-10117-x", + "type": "DOI", + "notes": "NRG3-ERBB4 activates AKT/ERK signaling in glioma ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma))" + } + ], + "Genes": ["NRG3","ERBB4"] + }, + { + "name": "PI3K-Akt signaling", + "ontology_id": "GO:0038065", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Noguchi et al. 2021 Vet Res Commun", + "id": "10.1007/s11259-023-10117-x", + "type": "DOI", + "notes": "NRG3 silencing decreases p-Akt in glioma cells ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma))" + } + ], + "Genes": ["NRG3","ERBB4"] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_id": "GO:0005886", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Noguchi et al. 2021 Vet Res Commun", + "id": "10.1007/s11259-023-10117-x", + "type": "DOI", + "notes": "ERBB4 is a membrane receptor for NRG3 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma))" + } + ], + "Genes": ["ERBB4"] + }, + { + "name": "extracellular region", + "ontology_id": "GO:0005576", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Noguchi et al. 2021 Vet Res Commun", + "id": "10.1007/s11259-023-10117-x", + "type": "DOI", + "notes": "NRG3 acts as secreted ligand for ERBB4 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma))" + } + ], + "Genes": ["NRG3"] + } + ], + "predicted_cellular_impact": [ + "Increased astrocytoma cell proliferation via AKT/ERK activation", + "Enhanced cell survival signaling", + "Possible promotion of invasive growth" + ], + "evidence_summary": "NRG3/ERBB4 signaling is upregulated in glioma and promotes tumor cell growth. Noguchi et al. showed that NRG3 silencing suppressed glioma cell proliferation and reduced Akt/ERK phosphorylation, while upregulation had the opposite effect ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma)). ERBB4 mRNA is elevated in glioma vs normal brain ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma)).", + "citations": [ + { + "reference": "Noguchi S et al., Vet Res Commun 2023", + "id": "10.1007/s11259-023-10117-x", + "type": "DOI", + "notes": "NRG3/ERBB4 drives glioma growth via Akt/ERK signaling ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33508276/#:~:text=decreased%20by%20transfection%20with%20miR,therapeutic%20target%20in%20canine%20glioma))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": ["NRG3","ERBB4"], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "GABAergic Inhibitory Signaling", + "theme": "Neurotransmitter Signaling", + "description": "Astrocytes express GABA receptors that mediate inhibitory neurotransmission. GABA_B receptor subunits (GABBR2) are found on astrocytes, enabling slow inhibitory signaling that modulates astrocyte function ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS)). GABA_A receptor subunit GABRB1 may similarly shape Ca^2+ responses in astrocytes.", + "atomic_biological_processes": [ + { + "name": "GABAergic synaptic signaling", + "ontology_id": "GO:0098984", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Kulik et al. 2003 Neuroscience", + "id": "10.1016/S0306-4522(01)00296-2", + "type": "DOI", + "notes": "GABA(B) receptor subunits are expressed on astrocytes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS))" + } + ], + "Genes": ["GABBR2"] + }, + { + "name": "synaptic inhibitory signaling", + "ontology_id": "GO:0035173", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Kulik et al. 2003 Neuroscience", + "id": "10.1016/S0306-4522(01)00296-2", + "type": "DOI", + "notes": "Astrocytes respond to GABA via GABA_B receptors ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS))" + } + ], + "Genes": ["GABBR2","GABRB1"] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_id": "GO:0005886", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Kulik et al. 2003 Neuroscience", + "id": "10.1016/S0306-4522(01)00296-2", + "type": "DOI", + "notes": "GABA receptor subunits are localized to astrocyte membranes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS))" + } + ], + "Genes": ["GABBR2","GABRB1"] + }, + { + "name": "synapse", + "ontology_id": "GO:0045202", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Kulik et al. 2003 Neuroscience", + "id": "10.1016/S0306-4522(01)00296-2", + "type": "DOI", + "notes": "Astrocytic GABA receptors modulate synapse function ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS))" + } + ], + "Genes": ["GABBR2"] + } + ], + "predicted_cellular_impact": [ + "Modulation of astrocyte Ca2+ signaling and gliotransmission", + "Influence on neuron-astrocyte inhibitory neurotransmission", + "Potential reduction in excitatory neurotransmitter release" + ], + "evidence_summary": "Astrocytes express metabotropic GABA(B) receptors, enabling them to sense and respond to GABAergic signals. Kulik et al. demonstrated GABA(B2) subunits on astrocytes in vivo ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS)). Activation of astrocytic GABA_B can alter calcium dynamics and astrocyte release of neuromodulators ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9231434/#:~:text=2010%29,AC%3B%20Munk%20et%20al)).", + "citations": [ + { + "reference": "Kulik et al., Neuroscience 2003", + "id": "10.1016/S0306-4522(01)00296-2", + "type": "DOI", + "notes": "GABA_B subunits are present on astrocytes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/14550781/#:~:text=expressed%20in%20astrocytes%20and%20microglia,in%20the%20rat%20CNS))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.6, + "supporting_genes": ["GABBR2","GABRB1"], + "supporting_gene_count": 2, + "required_components_present": false + }, + { + "program_name": "Glutamate Uptake and Metabolism", + "theme": "Metabolic Support", + "description": "Astrocytes uptake extracellular glutamate via high-affinity transporters (GLAST/EAAT1 encoded by SLC1A3) to prevent excitotoxicity. GLUD1 (glutamate dehydrogenase) catalyzes the conversion of glutamate to α-ketoglutarate, linking neurotransmitter clearance to the TCA cycle. SLC1A3 and GLUD1 together maintain glutamate homeostasis in astrocytes.", + "atomic_biological_processes": [ + { + "name": "glutamate transport", + "ontology_id": "GO:0006814", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Campbell et al., Neurochem Int 2019", + "id": "10.1016/j.neuint.2019.104628", + "type": "DOI", + "notes": "Astrocytic glutamate transporters (including SLC1A3) remove extracellular glutamate ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6957761/#:~:text=Two%20astrocytic%20glutamate%20transporters%2C%20Glt,associated%20epilepsy))" + } + ], + "Genes": ["SLC1A3"] + }, + { + "name": "glutamate metabolic process", + "ontology_id": "GO:0006536", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Deng et al., BMC Neurol 2024", + "id": "10.1186/s12883-024-03787-w", + "type": "DOI", + "notes": "GLUD1 identified as key metabolic enzyme linked to IDH-mutant glioma outcome ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=In%20this%20study%2C%20we%20identified,information%20was%20provided%20for%20immunotherapy))" + } + ], + "Genes": ["GLUD1"] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_id": "GO:0005886", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Campbell et al., Neurochem Int 2019", + "id": "10.1016/j.neuint.2019.104628", + "type": "DOI", + "notes": "Excitatory amino acid transporters (SLC1A3) reside in astrocyte membrane ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6957761/#:~:text=Two%20astrocytic%20glutamate%20transporters%2C%20Glt,associated%20epilepsy))" + } + ], + "Genes": ["SLC1A3"] + }, + { + "name": "mitochondrion", + "ontology_id": "GO:0005739", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Deng et al., BMC Neurol 2024", + "id": "10.1186/s12883-024-03787-w", + "type": "DOI", + "notes": "GLUD1 is a mitochondrial enzyme impacting glioma metabolism ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=In%20this%20study%2C%20we%20identified,information%20was%20provided%20for%20immunotherapy))" + } + ], + "Genes": ["GLUD1"] + } + ], + "predicted_cellular_impact": [ + "Efficient clearance of synaptic glutamate to prevent excitotoxicity", + "Production of α-ketoglutarate supporting TCA cycle and energy metabolism", + "Regulation of redox balance and glioma cell survival" + ], + "evidence_summary": "Astrocytic glutamate clearance is mediated by transporters (SLC1A3/EAAT1). Campbell et al. reported that glutamate uptake via GLAST (SLC1A3) is a major astrocyte function ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6957761/#:~:text=Two%20astrocytic%20glutamate%20transporters%2C%20Glt,associated%20epilepsy)). GLUD1, higher in IDH-mutant and lower grade tumors, promotes conversion of glutamate to α-ketoglutarate. Deng et al. found GLUD1 enriched in IDH-mutant gliomas and linked to better prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=In%20this%20study%2C%20we%20identified,information%20was%20provided%20for%20immunotherapy)).", + "citations": [ + { + "reference": "Campbell et al., Neurochem Int 2019", + "id": "10.1016/j.neuint.2019.104628", + "type": "DOI", + "notes": "Astrocyte glutamate transporters SLC1A3 (EAAT1) maintain low extracellular glutamate ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC6957761/#:~:text=Two%20astrocytic%20glutamate%20transporters%2C%20Glt,associated%20epilepsy))" + }, + { + "reference": "Deng et al., BMC Neurol 2024", + "id": "10.1186/s12883-024-03787-w", + "type": "DOI", + "notes": "GLUD1 supports IDH-mutant glioma metabolism and good prognosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC11395857/#:~:text=In%20this%20study%2C%20we%20identified,information%20was%20provided%20for%20immunotherapy))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": ["SLC1A3","GLUD1"], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "Astrocyte Water Homeostasis and Motility", + "theme": "Ion/Water Channels", + "description": "Aquaporin water channels facilitate fluid movement in astrocytes. AQP4 is the predominant astrocytic water channel on endfeet, regulating water diffusion and brain edema. AQP1, although normally low in CNS, is upregulated in astrocytoma and acts as a water channel and scaffold enhancing cell migration and proliferation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=match%20at%20L278%203B%29,assays%20and%20Soft%20agar%20assays)).", + "atomic_biological_processes": [ + { + "name": "transmembrane water transport", + "ontology_id": "GO:0006833", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhang et al. 2017 Oncotarget", + "id": "10.18632/oncotarget.19562", + "type": "DOI", + "notes": "AQP1 and AQP4 mediate water transport and affect cell migration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility))" + } + ], + "Genes": ["AQP4","AQP1"] + }, + { + "name": "cell migration", + "ontology_id": "GO:0016477", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zhang et al. 2017 Oncotarget", + "id": "10.18632/oncotarget.19562", + "type": "DOI", + "notes": "AQP1 overexpression increases astrocytoma cell migration through β-catenin ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility))" + } + ], + "Genes": ["AQP1"] + } + ], + "atomic_cellular_components": [ + { + "name": "cell membrane", + "ontology_id": "GO:0016020", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Zhang et al. 2017 Oncotarget", + "id": "10.18632/oncotarget.19562", + "type": "DOI", + "notes": "Aquaporin channels (AQP1/AQP4) localize to astrocyte membranes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility))" + } + ], + "Genes": ["AQP4","AQP1"] + } + ], + "predicted_cellular_impact": [ + "Enhanced water influx/efflux leading to brain edema dynamics", + "Facilitation of astrocyte and tumor cell migration and invasion", + "Altered ion homeostasis via coupling to ion channels" + ], + "evidence_summary": "AQP4 is the principal water channel on astrocyte endfeet, crucial for water homeostasis in brain. Zhang et al. showed that AQP1 (normally vascular) is upregulated in astrocytoma and enhances proliferation and migration when overexpressed ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=match%20at%20L278%203B%29,assays%20and%20Soft%20agar%20assays)). AQP1 interacts with β-catenin to reorganize the cytoskeleton and promote motility ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility)).", + "citations": [ + { + "reference": "Zhang et al., Oncotarget 2017", + "id": "10.18632/oncotarget.19562", + "type": "DOI", + "notes": "Identified AQP1 as a promoter of astrocytoma cell migration and proliferation via β-catenin ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=Recently%2C%20%CE%B2,up%2C%20adhesion%20and%20motility)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5725103/#:~:text=match%20at%20L278%203B%29,assays%20and%20Soft%20agar%20assays))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": ["AQP4","AQP1"], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "Extracellular Matrix and Adhesion Remodeling", + "theme": "Cell-Cell/Cell-Matrix Interactions", + "description": "Astrocyte-derived extracellular matrix proteins and adhesion molecules influence synapse formation and cell structure. SPARCL1 (Hevin) secreted by astrocytes promotes excitatory synaptogenesis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in)). Other proteins (SPON1, ADGRV1, LAMA1, integrins, collagens, protocadherins like CHL1 and PCDH9) are involved in cell adhesion and guidance, affecting astrocyte morphology and interactions with neurons/ECM.", + "atomic_biological_processes": [ + { + "name": "extracellular matrix organization", + "ontology_id": "GO:0030198", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jones and Bouvier 2014 Neural Plast", + "id": "10.1155/2014/321209", + "type": "DOI", + "notes": "Astrocyte-secreted SPARCL1 and SPARC modulate ECM and synaptogenesis ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in))" + } + ], + "Genes": ["SPARCL1"] + }, + { + "name": "cell adhesion", + "ontology_id": "GO:0007155", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Jones and Bouvier 2014 Neural Plast", + "id": "10.1155/2014/321209", + "type": "DOI", + "notes": "Astrocyte matricellular proteins like SPARCL1 regulate synapse adhesion ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in))" + } + ], + "Genes": ["SPARCL1","SPON1","ADGRV1"] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular matrix", + "ontology_id": "GO:0031012", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jones and Bouvier 2014 Neural Plast", + "id": "10.1155/2014/321209", + "type": "DOI", + "notes": "SPARCL1/SPARC are secreted into the matrix by astrocytes ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in))" + } + ], + "Genes": ["SPARCL1","SPON1"] + }, + { + "name": "synapse", + "ontology_id": "GO:0045202", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Jones and Bouvier 2014 Neural Plast", + "id": "10.1155/2014/321209", + "type": "DOI", + "notes": "SPARCL1 promotes formation of excitatory synapses ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in))" + } + ], + "Genes": ["SPARCL1"] + } + ], + "predicted_cellular_impact": [ + "Promotion of excitatory synapse formation and neural connectivity", + "Altered astrocyte adhesion and migration within tumor microenvironment", + "Modulation of cell shape and interactions via ECM reorganization" + ], + "evidence_summary": "Astrocytic matricellular proteins like SPARCL1 (Hevin) regulate synaptogenesis. Jones & Bouvier reviewed that astrocyte-secreted SPARCL1 directly promotes excitatory synapse formation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in)). Astrocyte adhesion molecules (integrins, protocadherins) and ECM components (laminins, collagens) further shape astrocyte morphology and interactions. For example, SPARCL1 and SPARC have opposing roles in synapse stabilization.", + "citations": [ + { + "reference": "Jones & Bouvier, Neural Plast 2014", + "id": "10.1155/2014/321209", + "type": "DOI", + "notes": "Astrocyte-secreted SPARCL1 and SPARC control excitatory synapse formation ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/26500475/#:~:text=The%20matricellular%20proteins%2C%20secreted%20protein,maintain%20existing%20excitatory%20synapses%20in))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.7, + "supporting_genes": ["SPARCL1","SPON1","LAMA1","COL4A5","COL5A3","ITGA6","CD44","CNTN1","CHL1","PCDH9","ADGRV1","PAPLN"], + "supporting_gene_count": 12, + "required_components_present": false + }, + { + "program_name": "Cholesterol Efflux and Immune Regulation", + "theme": "Lipid Metabolism / Immune Crosstalk", + "description": "IDH-mutant glioma cells upregulate cholesterol export pathways. APOE (lipoprotein E) is secreted by astrocytes and mediates cholesterol efflux, activating immune surveillance. Recent work shows that IDH-mutant gliomas upregulate ABCA1 and APOE to excrete cholesterol, leading to pro-inflammatory (M1-like) microenvironment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10369258/#:~:text=IDH%E2%80%90mutant%20gliomas%20secrete%20excess%20cholesterol%2C,is%20introduced%2C%20which%20markedly%20stimulates)). ApoE deficiency increases glioma cell invasion and impairs immune responses ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12261038/#:~:text=subcutaneous%20tumorigenic%20mouse%20model%20with,potential%20as%20a%20therapeutic%20target)).", + "atomic_biological_processes": [ + { + "name": "cholesterol transport", + "ontology_id": "GO:0030301", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Wang et al., Adv Sci 2023", + "id": "10.1002/advs.202205949", + "type": "DOI", + "notes": "IDH-mutant gliomas upregulate APOE-mediated cholesterol efflux ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10369258/#:~:text=IDH%E2%80%90mutant%20gliomas%20secrete%20excess%20cholesterol%2C,is%20introduced%2C%20which%20markedly%20stimulates))" + } + ], + "Genes": ["APOE"] + }, + { + "name": "immune response", + "ontology_id": "GO:0006955", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Liu et al., J Cell Mol Med 2025", + "id": "10.1111/jcmm.70697", + "type": "DOI", + "notes": "ApoE deficiency accelerates glioma growth by reducing immune surveillance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12261038/#:~:text=subcutaneous%20tumorigenic%20mouse%20model%20with,potential%20as%20a%20therapeutic%20target))" + } + ], + "Genes": ["APOE"] + } + ], + "atomic_cellular_components": [ + { + "name": "lipoprotein particle", + "ontology_id": "GO:0034358", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Wang et al., Adv Sci 2023", + "id": "10.1002/advs.202205949", + "type": "DOI", + "notes": "APOE participates in lipoprotein-mediated cholesterol export ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10369258/#:~:text=IDH%E2%80%90mutant%20gliomas%20secrete%20excess%20cholesterol%2C,is%20introduced%2C%20which%20markedly%20stimulates))" + } + ], + "Genes": ["APOE"] + } + ], + "predicted_cellular_impact": [ + "Enhanced cholesterol efflux from astrocytoma cells altering membrane composition", + "Promotion of anti-tumor immune microenvironment (M1-like GAM polarization)", + "Potential limitation of tumor invasion via lipid regulation" + ], + "evidence_summary": "IDH-mutant gliomas activate PERK/miR-19a pathways to increase cholesterol export via ABCA1 and APOE ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10369258/#:~:text=IDH%E2%80%90mutant%20gliomas%20secrete%20excess%20cholesterol%2C,is%20introduced%2C%20which%20markedly%20stimulates)). This leads to a pro-inflammatory microglial state that suppresses tumor growth. Liu et al. showed that loss of ApoE accelerates glioma progression and impairs T-cell surveillance ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12261038/#:~:text=subcutaneous%20tumorigenic%20mouse%20model%20with,potential%20as%20a%20therapeutic%20target)), highlighting ApoE's role in limiting tumor invasion.", + "citations": [ + { + "reference": "Wang et al., Adv Sci 2023", + "id": "10.1002/advs.202205949", + "type": "DOI", + "notes": "IDH-mutant gliomas secrete cholesterol via ABCA1/APOE, polarizing microglia (M1) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC10369258/#:~:text=IDH%E2%80%90mutant%20gliomas%20secrete%20excess%20cholesterol%2C,is%20introduced%2C%20which%20markedly%20stimulates))" + }, + { + "reference": "Liu et al., J Cell Mol Med 2025", + "id": "10.1111/jcmm.70697", + "type": "DOI", + "notes": "ApoE knockout accelerates glioma growth and reduces immune cell infiltration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC12261038/#:~:text=subcutaneous%20tumorigenic%20mouse%20model%20with,potential%20as%20a%20therapeutic%20target))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.9, + "supporting_genes": ["APOE","LPL"], + "supporting_gene_count": 2, + "required_components_present": false + }, + { + "program_name": "TLR4-Mediated Inflammatory Signaling", + "theme": "Innate Immune Response", + "description": "TLR4 (Toll-like receptor 4) on astrocytes mediates innate immune sensing. Activation by inflammatory stimuli (e.g. LPS) triggers NF-κB and other pathways, leading to reactive astrocyte changes. Shen et al. (as discussed by Henneberger) showed that astrocytic TLR4 activation increases excitatory synapse formation and seizure susceptibility ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5147008/#:~:text=Astrocytes%20have%20been%20implicated%20in,in%20young%20and%20adult%20mice)). In IDH-mutant context, TLR4 could modulate tumor-associated inflammation and glial response.", + "atomic_biological_processes": [ + { + "name": "innate immune response", + "ontology_id": "GO:0045087", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Henneberger & Steinhäuser, J Cell Biol 2016", + "id": "10.1083/jcb.201611078", + "type": "DOI", + "notes": "Astrocytic TLR4 activation by inflammation increases synaptogenesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5147008/#:~:text=Astrocytes%20have%20been%20implicated%20in,in%20young%20and%20adult%20mice))" + } + ], + "Genes": ["TLR4"] + } + ], + "atomic_cellular_components": [ + { + "name": "plasma membrane", + "ontology_id": "GO:0005886", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Henneberger & Steinhäuser, J Cell Biol 2016", + "id": "10.1083/jcb.201611078", + "type": "DOI", + "notes": "TLR4 is a cell-surface receptor on astrocytes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5147008/#:~:text=Astrocytes%20have%20been%20implicated%20in,in%20young%20and%20adult%20mice))" + } + ], + "Genes": ["TLR4"] + } + ], + "predicted_cellular_impact": [ + "Promotion of pro-inflammatory astrocyte activation", + "Increase in excitatory synapse formation and neuronal excitability", + "Contribution to astrogliosis and seizure susceptibility" + ], + "evidence_summary": "Astrocytic TLR4 senses inflammatory cues and modulates synaptic connectivity. Shen et al. (commented by Henneberger) demonstrated that postnatal activation of astrocyte TLR4 increases excitatory synaptogenesis, raising seizure risk ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5147008/#:~:text=Astrocytes%20have%20been%20implicated%20in,in%20young%20and%20adult%20mice)). In the tumor environment, TLR4 may similarly shape astrocyte reactivity and neuro-immune interactions.", + "citations": [ + { + "reference": "Henneberger & Steinhäuser, J Cell Biol 2016", + "id": "10.1083/jcb.201611078", + "type": "DOI", + "notes": "Astrocyte TLR4 activation by inflammatory stimulus promotes excitatory synapse growth ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC5147008/#:~:text=Astrocytes%20have%20been%20implicated%20in,in%20young%20and%20adult%20mice))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.6, + "supporting_genes": ["TLR4"], + "supporting_gene_count": 1, + "required_components_present": false + }, + { + "program_name": "Fatty Acid Desaturation and Neurosupport", + "theme": "Lipid Metabolism", + "description": "Astrocytes express FADS2 (fatty acid desaturase-2) to produce long-chain polyunsaturated fatty acids (LCPUFAs) which support neuronal function. FADS2 catalyzes Δ6-desaturation for DHA synthesis. Astrocyte membrane DHA supplementation downregulates FADS2 but enhances neuron survival ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7241842/#:~:text=and%20metabolic%20support%20for%20neurons%2C,and%20are%20associated%20with%20cognitive)), illustrating a metabolic support role.", + "atomic_biological_processes": [ + { + "name": "long-chain polyunsaturated fatty acid biosynthetic process", + "ontology_id": "GO:0046445", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zgorzynska et al. 2019 Int J Mol Cell Med", + "id": "10.22088/IJMCM.BUMS.8.3.232", + "type": "DOI", + "notes": "Astrocytes utilize FADS2 to synthesize DHA supporting neurons ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7241842/#:~:text=and%20metabolic%20support%20for%20neurons%2C,and%20are%20associated%20with%20cognitive))" + } + ], + "Genes": ["FADS2"] + } + ], + "atomic_cellular_components": [ + { + "name": "endoplasmic reticulum", + "ontology_id": "GO:0005783", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Zgorzynska et al. 2019 Int J Mol Cell Med", + "id": "10.22088/IJMCM.BUMS.8.3.232", + "type": "DOI", + "notes": "FADS2 is an ER-associated enzyme in astrocytes ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7241842/#:~:text=and%20metabolic%20support%20for%20neurons%2C,and%20are%20associated%20with%20cognitive))" + } + ], + "Genes": ["FADS2"] + } + ], + "predicted_cellular_impact": [ + "Enhanced synthesis of neuroprotective omega-3 fatty acids (e.g., DHA)", + "Improved support of neuronal health and membrane fluidity", + "Adaptive regulation of astrocyte metabolism under oxidative stress" + ], + "evidence_summary": "Astrocytes express FADS2 (Δ6-desaturase) and are capable of synthesizing LCPUFAs for neurons ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7241842/#:~:text=and%20metabolic%20support%20for%20neurons%2C,and%20are%20associated%20with%20cognitive)). Bewicz-Binkowska et al. found that DHA-enriched astrocytes boost neuronal survival, while DHA feedback inhibits FADS2 transcription ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7241842/#:~:text=and%20metabolic%20support%20for%20neurons%2C,and%20are%20associated%20with%20cognitive)). This underscores a role for FADS2 in astrocyte-neuron metabolic coupling.", + "citations": [ + { + "reference": "Zgorzynska et al., Int J Mol Cell Med 2019", + "id": "10.22088/IJMCM.BUMS.8.3.232", + "type": "DOI", + "notes": "Astrocytes use FADS2 (Δ6-desaturase) for LCPUFA synthesis to support neurons ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC7241842/#:~:text=and%20metabolic%20support%20for%20neurons%2C,and%20are%20associated%20with%20cognitive))" + } + ], + "confidence_score": 0.7, + "significance_score": 0.5, + "supporting_genes": ["FADS2"], + "supporting_gene_count": 1, + "required_components_present": true + } + ], + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509252229_summary.tsv b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509252229_summary.tsv new file mode 100644 index 0000000..f50ae9a --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/results/Astrocytoma1_results_2509252229_summary.tsv @@ -0,0 +1,9 @@ + name genes citations +0 Neuregulin/ErbB Growth Signaling 2 1 +1 GABAergic Inhibitory Signaling 2 1 +2 Glutamate Uptake and Metabolism 2 2 +3 Astrocyte Water Homeostasis and Motility 2 1 +4 Extracellular Matrix and Adhesion Remodeling 12 1 +5 Cholesterol Efflux and Immune Regulation 2 2 +6 TLR4-Mediated Inflammatory Signaling 1 1 +7 Fatty Acid Desaturation and Neurosupport 1 1 diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/results/neutrophil_results.json b/cellsem_agent/services/gene_list_contextual_deepsearch/results/neutrophil_results.json new file mode 100644 index 0000000..699d1b0 --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/results/neutrophil_results.json @@ -0,0 +1,532 @@ +{ + "context": { + "cell_type": "Neutrophil", + "disease": "Inflammatory condition", + "tissue": "unspecified" + }, + "input_genes": [ + "CXCL8", + "CXCR2", + "CXCL6", + "CTSG", + "S100A9", + "S100A8", + "CXCR1", + "JAML", + "FCER1G", + "ITGB2", + "CSF3R", + "IL1B", + "TREM1", + "ANXA3", + "PECAM1", + "CD177", + "PRTN3" + ], + "programs": [ + { + "program_name": "Chemokine-Mediated Neutrophil Recruitment", + "theme": "Chemotaxis/Inflammation", + "description": "This program centers on CXCL8/IL-8 and CXCL6 chemokine production by neutrophils or surrounding stroma, engaging CXCR1 and CXCR2 on the same or adjacent neutrophils. The resulting autocrine/paracrine loop drives directed neutrophil migration into tissues. High local IL-8/CXCL6 induces chemotaxis and, at higher concentrations, neutrophil activation (including NET release) ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2577773/#:~:text=CXCL6%20is%20a%20potent%20pro,AF%29%20and%20if%20CXCL6)). The net effect is amplified recruitment and accumulation of neutrophils in inflamed tissue.", + "atomic_biological_processes": [ + { + "name": "neutrophil chemotaxis", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Planagum\u00e0 A et al. Differential IL-8 thresholds... J Leukoc Biol (2021)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "IL-8 (CXCL8) is a key chemokine driving neutrophil chemotaxis via CXCR1/2 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as))" + } + ], + "Genes": [ + "CXCL8", + "CXCL6" + ] + }, + { + "name": "chemokine receptor signaling", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Planagum\u00e0 A et al. Differential IL-8 thresholds... J Leukoc Biol (2021)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "IL-8 signals through CXCR1/CXCR2 to induce directional migration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as))" + } + ], + "Genes": [ + "CXCR1", + "CXCR2" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "extracellular chemokine milieu", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Simard JC et al. PLoS One (2013)", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "Chemokines like CXCL8 are secreted DAMPs mediating inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + } + ], + "Genes": [ + "CXCL8", + "CXCL6" + ] + }, + { + "name": "neutrophil plasma membrane (chemokine receptors)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Planagum\u00e0 A et al. Differential IL-8 thresholds... J Leukoc Biol (2021)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "CXCR1/CXCR2 are cell surface GPCRs for IL-8 on neutrophils ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as))" + } + ], + "Genes": [ + "CXCR1", + "CXCR2" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced neutrophil chemotaxis toward inflammatory signals", + "Autocrine amplification of neutrophil activation", + "Greater recruitment and accumulation of neutrophils" + ], + "evidence_summary": "CXCL8/IL-8 and CXCL6 are potent neutrophil chemoattractants. Planagum\u00e0 et al. confirmed that human IL-8 engages CXCR1/CXCR2 to drive PMN chemotaxis and NET release ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as)). CXCL6 is similarly a strong neutrophil chemoattractant ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2577773/#:~:text=CXCL6%20is%20a%20potent%20pro,AF%29%20and%20if%20CXCL6)). These ligands and receptors together create a feed-forward loop of neutrophil recruitment and activation in inflamed tissues.", + "citations": [ + { + "reference": "Planagum\u00e0 A et al. Differential IL-8 thresholds for chemotaxis and netosis in human neutrophils.", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "IL-8 (CXCL8) is a key chemokine driving neutrophil migration through CXCR1/CXCR2 ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/33963542/#:~:text=In%20humans%2C%20IL,NETosis%20than%20for%20chemotaxis%20as))" + }, + { + "reference": "Simard JC et al. S100A8/A9 induce IL-8 secretion via NF-\u03baB in phagocytes (PLOS One, 2013).", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "Demonstrates IL-8 (CXCL8) is produced as part of an innate inflammatory loop ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + }, + { + "reference": "Espinoza J et al. CXCL6 is a potent neutrophil chemoattractant (Am J Reprod Immunol, 2008).", + "id": "10.1111/j.1600-0897.2008.00637.x", + "type": "DOI", + "notes": "CXCL6 described as a strong neutrophil chemoattractant and activator ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2577773/#:~:text=CXCL6%20is%20a%20potent%20pro,AF%29%20and%20if%20CXCL6))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "CXCL8", + "CXCL6", + "CXCR1", + "CXCR2" + ], + "supporting_gene_count": 4, + "required_components_present": true + }, + { + "program_name": "Calprotectin-Driven Inflammatory Amplification", + "theme": "DAMP signaling/Inflammation", + "description": "S100A8 and S100A9 (calprotectin) are abundant cytosolic proteins that are released as alarmins by activated neutrophils (especially with NETosis). Extracellular S100A8/A9 engages TLR4/RAGE, triggering NF-\u03baB activation and secretion of cytokines (e.g. IL-1\u03b2, IL-8) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=biomarker%20for%20several%20inflammatory%20diseases,upon%20the%20formation%20of%20neutrophil)). They further upregulate neutrophil adhesion molecules (CD11b/ITGB2) and enhance ROS production ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=%28PMA%29,DAMP%20might%20amplify%20neutrophil%20activation)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=examined%20the%20effects%20of%20S100A8,by%20ATP%2C%20a%20known%20inflammasome)). This creates a positive feedback loop amplifying neutrophil-driven inflammation.", + "atomic_biological_processes": [ + { + "name": "NF-\u03baB pathway activation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Simard JC et al. PLoS One (2013)", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "S100A8/A9 activate NF-\u03baB, inducing expression of IL-8 and IL-1\u03b2 ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ] + }, + { + "name": "proinflammatory cytokine secretion (e.g. IL-1\u03b2)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Simard JC et al. PLoS One (2013)", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "S100A8/A9 induce secretion of IL-1\u03b2 and IL-8 via NF-\u03baB ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ] + }, + { + "name": "neutrophil activation and adhesion (integrin upregulation)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Sprenkeler EG et al. Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "Extracellular S100A8/A9 induces neutrophil adhesion and upregulation of CD11b (ITGB2) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=%28PMA%29,DAMP%20might%20amplify%20neutrophil%20activation))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ] + }, + { + "name": "neutrophil extracellular trap (NET) formation", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Sprenkeler EG et al. Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "S100A8/A9 are released during NETosis and can propagate NET formation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=biomarker%20for%20several%20inflammatory%20diseases,upon%20the%20formation%20of%20neutrophil))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "neutrophil cytosol", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Sprenkeler EG et al. Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "S100A8/A9 are highly abundant in the neutrophil cytosol (not in granules) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=biomarker%20for%20several%20inflammatory%20diseases,upon%20the%20formation%20of%20neutrophil))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ] + }, + { + "name": "extracellular space (almighty DAMP release)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Sprenkeler EG et al. Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "S100A8/A9 are released extracellularly (via NETs) and act as DAMPs ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=biomarker%20for%20several%20inflammatory%20diseases,upon%20the%20formation%20of%20neutrophil))" + } + ], + "Genes": [ + "S100A8", + "S100A9" + ] + } + ], + "predicted_cellular_impact": [ + "Enhanced inflammatory signaling via NF-\u03baB", + "Increased IL-1\u03b2 and IL-8 production", + "Upregulated neutrophil adhesion (CD11b/ITGB2 expression)", + "Positive feedback on neutrophil activation" + ], + "evidence_summary": "S100A8/A9 (calprotectin) are released by activated neutrophils and bind TLR4/RAGE, leading to NF-\u03baB-dependent expression of proinflammatory cytokines (IL-1\u03b2, IL-8) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using)). Sprenkeler et al. demonstrated that purified S100A8/A9 promote neutrophil activation including CD11b upregulation and adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=%28PMA%29,DAMP%20might%20amplify%20neutrophil%20activation)). These DAMPs therefore amplify neutrophil-driven inflammation and recruitment.", + "citations": [ + { + "reference": "Simard JC et al., PLoS One (2013)", + "id": "10.1371/journal.pone.0072138", + "type": "DOI", + "notes": "Shows S100A8/A9 induce IL-1\u03b2 and IL-8 via NF-\u03baB signaling ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC3747084/#:~:text=S100A8%20and%20S100A9%20are%20cytoplasmic,%CE%BAB.%20Inhibition%20studies%20using))" + }, + { + "reference": "Sprenkeler EG et al., Cells (2022)", + "id": "10.3390/cells11020236", + "type": "DOI", + "notes": "Reports that S100A8/A9 trigger neutrophil activation and CD11b (ITGB2) upregulation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC8773660/#:~:text=%28PMA%29,DAMP%20might%20amplify%20neutrophil%20activation))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.8, + "supporting_genes": [ + "S100A8", + "S100A9" + ], + "supporting_gene_count": 2, + "required_components_present": true + }, + { + "program_name": "Neutrophil Adhesion and Transmigration", + "theme": "Adhesion/Migration", + "description": "JAML on neutrophils binds epithelial CAR at tight junctions, enabling transepithelial migration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies)). Similarly, \u03b22-integrins (CD11/CD18; ITGB2) mediate firm adhesion to endothelial ICAMs, and PECAM1 on endothelial junctions facilitates diapedesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate)). Together these molecules drive neutrophil extravasation into tissues. High expression of these adhesion genes suggests this cell cluster is primed for tissue infiltration and barrier traversal.", + "atomic_biological_processes": [ + { + "name": "neutrophil transepithelial migration", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Zen K et al., Mol Biol Cell (2005)", + "id": "10.1091/mbc.e05-01-0036", + "type": "DOI", + "notes": "JAML binding to epithelial CAR is required for neutrophil migration across tight junctions ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies))" + } + ], + "Genes": [ + "JAML" + ] + }, + { + "name": "neutrophil transendothelial migration", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Woodfin A et al., Blood (2007)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "PECAM1 is a key endothelial junction molecule that mediates neutrophil transmigration into inflamed tissue ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate))" + } + ], + "Genes": [ + "ITGB2", + "PECAM1" + ] + }, + { + "name": "leukocyte adhesion to endothelium", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Pulikkottil S et al., Cells (2022)", + "id": "10.3390/cells11132025", + "type": "DOI", + "notes": "\u03b22 integrins (ITGB2) are critical for neutrophil adhesion and recruitment to sites of inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin))" + } + ], + "Genes": [ + "ITGB2" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "epithelial tight junction (subepithelial)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Zen K et al., Mol Biol Cell (2005)", + "id": "10.1091/mbc.e05-01-0036", + "type": "DOI", + "notes": "JAML on neutrophils binds CAR on epithelial tight junctions during transmigration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies))" + } + ], + "Genes": [ + "JAML" + ] + }, + { + "name": "endothelial cell junction", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Woodfin A et al., Blood (2007)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "PECAM1 at endothelial junctions facilitates neutrophil diapedesis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate))" + } + ], + "Genes": [ + "PECAM1" + ] + }, + { + "name": "neutrophil plasma membrane (adhesion complex)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Pulikkottil S et al., Cells (2022)", + "id": "10.3390/cells11132025", + "type": "DOI", + "notes": "\u03b22 integrins (containing ITGB2) localize to the neutrophil plasma membrane and mediate firm adhesion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin))" + } + ], + "Genes": [ + "ITGB2" + ] + } + ], + "predicted_cellular_impact": [ + "Increased adhesion to endothelium and epithelium", + "Efficient transendothelial and transepithelial migration", + "Enhanced tissue infiltration and recruitment to inflamed sites" + ], + "evidence_summary": "Neutrophil JAML has been shown to bind CAR on epithelial tight junctions, promoting transepithelial migration ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies)). \u03b22-integrins (e.g. LFA-1/Mac-1) mediate firm adhesion to endothelium, while PECAM1 at endothelial junctions is required for transmigration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate)) ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin)). Pulikkottil et al. review highlights integrins (including ITGB2) as essential for neutrophil recruitment ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin)). These molecules together enable neutrophils to exit vessels and enter tissues.", + "citations": [ + { + "reference": "Zen K et al. Mol Biol Cell (2005)", + "id": "10.1091/mbc.e05-01-0036", + "type": "DOI", + "notes": "Establishes that neutrophil JAML binding to epithelial CAR mediates migration across tight junctions ([pubmed.ncbi.nlm.nih.gov](https://pubmed.ncbi.nlm.nih.gov/15800062/#:~:text=distal%20immunoglobulin%20,inflammatory%20therapies))" + }, + { + "reference": "Woodfin A et al. Blood (2007)", + "id": "10.1182/blood-2006-09-047431", + "type": "DOI", + "notes": "Shows PECAM1 at endothelial junctions is critical for neutrophil transmigration ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2699241/#:~:text=Leukocyte%20transmigration%20is%20mediated%20by,%CE%B1%5D%29%2C%20and%20demonstrate))" + }, + { + "reference": "Pulikkottil S et al. Cells (2022)", + "id": "10.3390/cells11132025", + "type": "DOI", + "notes": "Review confirming \u03b22-integrins (ITGB2) are crucial for neutrophil adhesion and migration during inflammation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC9266208/#:~:text=Neutrophils%20are%20the%20most%20abundant,Many%20regulators%2C%20such%20as%20talin))" + } + ], + "confidence_score": 0.9, + "significance_score": 0.9, + "supporting_genes": [ + "JAML", + "ITGB2", + "PECAM1" + ], + "supporting_gene_count": 3, + "required_components_present": true + }, + { + "program_name": "Granule-Mediated Antimicrobial Activity", + "theme": "Defense/Proteolysis", + "description": "This program reflects neutrophil azurophilic granule exocytosis. PRTN3 (proteinase 3) and CTSG (cathepsin G) are serine proteases stored in neutrophil azurophilic granules ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the)). Upon activation, these enzymes are released to kill pathogens and degrade extracellular matrix. Annexin A3 (ANXA3) is associated with specific granules and regulates granule\u2013membrane fusion during exocytosis ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of)). Together, these components drive potent proteolytic and microbicidal responses (and can generate autoantigens on the neutrophil surface).", + "atomic_biological_processes": [ + { + "name": "neutrophil degranulation (azurophil granule exocytosis)", + "ontology_label": "biological_process", + "citation": [ + { + "reference": "Le Cabec V et al., Biochem J (1994)", + "id": "10.1042/bj3030481", + "type": "DOI", + "notes": "Annexin A3 is localized to neutrophil granules and may mediate granule fusion with the membrane ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of))" + } + ], + "Genes": [ + "ANXA3", + "PRTN3", + "CTSG" + ] + }, + { + "name": "serine-type endopeptidase (proteolytic) activity", + "ontology_label": "molecular_function", + "citation": [ + { + "reference": "Pepper RJ et al., Am J Pathol (2015)", + "id": "10.1016/j.ajpath.2015.01.015", + "type": "DOI", + "notes": "Describes proteinase 3 (PRTN3) as a neutrophil azurophilic granule protease with microbicidal activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the))" + } + ], + "Genes": [ + "PRTN3", + "CTSG" + ] + } + ], + "atomic_cellular_components": [ + { + "name": "neutrophil azurophilic granule lumen", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Pepper RJ et al., Am J Pathol (2015)", + "id": "10.1016/j.ajpath.2015.01.015", + "type": "DOI", + "notes": "PRTN3 (proteinase 3) is stored in neutrophil azurophil granules ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the))" + } + ], + "Genes": [ + "PRTN3", + "CTSG" + ] + }, + { + "name": "neutrophil plasma membrane (granule fusion site)", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Le Cabec V et al., Biochem J (1994)", + "id": "10.1042/bj3030481", + "type": "DOI", + "notes": "Annexin A3 translocates from granules to the plasma membrane upon activation, implicating it in granule fusion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of))" + } + ], + "Genes": [ + "ANXA3" + ] + }, + { + "name": "extracellular space", + "ontology_label": "cellular_component", + "citation": [ + { + "reference": "Pepper RJ et al., Am J Pathol (2015)", + "id": "10.1016/j.ajpath.2015.01.015", + "type": "DOI", + "notes": "Azurophil proteases like PRTN3 and CTSG are released extracellularly to enact microbicidal effects ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the))" + } + ], + "Genes": [ + "PRTN3", + "CTSG" + ] + } + ], + "predicted_cellular_impact": [ + "Potent antimicrobial killing via protease release", + "Extracellular matrix degradation and tissue remodeling", + "Generation of inflammatory mediators/autoantigens (e.g. membrane PR3)" + ], + "evidence_summary": "PRTN3 and CTSG are major azurophilic granule proteases in neutrophils ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the)). They mediate pathogen killing and contribute to extracellular matrix degradation. Le Cabec et al. showed Annexin A3 localizes to neutrophil granules and translocates to the plasma membrane during activation, suggesting it facilitates granule fusion ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of)). Together these proteins drive degranulation and proteolytic antimicrobial activity.", + "citations": [ + { + "reference": "Pepper RJ et al., Am J Pathol (2015)", + "id": "10.1016/j.ajpath.2015.01.015", + "type": "DOI", + "notes": "Confirms that proteinase 3 is a neutrophil azurophil granule protease with microbicidal activity ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC2940153/#:~:text=also%20found%20in%20the%20circulation,4%5D%20and%20on%20the))" + }, + { + "reference": "Le Cabec V et al., Biochem J (1994)", + "id": "10.1042/bj3030481", + "type": "DOI", + "notes": "Shows Annexin A3 is granule-associated in neutrophils and moves to membrane upon activation, implying a role in degranulation ([pmc.ncbi.nlm.nih.gov](https://pmc.ncbi.nlm.nih.gov/articles/PMC1137353/#:~:text=Both%20proteins%20were%20associated%20with,In%20conclusion%2C%20association%20of))" + } + ], + "confidence_score": 0.8, + "significance_score": 0.8, + "supporting_genes": [ + "CTSG", + "PRTN3", + "ANXA3" + ], + "supporting_gene_count": 3, + "required_components_present": true + } + ], + "method": { + "clustering_basis": [ + "known pathway interactions", + "literature co-citation" + ], + "notes": "Gene programs identified by grouping input genes with related functions (e.g. chemotaxis, adhesion, degranulation) based on literature and pathway context" + }, + "version": "1.0" +} \ No newline at end of file diff --git a/cellsem_agent/services/gene_list_contextual_deepsearch/schema/deepsearch_results_schema.json b/cellsem_agent/services/gene_list_contextual_deepsearch/schema/deepsearch_results_schema.json new file mode 100644 index 0000000..6e3da0a --- /dev/null +++ b/cellsem_agent/services/gene_list_contextual_deepsearch/schema/deepsearch_results_schema.json @@ -0,0 +1,174 @@ +{ + "$schema": "http://json-schema.org/draft-07/schema#", + "title": "Gene Program Functional Analysis", + "description": "Comprehensive literature-based functional analysis of gene lists in specific biological contexts. Perform systematic analysis to identify gene programs - clusters of genes acting together in pathways, processes, or cellular states. For each program, predict functional implications for the specified cell type in the context of the provided disease and tissue environment. Prioritize well-established functions with strong literature support, but highlight emerging evidence if contextually relevant. Rank predictions higher when multiple genes from input list act in same process and when most/all required pathway components are present.", + "type": "object", + "required": ["context", "input_genes", "programs", "version"], + "definitions": { + "atomic_term": { + "type": "object", + "required": ["name", "citation"], + "properties": { + "ontology_id": { + "type": "string", + "description": "ontology term CURIE e.g., GO:0005576, GO:0008150, GO:0003674." + }, + "name": { + "type": "string", + "description": "atomic term to be mapped" + }, + "ontology_label": { + "type": "string", + "description": "ontology label e.g., cellular_component, biological_process, molecular_function" + }, + "citation": { + "type":"array", + "items": { + "$ref": "#/definitions/citation" + }, + "description": "Citations supporting " + }, + "Genes": { + "type": "array", + "items": { + "type": "string" + }, + "description": "Genes of the program whose products are involved in this process or compoent." + } + }, + "additionalProperties": false + }, + "citation": { + "type": "object", + "required": ["reference"], + "properties": { + "reference": { + "type": "string", + "description": "Free-text reference (e.g., authors, title, journal, year)" + }, + "id": { + "type": "string", + "description": "Optional PMID, DOI, or URL" + }, + "type": { + "type": "string", + "enum": ["PMID", "DOI", "URL"] + }, + "notes": { + "type": "string", + "description": "Why this citation supports the claim" + } + }, + "additionalProperties": false + } + }, + "properties": { + "context": { + "type": "object", + "required": ["cell_type", "disease"], + "properties": { + "cell_type": { + "type": "string", + "description": "Extract and specify the primary cell type from the provided biological context (e.g., 'astrocytes', 'neurons', 'microglia'). Use standard cell type terminology. Leave blank if not specified." + }, + "disease": { + "type": "string", + "description": "Extract and specify the disease or pathological condition from the provided biological context (e.g., 'IDH-mutant astrocytoma', 'Alzheimer disease', 'multiple sclerosis'). Use standard disease terminology. Leave blank if not specified." + }, + "tissue": { + "type": "string", + "description": "Extract and specify the tissue or anatomical location if mentioned in the biological context (e.g., 'brain', 'cerebral cortex', 'hippocampus'). Leave blank if not specified." + } + }, + "additionalProperties": false + }, + "input_genes": { + "type": "array", + "items": { "type": "string", "minLength": 1 }, + "minItems": 1, + "uniqueItems": true + }, + "programs": { + "type": "array", + "minItems": 1, + "items": { + "type": "object", + "required": [ + "program_name", + "description", + "predicted_cellular_impact", + "evidence_summary", + "citations", + "confidence_score", + "significance_score", + "supporting_genes", + "supporting_gene_count" + ], + "properties": { + "program_name": { + "type": "string", + "minLength": 1, + "description": "Provide a concise, descriptive name for this gene program that captures its primary biological function or pathway (e.g., 'Astrocyte Water Homeostasis', 'Synaptic Vesicle Recycling', 'ECM Remodeling'). Use 2-5 words maximum. Avoid programs that group 2 loosely related processes with 'and'." + }, + "theme": { "type": "string", "description": "Optional higher-order theme" }, + "description": { "type": "string", "minLength": 1 }, + "atomic_biological_processes": { + "type": "array", + "description": "A list of atomic biological process terms extracted from the description.", + "items": { "$ref": "#/definitions/atomic_term" } + }, + "atomic_cellular_components": { + "type": "array", + "description": "A list of atomic cellular component terms extracted from the description.", + "items": { "$ref": "#/definitions/atomic_term" } + }, + "predicted_cellular_impact": { + "type": "array", + "minItems": 1, + "items": { + "type": "string", + "description": "Concise bullet-level impacts (e.g., ‘enhanced focal adhesion signaling’)" + } + }, + "evidence_summary": { "type": "string", "minLength": 1 }, + "citations": { + "type": "array", + "minItems": 1, + "items": { + "$ref": "#/definitions/citation" + } + }, + "confidence_score": { "type": "number", "minimum": 0.0, "maximum": 1.0 }, + "significance_score": { "type": "number", "minimum": 0.0, "maximum": 1.0 }, + "supporting_genes": { + "type": "array", + "minItems": 1, + "items": { "type": "string" }, + "uniqueItems": true + }, + "supporting_gene_count": { "type": "integer", "minimum": 1 }, + "required_components_present": { + "type": "boolean", + "description": "Whether most/all required pathway components are present" + } + }, + "additionalProperties": false + } + }, + "method": { + "type": "object", + "description": "Optional trace of how programs were derived", + "properties": { + "clustering_basis": { + "type": "array", + "items": { "type": "string" }, + "description": "e.g., pathway databases, co-citation, PPI, co-expression" + }, + "notes": { "type": "string" } + }, + "additionalProperties": false + }, + "version": { "type": "string" } + }, + "additionalProperties": false +} \ No newline at end of file diff --git a/cellsem_agent/utils/__init__.py b/cellsem_agent/utils/__init__.py index e69de29..3a11cf7 100644 --- a/cellsem_agent/utils/__init__.py +++ b/cellsem_agent/utils/__init__.py @@ -0,0 +1 @@ +"""Utility modules for cellsem-agent.""" \ No newline at end of file diff --git a/cellsem_agent/utils/openai/__init__.py b/cellsem_agent/utils/openai/__init__.py new file mode 100644 index 0000000..e69de29 diff --git a/cellsem_agent/utils/openai/deepsearch.py b/cellsem_agent/utils/openai/deepsearch.py new file mode 100644 index 0000000..22e6cf3 --- /dev/null +++ b/cellsem_agent/utils/openai/deepsearch.py @@ -0,0 +1,170 @@ +# deepresearch_wrapper.py +from dataclasses import dataclass +from typing import Optional, Dict, Any +import time +import httpx +from openai import OpenAI +from openai._exceptions import APIError, RateLimitError, APIStatusError + +DEEP_RESEARCH_MODEL = "o3-deep-research-2025-06-26" # or "o4-mini-deep-research-2025-06-26" + +@dataclass +class DeepResearchResult: + success: bool + status: str + response_id: Optional[str] + output_text: Optional[str] + error_type: Optional[str] + error_message: Optional[str] + started_at: float + completed_at: float + elapsed_sec: float + raw_response: Optional[Any] + +class DeepResearchClient: + def __init__(self, api_key: Optional[str] = None, timeout: float = 600.0, base_url: Optional[str] = None): + """ + timeout: total request timeout (Deep Research can take minutes). + base_url: override for OpenAI-compatible endpoints if needed. + """ + self.client = OpenAI(api_key=api_key, base_url=base_url, timeout=timeout) + + def run( + self, + user_query: str, + system_message: str = "You are a meticulous research analyst. Produce a structured, citation-backed report.", + model: str = DEEP_RESEARCH_MODEL, + tools: Optional[list] = None, + reasoning: Optional[Dict[str, Any]] = None, + background: bool = True, + poll_interval: float = 5.0, + max_wait_sec: float = 1800.0, + ) -> DeepResearchResult: + """ + background=True lets the API do long work server-side; we then poll by id. + """ + started = time.time() + if tools is None: + tools = [{"type": "web_search_preview"}] + if reasoning is None: + reasoning = {"summary": "auto"} + + try: + # Kick off the task + resp = self.client.responses.create( + model=model, + input=[ + {"role": "developer", "content": [{"type": "input_text", "text": system_message}]}, + {"role": "user", "content": [{"type": "input_text", "text": user_query}]}, + ], + reasoning=reasoning, + tools=tools, + # Background mode is supported by the Deep Research models via Responses API + background=background, + ) + resp_id = getattr(resp, "id", None) + status = getattr(resp, "status", "in_progress") + + # If not background, many servers will return the finished object directly + if not background and status in ("completed", "failed", "cancelled"): + output_text = _extract_output_text(resp) + done = time.time() + return DeepResearchResult( + success=(status == "completed"), + status=status, + response_id=resp_id, + output_text=output_text, + error_type=None if status == "completed" else "DeepResearchFailed", + error_message=None if status == "completed" else "Deep Research did not complete.", + started_at=started, + completed_at=done, + elapsed_sec=done - started, + raw_response=resp, + ) + + # Poll for completion + deadline = started + max_wait_sec + while time.time() < deadline: + cur = self.client.responses.retrieve(resp_id) + status = getattr(cur, "status", "in_progress") + if status in ("completed", "failed", "cancelled"): + output_text = _extract_output_text(cur) + done = time.time() + return DeepResearchResult( + success=(status == "completed"), + status=status, + response_id=resp_id, + output_text=output_text, + error_type=None if status == "completed" else "DeepResearchFailed", + error_message=None if status == "completed" else "Deep Research did not complete.", + started_at=started, + completed_at=done, + elapsed_sec=done - started, + raw_response=cur, + ) + time.sleep(poll_interval) + + # timed out locally + done = time.time() + return DeepResearchResult( + success=False, + status="client_timeout", + response_id=resp_id, + output_text=None, + error_type="TimeoutError", + error_message=f"Polling exceeded {max_wait_sec:.0f}s without completion.", + started_at=started, + completed_at=done, + elapsed_sec=done - started, + raw_response=None, + ) + + except (httpx.TimeoutException,) as e: + done = time.time() + return DeepResearchResult( + success=False, + status="http_timeout", + response_id=None, + output_text=None, + error_type="httpx.TimeoutException", + error_message=str(e), + started_at=started, + completed_at=done, + elapsed_sec=done - started, + raw_response=None, + ) + except (RateLimitError,) as e: + done = time.time() + return DeepResearchResult( + success=False, + status="rate_limited", + response_id=None, + output_text=None, + error_type="RateLimitError", + error_message=str(e), + started_at=started, + completed_at=done, + elapsed_sec=done - started, + raw_response=getattr(e, "response", None), + ) + except (APIStatusError, APIError) as e: + done = time.time() + return DeepResearchResult( + success=False, + status="api_error", + response_id=None, + output_text=None, + error_type=e.__class__.__name__, + error_message=str(e), + started_at=started, + completed_at=done, + elapsed_sec=done - started, + raw_response=getattr(e, "response", None), + ) + +def _extract_output_text(resp) -> Optional[str]: + try: + # Deep Research returns the final report at the end of response.output + return resp.output[-1].content[0].text + except Exception: + return None diff --git a/cellsem_agent/utils/openai/simple_response_wrapper.py b/cellsem_agent/utils/openai/simple_response_wrapper.py new file mode 100644 index 0000000..c6647be --- /dev/null +++ b/cellsem_agent/utils/openai/simple_response_wrapper.py @@ -0,0 +1,127 @@ +# simple_response_wrapper.py +from dataclasses import dataclass +from typing import Optional, Dict, Any +import time, httpx +from openai import OpenAI +from openai._exceptions import APIError, RateLimitError, APIStatusError + +DEFAULT_MODEL = "gpt-4o-mini" # pick any standard text model you use + + +@dataclass +class SingleResponseResult: + success: bool + status: str # "completed", "http_timeout", "rate_limited", "api_error" + response_id: Optional[str] + output_text: Optional[str] + error_type: Optional[str] + error_message: Optional[str] + started_at: float + completed_at: float + elapsed_sec: float + raw_response: Optional[Any] + + +class SimpleResponder: + def __init__( + self, + api_key: Optional[str] = None, + timeout: float = 60.0, + base_url: Optional[str] = None, + ): + # The official OpenAI Python SDK uses httpx under the hood and supports a per-client timeout. :contentReference[oaicite:3]{index=3} + self.client = OpenAI(api_key=api_key, base_url=base_url, timeout=timeout) + + def ask( + self, + prompt: str, + *, + model: str = DEFAULT_MODEL, + instructions: Optional[str] = None, + temperature: Optional[float] = None, + max_output_tokens: Optional[int] = None, + extra: Optional[Dict[str, Any]] = None, + ) -> SingleResponseResult: + """ + Make a single-shot Responses API call and return a normalized result. + """ + started = time.time() + try: + payload: Dict[str, Any] = dict( + model=model, + input=prompt, # Responses API accepts simple strings or rich content. :contentReference[oaicite:4]{index=4} + ) + if instructions: + payload["instructions"] = instructions + if temperature is not None and model not in ["gpt-5"]: + # gpt-5 do not support temperature param + payload["temperature"] = temperature + if max_output_tokens is not None: + payload["max_output_tokens"] = max_output_tokens + if extra: + payload.update(extra) + + resp = self.client.responses.create(**payload) + # GitHub README shows .output_text for convenience; you can also walk resp.output[]. :contentReference[oaicite:5]{index=5} + out_text = getattr(resp, "output_text", None) + status = getattr(resp, "status", "completed") + rid = getattr(resp, "id", None) + done = time.time() + return SingleResponseResult( + success=True, + status=status, + response_id=rid, + output_text=out_text, + error_type=None, + error_message=None, + started_at=started, + completed_at=done, + elapsed_sec=done - started, + raw_response=resp, + ) + + except httpx.TimeoutException as e: + print(e) + done = time.time() + return SingleResponseResult( + success=False, + status="http_timeout", + response_id=None, + output_text=None, + error_type="httpx.TimeoutException", + error_message=str(e), + started_at=started, + completed_at=done, + elapsed_sec=done - started, + raw_response=None, + ) + except RateLimitError as e: + print(e) + done = time.time() + return SingleResponseResult( + success=False, + status="rate_limited", + response_id=None, + output_text=None, + error_type="RateLimitError", + error_message=str(e), + started_at=started, + completed_at=done, + elapsed_sec=done - started, + raw_response=getattr(e, "response", None), + ) + except (APIStatusError, APIError) as e: + print(e) + done = time.time() + return SingleResponseResult( + success=False, + status="api_error", + response_id=None, + output_text=None, + error_type=e.__class__.__name__, + error_message=str(e), + started_at=started, + completed_at=done, + elapsed_sec=done - started, + raw_response=getattr(e, "response", None), + ) diff --git a/gene_list_annotation_cli.py b/gene_list_annotation_cli.py new file mode 100644 index 0000000..3e49cac --- /dev/null +++ b/gene_list_annotation_cli.py @@ -0,0 +1,609 @@ +#!/usr/bin/env python3 +""" +Modern CLI for Gene List Annotation Workflow + +This provides a clean, extensible command-line interface for the gene list annotation +system that could serve as a model for future CLI architecture. +""" +import asyncio +import json +import os +import sys +from pathlib import Path +from typing import List, Dict, Any, Optional + +import click +from dotenv import load_dotenv + +# Conditional import with mock fallback to handle dependency issues +try: + from cellsem_agent.graphs.gene_list_annotation.gene_list_annotation_graph import run_gene_annotation_workflow + WORKFLOW_AVAILABLE = True +except ImportError as e: + WORKFLOW_AVAILABLE = False + IMPORT_ERROR = str(e) + + # Mock function for testing CLI without dependencies + async def run_gene_annotation_workflow( + gene_list, + context_description, + output_schema_example=None, + is_test_mode=False, + deep_search_timeout=300 + ): + return f"[MOCK MODE] Would analyze {len(gene_list)} genes: {', '.join(gene_list[:3])}... with context: {context_description[:50]}... (timeout: {deep_search_timeout}s)" + + +# Version and metadata +__version__ = "0.1.0" + +# Default example datasets +EXAMPLE_DATASETS = { + "dna_repair": { + "genes": ["BRCA1", "BRCA2", "TP53", "ATM", "CHEK2", "PALB2", "RAD51", "BARD1", "NBN"], + "context": "DNA damage response and repair in breast cancer susceptibility", + "description": "DNA repair genes associated with hereditary breast cancer" + }, + "neuronal_dev": { + "genes": ["NEUROD1", "NEUROG2", "ASCL1", "HES1", "NOTCH1", "SOX2", "PAX6", "TBR2"], + "context": "Neuronal differentiation and cortical development", + "description": "Transcription factors controlling neurogenesis" + }, + "immune_response": { + "genes": ["TNF", "IL6", "IFNG", "TLR4", "MYD88", "STAT3", "NFKB1", "IRF3"], + "context": "Innate immune response to bacterial pathogens", + "description": "Key mediators of inflammatory and immune responses" + }, + "metabolism": { + "genes": ["PPARG", "SREBF1", "ACACA", "FASN", "SCD", "FABP4", "ADIPOQ", "LEP"], + "context": "Adipocyte differentiation and lipid metabolism", + "description": "Regulators of fat cell development and metabolic function" + } +} + + +class GeneAnnotationCLI: + """Clean, modular CLI for gene list annotation.""" + + def __init__(self): + self.output_dir = Path("./gene_annotation_output") + self.examples_dir = Path(__file__).parent / "cellsem_agent" / "graphs" / "gene_list_annotation" / "examples" + + def ensure_output_dir(self): + """Ensure output directory exists.""" + self.output_dir.mkdir(exist_ok=True) + + def load_gene_list_from_file(self, filepath: str, verbose: bool = False) -> List[str]: + """Load gene list from various file formats.""" + path = Path(filepath) + + if verbose: + click.echo(f"🔍 Loading gene list from: {filepath}") + + if not path.exists(): + raise click.FileError(f"Gene list file not found: {filepath}") + + try: + if path.suffix.lower() == '.json': + if verbose: + click.echo(f" 📄 Parsing as JSON file") + with open(path, 'r', encoding='utf-8') as f: + data = json.load(f) + if isinstance(data, list): + if verbose: + click.echo(f" ✅ Found gene list with {len(data)} entries") + return data + elif isinstance(data, dict) and 'genes' in data: + if verbose: + click.echo(f" ✅ Found 'genes' key with {len(data['genes'])} entries") + return data['genes'] + elif isinstance(data, dict) and 'gene_list' in data: + if verbose: + click.echo(f" ✅ Found 'gene_list' key with {len(data['gene_list'])} entries") + return data['gene_list'] + elif isinstance(data, dict) and 'gene_symbols' in data: + if verbose: + click.echo(f" ✅ Found 'gene_symbols' key with {len(data['gene_symbols'])} entries") + return data['gene_symbols'] + else: + if verbose: + click.echo(f" ❌ JSON structure not recognized. Keys: {list(data.keys()) if isinstance(data, dict) else 'not a dict'}") + raise click.BadParameter(f"JSON gene file must contain a list of genes or dict with 'genes'/'gene_list'/'gene_symbols' key. File: {filepath}") + + elif path.suffix.lower() in ['.txt', '.csv', '.tsv']: + if verbose: + click.echo(f" 📄 Parsing as {path.suffix.upper()} file") + + with open(path, 'r', encoding='utf-8') as f: + genes = [] + line_count = 0 + for line_num, line in enumerate(f, 1): + line = line.strip() + if line and not line.startswith('#') and not line.startswith('//'): + line_count += 1 + # Handle CSV/TSV format + if ',' in line: + line_genes = [g.strip() for g in line.split(',') if g.strip()] + genes.extend(line_genes) + if verbose and line_count <= 3: + click.echo(f" Line {line_num}: Found {len(line_genes)} genes (comma-separated)") + elif '\t' in line: + line_genes = [g.strip() for g in line.split('\t') if g.strip()] + genes.extend(line_genes) + if verbose and line_count <= 3: + click.echo(f" Line {line_num}: Found {len(line_genes)} genes (tab-separated)") + elif ' ' in line and not line.count(' ') > 10: # Likely space-separated, not description + line_genes = [g.strip() for g in line.split() if g.strip()] + genes.extend(line_genes) + if verbose and line_count <= 3: + click.echo(f" Line {line_num}: Found {len(line_genes)} genes (space-separated)") + else: + genes.append(line) + if verbose and line_count <= 3: + click.echo(f" Line {line_num}: Single gene: {line}") + + if verbose: + click.echo(f" ✅ Processed {line_count} lines, found {len(genes)} genes total") + + if not genes: + raise click.BadParameter(f"No genes found in file: {filepath}") + + return genes + + else: + raise click.BadParameter(f"Unsupported gene file format: {path.suffix}. Supported: .json, .txt, .csv, .tsv. File: {filepath}") + + except json.JSONDecodeError as e: + raise click.BadParameter(f"Invalid JSON in gene file {filepath}: {str(e)}") + except UnicodeDecodeError as e: + raise click.BadParameter(f"Unable to read gene file {filepath} - encoding issue: {str(e)}") + except Exception as e: + raise click.BadParameter(f"Error reading gene file {filepath}: {str(e)}") + + def load_context_from_file(self, filepath: str, verbose: bool = False) -> str: + """Load context description from a text file.""" + path = Path(filepath) + + if verbose: + click.echo(f"🔍 Loading context from: {filepath}") + + if not path.exists(): + raise click.FileError(f"Context file not found: {filepath}") + + try: + with open(path, 'r', encoding='utf-8') as f: + content = f.read().strip() + + if verbose: + click.echo(f" 📄 Read {len(content)} characters") + if content: + preview = content[:100] + "..." if len(content) > 100 else content + click.echo(f" 📝 Preview: {preview}") + + if not content: + raise click.BadParameter(f"Context file is empty: {filepath}") + + if verbose: + click.echo(f" ✅ Context loaded successfully") + + return content + + except UnicodeDecodeError as e: + raise click.BadParameter(f"Unable to read context file {filepath} - encoding issue: {str(e)}") + except Exception as e: + raise click.BadParameter(f"Error reading context file {filepath}: {str(e)}") + + def load_combined_input_file(self, filepath: str) -> Dict[str, Any]: + """Load combined input file containing genes, context, and optional schema.""" + path = Path(filepath) + + if not path.exists(): + raise click.FileError(f"File not found: {filepath}") + + if path.suffix.lower() == '.json': + with open(path, 'r', encoding='utf-8') as f: + data = json.load(f) + + result = {} + + # Extract genes + if 'genes' in data: + result['genes'] = data['genes'] + elif 'gene_list' in data: + result['genes'] = data['gene_list'] + elif 'gene_symbols' in data: + result['genes'] = data['gene_symbols'] + else: + raise click.BadParameter("Combined file must contain 'genes', 'gene_list', or 'gene_symbols'") + + # Extract context + if 'context' in data: + result['context'] = data['context'] + elif 'context_description' in data: + result['context'] = data['context_description'] + elif 'description' in data: + result['context'] = data['description'] + + # Extract optional schema + if 'schema' in data: + result['schema'] = data['schema'] + elif 'output_schema' in data: + result['schema'] = data['output_schema'] + elif 'schema_example' in data: + result['schema'] = data['schema_example'] + + return result + + elif path.suffix.lower() in ['.yaml', '.yml']: + try: + import yaml + with open(path, 'r', encoding='utf-8') as f: + data = yaml.safe_load(f) + return self._extract_from_structured_data(data) + except ImportError: + raise click.BadParameter("YAML support requires PyYAML: pip install pyyaml") + + else: + raise click.BadParameter(f"Combined input file must be JSON or YAML format, got: {path.suffix}") + + def _extract_from_structured_data(self, data: Dict[str, Any]) -> Dict[str, Any]: + """Extract genes, context, and schema from structured data.""" + result = {} + + # Extract genes + for key in ['genes', 'gene_list', 'gene_symbols']: + if key in data: + result['genes'] = data[key] + break + + # Extract context + for key in ['context', 'context_description', 'description']: + if key in data: + result['context'] = data[key] + break + + # Extract schema + for key in ['schema', 'output_schema', 'schema_example']: + if key in data: + result['schema'] = data[key] + break + + return result + + async def run_annotation( + self, + genes: List[str], + context: str, + output_prefix: Optional[str] = None, + schema_data: Optional[Dict[str, Any]] = None, + test_mode: bool = False, + timeout: int = 300 + ) -> str: + """Run the gene list annotation workflow.""" + + # Check if workflow is available + if not WORKFLOW_AVAILABLE: + click.echo(f"⚠️ Workflow not available due to dependency issue: {IMPORT_ERROR}") + click.echo("🔧 Running in mock mode for CLI testing...") + + # Use provided schema data + schema_example = schema_data + + # Set output directory in environment + os.environ['GENE_ANNOTATION_OUTPUT_DIR'] = str(self.output_dir.absolute()) + + try: + result = await run_gene_annotation_workflow( + gene_list=genes, + context_description=context, + output_schema_example=schema_example, + is_test_mode=test_mode, + deep_search_timeout=timeout + ) + return result + except Exception as e: + raise click.ClickException(f"Annotation workflow failed: {str(e)}") + + +# CLI command setup +@click.group(invoke_without_command=True) +@click.option('--version', is_flag=True, help='Show version and exit') +@click.option('-v', '--verbose', count=True, help='Increase verbosity') +@click.option('--output-dir', type=click.Path(), help='Output directory for results') +@click.pass_context +def cli(ctx, version, verbose, output_dir): + """ + Gene List Annotation CLI + + A modern command-line interface for annotating gene lists with cellular function + implications using a multi-agent workflow. + + Examples: + + \b + # Run with example dataset + gene-annotate run --example dna_repair + + \b + # Run with custom gene list + gene-annotate run --genes BRCA1,BRCA2,TP53 --context "DNA repair in cancer" + + \b + # Run with gene list from file + gene-annotate run --file genes.txt --context "Custom context" + + \b + # Launch interactive UI + gene-annotate ui + """ + if version: + click.echo(f"Gene List Annotation CLI v{__version__}") + return + + # Set up context + ctx.ensure_object(dict) + ctx.obj['verbose'] = verbose + + # Initialize CLI instance + cli_instance = GeneAnnotationCLI() + if output_dir: + cli_instance.output_dir = Path(output_dir) + ctx.obj['cli'] = cli_instance + + # If no command is provided, show help + if ctx.invoked_subcommand is None: + click.echo(ctx.get_help()) + + +@cli.command() +@click.option('--genes', '-g', help='Comma-separated list of gene symbols') +@click.option('--gene-file', '-f', type=click.Path(exists=True), + help='File containing gene list (JSON, TXT, CSV, TSV)') +@click.option('--context', '-c', help='Cellular/tissue/disease context for analysis') +@click.option('--context-file', type=click.Path(exists=True), + help='File containing context description (TXT)') +@click.option('--input-file', '-i', type=click.Path(exists=True), + help='Combined input file with genes, context, and optional schema (JSON/YAML)') +@click.option('--example', '-e', type=click.Choice(list(EXAMPLE_DATASETS.keys())), + help='Use a predefined example dataset') +@click.option('--schema', '-s', type=click.Path(exists=True), + help='JSON file with custom output schema example') +@click.option('--output-prefix', '-o', help='Prefix for output files') +@click.option('--test-mode', is_flag=True, help='Run in test mode (faster, limited scope)') +@click.option('--timeout', type=int, default=300, help='Deep research timeout in seconds (default: 300)') +@click.option('--dry-run', is_flag=True, help='Show what would be run without executing') +@click.option('--debug', is_flag=True, help='Enable debug mode with full stack traces') +@click.pass_context +def run(ctx, genes, gene_file, context, context_file, input_file, example, schema, output_prefix, test_mode, timeout, dry_run, debug): + """ + Run gene list annotation workflow. + + Specify input via: + - Individual options: --genes, --context + - File options: --gene-file, --context-file + - Combined file: --input-file (JSON/YAML with all data) + - Example: --example + """ + cli_instance = ctx.obj['cli'] + cli_instance.ensure_output_dir() + + # Set debug mode in context + ctx.obj['debug'] = debug + is_verbose = ctx.obj.get('verbose', 0) > 0 or debug + + if debug: + click.echo("🐛 Debug mode enabled - full stack traces will be shown") + # Enable debug logging for deep research + import logging + deepsearch_logger = logging.getLogger('cellsem_agent.agents.deepsearch.deepsearch_service') + deepsearch_logger.setLevel(logging.DEBUG) + # Ensure the console handler shows debug messages + for handler in deepsearch_logger.handlers: + handler.setLevel(logging.DEBUG) + + # Handle combined input file first + if input_file: + click.echo(f"Loading combined input from {input_file}") + combined_data = cli_instance.load_combined_input_file(input_file) + + gene_list = combined_data.get('genes', []) + context = combined_data.get('context', context) # CLI context can override + + # Handle embedded schema + if 'schema' in combined_data and not schema: + schema_data = combined_data['schema'] + else: + schema_data = None + + click.echo(f"Loaded {len(gene_list)} genes from combined input file") + + else: + # Determine gene list source + gene_list = None + schema_data = None + + if example: + dataset = EXAMPLE_DATASETS[example] + gene_list = dataset['genes'] + if not context or context == dataset['context']: + context = dataset['context'] + click.echo(f"Using example dataset: {example}") + click.echo(f"Description: {dataset['description']}") + elif gene_file: + gene_list = cli_instance.load_gene_list_from_file(gene_file, verbose=is_verbose) + click.echo(f"Loaded {len(gene_list)} genes from {gene_file}") + elif genes: + gene_list = [g.strip() for g in genes.split(',')] + click.echo(f"Using {len(gene_list)} genes from command line") + else: + raise click.BadParameter("Must specify genes via --genes, --gene-file, --input-file, or --example") + + # Handle context from file if provided + if context_file: + file_context = cli_instance.load_context_from_file(context_file, verbose=is_verbose) + if context and context != file_context: + click.echo(f"Warning: Using context from file, ignoring command-line context") + context = file_context + click.echo(f"Loaded context from {context_file}") + + # Validate inputs + if not gene_list: + raise click.BadParameter("No genes provided") + + if not context: + raise click.BadParameter("Context is required. Provide via --context, --context-file, --input-file, or --example") + + if len(gene_list) > 50 and not test_mode: + click.confirm(f"Processing {len(gene_list)} genes. This may take a while. Continue?", abort=True) + + # Show execution plan + click.echo(f"\nExecution Plan:") + click.echo(f" Genes: {', '.join(gene_list[:5])}{'...' if len(gene_list) > 5 else ''} ({len(gene_list)} total)") + click.echo(f" Context: {context}") + click.echo(f" Schema: {schema or 'default'}") + click.echo(f" Test mode: {test_mode}") + click.echo(f" Output directory: {cli_instance.output_dir}") + + if dry_run: + click.echo("\n[DRY RUN] Would execute the workflow with above parameters.") + return + + # Load environment + load_dotenv() + + # Run the workflow + click.echo("\n🚀 Starting gene list annotation workflow...") + + try: + # Handle schema - either from file or embedded in input + schema_to_use = None + if input_file and 'schema_data' in locals() and schema_data: + schema_to_use = schema_data + elif schema: + # Load schema from separate file + if is_verbose: + click.echo(f"🔍 Loading schema from: {schema}") + try: + with open(schema, 'r') as f: + schema_to_use = json.load(f) + if is_verbose: + click.echo(f" ✅ Schema loaded successfully") + except FileNotFoundError: + raise click.FileError(f"Schema file not found: {schema}") + except json.JSONDecodeError as e: + raise click.BadParameter(f"Invalid JSON in schema file {schema}: {str(e)}") + except Exception as e: + raise click.BadParameter(f"Error reading schema file {schema}: {str(e)}") + + result = asyncio.run(cli_instance.run_annotation( + genes=gene_list, + context=context, + output_prefix=output_prefix, + schema_data=schema_to_use, + test_mode=test_mode, + timeout=timeout + )) + + click.echo("\n✅ Workflow completed successfully!") + click.echo(result) + + except Exception as e: + if debug: + import traceback + click.echo(f"\n❌ Workflow failed with full stack trace:", err=True) + click.echo(traceback.format_exc(), err=True) + else: + click.echo(f"\n❌ Workflow failed: {str(e)}", err=True) + click.echo("💡 Use --debug for full stack trace", err=True) + sys.exit(1) + + +@cli.command() +@click.option('--port', '-p', default=7860, help='Port for Gradio interface') +@click.option('--share', is_flag=True, help='Create public shareable link') +@click.pass_context +def ui(ctx, port, share): + """Launch interactive Gradio interface for gene list annotation.""" + try: + from .gene_annotation_gradio import launch_gradio_interface + click.echo(f"🚀 Launching Gradio interface on port {port}...") + launch_gradio_interface(port=port, share=share) + except ImportError: + click.echo("❌ Gradio interface not available. Install with: pip install gradio", err=True) + sys.exit(1) + + +@cli.command() +def examples(): + """List available example datasets.""" + click.echo("Available example datasets:\n") + + for key, dataset in EXAMPLE_DATASETS.items(): + click.echo(f"🧬 {click.style(key, fg='blue', bold=True)}") + click.echo(f" Description: {dataset['description']}") + click.echo(f" Genes: {', '.join(dataset['genes'][:3])}... ({len(dataset['genes'])} total)") + click.echo(f" Context: {dataset['context']}") + click.echo() + + click.echo("Usage: gene-annotate run --example ") + + +@cli.command() +@click.option('--genes', prompt='Enter gene symbols (comma-separated)') +@click.option('--context', prompt='Enter cellular/tissue/disease context') +@click.option('--output-prefix', help='Prefix for output files') +@click.pass_context +def interactive(ctx, genes, context, output_prefix): + """Interactive mode with prompts for input.""" + cli_instance = ctx.obj['cli'] + cli_instance.ensure_output_dir() + + gene_list = [g.strip() for g in genes.split(',')] + + click.echo(f"\n📝 Summary:") + click.echo(f" Genes: {', '.join(gene_list)} ({len(gene_list)} total)") + click.echo(f" Context: {context}") + + if click.confirm('\nProceed with analysis?'): + load_dotenv() + + try: + result = asyncio.run(cli_instance.run_annotation( + genes=gene_list, + context=context, + output_prefix=output_prefix, + timeout=300 # Use default timeout for interactive mode + )) + + click.echo("\n✅ Analysis completed!") + click.echo(result) + + except Exception as e: + click.echo(f"\n❌ Analysis failed: {str(e)}", err=True) + + +@cli.command() +@click.pass_context +def config(ctx): + """Show configuration and environment information.""" + click.echo("🔧 Gene List Annotation CLI Configuration\n") + + cli_instance = ctx.obj['cli'] + + # Environment check + click.echo("Environment Variables:") + env_vars = ['OPENAI_API_KEY'] + for var in env_vars: + value = os.environ.get(var) + status = "✅ Set" if value else "❌ Not set" + click.echo(f" {var}: {status}") + + click.echo(f"\nPaths:") + click.echo(f" Output directory: {cli_instance.output_dir}") + click.echo(f" Examples directory: {cli_instance.examples_dir}") + + click.echo(f"\nCLI Version: {__version__}") + + +if __name__ == '__main__': + cli() \ No newline at end of file diff --git a/poetry.lock b/poetry.lock index 24b9973..e08d911 100644 --- a/poetry.lock +++ b/poetry.lock @@ -27,98 +27,132 @@ files = [ [[package]] name = "aiohttp" -version = "3.12.14" +version = "3.13.0" description = "Async http client/server framework (asyncio)" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "aiohttp-3.12.14-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:906d5075b5ba0dd1c66fcaaf60eb09926a9fef3ca92d912d2a0bbdbecf8b1248"}, - {file = "aiohttp-3.12.14-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:c875bf6fc2fd1a572aba0e02ef4e7a63694778c5646cdbda346ee24e630d30fb"}, - {file = "aiohttp-3.12.14-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:fbb284d15c6a45fab030740049d03c0ecd60edad9cd23b211d7e11d3be8d56fd"}, - {file = "aiohttp-3.12.14-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:38e360381e02e1a05d36b223ecab7bc4a6e7b5ab15760022dc92589ee1d4238c"}, - {file = "aiohttp-3.12.14-cp310-cp310-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:aaf90137b5e5d84a53632ad95ebee5c9e3e7468f0aab92ba3f608adcb914fa95"}, - {file = "aiohttp-3.12.14-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:e532a25e4a0a2685fa295a31acf65e027fbe2bea7a4b02cdfbbba8a064577663"}, - {file = "aiohttp-3.12.14-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:eab9762c4d1b08ae04a6c77474e6136da722e34fdc0e6d6eab5ee93ac29f35d1"}, - {file = "aiohttp-3.12.14-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:abe53c3812b2899889a7fca763cdfaeee725f5be68ea89905e4275476ffd7e61"}, - {file = "aiohttp-3.12.14-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:5760909b7080aa2ec1d320baee90d03b21745573780a072b66ce633eb77a8656"}, - {file = "aiohttp-3.12.14-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:02fcd3f69051467bbaa7f84d7ec3267478c7df18d68b2e28279116e29d18d4f3"}, - {file = "aiohttp-3.12.14-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:4dcd1172cd6794884c33e504d3da3c35648b8be9bfa946942d353b939d5f1288"}, - {file = "aiohttp-3.12.14-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:224d0da41355b942b43ad08101b1b41ce633a654128ee07e36d75133443adcda"}, - {file = "aiohttp-3.12.14-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:e387668724f4d734e865c1776d841ed75b300ee61059aca0b05bce67061dcacc"}, - {file = "aiohttp-3.12.14-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:dec9cde5b5a24171e0b0a4ca064b1414950904053fb77c707efd876a2da525d8"}, - {file = "aiohttp-3.12.14-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:bbad68a2af4877cc103cd94af9160e45676fc6f0c14abb88e6e092b945c2c8e3"}, - {file = "aiohttp-3.12.14-cp310-cp310-win32.whl", hash = "sha256:ee580cb7c00bd857b3039ebca03c4448e84700dc1322f860cf7a500a6f62630c"}, - {file = "aiohttp-3.12.14-cp310-cp310-win_amd64.whl", hash = "sha256:cf4f05b8cea571e2ccc3ca744e35ead24992d90a72ca2cf7ab7a2efbac6716db"}, - {file = "aiohttp-3.12.14-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:f4552ff7b18bcec18b60a90c6982049cdb9dac1dba48cf00b97934a06ce2e597"}, - {file = "aiohttp-3.12.14-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:8283f42181ff6ccbcf25acaae4e8ab2ff7e92b3ca4a4ced73b2c12d8cd971393"}, - {file = "aiohttp-3.12.14-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:040afa180ea514495aaff7ad34ec3d27826eaa5d19812730fe9e529b04bb2179"}, - {file = "aiohttp-3.12.14-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:b413c12f14c1149f0ffd890f4141a7471ba4b41234fe4fd4a0ff82b1dc299dbb"}, - {file = "aiohttp-3.12.14-cp311-cp311-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:1d6f607ce2e1a93315414e3d448b831238f1874b9968e1195b06efaa5c87e245"}, - {file = "aiohttp-3.12.14-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:565e70d03e924333004ed101599902bba09ebb14843c8ea39d657f037115201b"}, - {file = "aiohttp-3.12.14-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:4699979560728b168d5ab63c668a093c9570af2c7a78ea24ca5212c6cdc2b641"}, - {file = "aiohttp-3.12.14-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:ad5fdf6af93ec6c99bf800eba3af9a43d8bfd66dce920ac905c817ef4a712afe"}, - {file = "aiohttp-3.12.14-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:4ac76627c0b7ee0e80e871bde0d376a057916cb008a8f3ffc889570a838f5cc7"}, - {file = "aiohttp-3.12.14-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:798204af1180885651b77bf03adc903743a86a39c7392c472891649610844635"}, - {file = "aiohttp-3.12.14-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:4f1205f97de92c37dd71cf2d5bcfb65fdaed3c255d246172cce729a8d849b4da"}, - {file = "aiohttp-3.12.14-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:76ae6f1dd041f85065d9df77c6bc9c9703da9b5c018479d20262acc3df97d419"}, - {file = "aiohttp-3.12.14-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:a194ace7bc43ce765338ca2dfb5661489317db216ea7ea700b0332878b392cab"}, - {file = "aiohttp-3.12.14-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:16260e8e03744a6fe3fcb05259eeab8e08342c4c33decf96a9dad9f1187275d0"}, - {file = "aiohttp-3.12.14-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:8c779e5ebbf0e2e15334ea404fcce54009dc069210164a244d2eac8352a44b28"}, - {file = "aiohttp-3.12.14-cp311-cp311-win32.whl", hash = "sha256:a289f50bf1bd5be227376c067927f78079a7bdeccf8daa6a9e65c38bae14324b"}, - {file = "aiohttp-3.12.14-cp311-cp311-win_amd64.whl", hash = "sha256:0b8a69acaf06b17e9c54151a6c956339cf46db4ff72b3ac28516d0f7068f4ced"}, - {file = "aiohttp-3.12.14-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:a0ecbb32fc3e69bc25efcda7d28d38e987d007096cbbeed04f14a6662d0eee22"}, - {file = "aiohttp-3.12.14-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:0400f0ca9bb3e0b02f6466421f253797f6384e9845820c8b05e976398ac1d81a"}, - {file = "aiohttp-3.12.14-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:a56809fed4c8a830b5cae18454b7464e1529dbf66f71c4772e3cfa9cbec0a1ff"}, - {file = "aiohttp-3.12.14-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:27f2e373276e4755691a963e5d11756d093e346119f0627c2d6518208483fb6d"}, - {file = "aiohttp-3.12.14-cp312-cp312-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:ca39e433630e9a16281125ef57ece6817afd1d54c9f1bf32e901f38f16035869"}, - {file = "aiohttp-3.12.14-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:9c748b3f8b14c77720132b2510a7d9907a03c20ba80f469e58d5dfd90c079a1c"}, - {file = "aiohttp-3.12.14-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:f0a568abe1b15ce69d4cc37e23020720423f0728e3cb1f9bcd3f53420ec3bfe7"}, - {file = "aiohttp-3.12.14-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:9888e60c2c54eaf56704b17feb558c7ed6b7439bca1e07d4818ab878f2083660"}, - {file = "aiohttp-3.12.14-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:3006a1dc579b9156de01e7916d38c63dc1ea0679b14627a37edf6151bc530088"}, - {file = "aiohttp-3.12.14-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:aa8ec5c15ab80e5501a26719eb48a55f3c567da45c6ea5bb78c52c036b2655c7"}, - {file = "aiohttp-3.12.14-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:39b94e50959aa07844c7fe2206b9f75d63cc3ad1c648aaa755aa257f6f2498a9"}, - {file = "aiohttp-3.12.14-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:04c11907492f416dad9885d503fbfc5dcb6768d90cad8639a771922d584609d3"}, - {file = "aiohttp-3.12.14-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:88167bd9ab69bb46cee91bd9761db6dfd45b6e76a0438c7e884c3f8160ff21eb"}, - {file = "aiohttp-3.12.14-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:791504763f25e8f9f251e4688195e8b455f8820274320204f7eafc467e609425"}, - {file = "aiohttp-3.12.14-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:2785b112346e435dd3a1a67f67713a3fe692d288542f1347ad255683f066d8e0"}, - {file = "aiohttp-3.12.14-cp312-cp312-win32.whl", hash = "sha256:15f5f4792c9c999a31d8decf444e79fcfd98497bf98e94284bf390a7bb8c1729"}, - {file = "aiohttp-3.12.14-cp312-cp312-win_amd64.whl", hash = "sha256:3b66e1a182879f579b105a80d5c4bd448b91a57e8933564bf41665064796a338"}, - {file = "aiohttp-3.12.14-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:3143a7893d94dc82bc409f7308bc10d60285a3cd831a68faf1aa0836c5c3c767"}, - {file = "aiohttp-3.12.14-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:3d62ac3d506cef54b355bd34c2a7c230eb693880001dfcda0bf88b38f5d7af7e"}, - {file = "aiohttp-3.12.14-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:48e43e075c6a438937c4de48ec30fa8ad8e6dfef122a038847456bfe7b947b63"}, - {file = "aiohttp-3.12.14-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:077b4488411a9724cecc436cbc8c133e0d61e694995b8de51aaf351c7578949d"}, - {file = "aiohttp-3.12.14-cp313-cp313-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:d8c35632575653f297dcbc9546305b2c1133391089ab925a6a3706dfa775ccab"}, - {file = "aiohttp-3.12.14-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:6b8ce87963f0035c6834b28f061df90cf525ff7c9b6283a8ac23acee6502afd4"}, - {file = "aiohttp-3.12.14-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:f0a2cf66e32a2563bb0766eb24eae7e9a269ac0dc48db0aae90b575dc9583026"}, - {file = "aiohttp-3.12.14-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:cdea089caf6d5cde975084a884c72d901e36ef9c2fd972c9f51efbbc64e96fbd"}, - {file = "aiohttp-3.12.14-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:8a7865f27db67d49e81d463da64a59365ebd6b826e0e4847aa111056dcb9dc88"}, - {file = "aiohttp-3.12.14-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:0ab5b38a6a39781d77713ad930cb5e7feea6f253de656a5f9f281a8f5931b086"}, - {file = "aiohttp-3.12.14-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:9b3b15acee5c17e8848d90a4ebc27853f37077ba6aec4d8cb4dbbea56d156933"}, - {file = "aiohttp-3.12.14-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:e4c972b0bdaac167c1e53e16a16101b17c6d0ed7eac178e653a07b9f7fad7151"}, - {file = "aiohttp-3.12.14-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:7442488b0039257a3bdbc55f7209587911f143fca11df9869578db6c26feeeb8"}, - {file = "aiohttp-3.12.14-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:f68d3067eecb64c5e9bab4a26aa11bd676f4c70eea9ef6536b0a4e490639add3"}, - {file = "aiohttp-3.12.14-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:f88d3704c8b3d598a08ad17d06006cb1ca52a1182291f04979e305c8be6c9758"}, - {file = "aiohttp-3.12.14-cp313-cp313-win32.whl", hash = "sha256:a3c99ab19c7bf375c4ae3debd91ca5d394b98b6089a03231d4c580ef3c2ae4c5"}, - {file = "aiohttp-3.12.14-cp313-cp313-win_amd64.whl", hash = "sha256:3f8aad695e12edc9d571f878c62bedc91adf30c760c8632f09663e5f564f4baa"}, - {file = "aiohttp-3.12.14-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:b8cc6b05e94d837bcd71c6531e2344e1ff0fb87abe4ad78a9261d67ef5d83eae"}, - {file = "aiohttp-3.12.14-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:d1dcb015ac6a3b8facd3677597edd5ff39d11d937456702f0bb2b762e390a21b"}, - {file = "aiohttp-3.12.14-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:3779ed96105cd70ee5e85ca4f457adbce3d9ff33ec3d0ebcdf6c5727f26b21b3"}, - {file = "aiohttp-3.12.14-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:717a0680729b4ebd7569c1dcd718c46b09b360745fd8eb12317abc74b14d14d0"}, - {file = "aiohttp-3.12.14-cp39-cp39-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:b5dd3a2ef7c7e968dbbac8f5574ebeac4d2b813b247e8cec28174a2ba3627170"}, - {file = "aiohttp-3.12.14-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:4710f77598c0092239bc12c1fcc278a444e16c7032d91babf5abbf7166463f7b"}, - {file = "aiohttp-3.12.14-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:f3e9f75ae842a6c22a195d4a127263dbf87cbab729829e0bd7857fb1672400b2"}, - {file = "aiohttp-3.12.14-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:5f9c8d55d6802086edd188e3a7d85a77787e50d56ce3eb4757a3205fa4657922"}, - {file = "aiohttp-3.12.14-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:79b29053ff3ad307880d94562cca80693c62062a098a5776ea8ef5ef4b28d140"}, - {file = "aiohttp-3.12.14-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:23e1332fff36bebd3183db0c7a547a1da9d3b4091509f6d818e098855f2f27d3"}, - {file = "aiohttp-3.12.14-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:a564188ce831fd110ea76bcc97085dd6c625b427db3f1dbb14ca4baa1447dcbc"}, - {file = "aiohttp-3.12.14-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:a7a1b4302f70bb3ec40ca86de82def532c97a80db49cac6a6700af0de41af5ee"}, - {file = "aiohttp-3.12.14-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:1b07ccef62950a2519f9bfc1e5b294de5dd84329f444ca0b329605ea787a3de5"}, - {file = "aiohttp-3.12.14-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:938bd3ca6259e7e48b38d84f753d548bd863e0c222ed6ee6ace3fd6752768a84"}, - {file = "aiohttp-3.12.14-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:8bc784302b6b9f163b54c4e93d7a6f09563bd01ff2b841b29ed3ac126e5040bf"}, - {file = "aiohttp-3.12.14-cp39-cp39-win32.whl", hash = "sha256:a3416f95961dd7d5393ecff99e3f41dc990fb72eda86c11f2a60308ac6dcd7a0"}, - {file = "aiohttp-3.12.14-cp39-cp39-win_amd64.whl", hash = "sha256:196858b8820d7f60578f8b47e5669b3195c21d8ab261e39b1d705346458f445f"}, - {file = "aiohttp-3.12.14.tar.gz", hash = "sha256:6e06e120e34d93100de448fd941522e11dafa78ef1a893c179901b7d66aa29f2"}, + {file = "aiohttp-3.13.0-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:ca69ec38adf5cadcc21d0b25e2144f6a25b7db7bea7e730bac25075bc305eff0"}, + {file = "aiohttp-3.13.0-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:240f99f88a9a6beb53ebadac79a2e3417247aa756202ed234b1dbae13d248092"}, + {file = "aiohttp-3.13.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:a4676b978a9711531e7cea499d4cdc0794c617a1c0579310ab46c9fdf5877702"}, + {file = "aiohttp-3.13.0-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:48fcdd5bc771cbbab8ccc9588b8b6447f6a30f9fe00898b1a5107098e00d6793"}, + {file = "aiohttp-3.13.0-cp310-cp310-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:eeea0cdd2f687e210c8f605f322d7b0300ba55145014a5dbe98bd4be6fff1f6c"}, + {file = "aiohttp-3.13.0-cp310-cp310-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:10b3f01d5aeb632adaaf39c5e93f040a550464a768d54c514050c635adcbb9d0"}, + {file = "aiohttp-3.13.0-cp310-cp310-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:a4dc0b83e25267f42ef065ea57653de4365b56d7bc4e4cfc94fabe56998f8ee6"}, + {file = "aiohttp-3.13.0-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:72714919ed9b90f030f761c20670e529c4af96c31bd000917dd0c9afd1afb731"}, + {file = "aiohttp-3.13.0-cp310-cp310-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:564be41e85318403fdb176e9e5b3e852d528392f42f2c1d1efcbeeed481126d7"}, + {file = "aiohttp-3.13.0-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:84912962071087286333f70569362e10793f73f45c48854e6859df11001eb2d3"}, + {file = "aiohttp-3.13.0-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:90b570f1a146181c3d6ae8f755de66227ded49d30d050479b5ae07710f7894c5"}, + {file = "aiohttp-3.13.0-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:2d71ca30257ce756e37a6078b1dff2d9475fee13609ad831eac9a6531bea903b"}, + {file = "aiohttp-3.13.0-cp310-cp310-musllinux_1_2_riscv64.whl", hash = "sha256:cd45eb70eca63f41bb156b7dffbe1a7760153b69892d923bdb79a74099e2ed90"}, + {file = "aiohttp-3.13.0-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:5ae3a19949a27982c7425a7a5a963c1268fdbabf0be15ab59448cbcf0f992519"}, + {file = "aiohttp-3.13.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:ea6df292013c9f050cbf3f93eee9953d6e5acd9e64a0bf4ca16404bfd7aa9bcc"}, + {file = "aiohttp-3.13.0-cp310-cp310-win32.whl", hash = "sha256:3b64f22fbb6dcd5663de5ef2d847a5638646ef99112503e6f7704bdecb0d1c4d"}, + {file = "aiohttp-3.13.0-cp310-cp310-win_amd64.whl", hash = "sha256:f8d877aa60d80715b2afc565f0f1aea66565824c229a2d065b31670e09fed6d7"}, + {file = "aiohttp-3.13.0-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:99eb94e97a42367fef5fc11e28cb2362809d3e70837f6e60557816c7106e2e20"}, + {file = "aiohttp-3.13.0-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:4696665b2713021c6eba3e2b882a86013763b442577fe5d2056a42111e732eca"}, + {file = "aiohttp-3.13.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:3e6a38366f7f0d0f6ed7a1198055150c52fda552b107dad4785c0852ad7685d1"}, + {file = "aiohttp-3.13.0-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:aab715b1a0c37f7f11f9f1f579c6fbaa51ef569e47e3c0a4644fba46077a9409"}, + {file = "aiohttp-3.13.0-cp311-cp311-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:7972c82bed87d7bd8e374b60a6b6e816d75ba4f7c2627c2d14eed216e62738e1"}, + {file = "aiohttp-3.13.0-cp311-cp311-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:ca8313cb852af788c78d5afdea24c40172cbfff8b35e58b407467732fde20390"}, + {file = "aiohttp-3.13.0-cp311-cp311-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:6c333a2385d2a6298265f4b3e960590f787311b87f6b5e6e21bb8375914ef504"}, + {file = "aiohttp-3.13.0-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:cc6d5fc5edbfb8041d9607f6a417997fa4d02de78284d386bea7ab767b5ea4f3"}, + {file = "aiohttp-3.13.0-cp311-cp311-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:7ddedba3d0043349edc79df3dc2da49c72b06d59a45a42c1c8d987e6b8d175b8"}, + {file = "aiohttp-3.13.0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:23ca762140159417a6bbc959ca1927f6949711851e56f2181ddfe8d63512b5ad"}, + {file = "aiohttp-3.13.0-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:bfe824d6707a5dc3c5676685f624bc0c63c40d79dc0239a7fd6c034b98c25ebe"}, + {file = "aiohttp-3.13.0-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:3c11fa5dd2ef773a8a5a6daa40243d83b450915992eab021789498dc87acc114"}, + {file = "aiohttp-3.13.0-cp311-cp311-musllinux_1_2_riscv64.whl", hash = "sha256:00fdfe370cffede3163ba9d3f190b32c0cfc8c774f6f67395683d7b0e48cdb8a"}, + {file = "aiohttp-3.13.0-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:6475e42ef92717a678bfbf50885a682bb360a6f9c8819fb1a388d98198fdcb80"}, + {file = "aiohttp-3.13.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:77da5305a410910218b99f2a963092f4277d8a9c1f429c1ff1b026d1826bd0b6"}, + {file = "aiohttp-3.13.0-cp311-cp311-win32.whl", hash = "sha256:2f9d9ea547618d907f2ee6670c9a951f059c5994e4b6de8dcf7d9747b420c820"}, + {file = "aiohttp-3.13.0-cp311-cp311-win_amd64.whl", hash = "sha256:0f19f7798996d4458c669bd770504f710014926e9970f4729cf55853ae200469"}, + {file = "aiohttp-3.13.0-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:1c272a9a18a5ecc48a7101882230046b83023bb2a662050ecb9bfcb28d9ab53a"}, + {file = "aiohttp-3.13.0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:97891a23d7fd4e1afe9c2f4473e04595e4acb18e4733b910b6577b74e7e21985"}, + {file = "aiohttp-3.13.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:475bd56492ce5f4cffe32b5533c6533ee0c406d1d0e6924879f83adcf51da0ae"}, + {file = "aiohttp-3.13.0-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:c32ada0abb4bc94c30be2b681c42f058ab104d048da6f0148280a51ce98add8c"}, + {file = "aiohttp-3.13.0-cp312-cp312-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:4af1f8877ca46ecdd0bc0d4a6b66d4b2bddc84a79e2e8366bc0d5308e76bceb8"}, + {file = "aiohttp-3.13.0-cp312-cp312-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:e04ab827ec4f775817736b20cdc8350f40327f9b598dec4e18c9ffdcbea88a93"}, + {file = "aiohttp-3.13.0-cp312-cp312-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:a6d9487b9471ec36b0faedf52228cd732e89be0a2bbd649af890b5e2ce422353"}, + {file = "aiohttp-3.13.0-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:2e66c57416352f36bf98f6641ddadd47c93740a22af7150d3e9a1ef6e983f9a8"}, + {file = "aiohttp-3.13.0-cp312-cp312-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:469167d5372f5bb3aedff4fc53035d593884fff2617a75317740e885acd48b04"}, + {file = "aiohttp-3.13.0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:a9f3546b503975a69b547c9fd1582cad10ede1ce6f3e313a2f547c73a3d7814f"}, + {file = "aiohttp-3.13.0-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:6b4174fcec98601f0cfdf308ee29a6ae53c55f14359e848dab4e94009112ee7d"}, + {file = "aiohttp-3.13.0-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:a533873a7a4ec2270fb362ee5a0d3b98752e4e1dc9042b257cd54545a96bd8ed"}, + {file = "aiohttp-3.13.0-cp312-cp312-musllinux_1_2_riscv64.whl", hash = "sha256:ce887c5e54411d607ee0959cac15bb31d506d86a9bcaddf0b7e9d63325a7a802"}, + {file = "aiohttp-3.13.0-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:d871f6a30d43e32fc9252dc7b9febe1a042b3ff3908aa83868d7cf7c9579a59b"}, + {file = "aiohttp-3.13.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:222c828243b4789d79a706a876910f656fad4381661691220ba57b2ab4547865"}, + {file = "aiohttp-3.13.0-cp312-cp312-win32.whl", hash = "sha256:682d2e434ff2f1108314ff7f056ce44e457f12dbed0249b24e106e385cf154b9"}, + {file = "aiohttp-3.13.0-cp312-cp312-win_amd64.whl", hash = "sha256:0a2be20eb23888df130214b91c262a90e2de1553d6fb7de9e9010cec994c0ff2"}, + {file = "aiohttp-3.13.0-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:00243e51f16f6ec0fb021659d4af92f675f3cf9f9b39efd142aa3ad641d8d1e6"}, + {file = "aiohttp-3.13.0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:059978d2fddc462e9211362cbc8446747ecd930537fa559d3d25c256f032ff54"}, + {file = "aiohttp-3.13.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:564b36512a7da3b386143c611867e3f7cfb249300a1bf60889bd9985da67ab77"}, + {file = "aiohttp-3.13.0-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:4aa995b9156ae499393d949a456a7ab0b994a8241a96db73a3b73c7a090eff6a"}, + {file = "aiohttp-3.13.0-cp313-cp313-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:55ca0e95a3905f62f00900255ed807c580775174252999286f283e646d675a49"}, + {file = "aiohttp-3.13.0-cp313-cp313-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:49ce7525853a981fc35d380aa2353536a01a9ec1b30979ea4e35966316cace7e"}, + {file = "aiohttp-3.13.0-cp313-cp313-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:2117be9883501eaf95503bd313eb4c7a23d567edd44014ba15835a1e9ec6d852"}, + {file = "aiohttp-3.13.0-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:d169c47e40c911f728439da853b6fd06da83761012e6e76f11cb62cddae7282b"}, + {file = "aiohttp-3.13.0-cp313-cp313-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:703ad3f742fc81e543638a7bebddd35acadaa0004a5e00535e795f4b6f2c25ca"}, + {file = "aiohttp-3.13.0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:5bf635c3476f4119b940cc8d94ad454cbe0c377e61b4527f0192aabeac1e9370"}, + {file = "aiohttp-3.13.0-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:cfe6285ef99e7ee51cef20609be2bc1dd0e8446462b71c9db8bb296ba632810a"}, + {file = "aiohttp-3.13.0-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:34d8af6391c5f2e69749d7f037b614b8c5c42093c251f336bdbfa4b03c57d6c4"}, + {file = "aiohttp-3.13.0-cp313-cp313-musllinux_1_2_riscv64.whl", hash = "sha256:12f5d820fadc5848d4559ea838aef733cf37ed2a1103bba148ac2f5547c14c29"}, + {file = "aiohttp-3.13.0-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:0f1338b61ea66f4757a0544ed8a02ccbf60e38d9cfb3225888888dd4475ebb96"}, + {file = "aiohttp-3.13.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:582770f82513419512da096e8df21ca44f86a2e56e25dc93c5ab4df0fe065bf0"}, + {file = "aiohttp-3.13.0-cp313-cp313-win32.whl", hash = "sha256:3194b8cab8dbc882f37c13ef1262e0a3d62064fa97533d3aa124771f7bf1ecee"}, + {file = "aiohttp-3.13.0-cp313-cp313-win_amd64.whl", hash = "sha256:7897298b3eedc790257fef8a6ec582ca04e9dbe568ba4a9a890913b925b8ea21"}, + {file = "aiohttp-3.13.0-cp314-cp314-macosx_10_13_universal2.whl", hash = "sha256:c417f8c2e1137775569297c584a8a7144e5d1237789eae56af4faf1894a0b861"}, + {file = "aiohttp-3.13.0-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:f84b53326abf8e56ebc28a35cebf4a0f396a13a76300f500ab11fe0573bf0b52"}, + {file = "aiohttp-3.13.0-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:990a53b9d6a30b2878789e490758e568b12b4a7fb2527d0c89deb9650b0e5813"}, + {file = "aiohttp-3.13.0-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:c811612711e01b901e18964b3e5dec0d35525150f5f3f85d0aee2935f059910a"}, + {file = "aiohttp-3.13.0-cp314-cp314-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:ee433e594d7948e760b5c2a78cc06ac219df33b0848793cf9513d486a9f90a52"}, + {file = "aiohttp-3.13.0-cp314-cp314-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:19bb08e56f57c215e9572cd65cb6f8097804412c54081d933997ddde3e5ac579"}, + {file = "aiohttp-3.13.0-cp314-cp314-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:f27b7488144eb5dd9151cf839b195edd1569629d90ace4c5b6b18e4e75d1e63a"}, + {file = "aiohttp-3.13.0-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:d812838c109757a11354a161c95708ae4199c4fd4d82b90959b20914c1d097f6"}, + {file = "aiohttp-3.13.0-cp314-cp314-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:7c20db99da682f9180fa5195c90b80b159632fb611e8dbccdd99ba0be0970620"}, + {file = "aiohttp-3.13.0-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:cf8b0870047900eb1f17f453b4b3953b8ffbf203ef56c2f346780ff930a4d430"}, + {file = "aiohttp-3.13.0-cp314-cp314-musllinux_1_2_armv7l.whl", hash = "sha256:5b8a5557d5af3f4e3add52a58c4cf2b8e6e59fc56b261768866f5337872d596d"}, + {file = "aiohttp-3.13.0-cp314-cp314-musllinux_1_2_ppc64le.whl", hash = "sha256:052bcdd80c1c54b8a18a9ea0cd5e36f473dc8e38d51b804cea34841f677a9971"}, + {file = "aiohttp-3.13.0-cp314-cp314-musllinux_1_2_riscv64.whl", hash = "sha256:76484ba17b2832776581b7ab466d094e48eba74cb65a60aea20154dae485e8bd"}, + {file = "aiohttp-3.13.0-cp314-cp314-musllinux_1_2_s390x.whl", hash = "sha256:62d8a0adcdaf62ee56bfb37737153251ac8e4b27845b3ca065862fb01d99e247"}, + {file = "aiohttp-3.13.0-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:5004d727499ecb95f7c9147dd0bfc5b5670f71d355f0bd26d7af2d3af8e07d2f"}, + {file = "aiohttp-3.13.0-cp314-cp314-win32.whl", hash = "sha256:a1c20c26af48aea984f63f96e5d7af7567c32cb527e33b60a0ef0a6313cf8b03"}, + {file = "aiohttp-3.13.0-cp314-cp314-win_amd64.whl", hash = "sha256:56f7d230ec66e799fbfd8350e9544f8a45a4353f1cf40c1fea74c1780f555b8f"}, + {file = "aiohttp-3.13.0-cp314-cp314t-macosx_10_13_universal2.whl", hash = "sha256:2fd35177dc483ae702f07b86c782f4f4b100a8ce4e7c5778cea016979023d9fd"}, + {file = "aiohttp-3.13.0-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:4df1984c8804ed336089e88ac81a9417b1fd0db7c6f867c50a9264488797e778"}, + {file = "aiohttp-3.13.0-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:e68c0076052dd911a81d3acc4ef2911cc4ef65bf7cadbfbc8ae762da24da858f"}, + {file = "aiohttp-3.13.0-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:bc95c49853cd29613e4fe4ff96d73068ff89b89d61e53988442e127e8da8e7ba"}, + {file = "aiohttp-3.13.0-cp314-cp314t-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:3b3bdc89413117b40cc39baae08fd09cbdeb839d421c4e7dce6a34f6b54b3ac1"}, + {file = "aiohttp-3.13.0-cp314-cp314t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:3e77a729df23be2116acc4e9de2767d8e92445fbca68886dd991dc912f473755"}, + {file = "aiohttp-3.13.0-cp314-cp314t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:e88ab34826d6eeb6c67e6e92400b9ec653faf5092a35f07465f44c9f1c429f82"}, + {file = "aiohttp-3.13.0-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:019dbef24fe28ce2301419dd63a2b97250d9760ca63ee2976c2da2e3f182f82e"}, + {file = "aiohttp-3.13.0-cp314-cp314t-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:2c4aeaedd20771b7b4bcdf0ae791904445df6d856c02fc51d809d12d17cffdc7"}, + {file = "aiohttp-3.13.0-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:b3a8e6a2058a0240cfde542b641d0e78b594311bc1a710cbcb2e1841417d5cb3"}, + {file = "aiohttp-3.13.0-cp314-cp314t-musllinux_1_2_armv7l.whl", hash = "sha256:f8e38d55ca36c15f36d814ea414ecb2401d860de177c49f84a327a25b3ee752b"}, + {file = "aiohttp-3.13.0-cp314-cp314t-musllinux_1_2_ppc64le.whl", hash = "sha256:a921edbe971aade1bf45bcbb3494e30ba6863a5c78f28be992c42de980fd9108"}, + {file = "aiohttp-3.13.0-cp314-cp314t-musllinux_1_2_riscv64.whl", hash = "sha256:474cade59a447cb4019c0dce9f0434bf835fb558ea932f62c686fe07fe6db6a1"}, + {file = "aiohttp-3.13.0-cp314-cp314t-musllinux_1_2_s390x.whl", hash = "sha256:99a303ad960747c33b65b1cb65d01a62ac73fa39b72f08a2e1efa832529b01ed"}, + {file = "aiohttp-3.13.0-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:bb34001fc1f05f6b323e02c278090c07a47645caae3aa77ed7ed8a3ce6abcce9"}, + {file = "aiohttp-3.13.0-cp314-cp314t-win32.whl", hash = "sha256:dea698b64235d053def7d2f08af9302a69fcd760d1c7bd9988fd5d3b6157e657"}, + {file = "aiohttp-3.13.0-cp314-cp314t-win_amd64.whl", hash = "sha256:1f164699a060c0b3616459d13c1464a981fddf36f892f0a5027cbd45121fb14b"}, + {file = "aiohttp-3.13.0-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:fcc425fb6fd2a00c6d91c85d084c6b75a61bc8bc12159d08e17c5711df6c5ba4"}, + {file = "aiohttp-3.13.0-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:7c2c4c9ce834801651f81d6760d0a51035b8b239f58f298de25162fcf6f8bb64"}, + {file = "aiohttp-3.13.0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:f91e8f9053a07177868e813656ec57599cd2a63238844393cd01bd69c2e40147"}, + {file = "aiohttp-3.13.0-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:df46d9a3d78ec19b495b1107bf26e4fcf97c900279901f4f4819ac5bb2a02a4c"}, + {file = "aiohttp-3.13.0-cp39-cp39-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:3b1eb9871cbe43b6ca6fac3544682971539d8a1d229e6babe43446279679609d"}, + {file = "aiohttp-3.13.0-cp39-cp39-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:62a3cddf8d9a2eae1f79585fa81d32e13d0c509bb9e7ad47d33c83b45a944df7"}, + {file = "aiohttp-3.13.0-cp39-cp39-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:0f735e680c323ee7e9ef8e2ea26425c7dbc2ede0086fa83ce9d7ccab8a089f26"}, + {file = "aiohttp-3.13.0-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:6a51839f778b0e283b43cd82bb17f1835ee2cc1bf1101765e90ae886e53e751c"}, + {file = "aiohttp-3.13.0-cp39-cp39-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:ac90cfab65bc281d6752f22db5fa90419e33220af4b4fa53b51f5948f414c0e7"}, + {file = "aiohttp-3.13.0-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:62fd54f3e6f17976962ba67f911d62723c760a69d54f5d7b74c3ceb1a4e9ef8d"}, + {file = "aiohttp-3.13.0-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:cf2b60b65df05b6b2fa0d887f2189991a0dbf44a0dd18359001dc8fcdb7f1163"}, + {file = "aiohttp-3.13.0-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:1ccedfe280e804d9a9d7fe8b8c4309d28e364b77f40309c86596baa754af50b1"}, + {file = "aiohttp-3.13.0-cp39-cp39-musllinux_1_2_riscv64.whl", hash = "sha256:ea01ffbe23df53ece0c8732d1585b3d6079bb8c9ee14f3745daf000051415a31"}, + {file = "aiohttp-3.13.0-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:19ba8625fa69523627b67f7e9901b587a4952470f68814d79cdc5bc460e9b885"}, + {file = "aiohttp-3.13.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:4b14bfae90598d331b5061fd15a7c290ea0c15b34aeb1cf620464bb5ec02a602"}, + {file = "aiohttp-3.13.0-cp39-cp39-win32.whl", hash = "sha256:cf7a4b976da219e726d0043fc94ae8169c0dba1d3a059b3c1e2c964bafc5a77d"}, + {file = "aiohttp-3.13.0-cp39-cp39-win_amd64.whl", hash = "sha256:6b9697d15231aeaed4786f090c9c8bc3ab5f0e0a6da1e76c135a310def271020"}, + {file = "aiohttp-3.13.0.tar.gz", hash = "sha256:378dbc57dd8cf341ce243f13fa1fa5394d68e2e02c15cd5f28eae35a70ec7f67"}, ] [package.dependencies] @@ -131,7 +165,7 @@ propcache = ">=0.2.0" yarl = ">=1.17.0,<2.0" [package.extras] -speedups = ["Brotli ; platform_python_implementation == \"CPython\"", "aiodns (>=3.3.0)", "brotlicffi ; platform_python_implementation != \"CPython\""] +speedups = ["Brotli ; platform_python_implementation == \"CPython\"", "aiodns (>=3.3.0)", "brotlicffi ; platform_python_implementation != \"CPython\"", "zstandard ; platform_python_implementation == \"CPython\" and python_version < \"3.14\""] [[package]] name = "aiosignal" @@ -191,14 +225,14 @@ files = [ [[package]] name = "anthropic" -version = "0.68.0" +version = "0.69.0" description = "The official Python library for the anthropic API" optional = false python-versions = ">=3.8" groups = ["main"] files = [ - {file = "anthropic-0.68.0-py3-none-any.whl", hash = "sha256:ac579ea5eca22a7165b1042e6af57c4bf556e51afae3ca80e24768d4756b78c0"}, - {file = "anthropic-0.68.0.tar.gz", hash = "sha256:507e9b5f627d1b249128ff15b21855e718fa4ed8dabc787d0e68860a4b32a7a8"}, + {file = "anthropic-0.69.0-py3-none-any.whl", hash = "sha256:1f73193040f33f11e27c2cd6ec25f24fe7c3f193dc1c5cde6b7a08b18a16bcc5"}, + {file = "anthropic-0.69.0.tar.gz", hash = "sha256:c604d287f4d73640f40bd2c0f3265a2eb6ce034217ead0608f6b07a8bc5ae5f2"}, ] [package.dependencies] @@ -229,14 +263,14 @@ files = [ [[package]] name = "anyio" -version = "4.9.0" -description = "High level compatibility layer for multiple asynchronous event loop implementations" +version = "4.11.0" +description = "High-level concurrency and networking framework on top of asyncio or Trio" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "anyio-4.9.0-py3-none-any.whl", hash = "sha256:9f76d541cad6e36af7beb62e978876f3b41e3e04f2c1fbf0884604c0a9c4d93c"}, - {file = "anyio-4.9.0.tar.gz", hash = "sha256:673c0c244e15788651a4ff38710fea9675823028a6f08a5eda409e0c9840a028"}, + {file = "anyio-4.11.0-py3-none-any.whl", hash = "sha256:0287e96f4d26d4149305414d4e3bc32f0dcd0862365a4bddea19d7a1ec38c4fc"}, + {file = "anyio-4.11.0.tar.gz", hash = "sha256:82a8d0b81e318cc5ce71a5f1f8b5c4e63619620b63141ef8c995fa0db95a57c4"}, ] [package.dependencies] @@ -245,9 +279,7 @@ sniffio = ">=1.1" typing_extensions = {version = ">=4.5", markers = "python_version < \"3.13\""} [package.extras] -doc = ["Sphinx (>=8.2,<9.0)", "packaging", "sphinx-autodoc-typehints (>=1.2.0)", "sphinx_rtd_theme"] -test = ["anyio[trio]", "blockbuster (>=1.5.23)", "coverage[toml] (>=7)", "exceptiongroup (>=1.2.0)", "hypothesis (>=4.0)", "psutil (>=5.9)", "pytest (>=7.0)", "trustme", "truststore (>=0.9.1) ; python_version >= \"3.10\"", "uvloop (>=0.21) ; platform_python_implementation == \"CPython\" and platform_system != \"Windows\" and python_version < \"3.14\""] -trio = ["trio (>=0.26.1)"] +trio = ["trio (>=0.31.0)"] [[package]] name = "appdirs" @@ -310,66 +342,74 @@ files = [ [[package]] name = "attrs" -version = "25.3.0" +version = "25.4.0" description = "Classes Without Boilerplate" optional = false -python-versions = ">=3.8" +python-versions = ">=3.9" groups = ["main"] files = [ - {file = "attrs-25.3.0-py3-none-any.whl", hash = "sha256:427318ce031701fea540783410126f03899a97ffc6f61596ad581ac2e40e3bc3"}, - {file = "attrs-25.3.0.tar.gz", hash = "sha256:75d7cefc7fb576747b2c81b4442d4d4a1ce0900973527c011d1030fd3bf4af1b"}, + {file = "attrs-25.4.0-py3-none-any.whl", hash = "sha256:adcf7e2a1fb3b36ac48d97835bb6d8ade15b8dcce26aba8bf1d14847b57a3373"}, + {file = "attrs-25.4.0.tar.gz", hash = "sha256:16d5969b87f0859ef33a48b35d55ac1be6e42ae49d5e853b597db70c35c57e11"}, ] -[package.extras] -benchmark = ["cloudpickle ; platform_python_implementation == \"CPython\"", "hypothesis", "mypy (>=1.11.1) ; platform_python_implementation == \"CPython\" and python_version >= \"3.10\"", "pympler", "pytest (>=4.3.0)", "pytest-codspeed", "pytest-mypy-plugins ; platform_python_implementation == \"CPython\" and python_version >= \"3.10\"", "pytest-xdist[psutil]"] -cov = ["cloudpickle ; platform_python_implementation == \"CPython\"", "coverage[toml] (>=5.3)", "hypothesis", "mypy (>=1.11.1) ; platform_python_implementation == \"CPython\" and python_version >= \"3.10\"", "pympler", "pytest (>=4.3.0)", "pytest-mypy-plugins ; platform_python_implementation == \"CPython\" and python_version >= \"3.10\"", "pytest-xdist[psutil]"] -dev = ["cloudpickle ; platform_python_implementation == \"CPython\"", "hypothesis", "mypy (>=1.11.1) ; platform_python_implementation == \"CPython\" and python_version >= \"3.10\"", "pre-commit-uv", "pympler", "pytest (>=4.3.0)", "pytest-mypy-plugins ; platform_python_implementation == \"CPython\" and python_version >= \"3.10\"", "pytest-xdist[psutil]"] -docs = ["cogapp", "furo", "myst-parser", "sphinx", "sphinx-notfound-page", "sphinxcontrib-towncrier", "towncrier"] -tests = ["cloudpickle ; platform_python_implementation == \"CPython\"", "hypothesis", "mypy (>=1.11.1) ; platform_python_implementation == \"CPython\" and python_version >= \"3.10\"", "pympler", "pytest (>=4.3.0)", "pytest-mypy-plugins ; platform_python_implementation == \"CPython\" and python_version >= \"3.10\"", "pytest-xdist[psutil]"] -tests-mypy = ["mypy (>=1.11.1) ; platform_python_implementation == \"CPython\" and python_version >= \"3.10\"", "pytest-mypy-plugins ; platform_python_implementation == \"CPython\" and python_version >= \"3.10\""] - [[package]] name = "audioop-lts" -version = "0.2.1" +version = "0.2.2" description = "LTS Port of Python audioop" optional = false python-versions = ">=3.13" groups = ["main"] markers = "python_version >= \"3.13\" and extra == \"gradio\"" files = [ - {file = "audioop_lts-0.2.1-cp313-abi3-macosx_10_13_universal2.whl", hash = "sha256:fd1345ae99e17e6910f47ce7d52673c6a1a70820d78b67de1b7abb3af29c426a"}, - {file = "audioop_lts-0.2.1-cp313-abi3-macosx_10_13_x86_64.whl", hash = "sha256:e175350da05d2087e12cea8e72a70a1a8b14a17e92ed2022952a4419689ede5e"}, - {file = "audioop_lts-0.2.1-cp313-abi3-macosx_11_0_arm64.whl", hash = "sha256:4a8dd6a81770f6ecf019c4b6d659e000dc26571b273953cef7cd1d5ce2ff3ae6"}, - {file = "audioop_lts-0.2.1-cp313-abi3-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:d1cd3c0b6f2ca25c7d2b1c3adeecbe23e65689839ba73331ebc7d893fcda7ffe"}, - {file = "audioop_lts-0.2.1-cp313-abi3-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:ff3f97b3372c97782e9c6d3d7fdbe83bce8f70de719605bd7ee1839cd1ab360a"}, - {file = "audioop_lts-0.2.1-cp313-abi3-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:a351af79edefc2a1bd2234bfd8b339935f389209943043913a919df4b0f13300"}, - {file = "audioop_lts-0.2.1-cp313-abi3-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:2aeb6f96f7f6da80354330470b9134d81b4cf544cdd1c549f2f45fe964d28059"}, - {file = "audioop_lts-0.2.1-cp313-abi3-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:c589f06407e8340e81962575fcffbba1e92671879a221186c3d4662de9fe804e"}, - {file = "audioop_lts-0.2.1-cp313-abi3-musllinux_1_2_aarch64.whl", hash = "sha256:fbae5d6925d7c26e712f0beda5ed69ebb40e14212c185d129b8dfbfcc335eb48"}, - {file = "audioop_lts-0.2.1-cp313-abi3-musllinux_1_2_i686.whl", hash = "sha256:d2d5434717f33117f29b5691fbdf142d36573d751716249a288fbb96ba26a281"}, - {file = "audioop_lts-0.2.1-cp313-abi3-musllinux_1_2_ppc64le.whl", hash = "sha256:f626a01c0a186b08f7ff61431c01c055961ee28769591efa8800beadd27a2959"}, - {file = "audioop_lts-0.2.1-cp313-abi3-musllinux_1_2_s390x.whl", hash = "sha256:05da64e73837f88ee5c6217d732d2584cf638003ac72df124740460531e95e47"}, - {file = "audioop_lts-0.2.1-cp313-abi3-musllinux_1_2_x86_64.whl", hash = "sha256:56b7a0a4dba8e353436f31a932f3045d108a67b5943b30f85a5563f4d8488d77"}, - {file = "audioop_lts-0.2.1-cp313-abi3-win32.whl", hash = "sha256:6e899eb8874dc2413b11926b5fb3857ec0ab55222840e38016a6ba2ea9b7d5e3"}, - {file = "audioop_lts-0.2.1-cp313-abi3-win_amd64.whl", hash = "sha256:64562c5c771fb0a8b6262829b9b4f37a7b886c01b4d3ecdbae1d629717db08b4"}, - {file = "audioop_lts-0.2.1-cp313-abi3-win_arm64.whl", hash = "sha256:c45317debeb64002e980077642afbd977773a25fa3dfd7ed0c84dccfc1fafcb0"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:3827e3fce6fee4d69d96a3d00cd2ab07f3c0d844cb1e44e26f719b34a5b15455"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:161249db9343b3c9780ca92c0be0d1ccbfecdbccac6844f3d0d44b9c4a00a17f"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:5b7b4ff9de7a44e0ad2618afdc2ac920b91f4a6d3509520ee65339d4acde5abf"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:72e37f416adb43b0ced93419de0122b42753ee74e87070777b53c5d2241e7fab"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:534ce808e6bab6adb65548723c8cbe189a3379245db89b9d555c4210b4aaa9b6"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:d2de9b6fb8b1cf9f03990b299a9112bfdf8b86b6987003ca9e8a6c4f56d39543"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:f24865991b5ed4b038add5edbf424639d1358144f4e2a3e7a84bc6ba23e35074"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:2bdb3b7912ccd57ea53197943f1bbc67262dcf29802c4a6df79ec1c715d45a78"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:120678b208cca1158f0a12d667af592e067f7a50df9adc4dc8f6ad8d065a93fb"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-musllinux_1_2_i686.whl", hash = "sha256:54cd4520fc830b23c7d223693ed3e1b4d464997dd3abc7c15dce9a1f9bd76ab2"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-musllinux_1_2_ppc64le.whl", hash = "sha256:d6bd20c7a10abcb0fb3d8aaa7508c0bf3d40dfad7515c572014da4b979d3310a"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-musllinux_1_2_s390x.whl", hash = "sha256:f0ed1ad9bd862539ea875fb339ecb18fcc4148f8d9908f4502df28f94d23491a"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:e1af3ff32b8c38a7d900382646e91f2fc515fd19dea37e9392275a5cbfdbff63"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-win32.whl", hash = "sha256:f51bb55122a89f7a0817d7ac2319744b4640b5b446c4c3efcea5764ea99ae509"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-win_amd64.whl", hash = "sha256:f0f2f336aa2aee2bce0b0dcc32bbba9178995454c7b979cf6ce086a8801e14c7"}, - {file = "audioop_lts-0.2.1-cp313-cp313t-win_arm64.whl", hash = "sha256:78bfb3703388c780edf900be66e07de5a3d4105ca8e8720c5c4d67927e0b15d0"}, - {file = "audioop_lts-0.2.1.tar.gz", hash = "sha256:e81268da0baa880431b68b1308ab7257eb33f356e57a5f9b1f915dfb13dd1387"}, + {file = "audioop_lts-0.2.2-cp313-abi3-macosx_10_13_universal2.whl", hash = "sha256:fd3d4602dc64914d462924a08c1a9816435a2155d74f325853c1f1ac3b2d9800"}, + {file = "audioop_lts-0.2.2-cp313-abi3-macosx_10_13_x86_64.whl", hash = "sha256:550c114a8df0aafe9a05442a1162dfc8fec37e9af1d625ae6060fed6e756f303"}, + {file = "audioop_lts-0.2.2-cp313-abi3-macosx_11_0_arm64.whl", hash = "sha256:9a13dc409f2564de15dd68be65b462ba0dde01b19663720c68c1140c782d1d75"}, + {file = "audioop_lts-0.2.2-cp313-abi3-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:51c916108c56aa6e426ce611946f901badac950ee2ddaf302b7ed35d9958970d"}, + {file = "audioop_lts-0.2.2-cp313-abi3-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:47eba38322370347b1c47024defbd36374a211e8dd5b0dcbce7b34fdb6f8847b"}, + {file = "audioop_lts-0.2.2-cp313-abi3-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:ba7c3a7e5f23e215cb271516197030c32aef2e754252c4c70a50aaff7031a2c8"}, + {file = "audioop_lts-0.2.2-cp313-abi3-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:def246fe9e180626731b26e89816e79aae2276f825420a07b4a647abaa84becc"}, + {file = "audioop_lts-0.2.2-cp313-abi3-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:e160bf9df356d841bb6c180eeeea1834085464626dc1b68fa4e1d59070affdc3"}, + {file = "audioop_lts-0.2.2-cp313-abi3-musllinux_1_2_aarch64.whl", hash = "sha256:4b4cd51a57b698b2d06cb9993b7ac8dfe89a3b2878e96bc7948e9f19ff51dba6"}, + {file = "audioop_lts-0.2.2-cp313-abi3-musllinux_1_2_ppc64le.whl", hash = "sha256:4a53aa7c16a60a6857e6b0b165261436396ef7293f8b5c9c828a3a203147ed4a"}, + {file = "audioop_lts-0.2.2-cp313-abi3-musllinux_1_2_riscv64.whl", hash = "sha256:3fc38008969796f0f689f1453722a0f463da1b8a6fbee11987830bfbb664f623"}, + {file = "audioop_lts-0.2.2-cp313-abi3-musllinux_1_2_s390x.whl", hash = "sha256:15ab25dd3e620790f40e9ead897f91e79c0d3ce65fe193c8ed6c26cffdd24be7"}, + {file = "audioop_lts-0.2.2-cp313-abi3-musllinux_1_2_x86_64.whl", hash = "sha256:03f061a1915538fd96272bac9551841859dbb2e3bf73ebe4a23ef043766f5449"}, + {file = "audioop_lts-0.2.2-cp313-abi3-win32.whl", hash = "sha256:3bcddaaf6cc5935a300a8387c99f7a7fbbe212a11568ec6cf6e4bc458c048636"}, + {file = "audioop_lts-0.2.2-cp313-abi3-win_amd64.whl", hash = "sha256:a2c2a947fae7d1062ef08c4e369e0ba2086049a5e598fda41122535557012e9e"}, + {file = "audioop_lts-0.2.2-cp313-abi3-win_arm64.whl", hash = "sha256:5f93a5db13927a37d2d09637ccca4b2b6b48c19cd9eda7b17a2e9f77edee6a6f"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:73f80bf4cd5d2ca7814da30a120de1f9408ee0619cc75da87d0641273d202a09"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:106753a83a25ee4d6f473f2be6b0966fc1c9af7e0017192f5531a3e7463dce58"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:fbdd522624141e40948ab3e8cdae6e04c748d78710e9f0f8d4dae2750831de19"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:143fad0311e8209ece30a8dbddab3b65ab419cbe8c0dde6e8828da25999be911"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:dfbbc74ec68a0fd08cfec1f4b5e8cca3d3cd7de5501b01c4b5d209995033cde9"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:cfcac6aa6f42397471e4943e0feb2244549db5c5d01efcd02725b96af417f3fe"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:752d76472d9804ac60f0078c79cdae8b956f293177acd2316cd1e15149aee132"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:83c381767e2cc10e93e40281a04852facc4cd9334550e0f392f72d1c0a9c5753"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:c0022283e9556e0f3643b7c3c03f05063ca72b3063291834cca43234f20c60bb"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-musllinux_1_2_ppc64le.whl", hash = "sha256:a2d4f1513d63c795e82948e1305f31a6d530626e5f9f2605408b300ae6095093"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-musllinux_1_2_riscv64.whl", hash = "sha256:c9c8e68d8b4a56fda8c025e538e639f8c5953f5073886b596c93ec9b620055e7"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-musllinux_1_2_s390x.whl", hash = "sha256:96f19de485a2925314f5020e85911fb447ff5fbef56e8c7c6927851b95533a1c"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:e541c3ef484852ef36545f66209444c48b28661e864ccadb29daddb6a4b8e5f5"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-win32.whl", hash = "sha256:d5e73fa573e273e4f2e5ff96f9043858a5e9311e94ffefd88a3186a910c70917"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-win_amd64.whl", hash = "sha256:9191d68659eda01e448188f60364c7763a7ca6653ed3f87ebb165822153a8547"}, + {file = "audioop_lts-0.2.2-cp313-cp313t-win_arm64.whl", hash = "sha256:c174e322bb5783c099aaf87faeb240c8d210686b04bd61dfd05a8e5a83d88969"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-macosx_10_13_universal2.whl", hash = "sha256:f9ee9b52f5f857fbaf9d605a360884f034c92c1c23021fb90b2e39b8e64bede6"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:49ee1a41738a23e98d98b937a0638357a2477bc99e61b0f768a8f654f45d9b7a"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:5b00be98ccd0fc123dcfad31d50030d25fcf31488cde9e61692029cd7394733b"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:a6d2e0f9f7a69403e388894d4ca5ada5c47230716a03f2847cfc7bd1ecb589d6"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:f9b0b8a03ef474f56d1a842af1a2e01398b8f7654009823c6d9e0ecff4d5cfbf"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:2b267b70747d82125f1a021506565bdc5609a2b24bcb4773c16d79d2bb260bbd"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:0337d658f9b81f4cd0fdb1f47635070cc084871a3d4646d9de74fdf4e7c3d24a"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:167d3b62586faef8b6b2275c3218796b12621a60e43f7e9d5845d627b9c9b80e"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:0d9385e96f9f6da847f4d571ce3cb15b5091140edf3db97276872647ce37efd7"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-musllinux_1_2_ppc64le.whl", hash = "sha256:48159d96962674eccdca9a3df280e864e8ac75e40a577cc97c5c42667ffabfc5"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-musllinux_1_2_riscv64.whl", hash = "sha256:8fefe5868cd082db1186f2837d64cfbfa78b548ea0d0543e9b28935ccce81ce9"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-musllinux_1_2_s390x.whl", hash = "sha256:58cf54380c3884fb49fdd37dfb7a772632b6701d28edd3e2904743c5e1773602"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:088327f00488cdeed296edd9215ca159f3a5a5034741465789cad403fcf4bec0"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-win32.whl", hash = "sha256:068aa17a38b4e0e7de771c62c60bbca2455924b67a8814f3b0dee92b5820c0b3"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-win_amd64.whl", hash = "sha256:a5bf613e96f49712073de86f20dbdd4014ca18efd4d34ed18c75bd808337851b"}, + {file = "audioop_lts-0.2.2-cp314-cp314t-win_arm64.whl", hash = "sha256:b492c3b040153e68b9fdaff5913305aaaba5bb433d8a7f73d5cf6a64ed3cc1dd"}, + {file = "audioop_lts-0.2.2.tar.gz", hash = "sha256:64d0c62d88e67b98a1a5e71987b7aa7b5bcffc7dcee65b635823dbdd0a8dbbd0"}, ] [[package]] @@ -396,7 +436,7 @@ mcp = {version = ">=1.3.0,<2", extras = ["cli"]} oaklib = ">=0.6.19" onnxruntime = "<=1.19.0" paper-qa = ">=5.20.0,<6" -pydantic-ai = "==0.2.0" +pydantic-ai = ">=0.2.0" pytest-asyncio = ">=0.25.3,<0.26" tabulate = ">=0.9.0" undetected-chromedriver = ">=3.5.5" @@ -468,33 +508,33 @@ files = [ [[package]] name = "beartype" -version = "0.21.0" +version = "0.22.2" description = "Unbearably fast near-real-time hybrid runtime-static type-checking in pure Python." optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "beartype-0.21.0-py3-none-any.whl", hash = "sha256:b6a1bd56c72f31b0a496a36cc55df6e2f475db166ad07fa4acc7e74f4c7f34c0"}, - {file = "beartype-0.21.0.tar.gz", hash = "sha256:f9a5078f5ce87261c2d22851d19b050b64f6a805439e8793aecf01ce660d3244"}, + {file = "beartype-0.22.2-py3-none-any.whl", hash = "sha256:12077afe3528eba5c5b801f816712f7ff06f6da5509994c79561e29b48bcedb8"}, + {file = "beartype-0.22.2.tar.gz", hash = "sha256:ff3a7df26af8d15fa87f97934f0f6d41bbdadca971c410819104998dd26013d2"}, ] [package.extras] -dev = ["autoapi (>=0.9.0)", "click", "coverage (>=5.5)", "equinox ; sys_platform == \"linux\"", "jax[cpu] ; sys_platform == \"linux\"", "jaxtyping ; sys_platform == \"linux\"", "langchain", "mypy (>=0.800) ; platform_python_implementation != \"PyPy\"", "nuitka (>=1.2.6) ; sys_platform == \"linux\"", "numba ; python_version < \"3.13.0\"", "numpy ; sys_platform != \"darwin\" and platform_python_implementation != \"PyPy\"", "pandera", "pydata-sphinx-theme (<=0.7.2)", "pygments", "pyright (>=1.1.370)", "pytest (>=4.0.0)", "rich-click", "sphinx", "sphinx (>=4.2.0,<6.0.0)", "sphinxext-opengraph (>=0.7.5)", "sqlalchemy", "tox (>=3.20.1)", "typing-extensions (>=3.10.0.0)", "xarray"] -doc-rtd = ["autoapi (>=0.9.0)", "pydata-sphinx-theme (<=0.7.2)", "sphinx (>=4.2.0,<6.0.0)", "sphinxext-opengraph (>=0.7.5)"] -test = ["click", "coverage (>=5.5)", "equinox ; sys_platform == \"linux\"", "jax[cpu] ; sys_platform == \"linux\"", "jaxtyping ; sys_platform == \"linux\"", "langchain", "mypy (>=0.800) ; platform_python_implementation != \"PyPy\"", "nuitka (>=1.2.6) ; sys_platform == \"linux\"", "numba ; python_version < \"3.13.0\"", "numpy ; sys_platform != \"darwin\" and platform_python_implementation != \"PyPy\"", "pandera", "pygments", "pyright (>=1.1.370)", "pytest (>=4.0.0)", "rich-click", "sphinx", "sqlalchemy", "tox (>=3.20.1)", "typing-extensions (>=3.10.0.0)", "xarray"] -test-tox = ["click", "equinox ; sys_platform == \"linux\"", "jax[cpu] ; sys_platform == \"linux\"", "jaxtyping ; sys_platform == \"linux\"", "langchain", "mypy (>=0.800) ; platform_python_implementation != \"PyPy\"", "nuitka (>=1.2.6) ; sys_platform == \"linux\"", "numba ; python_version < \"3.13.0\"", "numpy ; sys_platform != \"darwin\" and platform_python_implementation != \"PyPy\"", "pandera", "pygments", "pyright (>=1.1.370)", "pytest (>=4.0.0)", "rich-click", "sphinx", "sqlalchemy", "typing-extensions (>=3.10.0.0)", "xarray"] +dev = ["autoapi (>=0.9.0)", "celery", "click", "coverage (>=5.5)", "equinox ; sys_platform == \"linux\" and python_version < \"3.14.0\"", "fastmcp ; python_version > \"3.9.0\" and python_version < \"3.14.0\"", "jax[cpu] ; sys_platform == \"linux\" and python_version < \"3.14.0\"", "jaxtyping ; sys_platform == \"linux\"", "langchain ; python_version < \"3.14.0\" and sys_platform != \"darwin\" and platform_python_implementation != \"PyPy\"", "mypy (>=0.800) ; platform_python_implementation != \"PyPy\"", "nuitka (>=1.2.6) ; sys_platform == \"linux\" and python_version < \"3.14.0\"", "numba ; python_version < \"3.14.0\"", "numpy ; python_version < \"3.14.0\" and sys_platform != \"darwin\" and platform_python_implementation != \"PyPy\"", "pandera (>=0.26.0) ; python_version < \"3.14.0\"", "polars ; python_version < \"3.14.0\"", "pydata-sphinx-theme (<=0.7.2)", "pygments", "pyright (>=1.1.370)", "pytest (>=4.0.0)", "rich-click", "setuptools", "sphinx", "sphinx (>=4.2.0,<6.0.0)", "sphinxext-opengraph (>=0.7.5)", "sqlalchemy", "torch ; sys_platform == \"linux\" and python_version < \"3.14.0\"", "tox (>=3.20.1)", "typer", "typing-extensions (>=3.10.0.0)", "xarray ; python_version < \"3.14.0\""] +doc-rtd = ["autoapi (>=0.9.0)", "pydata-sphinx-theme (<=0.7.2)", "setuptools", "sphinx (>=4.2.0,<6.0.0)", "sphinxext-opengraph (>=0.7.5)"] +test = ["celery", "click", "coverage (>=5.5)", "equinox ; sys_platform == \"linux\" and python_version < \"3.14.0\"", "fastmcp ; python_version > \"3.9.0\" and python_version < \"3.14.0\"", "jax[cpu] ; sys_platform == \"linux\" and python_version < \"3.14.0\"", "jaxtyping ; sys_platform == \"linux\"", "langchain ; python_version < \"3.14.0\" and sys_platform != \"darwin\" and platform_python_implementation != \"PyPy\"", "mypy (>=0.800) ; platform_python_implementation != \"PyPy\"", "nuitka (>=1.2.6) ; sys_platform == \"linux\" and python_version < \"3.14.0\"", "numba ; python_version < \"3.14.0\"", "numpy ; python_version < \"3.14.0\" and sys_platform != \"darwin\" and platform_python_implementation != \"PyPy\"", "pandera (>=0.26.0) ; python_version < \"3.14.0\"", "polars ; python_version < \"3.14.0\"", "pygments", "pyright (>=1.1.370)", "pytest (>=4.0.0)", "rich-click", "sphinx", "sqlalchemy", "torch ; sys_platform == \"linux\" and python_version < \"3.14.0\"", "tox (>=3.20.1)", "typer", "typing-extensions (>=3.10.0.0)", "xarray ; python_version < \"3.14.0\""] +test-tox = ["celery", "click", "equinox ; sys_platform == \"linux\" and python_version < \"3.14.0\"", "fastmcp ; python_version > \"3.9.0\" and python_version < \"3.14.0\"", "jax[cpu] ; sys_platform == \"linux\" and python_version < \"3.14.0\"", "jaxtyping ; sys_platform == \"linux\"", "langchain ; python_version < \"3.14.0\" and sys_platform != \"darwin\" and platform_python_implementation != \"PyPy\"", "mypy (>=0.800) ; platform_python_implementation != \"PyPy\"", "nuitka (>=1.2.6) ; sys_platform == \"linux\" and python_version < \"3.14.0\"", "numba ; python_version < \"3.14.0\"", "numpy ; python_version < \"3.14.0\" and sys_platform != \"darwin\" and platform_python_implementation != \"PyPy\"", "pandera (>=0.26.0) ; python_version < \"3.14.0\"", "polars ; python_version < \"3.14.0\"", "pygments", "pyright (>=1.1.370)", "pytest (>=4.0.0)", "rich-click", "sphinx", "sqlalchemy", "torch ; sys_platform == \"linux\" and python_version < \"3.14.0\"", "typer", "typing-extensions (>=3.10.0.0)", "xarray ; python_version < \"3.14.0\""] test-tox-coverage = ["coverage (>=5.5)"] [[package]] name = "beautifulsoup4" -version = "4.13.4" +version = "4.14.2" description = "Screen-scraping library" optional = false python-versions = ">=3.7.0" groups = ["main"] files = [ - {file = "beautifulsoup4-4.13.4-py3-none-any.whl", hash = "sha256:9bbbb14bfde9d79f38b8cd5f8c7c85f4b8f2523190ebed90e950a8dea4cb1c4b"}, - {file = "beautifulsoup4-4.13.4.tar.gz", hash = "sha256:dbb3c4e1ceae6aefebdaf2423247260cd062430a410e38c66f2baa50a8437195"}, + {file = "beautifulsoup4-4.14.2-py3-none-any.whl", hash = "sha256:5ef6fa3a8cbece8488d66985560f97ed091e22bbc4e9c2338508a9d5de6d4515"}, + {file = "beautifulsoup4-4.14.2.tar.gz", hash = "sha256:2a98ab9f944a11acee9cc848508ec28d9228abfd522ef0fad6a02a72e0ded69e"}, ] [package.dependencies] @@ -510,34 +550,34 @@ lxml = ["lxml"] [[package]] name = "boto3" -version = "1.39.9" +version = "1.40.51" description = "The AWS SDK for Python" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "boto3-1.39.9-py3-none-any.whl", hash = "sha256:5bc85e9fdec4e21ef5ca2c22b4d51a3e32b53f3da36ce51f5a3ea4dbde07b132"}, - {file = "boto3-1.39.9.tar.gz", hash = "sha256:e3d3a6b617e1575e7ec854c820a882ab2e189a0421e74dc0dca2c9e13d4370a5"}, + {file = "boto3-1.40.51-py3-none-any.whl", hash = "sha256:6aa81b9acb4eff87b5505ae26c948883a2015cc3308ce5168a9df6e00ab815d2"}, + {file = "boto3-1.40.51.tar.gz", hash = "sha256:ed1b7750df07b2f2ece0141ff2ed0489db2ec2b5311a956d00a496b05fd4fadb"}, ] [package.dependencies] -botocore = ">=1.39.9,<1.40.0" +botocore = ">=1.40.51,<1.41.0" jmespath = ">=0.7.1,<2.0.0" -s3transfer = ">=0.13.0,<0.14.0" +s3transfer = ">=0.14.0,<0.15.0" [package.extras] crt = ["botocore[crt] (>=1.21.0,<2.0a0)"] [[package]] name = "botocore" -version = "1.39.9" +version = "1.40.51" description = "Low-level, data-driven core of boto 3." optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "botocore-1.39.9-py3-none-any.whl", hash = "sha256:a9691cbe03a3bc8b2720b3c36e5c5a2eecace6acd72bfb1107f00e75edaec4f3"}, - {file = "botocore-1.39.9.tar.gz", hash = "sha256:02f141c2849e4589a79feea245ce4ecc478d48b7865572445af8aae3b041772d"}, + {file = "botocore-1.40.51-py3-none-any.whl", hash = "sha256:d5811a834bbdec6dac540565eab9f5ad954ed439b535686fbc3219e1cbfbfc49"}, + {file = "botocore-1.40.51.tar.gz", hash = "sha256:a06de20408c3009e59e8f161a1146f1801d279d0923ab950349154900951bb20"}, ] [package.dependencies] @@ -546,7 +586,7 @@ python-dateutil = ">=2.1,<3.0.0" urllib3 = {version = ">=1.25.4,<2.2.0 || >2.2.0,<3", markers = "python_version >= \"3.10\""} [package.extras] -crt = ["awscrt (==0.23.8)"] +crt = ["awscrt (==0.27.6)"] [[package]] name = "brotli" @@ -701,14 +741,14 @@ beautifulsoup4 = "*" [[package]] name = "cachetools" -version = "5.5.2" +version = "6.2.1" description = "Extensible memoizing collections and decorators" optional = false -python-versions = ">=3.7" +python-versions = ">=3.9" groups = ["main", "dev"] files = [ - {file = "cachetools-5.5.2-py3-none-any.whl", hash = "sha256:d26a22bcc62eb95c3beabd9f1ee5e820d3d2704fe2967cbe350e20c8ffcd3f0a"}, - {file = "cachetools-5.5.2.tar.gz", hash = "sha256:1a661caa9175d26759571b2e19580f9d6393969e5dfca11fdb1f947a23e640d4"}, + {file = "cachetools-6.2.1-py3-none-any.whl", hash = "sha256:09868944b6dde876dfd44e1d47e18484541eaf12f26f29b7af91b26cc892d701"}, + {file = "cachetools-6.2.1.tar.gz", hash = "sha256:3f391e4bd8f8bf0931169baf7456cc822705f4e2a31f840d218f445b9a854201"}, ] [[package]] @@ -756,121 +796,138 @@ test = ["flake8", "isort", "pytest"] [[package]] name = "cattrs" -version = "25.1.1" +version = "25.3.0" description = "Composable complex class support for attrs and dataclasses." optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "cattrs-25.1.1-py3-none-any.whl", hash = "sha256:1b40b2d3402af7be79a7e7e097a9b4cd16d4c06e6d526644b0b26a063a1cc064"}, - {file = "cattrs-25.1.1.tar.gz", hash = "sha256:c914b734e0f2d59e5b720d145ee010f1fd9a13ee93900922a2f3f9d593b8382c"}, + {file = "cattrs-25.3.0-py3-none-any.whl", hash = "sha256:9896e84e0a5bf723bc7b4b68f4481785367ce07a8a02e7e9ee6eb2819bc306ff"}, + {file = "cattrs-25.3.0.tar.gz", hash = "sha256:1ac88d9e5eda10436c4517e390a4142d88638fe682c436c93db7ce4a277b884a"}, ] [package.dependencies] -attrs = ">=24.3.0" -typing-extensions = ">=4.12.2" +attrs = ">=25.4.0" +typing-extensions = ">=4.14.0" [package.extras] bson = ["pymongo (>=4.4.0)"] cbor2 = ["cbor2 (>=5.4.6)"] msgpack = ["msgpack (>=1.0.5)"] msgspec = ["msgspec (>=0.19.0) ; implementation_name == \"cpython\""] -orjson = ["orjson (>=3.10.7) ; implementation_name == \"cpython\""] +orjson = ["orjson (>=3.11.3) ; implementation_name == \"cpython\""] pyyaml = ["pyyaml (>=6.0)"] tomlkit = ["tomlkit (>=0.11.8)"] ujson = ["ujson (>=5.10.0)"] [[package]] name = "certifi" -version = "2025.7.14" +version = "2025.10.5" description = "Python package for providing Mozilla's CA Bundle." optional = false python-versions = ">=3.7" groups = ["main", "docs"] files = [ - {file = "certifi-2025.7.14-py3-none-any.whl", hash = "sha256:6b31f564a415d79ee77df69d757bb49a5bb53bd9f756cbbe24394ffd6fc1f4b2"}, - {file = "certifi-2025.7.14.tar.gz", hash = "sha256:8ea99dbdfaaf2ba2f9bac77b9249ef62ec5218e7c2b2e903378ed5fccf765995"}, + {file = "certifi-2025.10.5-py3-none-any.whl", hash = "sha256:0f212c2744a9bb6de0c56639a6f68afe01ecd92d91f14ae897c4fe7bbeeef0de"}, + {file = "certifi-2025.10.5.tar.gz", hash = "sha256:47c09d31ccf2acf0be3f701ea53595ee7e0b8fa08801c6624be771df09ae7b43"}, ] [[package]] name = "cffi" -version = "1.17.1" +version = "2.0.0" description = "Foreign Function Interface for Python calling C code." optional = false -python-versions = ">=3.8" +python-versions = ">=3.9" groups = ["main"] files = [ - {file = "cffi-1.17.1-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:df8b1c11f177bc2313ec4b2d46baec87a5f3e71fc8b45dab2ee7cae86d9aba14"}, - {file = "cffi-1.17.1-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:8f2cdc858323644ab277e9bb925ad72ae0e67f69e804f4898c070998d50b1a67"}, - {file = "cffi-1.17.1-cp310-cp310-manylinux_2_12_i686.manylinux2010_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:edae79245293e15384b51f88b00613ba9f7198016a5948b5dddf4917d4d26382"}, - {file = "cffi-1.17.1-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:45398b671ac6d70e67da8e4224a065cec6a93541bb7aebe1b198a61b58c7b702"}, - {file = "cffi-1.17.1-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:ad9413ccdeda48c5afdae7e4fa2192157e991ff761e7ab8fdd8926f40b160cc3"}, - {file = "cffi-1.17.1-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:5da5719280082ac6bd9aa7becb3938dc9f9cbd57fac7d2871717b1feb0902ab6"}, - {file = "cffi-1.17.1-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:2bb1a08b8008b281856e5971307cc386a8e9c5b625ac297e853d36da6efe9c17"}, - {file = "cffi-1.17.1-cp310-cp310-musllinux_1_1_aarch64.whl", hash = "sha256:045d61c734659cc045141be4bae381a41d89b741f795af1dd018bfb532fd0df8"}, - {file = "cffi-1.17.1-cp310-cp310-musllinux_1_1_i686.whl", hash = "sha256:6883e737d7d9e4899a8a695e00ec36bd4e5e4f18fabe0aca0efe0a4b44cdb13e"}, - {file = "cffi-1.17.1-cp310-cp310-musllinux_1_1_x86_64.whl", hash = "sha256:6b8b4a92e1c65048ff98cfe1f735ef8f1ceb72e3d5f0c25fdb12087a23da22be"}, - {file = "cffi-1.17.1-cp310-cp310-win32.whl", hash = "sha256:c9c3d058ebabb74db66e431095118094d06abf53284d9c81f27300d0e0d8bc7c"}, - {file = "cffi-1.17.1-cp310-cp310-win_amd64.whl", hash = "sha256:0f048dcf80db46f0098ccac01132761580d28e28bc0f78ae0d58048063317e15"}, - {file = "cffi-1.17.1-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:a45e3c6913c5b87b3ff120dcdc03f6131fa0065027d0ed7ee6190736a74cd401"}, - {file = "cffi-1.17.1-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:30c5e0cb5ae493c04c8b42916e52ca38079f1b235c2f8ae5f4527b963c401caf"}, - {file = "cffi-1.17.1-cp311-cp311-manylinux_2_12_i686.manylinux2010_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:f75c7ab1f9e4aca5414ed4d8e5c0e303a34f4421f8a0d47a4d019ceff0ab6af4"}, - {file = "cffi-1.17.1-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:a1ed2dd2972641495a3ec98445e09766f077aee98a1c896dcb4ad0d303628e41"}, - {file = "cffi-1.17.1-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:46bf43160c1a35f7ec506d254e5c890f3c03648a4dbac12d624e4490a7046cd1"}, - {file = "cffi-1.17.1-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:a24ed04c8ffd54b0729c07cee15a81d964e6fee0e3d4d342a27b020d22959dc6"}, - {file = "cffi-1.17.1-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:610faea79c43e44c71e1ec53a554553fa22321b65fae24889706c0a84d4ad86d"}, - {file = "cffi-1.17.1-cp311-cp311-musllinux_1_1_aarch64.whl", hash = "sha256:a9b15d491f3ad5d692e11f6b71f7857e7835eb677955c00cc0aefcd0669adaf6"}, - {file = "cffi-1.17.1-cp311-cp311-musllinux_1_1_i686.whl", hash = "sha256:de2ea4b5833625383e464549fec1bc395c1bdeeb5f25c4a3a82b5a8c756ec22f"}, - {file = "cffi-1.17.1-cp311-cp311-musllinux_1_1_x86_64.whl", hash = "sha256:fc48c783f9c87e60831201f2cce7f3b2e4846bf4d8728eabe54d60700b318a0b"}, - {file = "cffi-1.17.1-cp311-cp311-win32.whl", hash = "sha256:85a950a4ac9c359340d5963966e3e0a94a676bd6245a4b55bc43949eee26a655"}, - {file = "cffi-1.17.1-cp311-cp311-win_amd64.whl", hash = "sha256:caaf0640ef5f5517f49bc275eca1406b0ffa6aa184892812030f04c2abf589a0"}, - {file = "cffi-1.17.1-cp312-cp312-macosx_10_9_x86_64.whl", hash = "sha256:805b4371bf7197c329fcb3ead37e710d1bca9da5d583f5073b799d5c5bd1eee4"}, - {file = "cffi-1.17.1-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:733e99bc2df47476e3848417c5a4540522f234dfd4ef3ab7fafdf555b082ec0c"}, - {file = "cffi-1.17.1-cp312-cp312-manylinux_2_12_i686.manylinux2010_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:1257bdabf294dceb59f5e70c64a3e2f462c30c7ad68092d01bbbfb1c16b1ba36"}, - {file = "cffi-1.17.1-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:da95af8214998d77a98cc14e3a3bd00aa191526343078b530ceb0bd710fb48a5"}, - {file = "cffi-1.17.1-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:d63afe322132c194cf832bfec0dc69a99fb9bb6bbd550f161a49e9e855cc78ff"}, - {file = "cffi-1.17.1-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:f79fc4fc25f1c8698ff97788206bb3c2598949bfe0fef03d299eb1b5356ada99"}, - {file = "cffi-1.17.1-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:b62ce867176a75d03a665bad002af8e6d54644fad99a3c70905c543130e39d93"}, - {file = "cffi-1.17.1-cp312-cp312-musllinux_1_1_aarch64.whl", hash = "sha256:386c8bf53c502fff58903061338ce4f4950cbdcb23e2902d86c0f722b786bbe3"}, - {file = "cffi-1.17.1-cp312-cp312-musllinux_1_1_x86_64.whl", hash = "sha256:4ceb10419a9adf4460ea14cfd6bc43d08701f0835e979bf821052f1805850fe8"}, - {file = "cffi-1.17.1-cp312-cp312-win32.whl", hash = "sha256:a08d7e755f8ed21095a310a693525137cfe756ce62d066e53f502a83dc550f65"}, - {file = "cffi-1.17.1-cp312-cp312-win_amd64.whl", hash = "sha256:51392eae71afec0d0c8fb1a53b204dbb3bcabcb3c9b807eedf3e1e6ccf2de903"}, - {file = "cffi-1.17.1-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:f3a2b4222ce6b60e2e8b337bb9596923045681d71e5a082783484d845390938e"}, - {file = "cffi-1.17.1-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:0984a4925a435b1da406122d4d7968dd861c1385afe3b45ba82b750f229811e2"}, - {file = "cffi-1.17.1-cp313-cp313-manylinux_2_12_i686.manylinux2010_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:d01b12eeeb4427d3110de311e1774046ad344f5b1a7403101878976ecd7a10f3"}, - {file = "cffi-1.17.1-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:706510fe141c86a69c8ddc029c7910003a17353970cff3b904ff0686a5927683"}, - {file = "cffi-1.17.1-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:de55b766c7aa2e2a3092c51e0483d700341182f08e67c63630d5b6f200bb28e5"}, - {file = "cffi-1.17.1-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:c59d6e989d07460165cc5ad3c61f9fd8f1b4796eacbd81cee78957842b834af4"}, - {file = "cffi-1.17.1-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:dd398dbc6773384a17fe0d3e7eeb8d1a21c2200473ee6806bb5e6a8e62bb73dd"}, - {file = "cffi-1.17.1-cp313-cp313-musllinux_1_1_aarch64.whl", hash = "sha256:3edc8d958eb099c634dace3c7e16560ae474aa3803a5df240542b305d14e14ed"}, - {file = "cffi-1.17.1-cp313-cp313-musllinux_1_1_x86_64.whl", hash = "sha256:72e72408cad3d5419375fc87d289076ee319835bdfa2caad331e377589aebba9"}, - {file = "cffi-1.17.1-cp313-cp313-win32.whl", hash = "sha256:e03eab0a8677fa80d646b5ddece1cbeaf556c313dcfac435ba11f107ba117b5d"}, - {file = "cffi-1.17.1-cp313-cp313-win_amd64.whl", hash = "sha256:f6a16c31041f09ead72d69f583767292f750d24913dadacf5756b966aacb3f1a"}, - {file = "cffi-1.17.1-cp38-cp38-macosx_10_9_x86_64.whl", hash = "sha256:636062ea65bd0195bc012fea9321aca499c0504409f413dc88af450b57ffd03b"}, - {file = "cffi-1.17.1-cp38-cp38-manylinux_2_12_i686.manylinux2010_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:c7eac2ef9b63c79431bc4b25f1cd649d7f061a28808cbc6c47b534bd789ef964"}, - {file = "cffi-1.17.1-cp38-cp38-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:e221cf152cff04059d011ee126477f0d9588303eb57e88923578ace7baad17f9"}, - {file = "cffi-1.17.1-cp38-cp38-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:31000ec67d4221a71bd3f67df918b1f88f676f1c3b535a7eb473255fdc0b83fc"}, - {file = "cffi-1.17.1-cp38-cp38-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:6f17be4345073b0a7b8ea599688f692ac3ef23ce28e5df79c04de519dbc4912c"}, - {file = "cffi-1.17.1-cp38-cp38-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:0e2b1fac190ae3ebfe37b979cc1ce69c81f4e4fe5746bb401dca63a9062cdaf1"}, - {file = "cffi-1.17.1-cp38-cp38-win32.whl", hash = "sha256:7596d6620d3fa590f677e9ee430df2958d2d6d6de2feeae5b20e82c00b76fbf8"}, - {file = "cffi-1.17.1-cp38-cp38-win_amd64.whl", hash = "sha256:78122be759c3f8a014ce010908ae03364d00a1f81ab5c7f4a7a5120607ea56e1"}, - {file = "cffi-1.17.1-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:b2ab587605f4ba0bf81dc0cb08a41bd1c0a5906bd59243d56bad7668a6fc6c16"}, - {file = "cffi-1.17.1-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:28b16024becceed8c6dfbc75629e27788d8a3f9030691a1dbf9821a128b22c36"}, - {file = "cffi-1.17.1-cp39-cp39-manylinux_2_12_i686.manylinux2010_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:1d599671f396c4723d016dbddb72fe8e0397082b0a77a4fab8028923bec050e8"}, - {file = "cffi-1.17.1-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:ca74b8dbe6e8e8263c0ffd60277de77dcee6c837a3d0881d8c1ead7268c9e576"}, - {file = "cffi-1.17.1-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:f7f5baafcc48261359e14bcd6d9bff6d4b28d9103847c9e136694cb0501aef87"}, - {file = "cffi-1.17.1-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:98e3969bcff97cae1b2def8ba499ea3d6f31ddfdb7635374834cf89a1a08ecf0"}, - {file = "cffi-1.17.1-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:cdf5ce3acdfd1661132f2a9c19cac174758dc2352bfe37d98aa7512c6b7178b3"}, - {file = "cffi-1.17.1-cp39-cp39-musllinux_1_1_aarch64.whl", hash = "sha256:9755e4345d1ec879e3849e62222a18c7174d65a6a92d5b346b1863912168b595"}, - {file = "cffi-1.17.1-cp39-cp39-musllinux_1_1_i686.whl", hash = "sha256:f1e22e8c4419538cb197e4dd60acc919d7696e5ef98ee4da4e01d3f8cfa4cc5a"}, - {file = "cffi-1.17.1-cp39-cp39-musllinux_1_1_x86_64.whl", hash = "sha256:c03e868a0b3bc35839ba98e74211ed2b05d2119be4e8a0f224fba9384f1fe02e"}, - {file = "cffi-1.17.1-cp39-cp39-win32.whl", hash = "sha256:e31ae45bc2e29f6b2abd0de1cc3b9d5205aa847cafaecb8af1476a609a2f6eb7"}, - {file = "cffi-1.17.1-cp39-cp39-win_amd64.whl", hash = "sha256:d016c76bdd850f3c626af19b0542c9677ba156e4ee4fccfdd7848803533ef662"}, - {file = "cffi-1.17.1.tar.gz", hash = "sha256:1c39c6016c32bc48dd54561950ebd6836e1670f2ae46128f67cf49e789c52824"}, -] - -[package.dependencies] -pycparser = "*" + {file = "cffi-2.0.0-cp310-cp310-macosx_10_13_x86_64.whl", hash = "sha256:0cf2d91ecc3fcc0625c2c530fe004f82c110405f101548512cce44322fa8ac44"}, + {file = "cffi-2.0.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:f73b96c41e3b2adedc34a7356e64c8eb96e03a3782b535e043a986276ce12a49"}, + {file = "cffi-2.0.0-cp310-cp310-manylinux1_i686.manylinux2014_i686.manylinux_2_17_i686.manylinux_2_5_i686.whl", hash = "sha256:53f77cbe57044e88bbd5ed26ac1d0514d2acf0591dd6bb02a3ae37f76811b80c"}, + {file = "cffi-2.0.0-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:3e837e369566884707ddaf85fc1744b47575005c0a229de3327f8f9a20f4efeb"}, + {file = "cffi-2.0.0-cp310-cp310-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:5eda85d6d1879e692d546a078b44251cdd08dd1cfb98dfb77b670c97cee49ea0"}, + {file = "cffi-2.0.0-cp310-cp310-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:9332088d75dc3241c702d852d4671613136d90fa6881da7d770a483fd05248b4"}, + {file = "cffi-2.0.0-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:fc7de24befaeae77ba923797c7c87834c73648a05a4bde34b3b7e5588973a453"}, + {file = "cffi-2.0.0-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:cf364028c016c03078a23b503f02058f1814320a56ad535686f90565636a9495"}, + {file = "cffi-2.0.0-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:e11e82b744887154b182fd3e7e8512418446501191994dbf9c9fc1f32cc8efd5"}, + {file = "cffi-2.0.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:8ea985900c5c95ce9db1745f7933eeef5d314f0565b27625d9a10ec9881e1bfb"}, + {file = "cffi-2.0.0-cp310-cp310-win32.whl", hash = "sha256:1f72fb8906754ac8a2cc3f9f5aaa298070652a0ffae577e0ea9bd480dc3c931a"}, + {file = "cffi-2.0.0-cp310-cp310-win_amd64.whl", hash = "sha256:b18a3ed7d5b3bd8d9ef7a8cb226502c6bf8308df1525e1cc676c3680e7176739"}, + {file = "cffi-2.0.0-cp311-cp311-macosx_10_13_x86_64.whl", hash = "sha256:b4c854ef3adc177950a8dfc81a86f5115d2abd545751a304c5bcf2c2c7283cfe"}, + {file = "cffi-2.0.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:2de9a304e27f7596cd03d16f1b7c72219bd944e99cc52b84d0145aefb07cbd3c"}, + {file = "cffi-2.0.0-cp311-cp311-manylinux1_i686.manylinux2014_i686.manylinux_2_17_i686.manylinux_2_5_i686.whl", hash = "sha256:baf5215e0ab74c16e2dd324e8ec067ef59e41125d3eade2b863d294fd5035c92"}, + {file = "cffi-2.0.0-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:730cacb21e1bdff3ce90babf007d0a0917cc3e6492f336c2f0134101e0944f93"}, + {file = "cffi-2.0.0-cp311-cp311-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:6824f87845e3396029f3820c206e459ccc91760e8fa24422f8b0c3d1731cbec5"}, + {file = "cffi-2.0.0-cp311-cp311-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:9de40a7b0323d889cf8d23d1ef214f565ab154443c42737dfe52ff82cf857664"}, + {file = "cffi-2.0.0-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:8941aaadaf67246224cee8c3803777eed332a19d909b47e29c9842ef1e79ac26"}, + {file = "cffi-2.0.0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:a05d0c237b3349096d3981b727493e22147f934b20f6f125a3eba8f994bec4a9"}, + {file = "cffi-2.0.0-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:94698a9c5f91f9d138526b48fe26a199609544591f859c870d477351dc7b2414"}, + {file = "cffi-2.0.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:5fed36fccc0612a53f1d4d9a816b50a36702c28a2aa880cb8a122b3466638743"}, + {file = "cffi-2.0.0-cp311-cp311-win32.whl", hash = "sha256:c649e3a33450ec82378822b3dad03cc228b8f5963c0c12fc3b1e0ab940f768a5"}, + {file = "cffi-2.0.0-cp311-cp311-win_amd64.whl", hash = "sha256:66f011380d0e49ed280c789fbd08ff0d40968ee7b665575489afa95c98196ab5"}, + {file = "cffi-2.0.0-cp311-cp311-win_arm64.whl", hash = "sha256:c6638687455baf640e37344fe26d37c404db8b80d037c3d29f58fe8d1c3b194d"}, + {file = "cffi-2.0.0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:6d02d6655b0e54f54c4ef0b94eb6be0607b70853c45ce98bd278dc7de718be5d"}, + {file = "cffi-2.0.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:8eca2a813c1cb7ad4fb74d368c2ffbbb4789d377ee5bb8df98373c2cc0dee76c"}, + {file = "cffi-2.0.0-cp312-cp312-manylinux1_i686.manylinux2014_i686.manylinux_2_17_i686.manylinux_2_5_i686.whl", hash = "sha256:21d1152871b019407d8ac3985f6775c079416c282e431a4da6afe7aefd2bccbe"}, + {file = "cffi-2.0.0-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:b21e08af67b8a103c71a250401c78d5e0893beff75e28c53c98f4de42f774062"}, + {file = "cffi-2.0.0-cp312-cp312-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:1e3a615586f05fc4065a8b22b8152f0c1b00cdbc60596d187c2a74f9e3036e4e"}, + {file = "cffi-2.0.0-cp312-cp312-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:81afed14892743bbe14dacb9e36d9e0e504cd204e0b165062c488942b9718037"}, + {file = "cffi-2.0.0-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:3e17ed538242334bf70832644a32a7aae3d83b57567f9fd60a26257e992b79ba"}, + {file = "cffi-2.0.0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:3925dd22fa2b7699ed2617149842d2e6adde22b262fcbfada50e3d195e4b3a94"}, + {file = "cffi-2.0.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:2c8f814d84194c9ea681642fd164267891702542f028a15fc97d4674b6206187"}, + {file = "cffi-2.0.0-cp312-cp312-win32.whl", hash = "sha256:da902562c3e9c550df360bfa53c035b2f241fed6d9aef119048073680ace4a18"}, + {file = "cffi-2.0.0-cp312-cp312-win_amd64.whl", hash = "sha256:da68248800ad6320861f129cd9c1bf96ca849a2771a59e0344e88681905916f5"}, + {file = "cffi-2.0.0-cp312-cp312-win_arm64.whl", hash = "sha256:4671d9dd5ec934cb9a73e7ee9676f9362aba54f7f34910956b84d727b0d73fb6"}, + {file = "cffi-2.0.0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:00bdf7acc5f795150faa6957054fbbca2439db2f775ce831222b66f192f03beb"}, + {file = "cffi-2.0.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:45d5e886156860dc35862657e1494b9bae8dfa63bf56796f2fb56e1679fc0bca"}, + {file = "cffi-2.0.0-cp313-cp313-manylinux1_i686.manylinux2014_i686.manylinux_2_17_i686.manylinux_2_5_i686.whl", hash = "sha256:07b271772c100085dd28b74fa0cd81c8fb1a3ba18b21e03d7c27f3436a10606b"}, + {file = "cffi-2.0.0-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:d48a880098c96020b02d5a1f7d9251308510ce8858940e6fa99ece33f610838b"}, + {file = "cffi-2.0.0-cp313-cp313-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:f93fd8e5c8c0a4aa1f424d6173f14a892044054871c771f8566e4008eaa359d2"}, + {file = "cffi-2.0.0-cp313-cp313-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:dd4f05f54a52fb558f1ba9f528228066954fee3ebe629fc1660d874d040ae5a3"}, + {file = "cffi-2.0.0-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:c8d3b5532fc71b7a77c09192b4a5a200ea992702734a2e9279a37f2478236f26"}, + {file = "cffi-2.0.0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:d9b29c1f0ae438d5ee9acb31cadee00a58c46cc9c0b2f9038c6b0b3470877a8c"}, + {file = "cffi-2.0.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:6d50360be4546678fc1b79ffe7a66265e28667840010348dd69a314145807a1b"}, + {file = "cffi-2.0.0-cp313-cp313-win32.whl", hash = "sha256:74a03b9698e198d47562765773b4a8309919089150a0bb17d829ad7b44b60d27"}, + {file = "cffi-2.0.0-cp313-cp313-win_amd64.whl", hash = "sha256:19f705ada2530c1167abacb171925dd886168931e0a7b78f5bffcae5c6b5be75"}, + {file = "cffi-2.0.0-cp313-cp313-win_arm64.whl", hash = "sha256:256f80b80ca3853f90c21b23ee78cd008713787b1b1e93eae9f3d6a7134abd91"}, + {file = "cffi-2.0.0-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:fc33c5141b55ed366cfaad382df24fe7dcbc686de5be719b207bb248e3053dc5"}, + {file = "cffi-2.0.0-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:c654de545946e0db659b3400168c9ad31b5d29593291482c43e3564effbcee13"}, + {file = "cffi-2.0.0-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:24b6f81f1983e6df8db3adc38562c83f7d4a0c36162885ec7f7b77c7dcbec97b"}, + {file = "cffi-2.0.0-cp314-cp314-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:12873ca6cb9b0f0d3a0da705d6086fe911591737a59f28b7936bdfed27c0d47c"}, + {file = "cffi-2.0.0-cp314-cp314-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:d9b97165e8aed9272a6bb17c01e3cc5871a594a446ebedc996e2397a1c1ea8ef"}, + {file = "cffi-2.0.0-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:afb8db5439b81cf9c9d0c80404b60c3cc9c3add93e114dcae767f1477cb53775"}, + {file = "cffi-2.0.0-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:737fe7d37e1a1bffe70bd5754ea763a62a066dc5913ca57e957824b72a85e205"}, + {file = "cffi-2.0.0-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:38100abb9d1b1435bc4cc340bb4489635dc2f0da7456590877030c9b3d40b0c1"}, + {file = "cffi-2.0.0-cp314-cp314-win32.whl", hash = "sha256:087067fa8953339c723661eda6b54bc98c5625757ea62e95eb4898ad5e776e9f"}, + {file = "cffi-2.0.0-cp314-cp314-win_amd64.whl", hash = "sha256:203a48d1fb583fc7d78a4c6655692963b860a417c0528492a6bc21f1aaefab25"}, + {file = "cffi-2.0.0-cp314-cp314-win_arm64.whl", hash = "sha256:dbd5c7a25a7cb98f5ca55d258b103a2054f859a46ae11aaf23134f9cc0d356ad"}, + {file = "cffi-2.0.0-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:9a67fc9e8eb39039280526379fb3a70023d77caec1852002b4da7e8b270c4dd9"}, + {file = "cffi-2.0.0-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:7a66c7204d8869299919db4d5069a82f1561581af12b11b3c9f48c584eb8743d"}, + {file = "cffi-2.0.0-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:7cc09976e8b56f8cebd752f7113ad07752461f48a58cbba644139015ac24954c"}, + {file = "cffi-2.0.0-cp314-cp314t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:92b68146a71df78564e4ef48af17551a5ddd142e5190cdf2c5624d0c3ff5b2e8"}, + {file = "cffi-2.0.0-cp314-cp314t-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:b1e74d11748e7e98e2f426ab176d4ed720a64412b6a15054378afdb71e0f37dc"}, + {file = "cffi-2.0.0-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:28a3a209b96630bca57cce802da70c266eb08c6e97e5afd61a75611ee6c64592"}, + {file = "cffi-2.0.0-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:7553fb2090d71822f02c629afe6042c299edf91ba1bf94951165613553984512"}, + {file = "cffi-2.0.0-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:6c6c373cfc5c83a975506110d17457138c8c63016b563cc9ed6e056a82f13ce4"}, + {file = "cffi-2.0.0-cp314-cp314t-win32.whl", hash = "sha256:1fc9ea04857caf665289b7a75923f2c6ed559b8298a1b8c49e59f7dd95c8481e"}, + {file = "cffi-2.0.0-cp314-cp314t-win_amd64.whl", hash = "sha256:d68b6cef7827e8641e8ef16f4494edda8b36104d79773a334beaa1e3521430f6"}, + {file = "cffi-2.0.0-cp314-cp314t-win_arm64.whl", hash = "sha256:0a1527a803f0a659de1af2e1fd700213caba79377e27e4693648c2923da066f9"}, + {file = "cffi-2.0.0-cp39-cp39-macosx_10_13_x86_64.whl", hash = "sha256:fe562eb1a64e67dd297ccc4f5addea2501664954f2692b69a76449ec7913ecbf"}, + {file = "cffi-2.0.0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:de8dad4425a6ca6e4e5e297b27b5c824ecc7581910bf9aee86cb6835e6812aa7"}, + {file = "cffi-2.0.0-cp39-cp39-manylinux1_i686.manylinux2014_i686.manylinux_2_17_i686.manylinux_2_5_i686.whl", hash = "sha256:4647afc2f90d1ddd33441e5b0e85b16b12ddec4fca55f0d9671fef036ecca27c"}, + {file = "cffi-2.0.0-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:3f4d46d8b35698056ec29bca21546e1551a205058ae1a181d871e278b0b28165"}, + {file = "cffi-2.0.0-cp39-cp39-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:e6e73b9e02893c764e7e8d5bb5ce277f1a009cd5243f8228f75f842bf937c534"}, + {file = "cffi-2.0.0-cp39-cp39-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:cb527a79772e5ef98fb1d700678fe031e353e765d1ca2d409c92263c6d43e09f"}, + {file = "cffi-2.0.0-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:61d028e90346df14fedc3d1e5441df818d095f3b87d286825dfcbd6459b7ef63"}, + {file = "cffi-2.0.0-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:0f6084a0ea23d05d20c3edcda20c3d006f9b6f3fefeac38f59262e10cef47ee2"}, + {file = "cffi-2.0.0-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:1cd13c99ce269b3ed80b417dcd591415d3372bcac067009b6e0f59c7d4015e65"}, + {file = "cffi-2.0.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:89472c9762729b5ae1ad974b777416bfda4ac5642423fa93bd57a09204712322"}, + {file = "cffi-2.0.0-cp39-cp39-win32.whl", hash = "sha256:2081580ebb843f759b9f617314a24ed5738c51d2aee65d31e02f6f7a2b97707a"}, + {file = "cffi-2.0.0-cp39-cp39-win_amd64.whl", hash = "sha256:b882b3df248017dba09d6b16defe9b5c407fe32fc7c65a9c69798e6175601be9"}, + {file = "cffi-2.0.0.tar.gz", hash = "sha256:44d1b5909021139fe36001ae048dbdde8214afa20200eda0f64c068cac5d5529"}, +] + +[package.dependencies] +pycparser = {version = "*", markers = "implementation_name != \"PyPy\""} [[package]] name = "cfgraph" @@ -912,123 +969,144 @@ files = [ [[package]] name = "charset-normalizer" -version = "3.4.2" +version = "3.4.4" description = "The Real First Universal Charset Detector. Open, modern and actively maintained alternative to Chardet." optional = false python-versions = ">=3.7" groups = ["main", "docs"] files = [ - {file = "charset_normalizer-3.4.2-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:7c48ed483eb946e6c04ccbe02c6b4d1d48e51944b6db70f697e089c193404941"}, - {file = "charset_normalizer-3.4.2-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:b2d318c11350e10662026ad0eb71bb51c7812fc8590825304ae0bdd4ac283acd"}, - {file = "charset_normalizer-3.4.2-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:9cbfacf36cb0ec2897ce0ebc5d08ca44213af24265bd56eca54bee7923c48fd6"}, - {file = "charset_normalizer-3.4.2-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:18dd2e350387c87dabe711b86f83c9c78af772c748904d372ade190b5c7c9d4d"}, - {file = "charset_normalizer-3.4.2-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:8075c35cd58273fee266c58c0c9b670947c19df5fb98e7b66710e04ad4e9ff86"}, - {file = "charset_normalizer-3.4.2-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:5bf4545e3b962767e5c06fe1738f951f77d27967cb2caa64c28be7c4563e162c"}, - {file = "charset_normalizer-3.4.2-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:7a6ab32f7210554a96cd9e33abe3ddd86732beeafc7a28e9955cdf22ffadbab0"}, - {file = "charset_normalizer-3.4.2-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:b33de11b92e9f75a2b545d6e9b6f37e398d86c3e9e9653c4864eb7e89c5773ef"}, - {file = "charset_normalizer-3.4.2-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:8755483f3c00d6c9a77f490c17e6ab0c8729e39e6390328e42521ef175380ae6"}, - {file = "charset_normalizer-3.4.2-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:68a328e5f55ec37c57f19ebb1fdc56a248db2e3e9ad769919a58672958e8f366"}, - {file = "charset_normalizer-3.4.2-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:21b2899062867b0e1fde9b724f8aecb1af14f2778d69aacd1a5a1853a597a5db"}, - {file = "charset_normalizer-3.4.2-cp310-cp310-win32.whl", hash = "sha256:e8082b26888e2f8b36a042a58307d5b917ef2b1cacab921ad3323ef91901c71a"}, - {file = "charset_normalizer-3.4.2-cp310-cp310-win_amd64.whl", hash = "sha256:f69a27e45c43520f5487f27627059b64aaf160415589230992cec34c5e18a509"}, - {file = "charset_normalizer-3.4.2-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:be1e352acbe3c78727a16a455126d9ff83ea2dfdcbc83148d2982305a04714c2"}, - {file = "charset_normalizer-3.4.2-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:aa88ca0b1932e93f2d961bf3addbb2db902198dca337d88c89e1559e066e7645"}, - {file = "charset_normalizer-3.4.2-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:d524ba3f1581b35c03cb42beebab4a13e6cdad7b36246bd22541fa585a56cccd"}, - {file = "charset_normalizer-3.4.2-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:28a1005facc94196e1fb3e82a3d442a9d9110b8434fc1ded7a24a2983c9888d8"}, - {file = "charset_normalizer-3.4.2-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:fdb20a30fe1175ecabed17cbf7812f7b804b8a315a25f24678bcdf120a90077f"}, - {file = "charset_normalizer-3.4.2-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:0f5d9ed7f254402c9e7d35d2f5972c9bbea9040e99cd2861bd77dc68263277c7"}, - {file = "charset_normalizer-3.4.2-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:efd387a49825780ff861998cd959767800d54f8308936b21025326de4b5a42b9"}, - {file = "charset_normalizer-3.4.2-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:f0aa37f3c979cf2546b73e8222bbfa3dc07a641585340179d768068e3455e544"}, - {file = "charset_normalizer-3.4.2-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:e70e990b2137b29dc5564715de1e12701815dacc1d056308e2b17e9095372a82"}, - {file = "charset_normalizer-3.4.2-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:0c8c57f84ccfc871a48a47321cfa49ae1df56cd1d965a09abe84066f6853b9c0"}, - {file = "charset_normalizer-3.4.2-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:6b66f92b17849b85cad91259efc341dce9c1af48e2173bf38a85c6329f1033e5"}, - {file = "charset_normalizer-3.4.2-cp311-cp311-win32.whl", hash = "sha256:daac4765328a919a805fa5e2720f3e94767abd632ae410a9062dff5412bae65a"}, - {file = "charset_normalizer-3.4.2-cp311-cp311-win_amd64.whl", hash = "sha256:e53efc7c7cee4c1e70661e2e112ca46a575f90ed9ae3fef200f2a25e954f4b28"}, - {file = "charset_normalizer-3.4.2-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:0c29de6a1a95f24b9a1aa7aefd27d2487263f00dfd55a77719b530788f75cff7"}, - {file = "charset_normalizer-3.4.2-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:cddf7bd982eaa998934a91f69d182aec997c6c468898efe6679af88283b498d3"}, - {file = "charset_normalizer-3.4.2-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:fcbe676a55d7445b22c10967bceaaf0ee69407fbe0ece4d032b6eb8d4565982a"}, - {file = "charset_normalizer-3.4.2-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:d41c4d287cfc69060fa91cae9683eacffad989f1a10811995fa309df656ec214"}, - {file = "charset_normalizer-3.4.2-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:4e594135de17ab3866138f496755f302b72157d115086d100c3f19370839dd3a"}, - {file = "charset_normalizer-3.4.2-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:cf713fe9a71ef6fd5adf7a79670135081cd4431c2943864757f0fa3a65b1fafd"}, - {file = "charset_normalizer-3.4.2-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:a370b3e078e418187da8c3674eddb9d983ec09445c99a3a263c2011993522981"}, - {file = "charset_normalizer-3.4.2-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:a955b438e62efdf7e0b7b52a64dc5c3396e2634baa62471768a64bc2adb73d5c"}, - {file = "charset_normalizer-3.4.2-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:7222ffd5e4de8e57e03ce2cef95a4c43c98fcb72ad86909abdfc2c17d227fc1b"}, - {file = "charset_normalizer-3.4.2-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:bee093bf902e1d8fc0ac143c88902c3dfc8941f7ea1d6a8dd2bcb786d33db03d"}, - {file = "charset_normalizer-3.4.2-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:dedb8adb91d11846ee08bec4c8236c8549ac721c245678282dcb06b221aab59f"}, - {file = "charset_normalizer-3.4.2-cp312-cp312-win32.whl", hash = "sha256:db4c7bf0e07fc3b7d89ac2a5880a6a8062056801b83ff56d8464b70f65482b6c"}, - {file = "charset_normalizer-3.4.2-cp312-cp312-win_amd64.whl", hash = "sha256:5a9979887252a82fefd3d3ed2a8e3b937a7a809f65dcb1e068b090e165bbe99e"}, - {file = "charset_normalizer-3.4.2-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:926ca93accd5d36ccdabd803392ddc3e03e6d4cd1cf17deff3b989ab8e9dbcf0"}, - {file = "charset_normalizer-3.4.2-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:eba9904b0f38a143592d9fc0e19e2df0fa2e41c3c3745554761c5f6447eedabf"}, - {file = "charset_normalizer-3.4.2-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:3fddb7e2c84ac87ac3a947cb4e66d143ca5863ef48e4a5ecb83bd48619e4634e"}, - {file = "charset_normalizer-3.4.2-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:98f862da73774290f251b9df8d11161b6cf25b599a66baf087c1ffe340e9bfd1"}, - {file = "charset_normalizer-3.4.2-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:6c9379d65defcab82d07b2a9dfbfc2e95bc8fe0ebb1b176a3190230a3ef0e07c"}, - {file = "charset_normalizer-3.4.2-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:e635b87f01ebc977342e2697d05b56632f5f879a4f15955dfe8cef2448b51691"}, - {file = "charset_normalizer-3.4.2-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:1c95a1e2902a8b722868587c0e1184ad5c55631de5afc0eb96bc4b0d738092c0"}, - {file = "charset_normalizer-3.4.2-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:ef8de666d6179b009dce7bcb2ad4c4a779f113f12caf8dc77f0162c29d20490b"}, - {file = "charset_normalizer-3.4.2-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:32fc0341d72e0f73f80acb0a2c94216bd704f4f0bce10aedea38f30502b271ff"}, - {file = "charset_normalizer-3.4.2-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:289200a18fa698949d2b39c671c2cc7a24d44096784e76614899a7ccf2574b7b"}, - {file = "charset_normalizer-3.4.2-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:4a476b06fbcf359ad25d34a057b7219281286ae2477cc5ff5e3f70a246971148"}, - {file = "charset_normalizer-3.4.2-cp313-cp313-win32.whl", hash = "sha256:aaeeb6a479c7667fbe1099af9617c83aaca22182d6cf8c53966491a0f1b7ffb7"}, - {file = "charset_normalizer-3.4.2-cp313-cp313-win_amd64.whl", hash = "sha256:aa6af9e7d59f9c12b33ae4e9450619cf2488e2bbe9b44030905877f0b2324980"}, - {file = "charset_normalizer-3.4.2-cp37-cp37m-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:1cad5f45b3146325bb38d6855642f6fd609c3f7cad4dbaf75549bf3b904d3184"}, - {file = "charset_normalizer-3.4.2-cp37-cp37m-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:b2680962a4848b3c4f155dc2ee64505a9c57186d0d56b43123b17ca3de18f0fa"}, - {file = "charset_normalizer-3.4.2-cp37-cp37m-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:36b31da18b8890a76ec181c3cf44326bf2c48e36d393ca1b72b3f484113ea344"}, - {file = "charset_normalizer-3.4.2-cp37-cp37m-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:f4074c5a429281bf056ddd4c5d3b740ebca4d43ffffe2ef4bf4d2d05114299da"}, - {file = "charset_normalizer-3.4.2-cp37-cp37m-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:c9e36a97bee9b86ef9a1cf7bb96747eb7a15c2f22bdb5b516434b00f2a599f02"}, - {file = "charset_normalizer-3.4.2-cp37-cp37m-musllinux_1_2_aarch64.whl", hash = "sha256:1b1bde144d98e446b056ef98e59c256e9294f6b74d7af6846bf5ffdafd687a7d"}, - {file = "charset_normalizer-3.4.2-cp37-cp37m-musllinux_1_2_i686.whl", hash = "sha256:915f3849a011c1f593ab99092f3cecfcb4d65d8feb4a64cf1bf2d22074dc0ec4"}, - {file = "charset_normalizer-3.4.2-cp37-cp37m-musllinux_1_2_ppc64le.whl", hash = "sha256:fb707f3e15060adf5b7ada797624a6c6e0138e2a26baa089df64c68ee98e040f"}, - {file = "charset_normalizer-3.4.2-cp37-cp37m-musllinux_1_2_s390x.whl", hash = "sha256:25a23ea5c7edc53e0f29bae2c44fcb5a1aa10591aae107f2a2b2583a9c5cbc64"}, - {file = "charset_normalizer-3.4.2-cp37-cp37m-musllinux_1_2_x86_64.whl", hash = "sha256:770cab594ecf99ae64c236bc9ee3439c3f46be49796e265ce0cc8bc17b10294f"}, - {file = "charset_normalizer-3.4.2-cp37-cp37m-win32.whl", hash = "sha256:6a0289e4589e8bdfef02a80478f1dfcb14f0ab696b5a00e1f4b8a14a307a3c58"}, - {file = "charset_normalizer-3.4.2-cp37-cp37m-win_amd64.whl", hash = "sha256:6fc1f5b51fa4cecaa18f2bd7a003f3dd039dd615cd69a2afd6d3b19aed6775f2"}, - {file = "charset_normalizer-3.4.2-cp38-cp38-macosx_10_9_universal2.whl", hash = "sha256:76af085e67e56c8816c3ccf256ebd136def2ed9654525348cfa744b6802b69eb"}, - {file = "charset_normalizer-3.4.2-cp38-cp38-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:e45ba65510e2647721e35323d6ef54c7974959f6081b58d4ef5d87c60c84919a"}, - {file = "charset_normalizer-3.4.2-cp38-cp38-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:046595208aae0120559a67693ecc65dd75d46f7bf687f159127046628178dc45"}, - {file = "charset_normalizer-3.4.2-cp38-cp38-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:75d10d37a47afee94919c4fab4c22b9bc2a8bf7d4f46f87363bcf0573f3ff4f5"}, - {file = "charset_normalizer-3.4.2-cp38-cp38-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:6333b3aa5a12c26b2a4d4e7335a28f1475e0e5e17d69d55141ee3cab736f66d1"}, - {file = "charset_normalizer-3.4.2-cp38-cp38-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:e8323a9b031aa0393768b87f04b4164a40037fb2a3c11ac06a03ffecd3618027"}, - {file = "charset_normalizer-3.4.2-cp38-cp38-musllinux_1_2_aarch64.whl", hash = "sha256:24498ba8ed6c2e0b56d4acbf83f2d989720a93b41d712ebd4f4979660db4417b"}, - {file = "charset_normalizer-3.4.2-cp38-cp38-musllinux_1_2_i686.whl", hash = "sha256:844da2b5728b5ce0e32d863af26f32b5ce61bc4273a9c720a9f3aa9df73b1455"}, - {file = "charset_normalizer-3.4.2-cp38-cp38-musllinux_1_2_ppc64le.whl", hash = "sha256:65c981bdbd3f57670af8b59777cbfae75364b483fa8a9f420f08094531d54a01"}, - {file = "charset_normalizer-3.4.2-cp38-cp38-musllinux_1_2_s390x.whl", hash = "sha256:3c21d4fca343c805a52c0c78edc01e3477f6dd1ad7c47653241cf2a206d4fc58"}, - {file = "charset_normalizer-3.4.2-cp38-cp38-musllinux_1_2_x86_64.whl", hash = "sha256:dc7039885fa1baf9be153a0626e337aa7ec8bf96b0128605fb0d77788ddc1681"}, - {file = "charset_normalizer-3.4.2-cp38-cp38-win32.whl", hash = "sha256:8272b73e1c5603666618805fe821edba66892e2870058c94c53147602eab29c7"}, - {file = "charset_normalizer-3.4.2-cp38-cp38-win_amd64.whl", hash = "sha256:70f7172939fdf8790425ba31915bfbe8335030f05b9913d7ae00a87d4395620a"}, - {file = "charset_normalizer-3.4.2-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:005fa3432484527f9732ebd315da8da8001593e2cf46a3d817669f062c3d9ed4"}, - {file = "charset_normalizer-3.4.2-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:e92fca20c46e9f5e1bb485887d074918b13543b1c2a1185e69bb8d17ab6236a7"}, - {file = "charset_normalizer-3.4.2-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:50bf98d5e563b83cc29471fa114366e6806bc06bc7a25fd59641e41445327836"}, - {file = "charset_normalizer-3.4.2-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:721c76e84fe669be19c5791da68232ca2e05ba5185575086e384352e2c309597"}, - {file = "charset_normalizer-3.4.2-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:82d8fd25b7f4675d0c47cf95b594d4e7b158aca33b76aa63d07186e13c0e0ab7"}, - {file = "charset_normalizer-3.4.2-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:b3daeac64d5b371dea99714f08ffc2c208522ec6b06fbc7866a450dd446f5c0f"}, - {file = "charset_normalizer-3.4.2-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:dccab8d5fa1ef9bfba0590ecf4d46df048d18ffe3eec01eeb73a42e0d9e7a8ba"}, - {file = "charset_normalizer-3.4.2-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:aaf27faa992bfee0264dc1f03f4c75e9fcdda66a519db6b957a3f826e285cf12"}, - {file = "charset_normalizer-3.4.2-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:eb30abc20df9ab0814b5a2524f23d75dcf83cde762c161917a2b4b7b55b1e518"}, - {file = "charset_normalizer-3.4.2-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:c72fbbe68c6f32f251bdc08b8611c7b3060612236e960ef848e0a517ddbe76c5"}, - {file = "charset_normalizer-3.4.2-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:982bb1e8b4ffda883b3d0a521e23abcd6fd17418f6d2c4118d257a10199c0ce3"}, - {file = "charset_normalizer-3.4.2-cp39-cp39-win32.whl", hash = "sha256:43e0933a0eff183ee85833f341ec567c0980dae57c464d8a508e1b2ceb336471"}, - {file = "charset_normalizer-3.4.2-cp39-cp39-win_amd64.whl", hash = "sha256:d11b54acf878eef558599658b0ffca78138c8c3655cf4f3a4a673c437e67732e"}, - {file = "charset_normalizer-3.4.2-py3-none-any.whl", hash = "sha256:7f56930ab0abd1c45cd15be65cc741c28b1c9a34876ce8c17a2fa107810c0af0"}, - {file = "charset_normalizer-3.4.2.tar.gz", hash = "sha256:5baececa9ecba31eff645232d59845c07aa030f0c81ee70184a90d35099a0e63"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:e824f1492727fa856dd6eda4f7cee25f8518a12f3c4a56a74e8095695089cf6d"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:4bd5d4137d500351a30687c2d3971758aac9a19208fc110ccb9d7188fbe709e8"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:027f6de494925c0ab2a55eab46ae5129951638a49a34d87f4c3eda90f696b4ad"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:f820802628d2694cb7e56db99213f930856014862f3fd943d290ea8438d07ca8"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:798d75d81754988d2565bff1b97ba5a44411867c0cf32b77a7e8f8d84796b10d"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:9d1bb833febdff5c8927f922386db610b49db6e0d4f4ee29601d71e7c2694313"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:9cd98cdc06614a2f768d2b7286d66805f94c48cde050acdbbb7db2600ab3197e"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:077fbb858e903c73f6c9db43374fd213b0b6a778106bc7032446a8e8b5b38b93"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:244bfb999c71b35de57821b8ea746b24e863398194a4014e4c76adc2bbdfeff0"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:64b55f9dce520635f018f907ff1b0df1fdc31f2795a922fb49dd14fbcdf48c84"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-musllinux_1_2_riscv64.whl", hash = "sha256:faa3a41b2b66b6e50f84ae4a68c64fcd0c44355741c6374813a800cd6695db9e"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:6515f3182dbe4ea06ced2d9e8666d97b46ef4c75e326b79bb624110f122551db"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:cc00f04ed596e9dc0da42ed17ac5e596c6ccba999ba6bd92b0e0aef2f170f2d6"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-win32.whl", hash = "sha256:f34be2938726fc13801220747472850852fe6b1ea75869a048d6f896838c896f"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-win_amd64.whl", hash = "sha256:a61900df84c667873b292c3de315a786dd8dac506704dea57bc957bd31e22c7d"}, + {file = "charset_normalizer-3.4.4-cp310-cp310-win_arm64.whl", hash = "sha256:cead0978fc57397645f12578bfd2d5ea9138ea0fac82b2f63f7f7c6877986a69"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:6e1fcf0720908f200cd21aa4e6750a48ff6ce4afe7ff5a79a90d5ed8a08296f8"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:5f819d5fe9234f9f82d75bdfa9aef3a3d72c4d24a6e57aeaebba32a704553aa0"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:a59cb51917aa591b1c4e6a43c132f0cdc3c76dbad6155df4e28ee626cc77a0a3"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:8ef3c867360f88ac904fd3f5e1f902f13307af9052646963ee08ff4f131adafc"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:d9e45d7faa48ee908174d8fe84854479ef838fc6a705c9315372eacbc2f02897"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:840c25fb618a231545cbab0564a799f101b63b9901f2569faecd6b222ac72381"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:ca5862d5b3928c4940729dacc329aa9102900382fea192fc5e52eb69d6093815"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:d9c7f57c3d666a53421049053eaacdd14bbd0a528e2186fcb2e672effd053bb0"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:277e970e750505ed74c832b4bf75dac7476262ee2a013f5574dd49075879e161"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:31fd66405eaf47bb62e8cd575dc621c56c668f27d46a61d975a249930dd5e2a4"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-musllinux_1_2_riscv64.whl", hash = "sha256:0d3d8f15c07f86e9ff82319b3d9ef6f4bf907608f53fe9d92b28ea9ae3d1fd89"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:9f7fcd74d410a36883701fafa2482a6af2ff5ba96b9a620e9e0721e28ead5569"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:ebf3e58c7ec8a8bed6d66a75d7fb37b55e5015b03ceae72a8e7c74495551e224"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-win32.whl", hash = "sha256:eecbc200c7fd5ddb9a7f16c7decb07b566c29fa2161a16cf67b8d068bd21690a"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-win_amd64.whl", hash = "sha256:5ae497466c7901d54b639cf42d5b8c1b6a4fead55215500d2f486d34db48d016"}, + {file = "charset_normalizer-3.4.4-cp311-cp311-win_arm64.whl", hash = "sha256:65e2befcd84bc6f37095f5961e68a6f077bf44946771354a28ad434c2cce0ae1"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:0a98e6759f854bd25a58a73fa88833fba3b7c491169f86ce1180c948ab3fd394"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b5b290ccc2a263e8d185130284f8501e3e36c5e02750fc6b6bdeb2e9e96f1e25"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:74bb723680f9f7a6234dcf67aea57e708ec1fbdf5699fb91dfd6f511b0a320ef"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:f1e34719c6ed0b92f418c7c780480b26b5d9c50349e9a9af7d76bf757530350d"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:2437418e20515acec67d86e12bf70056a33abdacb5cb1655042f6538d6b085a8"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:11d694519d7f29d6cd09f6ac70028dba10f92f6cdd059096db198c283794ac86"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:ac1c4a689edcc530fc9d9aa11f5774b9e2f33f9a0c6a57864e90908f5208d30a"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:21d142cc6c0ec30d2efee5068ca36c128a30b0f2c53c1c07bd78cb6bc1d3be5f"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:5dbe56a36425d26d6cfb40ce79c314a2e4dd6211d51d6d2191c00bed34f354cc"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:5bfbb1b9acf3334612667b61bd3002196fe2a1eb4dd74d247e0f2a4d50ec9bbf"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-musllinux_1_2_riscv64.whl", hash = "sha256:d055ec1e26e441f6187acf818b73564e6e6282709e9bcb5b63f5b23068356a15"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:af2d8c67d8e573d6de5bc30cdb27e9b95e49115cd9baad5ddbd1a6207aaa82a9"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:780236ac706e66881f3b7f2f32dfe90507a09e67d1d454c762cf642e6e1586e0"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-win32.whl", hash = "sha256:5833d2c39d8896e4e19b689ffc198f08ea58116bee26dea51e362ecc7cd3ed26"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-win_amd64.whl", hash = "sha256:a79cfe37875f822425b89a82333404539ae63dbdddf97f84dcbc3d339aae9525"}, + {file = "charset_normalizer-3.4.4-cp312-cp312-win_arm64.whl", hash = "sha256:376bec83a63b8021bb5c8ea75e21c4ccb86e7e45ca4eb81146091b56599b80c3"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:e1f185f86a6f3403aa2420e815904c67b2f9ebc443f045edd0de921108345794"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:6b39f987ae8ccdf0d2642338faf2abb1862340facc796048b604ef14919e55ed"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:3162d5d8ce1bb98dd51af660f2121c55d0fa541b46dff7bb9b9f86ea1d87de72"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:81d5eb2a312700f4ecaa977a8235b634ce853200e828fbadf3a9c50bab278328"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:5bd2293095d766545ec1a8f612559f6b40abc0eb18bb2f5d1171872d34036ede"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:a8a8b89589086a25749f471e6a900d3f662d1d3b6e2e59dcecf787b1cc3a1894"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:bc7637e2f80d8530ee4a78e878bce464f70087ce73cf7c1caf142416923b98f1"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:f8bf04158c6b607d747e93949aa60618b61312fe647a6369f88ce2ff16043490"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:554af85e960429cf30784dd47447d5125aaa3b99a6f0683589dbd27e2f45da44"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:74018750915ee7ad843a774364e13a3db91682f26142baddf775342c3f5b1133"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-musllinux_1_2_riscv64.whl", hash = "sha256:c0463276121fdee9c49b98908b3a89c39be45d86d1dbaa22957e38f6321d4ce3"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:362d61fd13843997c1c446760ef36f240cf81d3ebf74ac62652aebaf7838561e"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:9a26f18905b8dd5d685d6d07b0cdf98a79f3c7a918906af7cc143ea2e164c8bc"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-win32.whl", hash = "sha256:9b35f4c90079ff2e2edc5b26c0c77925e5d2d255c42c74fdb70fb49b172726ac"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-win_amd64.whl", hash = "sha256:b435cba5f4f750aa6c0a0d92c541fb79f69a387c91e61f1795227e4ed9cece14"}, + {file = "charset_normalizer-3.4.4-cp313-cp313-win_arm64.whl", hash = "sha256:542d2cee80be6f80247095cc36c418f7bddd14f4a6de45af91dfad36d817bba2"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-macosx_10_13_universal2.whl", hash = "sha256:da3326d9e65ef63a817ecbcc0df6e94463713b754fe293eaa03da99befb9a5bd"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:8af65f14dc14a79b924524b1e7fffe304517b2bff5a58bf64f30b98bbc5079eb"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:74664978bb272435107de04e36db5a9735e78232b85b77d45cfb38f758efd33e"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:752944c7ffbfdd10c074dc58ec2d5a8a4cd9493b314d367c14d24c17684ddd14"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:d1f13550535ad8cff21b8d757a3257963e951d96e20ec82ab44bc64aeb62a191"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:ecaae4149d99b1c9e7b88bb03e3221956f68fd6d50be2ef061b2381b61d20838"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:cb6254dc36b47a990e59e1068afacdcd02958bdcce30bb50cc1700a8b9d624a6"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:c8ae8a0f02f57a6e61203a31428fa1d677cbe50c93622b4149d5c0f319c1d19e"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-musllinux_1_2_armv7l.whl", hash = "sha256:47cc91b2f4dd2833fddaedd2893006b0106129d4b94fdb6af1f4ce5a9965577c"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-musllinux_1_2_ppc64le.whl", hash = "sha256:82004af6c302b5d3ab2cfc4cc5f29db16123b1a8417f2e25f9066f91d4411090"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-musllinux_1_2_riscv64.whl", hash = "sha256:2b7d8f6c26245217bd2ad053761201e9f9680f8ce52f0fcd8d0755aeae5b2152"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-musllinux_1_2_s390x.whl", hash = "sha256:799a7a5e4fb2d5898c60b640fd4981d6a25f1c11790935a44ce38c54e985f828"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:99ae2cffebb06e6c22bdc25801d7b30f503cc87dbd283479e7b606f70aff57ec"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-win32.whl", hash = "sha256:f9d332f8c2a2fcbffe1378594431458ddbef721c1769d78e2cbc06280d8155f9"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-win_amd64.whl", hash = "sha256:8a6562c3700cce886c5be75ade4a5db4214fda19fede41d9792d100288d8f94c"}, + {file = "charset_normalizer-3.4.4-cp314-cp314-win_arm64.whl", hash = "sha256:de00632ca48df9daf77a2c65a484531649261ec9f25489917f09e455cb09ddb2"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-macosx_10_9_universal2.whl", hash = "sha256:ce8a0633f41a967713a59c4139d29110c07e826d131a316b50ce11b1d79b4f84"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:eaabd426fe94daf8fd157c32e571c85cb12e66692f15516a83a03264b08d06c3"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:c4ef880e27901b6cc782f1b95f82da9313c0eb95c3af699103088fa0ac3ce9ac"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:2aaba3b0819274cc41757a1da876f810a3e4d7b6eb25699253a4effef9e8e4af"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:778d2e08eda00f4256d7f672ca9fef386071c9202f5e4607920b86d7803387f2"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:f155a433c2ec037d4e8df17d18922c3a0d9b3232a396690f17175d2946f0218d"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:a8bf8d0f749c5757af2142fe7903a9df1d2e8aa3841559b2bad34b08d0e2bcf3"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-musllinux_1_2_aarch64.whl", hash = "sha256:194f08cbb32dc406d6e1aea671a68be0823673db2832b38405deba2fb0d88f63"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-musllinux_1_2_armv7l.whl", hash = "sha256:6aee717dcfead04c6eb1ce3bd29ac1e22663cdea57f943c87d1eab9a025438d7"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-musllinux_1_2_ppc64le.whl", hash = "sha256:cd4b7ca9984e5e7985c12bc60a6f173f3c958eae74f3ef6624bb6b26e2abbae4"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-musllinux_1_2_riscv64.whl", hash = "sha256:b7cf1017d601aa35e6bb650b6ad28652c9cd78ee6caff19f3c28d03e1c80acbf"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-musllinux_1_2_s390x.whl", hash = "sha256:e912091979546adf63357d7e2ccff9b44f026c075aeaf25a52d0e95ad2281074"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-musllinux_1_2_x86_64.whl", hash = "sha256:5cb4d72eea50c8868f5288b7f7f33ed276118325c1dfd3957089f6b519e1382a"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-win32.whl", hash = "sha256:837c2ce8c5a65a2035be9b3569c684358dfbf109fd3b6969630a87535495ceaa"}, + {file = "charset_normalizer-3.4.4-cp38-cp38-win_amd64.whl", hash = "sha256:44c2a8734b333e0578090c4cd6b16f275e07aa6614ca8715e6c038e865e70576"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:a9768c477b9d7bd54bc0c86dbaebdec6f03306675526c9927c0e8a04e8f94af9"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:1bee1e43c28aa63cb16e5c14e582580546b08e535299b8b6158a7c9c768a1f3d"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:fd44c878ea55ba351104cb93cc85e74916eb8fa440ca7903e57575e97394f608"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:0f04b14ffe5fdc8c4933862d8306109a2c51e0704acfa35d51598eb45a1e89fc"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:cd09d08005f958f370f539f186d10aec3377d55b9eeb0d796025d4886119d76e"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:4fe7859a4e3e8457458e2ff592f15ccb02f3da787fcd31e0183879c3ad4692a1"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:fa09f53c465e532f4d3db095e0c55b615f010ad81803d383195b6b5ca6cbf5f3"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:7fa17817dc5625de8a027cb8b26d9fefa3ea28c8253929b8d6649e705d2835b6"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:5947809c8a2417be3267efc979c47d76a079758166f7d43ef5ae8e9f92751f88"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:4902828217069c3c5c71094537a8e623f5d097858ac6ca8252f7b4d10b7560f1"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-musllinux_1_2_riscv64.whl", hash = "sha256:7c308f7e26e4363d79df40ca5b2be1c6ba9f02bdbccfed5abddb7859a6ce72cf"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:2c9d3c380143a1fedbff95a312aa798578371eb29da42106a29019368a475318"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:cb01158d8b88ee68f15949894ccc6712278243d95f344770fa7593fa2d94410c"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-win32.whl", hash = "sha256:2677acec1a2f8ef614c6888b5b4ae4060cc184174a938ed4e8ef690e15d3e505"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-win_amd64.whl", hash = "sha256:f8e160feb2aed042cd657a72acc0b481212ed28b1b9a95c0cee1621b524e1966"}, + {file = "charset_normalizer-3.4.4-cp39-cp39-win_arm64.whl", hash = "sha256:b5d84d37db046c5ca74ee7bb47dd6cbc13f80665fdde3e8040bdd3fb015ecb50"}, + {file = "charset_normalizer-3.4.4-py3-none-any.whl", hash = "sha256:7a32c560861a02ff789ad905a2fe94e3f840803362c84fecf1851cb4cf3dc37f"}, + {file = "charset_normalizer-3.4.4.tar.gz", hash = "sha256:94537985111c35f28720e43603b8e7b43a6ecfb2ce1d3058bbe955b73404e21a"}, ] [[package]] name = "class-resolver" -version = "0.6.0" +version = "0.7.1" description = "Lookup and instantiate classes with style." optional = false -python-versions = ">=3.9" +python-versions = ">=3.10" groups = ["main"] files = [ - {file = "class_resolver-0.6.0-py3-none-any.whl", hash = "sha256:cc629187a10bacff2e360939f8a4e8e7d209583dc8b318485ff91a0d24d5c9d0"}, - {file = "class_resolver-0.6.0.tar.gz", hash = "sha256:8a3c20ab771925477f65cad8a49bb431e11543c82fbfadbf611c6769228a6cae"}, + {file = "class_resolver-0.7.1-py3-none-any.whl", hash = "sha256:d177909a48fdf6d6a0c297d117742a83ea799e0f601a922aa9ccb23ca1200e00"}, + {file = "class_resolver-0.7.1.tar.gz", hash = "sha256:86f73b8cc5ed9111b7d9c5e331b51856a32f205179c66a56a9c520d0f6e82f66"}, ] [package.dependencies] typing-extensions = "*" [package.extras] -click = ["click"] +click = ["click (>=8.2)"] numpy = ["numpy"] optuna = ["optuna"] sklearn = ["scikit-learn"] @@ -1038,14 +1116,14 @@ torch-geometric = ["torch", "torch-geometric", "torch-sparse"] [[package]] name = "click" -version = "8.2.1" +version = "8.3.0" description = "Composable command line interface toolkit" optional = false python-versions = ">=3.10" groups = ["main", "docs"] files = [ - {file = "click-8.2.1-py3-none-any.whl", hash = "sha256:61a3265b914e850b85317d0b3109c7f8cd35a670f963866005d6ef1d5175a12b"}, - {file = "click-8.2.1.tar.gz", hash = "sha256:27c491cc05d968d271d5a1db13e3b5a184636d9d930f148c50b038f0d0646202"}, + {file = "click-8.3.0-py3-none-any.whl", hash = "sha256:9b9f285302c6e3064f4330c05f05b81945b2a39544279343e6e7c5f27a9baddc"}, + {file = "click-8.3.0.tar.gz", hash = "sha256:e7b8232224eba16f4ebe410c25ced9f7875cb5f3263ffc93cc3e8da705e229c4"}, ] [package.dependencies] @@ -1140,182 +1218,217 @@ test = ["mypy", "pytest"] [[package]] name = "contourpy" -version = "1.3.2" +version = "1.3.3" description = "Python library for calculating contours of 2D quadrilateral grids" optional = false -python-versions = ">=3.10" +python-versions = ">=3.11" groups = ["main"] files = [ - {file = "contourpy-1.3.2-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:ba38e3f9f330af820c4b27ceb4b9c7feee5fe0493ea53a8720f4792667465934"}, - {file = "contourpy-1.3.2-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:dc41ba0714aa2968d1f8674ec97504a8f7e334f48eeacebcaa6256213acb0989"}, - {file = "contourpy-1.3.2-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:9be002b31c558d1ddf1b9b415b162c603405414bacd6932d031c5b5a8b757f0d"}, - {file = "contourpy-1.3.2-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:8d2e74acbcba3bfdb6d9d8384cdc4f9260cae86ed9beee8bd5f54fee49a430b9"}, - {file = "contourpy-1.3.2-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:e259bced5549ac64410162adc973c5e2fb77f04df4a439d00b478e57a0e65512"}, - {file = "contourpy-1.3.2-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:ad687a04bc802cbe8b9c399c07162a3c35e227e2daccf1668eb1f278cb698631"}, - {file = "contourpy-1.3.2-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:cdd22595308f53ef2f891040ab2b93d79192513ffccbd7fe19be7aa773a5e09f"}, - {file = "contourpy-1.3.2-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:b4f54d6a2defe9f257327b0f243612dd051cc43825587520b1bf74a31e2f6ef2"}, - {file = "contourpy-1.3.2-cp310-cp310-win32.whl", hash = "sha256:f939a054192ddc596e031e50bb13b657ce318cf13d264f095ce9db7dc6ae81c0"}, - {file = "contourpy-1.3.2-cp310-cp310-win_amd64.whl", hash = "sha256:c440093bbc8fc21c637c03bafcbef95ccd963bc6e0514ad887932c18ca2a759a"}, - {file = "contourpy-1.3.2-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:6a37a2fb93d4df3fc4c0e363ea4d16f83195fc09c891bc8ce072b9d084853445"}, - {file = "contourpy-1.3.2-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:b7cd50c38f500bbcc9b6a46643a40e0913673f869315d8e70de0438817cb7773"}, - {file = "contourpy-1.3.2-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:d6658ccc7251a4433eebd89ed2672c2ed96fba367fd25ca9512aa92a4b46c4f1"}, - {file = "contourpy-1.3.2-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:70771a461aaeb335df14deb6c97439973d253ae70660ca085eec25241137ef43"}, - {file = "contourpy-1.3.2-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:65a887a6e8c4cd0897507d814b14c54a8c2e2aa4ac9f7686292f9769fcf9a6ab"}, - {file = "contourpy-1.3.2-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:3859783aefa2b8355697f16642695a5b9792e7a46ab86da1118a4a23a51a33d7"}, - {file = "contourpy-1.3.2-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:eab0f6db315fa4d70f1d8ab514e527f0366ec021ff853d7ed6a2d33605cf4b83"}, - {file = "contourpy-1.3.2-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:d91a3ccc7fea94ca0acab82ceb77f396d50a1f67412efe4c526f5d20264e6ecd"}, - {file = "contourpy-1.3.2-cp311-cp311-win32.whl", hash = "sha256:1c48188778d4d2f3d48e4643fb15d8608b1d01e4b4d6b0548d9b336c28fc9b6f"}, - {file = "contourpy-1.3.2-cp311-cp311-win_amd64.whl", hash = "sha256:5ebac872ba09cb8f2131c46b8739a7ff71de28a24c869bcad554477eb089a878"}, - {file = "contourpy-1.3.2-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:4caf2bcd2969402bf77edc4cb6034c7dd7c0803213b3523f111eb7460a51b8d2"}, - {file = "contourpy-1.3.2-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:82199cb78276249796419fe36b7386bd8d2cc3f28b3bc19fe2454fe2e26c4c15"}, - {file = "contourpy-1.3.2-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:106fab697af11456fcba3e352ad50effe493a90f893fca6c2ca5c033820cea92"}, - {file = "contourpy-1.3.2-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:d14f12932a8d620e307f715857107b1d1845cc44fdb5da2bc8e850f5ceba9f87"}, - {file = "contourpy-1.3.2-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:532fd26e715560721bb0d5fc7610fce279b3699b018600ab999d1be895b09415"}, - {file = "contourpy-1.3.2-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:f26b383144cf2d2c29f01a1e8170f50dacf0eac02d64139dcd709a8ac4eb3cfe"}, - {file = "contourpy-1.3.2-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:c49f73e61f1f774650a55d221803b101d966ca0c5a2d6d5e4320ec3997489441"}, - {file = "contourpy-1.3.2-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:3d80b2c0300583228ac98d0a927a1ba6a2ba6b8a742463c564f1d419ee5b211e"}, - {file = "contourpy-1.3.2-cp312-cp312-win32.whl", hash = "sha256:90df94c89a91b7362e1142cbee7568f86514412ab8a2c0d0fca72d7e91b62912"}, - {file = "contourpy-1.3.2-cp312-cp312-win_amd64.whl", hash = "sha256:8c942a01d9163e2e5cfb05cb66110121b8d07ad438a17f9e766317bcb62abf73"}, - {file = "contourpy-1.3.2-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:de39db2604ae755316cb5967728f4bea92685884b1e767b7c24e983ef5f771cb"}, - {file = "contourpy-1.3.2-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:3f9e896f447c5c8618f1edb2bafa9a4030f22a575ec418ad70611450720b5b08"}, - {file = "contourpy-1.3.2-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:71e2bd4a1c4188f5c2b8d274da78faab884b59df20df63c34f74aa1813c4427c"}, - {file = "contourpy-1.3.2-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:de425af81b6cea33101ae95ece1f696af39446db9682a0b56daaa48cfc29f38f"}, - {file = "contourpy-1.3.2-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:977e98a0e0480d3fe292246417239d2d45435904afd6d7332d8455981c408b85"}, - {file = "contourpy-1.3.2-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:434f0adf84911c924519d2b08fc10491dd282b20bdd3fa8f60fd816ea0b48841"}, - {file = "contourpy-1.3.2-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:c66c4906cdbc50e9cba65978823e6e00b45682eb09adbb78c9775b74eb222422"}, - {file = "contourpy-1.3.2-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:8b7fc0cd78ba2f4695fd0a6ad81a19e7e3ab825c31b577f384aa9d7817dc3bef"}, - {file = "contourpy-1.3.2-cp313-cp313-win32.whl", hash = "sha256:15ce6ab60957ca74cff444fe66d9045c1fd3e92c8936894ebd1f3eef2fff075f"}, - {file = "contourpy-1.3.2-cp313-cp313-win_amd64.whl", hash = "sha256:e1578f7eafce927b168752ed7e22646dad6cd9bca673c60bff55889fa236ebf9"}, - {file = "contourpy-1.3.2-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:0475b1f6604896bc7c53bb070e355e9321e1bc0d381735421a2d2068ec56531f"}, - {file = "contourpy-1.3.2-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:c85bb486e9be652314bb5b9e2e3b0d1b2e643d5eec4992c0fbe8ac71775da739"}, - {file = "contourpy-1.3.2-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:745b57db7758f3ffc05a10254edd3182a2a83402a89c00957a8e8a22f5582823"}, - {file = "contourpy-1.3.2-cp313-cp313t-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:970e9173dbd7eba9b4e01aab19215a48ee5dd3f43cef736eebde064a171f89a5"}, - {file = "contourpy-1.3.2-cp313-cp313t-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:c6c4639a9c22230276b7bffb6a850dfc8258a2521305e1faefe804d006b2e532"}, - {file = "contourpy-1.3.2-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:cc829960f34ba36aad4302e78eabf3ef16a3a100863f0d4eeddf30e8a485a03b"}, - {file = "contourpy-1.3.2-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:d32530b534e986374fc19eaa77fcb87e8a99e5431499949b828312bdcd20ac52"}, - {file = "contourpy-1.3.2-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:e298e7e70cf4eb179cc1077be1c725b5fd131ebc81181bf0c03525c8abc297fd"}, - {file = "contourpy-1.3.2-cp313-cp313t-win32.whl", hash = "sha256:d0e589ae0d55204991450bb5c23f571c64fe43adaa53f93fc902a84c96f52fe1"}, - {file = "contourpy-1.3.2-cp313-cp313t-win_amd64.whl", hash = "sha256:78e9253c3de756b3f6a5174d024c4835acd59eb3f8e2ca13e775dbffe1558f69"}, - {file = "contourpy-1.3.2-pp310-pypy310_pp73-macosx_10_15_x86_64.whl", hash = "sha256:fd93cc7f3139b6dd7aab2f26a90dde0aa9fc264dbf70f6740d498a70b860b82c"}, - {file = "contourpy-1.3.2-pp310-pypy310_pp73-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:107ba8a6a7eec58bb475329e6d3b95deba9440667c4d62b9b6063942b61d7f16"}, - {file = "contourpy-1.3.2-pp310-pypy310_pp73-win_amd64.whl", hash = "sha256:ded1706ed0c1049224531b81128efbd5084598f18d8a2d9efae833edbd2b40ad"}, - {file = "contourpy-1.3.2-pp311-pypy311_pp73-macosx_10_15_x86_64.whl", hash = "sha256:5f5964cdad279256c084b69c3f412b7801e15356b16efa9d78aa974041903da0"}, - {file = "contourpy-1.3.2-pp311-pypy311_pp73-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:49b65a95d642d4efa8f64ba12558fcb83407e58a2dfba9d796d77b63ccfcaff5"}, - {file = "contourpy-1.3.2-pp311-pypy311_pp73-win_amd64.whl", hash = "sha256:8c5acb8dddb0752bf252e01a3035b21443158910ac16a3b0d20e7fed7d534ce5"}, - {file = "contourpy-1.3.2.tar.gz", hash = "sha256:b6945942715a034c671b7fc54f9588126b0b8bf23db2696e3ca8328f3ff0ab54"}, -] - -[package.dependencies] -numpy = ">=1.23" + {file = "contourpy-1.3.3-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:709a48ef9a690e1343202916450bc48b9e51c049b089c7f79a267b46cffcdaa1"}, + {file = "contourpy-1.3.3-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:23416f38bfd74d5d28ab8429cc4d63fa67d5068bd711a85edb1c3fb0c3e2f381"}, + {file = "contourpy-1.3.3-cp311-cp311-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:929ddf8c4c7f348e4c0a5a3a714b5c8542ffaa8c22954862a46ca1813b667ee7"}, + {file = "contourpy-1.3.3-cp311-cp311-manylinux_2_26_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:9e999574eddae35f1312c2b4b717b7885d4edd6cb46700e04f7f02db454e67c1"}, + {file = "contourpy-1.3.3-cp311-cp311-manylinux_2_26_s390x.manylinux_2_28_s390x.whl", hash = "sha256:0bf67e0e3f482cb69779dd3061b534eb35ac9b17f163d851e2a547d56dba0a3a"}, + {file = "contourpy-1.3.3-cp311-cp311-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:51e79c1f7470158e838808d4a996fa9bac72c498e93d8ebe5119bc1e6becb0db"}, + {file = "contourpy-1.3.3-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:598c3aaece21c503615fd59c92a3598b428b2f01bfb4b8ca9c4edeecc2438620"}, + {file = "contourpy-1.3.3-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:322ab1c99b008dad206d406bb61d014cf0174df491ae9d9d0fac6a6fda4f977f"}, + {file = "contourpy-1.3.3-cp311-cp311-win32.whl", hash = "sha256:fd907ae12cd483cd83e414b12941c632a969171bf90fc937d0c9f268a31cafff"}, + {file = "contourpy-1.3.3-cp311-cp311-win_amd64.whl", hash = "sha256:3519428f6be58431c56581f1694ba8e50626f2dd550af225f82fb5f5814d2a42"}, + {file = "contourpy-1.3.3-cp311-cp311-win_arm64.whl", hash = "sha256:15ff10bfada4bf92ec8b31c62bf7c1834c244019b4a33095a68000d7075df470"}, + {file = "contourpy-1.3.3-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:b08a32ea2f8e42cf1d4be3169a98dd4be32bafe4f22b6c4cb4ba810fa9e5d2cb"}, + {file = "contourpy-1.3.3-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:556dba8fb6f5d8742f2923fe9457dbdd51e1049c4a43fd3986a0b14a1d815fc6"}, + {file = "contourpy-1.3.3-cp312-cp312-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:92d9abc807cf7d0e047b95ca5d957cf4792fcd04e920ca70d48add15c1a90ea7"}, + {file = "contourpy-1.3.3-cp312-cp312-manylinux_2_26_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:b2e8faa0ed68cb29af51edd8e24798bb661eac3bd9f65420c1887b6ca89987c8"}, + {file = "contourpy-1.3.3-cp312-cp312-manylinux_2_26_s390x.manylinux_2_28_s390x.whl", hash = "sha256:626d60935cf668e70a5ce6ff184fd713e9683fb458898e4249b63be9e28286ea"}, + {file = "contourpy-1.3.3-cp312-cp312-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:4d00e655fcef08aba35ec9610536bfe90267d7ab5ba944f7032549c55a146da1"}, + {file = "contourpy-1.3.3-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:451e71b5a7d597379ef572de31eeb909a87246974d960049a9848c3bc6c41bf7"}, + {file = "contourpy-1.3.3-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:459c1f020cd59fcfe6650180678a9993932d80d44ccde1fa1868977438f0b411"}, + {file = "contourpy-1.3.3-cp312-cp312-win32.whl", hash = "sha256:023b44101dfe49d7d53932be418477dba359649246075c996866106da069af69"}, + {file = "contourpy-1.3.3-cp312-cp312-win_amd64.whl", hash = "sha256:8153b8bfc11e1e4d75bcb0bff1db232f9e10b274e0929de9d608027e0d34ff8b"}, + {file = "contourpy-1.3.3-cp312-cp312-win_arm64.whl", hash = "sha256:07ce5ed73ecdc4a03ffe3e1b3e3c1166db35ae7584be76f65dbbe28a7791b0cc"}, + {file = "contourpy-1.3.3-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:177fb367556747a686509d6fef71d221a4b198a3905fe824430e5ea0fda54eb5"}, + {file = "contourpy-1.3.3-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:d002b6f00d73d69333dac9d0b8d5e84d9724ff9ef044fd63c5986e62b7c9e1b1"}, + {file = "contourpy-1.3.3-cp313-cp313-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:348ac1f5d4f1d66d3322420f01d42e43122f43616e0f194fc1c9f5d830c5b286"}, + {file = "contourpy-1.3.3-cp313-cp313-manylinux_2_26_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:655456777ff65c2c548b7c454af9c6f33f16c8884f11083244b5819cc214f1b5"}, + {file = "contourpy-1.3.3-cp313-cp313-manylinux_2_26_s390x.manylinux_2_28_s390x.whl", hash = "sha256:644a6853d15b2512d67881586bd03f462c7ab755db95f16f14d7e238f2852c67"}, + {file = "contourpy-1.3.3-cp313-cp313-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:4debd64f124ca62069f313a9cb86656ff087786016d76927ae2cf37846b006c9"}, + {file = "contourpy-1.3.3-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:a15459b0f4615b00bbd1e91f1b9e19b7e63aea7483d03d804186f278c0af2659"}, + {file = "contourpy-1.3.3-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:ca0fdcd73925568ca027e0b17ab07aad764be4706d0a925b89227e447d9737b7"}, + {file = "contourpy-1.3.3-cp313-cp313-win32.whl", hash = "sha256:b20c7c9a3bf701366556e1b1984ed2d0cedf999903c51311417cf5f591d8c78d"}, + {file = "contourpy-1.3.3-cp313-cp313-win_amd64.whl", hash = "sha256:1cadd8b8969f060ba45ed7c1b714fe69185812ab43bd6b86a9123fe8f99c3263"}, + {file = "contourpy-1.3.3-cp313-cp313-win_arm64.whl", hash = "sha256:fd914713266421b7536de2bfa8181aa8c699432b6763a0ea64195ebe28bff6a9"}, + {file = "contourpy-1.3.3-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:88df9880d507169449d434c293467418b9f6cbe82edd19284aa0409e7fdb933d"}, + {file = "contourpy-1.3.3-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:d06bb1f751ba5d417047db62bca3c8fde202b8c11fb50742ab3ab962c81e8216"}, + {file = "contourpy-1.3.3-cp313-cp313t-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:e4e6b05a45525357e382909a4c1600444e2a45b4795163d3b22669285591c1ae"}, + {file = "contourpy-1.3.3-cp313-cp313t-manylinux_2_26_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:ab3074b48c4e2cf1a960e6bbeb7f04566bf36b1861d5c9d4d8ac04b82e38ba20"}, + {file = "contourpy-1.3.3-cp313-cp313t-manylinux_2_26_s390x.manylinux_2_28_s390x.whl", hash = "sha256:6c3d53c796f8647d6deb1abe867daeb66dcc8a97e8455efa729516b997b8ed99"}, + {file = "contourpy-1.3.3-cp313-cp313t-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:50ed930df7289ff2a8d7afeb9603f8289e5704755c7e5c3bbd929c90c817164b"}, + {file = "contourpy-1.3.3-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:4feffb6537d64b84877da813a5c30f1422ea5739566abf0bd18065ac040e120a"}, + {file = "contourpy-1.3.3-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:2b7e9480ffe2b0cd2e787e4df64270e3a0440d9db8dc823312e2c940c167df7e"}, + {file = "contourpy-1.3.3-cp313-cp313t-win32.whl", hash = "sha256:283edd842a01e3dcd435b1c5116798d661378d83d36d337b8dde1d16a5fc9ba3"}, + {file = "contourpy-1.3.3-cp313-cp313t-win_amd64.whl", hash = "sha256:87acf5963fc2b34825e5b6b048f40e3635dd547f590b04d2ab317c2619ef7ae8"}, + {file = "contourpy-1.3.3-cp313-cp313t-win_arm64.whl", hash = "sha256:3c30273eb2a55024ff31ba7d052dde990d7d8e5450f4bbb6e913558b3d6c2301"}, + {file = "contourpy-1.3.3-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:fde6c716d51c04b1c25d0b90364d0be954624a0ee9d60e23e850e8d48353d07a"}, + {file = "contourpy-1.3.3-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:cbedb772ed74ff5be440fa8eee9bd49f64f6e3fc09436d9c7d8f1c287b121d77"}, + {file = "contourpy-1.3.3-cp314-cp314-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:22e9b1bd7a9b1d652cd77388465dc358dafcd2e217d35552424aa4f996f524f5"}, + {file = "contourpy-1.3.3-cp314-cp314-manylinux_2_26_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:a22738912262aa3e254e4f3cb079a95a67132fc5a063890e224393596902f5a4"}, + {file = "contourpy-1.3.3-cp314-cp314-manylinux_2_26_s390x.manylinux_2_28_s390x.whl", hash = "sha256:afe5a512f31ee6bd7d0dda52ec9864c984ca3d66664444f2d72e0dc4eb832e36"}, + {file = "contourpy-1.3.3-cp314-cp314-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:f64836de09927cba6f79dcd00fdd7d5329f3fccc633468507079c829ca4db4e3"}, + {file = "contourpy-1.3.3-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:1fd43c3be4c8e5fd6e4f2baeae35ae18176cf2e5cced681cca908addf1cdd53b"}, + {file = "contourpy-1.3.3-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:6afc576f7b33cf00996e5c1102dc2a8f7cc89e39c0b55df93a0b78c1bd992b36"}, + {file = "contourpy-1.3.3-cp314-cp314-win32.whl", hash = "sha256:66c8a43a4f7b8df8b71ee1840e4211a3c8d93b214b213f590e18a1beca458f7d"}, + {file = "contourpy-1.3.3-cp314-cp314-win_amd64.whl", hash = "sha256:cf9022ef053f2694e31d630feaacb21ea24224be1c3ad0520b13d844274614fd"}, + {file = "contourpy-1.3.3-cp314-cp314-win_arm64.whl", hash = "sha256:95b181891b4c71de4bb404c6621e7e2390745f887f2a026b2d99e92c17892339"}, + {file = "contourpy-1.3.3-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:33c82d0138c0a062380332c861387650c82e4cf1747aaa6938b9b6516762e772"}, + {file = "contourpy-1.3.3-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:ea37e7b45949df430fe649e5de8351c423430046a2af20b1c1961cae3afcda77"}, + {file = "contourpy-1.3.3-cp314-cp314t-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:d304906ecc71672e9c89e87c4675dc5c2645e1f4269a5063b99b0bb29f232d13"}, + {file = "contourpy-1.3.3-cp314-cp314t-manylinux_2_26_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:ca658cd1a680a5c9ea96dc61cdbae1e85c8f25849843aa799dfd3cb370ad4fbe"}, + {file = "contourpy-1.3.3-cp314-cp314t-manylinux_2_26_s390x.manylinux_2_28_s390x.whl", hash = "sha256:ab2fd90904c503739a75b7c8c5c01160130ba67944a7b77bbf36ef8054576e7f"}, + {file = "contourpy-1.3.3-cp314-cp314t-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:b7301b89040075c30e5768810bc96a8e8d78085b47d8be6e4c3f5a0b4ed478a0"}, + {file = "contourpy-1.3.3-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:2a2a8b627d5cc6b7c41a4beff6c5ad5eb848c88255fda4a8745f7e901b32d8e4"}, + {file = "contourpy-1.3.3-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:fd6ec6be509c787f1caf6b247f0b1ca598bef13f4ddeaa126b7658215529ba0f"}, + {file = "contourpy-1.3.3-cp314-cp314t-win32.whl", hash = "sha256:e74a9a0f5e3fff48fb5a7f2fd2b9b70a3fe014a67522f79b7cca4c0c7e43c9ae"}, + {file = "contourpy-1.3.3-cp314-cp314t-win_amd64.whl", hash = "sha256:13b68d6a62db8eafaebb8039218921399baf6e47bf85006fd8529f2a08ef33fc"}, + {file = "contourpy-1.3.3-cp314-cp314t-win_arm64.whl", hash = "sha256:b7448cb5a725bb1e35ce88771b86fba35ef418952474492cf7c764059933ff8b"}, + {file = "contourpy-1.3.3-pp311-pypy311_pp73-macosx_10_15_x86_64.whl", hash = "sha256:cd5dfcaeb10f7b7f9dc8941717c6c2ade08f587be2226222c12b25f0483ed497"}, + {file = "contourpy-1.3.3-pp311-pypy311_pp73-macosx_11_0_arm64.whl", hash = "sha256:0c1fc238306b35f246d61a1d416a627348b5cf0648648a031e14bb8705fcdfe8"}, + {file = "contourpy-1.3.3-pp311-pypy311_pp73-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:70f9aad7de812d6541d29d2bbf8feb22ff7e1c299523db288004e3157ff4674e"}, + {file = "contourpy-1.3.3-pp311-pypy311_pp73-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:5ed3657edf08512fc3fe81b510e35c2012fbd3081d2e26160f27ca28affec989"}, + {file = "contourpy-1.3.3-pp311-pypy311_pp73-win_amd64.whl", hash = "sha256:3d1a3799d62d45c18bafd41c5fa05120b96a28079f2393af559b843d1a966a77"}, + {file = "contourpy-1.3.3.tar.gz", hash = "sha256:083e12155b210502d0bca491432bb04d56dc3432f95a979b429f2848c3dbe880"}, +] + +[package.dependencies] +numpy = ">=1.25" [package.extras] bokeh = ["bokeh", "selenium"] docs = ["furo", "sphinx (>=7.2)", "sphinx-copybutton"] -mypy = ["bokeh", "contourpy[bokeh,docs]", "docutils-stubs", "mypy (==1.15.0)", "types-Pillow"] +mypy = ["bokeh", "contourpy[bokeh,docs]", "docutils-stubs", "mypy (==1.17.0)", "types-Pillow"] test = ["Pillow", "contourpy[test-no-images]", "matplotlib"] test-no-images = ["pytest", "pytest-cov", "pytest-rerunfailures", "pytest-xdist", "wurlitzer"] [[package]] name = "coredis" -version = "5.0.1" +version = "5.3.0" description = "Python async client for Redis key-value store" optional = false python-versions = ">=3.10" groups = ["main"] files = [ - {file = "coredis-5.0.1-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:2592b58b7c74646213a8493d9578cb9a2861f15bd5ba7400d9beaad897ed6e8c"}, - {file = "coredis-5.0.1-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:0317b2212fd36057eb4866e79ffc722d76c87d4481dd1f73eae72d5850dd333d"}, - {file = "coredis-5.0.1-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:d569ae964da91f805e60494179c3871eb5e0ed34c3a8f279a086a34f7b40d70f"}, - {file = "coredis-5.0.1-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:7562e6f4b261160eb130eb4a7d17f344870496edb06371c5304c86289bac4f37"}, - {file = "coredis-5.0.1-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:8a26f6671b29bd5c8f6902be736770e6b15564d765707b5014d05ba837d477ce"}, - {file = "coredis-5.0.1-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:3fdaad2567aea8281fbbd99ec9e153722f08e5e87eb2e75848873cea44245fe8"}, - {file = "coredis-5.0.1-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:46b9973fe126f35083d0200a7749e48a25ac0c6faa2b42284cd733267520357b"}, - {file = "coredis-5.0.1-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:c793028b5386166316cb268cd832e5b451a4efab908179449f16bc026a1f763b"}, - {file = "coredis-5.0.1-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:1705038b9fac64443e42f6707892f8560c98673e209e5a9d0c93cd0ae3640a50"}, - {file = "coredis-5.0.1-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:1386440fa0bd5acf01e11e4edc26c217f65096ae3a00c72910bdc6a3ae39d432"}, - {file = "coredis-5.0.1-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:1e34fe52965ce80ae33a662a47e140623666998a778a059403a5b3493a3aad5e"}, - {file = "coredis-5.0.1-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:d0e79e288306a080dfb5a4553734de652c49c3653ca7c6de748846e30f6d1bd0"}, - {file = "coredis-5.0.1-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:bdc0137077cca1f29f659711bd98e36bb8da3c75451e6374c0e462e2ec54238c"}, - {file = "coredis-5.0.1-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:27123964f0609f2d361f668f406c0a284c7362f3d4e56b25646f87445036af23"}, - {file = "coredis-5.0.1-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:856a955fc5c6ecc40889b67b605b23082d77a6da2b404b73f0cca8721868e182"}, - {file = "coredis-5.0.1-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:70a1311ba33d3b4f204d6670be16f269d5b1805237af6e211ca92872061e3e3d"}, - {file = "coredis-5.0.1-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:4948208e0f51a8b67c5a9d2bce808b4e86fe51adf09d11ba02ba2aa17e50ac62"}, - {file = "coredis-5.0.1-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:33a11a95308049df4f31c03df38012b7c532595095487cd49726df39f58bbf83"}, - {file = "coredis-5.0.1-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:ed99b915b31a17a3c67d7ea5a9558d70f4378408c2e16078b836538ae1198641"}, - {file = "coredis-5.0.1-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:8e45fa763cb20da9c37b71334c962126fdad16bb3db8aea8ea7dc8f69bdc5bca"}, - {file = "coredis-5.0.1-py3-none-any.whl", hash = "sha256:1bf6098a17832d232ca429640662b25be378139dd54574853ac21dc48cefd4ba"}, - {file = "coredis-5.0.1.tar.gz", hash = "sha256:c312dc11b785367b2da440cba3ebd7a47ca0bbf673d74d923a590aa77550c73f"}, -] - -[package.dependencies] -async_timeout = ">4,<6" + {file = "coredis-5.3.0-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:0779d16434658378d59a7a5952327f3b6d8242a3c21db21bd638dc18c12a86a8"}, + {file = "coredis-5.3.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:54b6abeae16e9d165229ebba18b3b94e612214eb9a1d487693b9c99f72f7bcee"}, + {file = "coredis-5.3.0-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:fe700b7d3673755aa42a4c95e9dd099fec1f39e2eecbb990fedc093125065b45"}, + {file = "coredis-5.3.0-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:a59792781ca594abbea0240e3cccb28ddfcb12e251f2b38cbf85c80bd1babbe1"}, + {file = "coredis-5.3.0-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:20043268f9ba63182a9305c80667278f1fb5dd1cdcb9a0b9b95c3b1db87a035c"}, + {file = "coredis-5.3.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:15a0c7d5fb3250e7abccd2c7903cd5f998d8b9c62e682a4107343e4f6e36d35f"}, + {file = "coredis-5.3.0-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:891287ef40af4cdae8def953afd68c909c8968ab7e36a60342276165b91a94b0"}, + {file = "coredis-5.3.0-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:77c03ed549faaf4a25ccad1d68e6aeb94c7b88ca4bd9d4c07bedcccbabd405f3"}, + {file = "coredis-5.3.0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:c5655fb6116686eddc6297c568903a1019a174c8b8a88c2b28fb23ab682a3145"}, + {file = "coredis-5.3.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:b86494ed20cc87d001e087fab4b0498913e3fee74c763e528ba779cd30dd88b8"}, + {file = "coredis-5.3.0-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:e0738b883f276c2eaaee991f5ba75181976ab9fbd422a0a3bb36e9ee0674c9ff"}, + {file = "coredis-5.3.0-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:6f772bdb123b05dc4d3bf63b8d81e36b3a6c7f8220085b112055c30eaecb45be"}, + {file = "coredis-5.3.0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:3bfa42210ef6c6d299096217684fdf5631d81b48884970ff725959c0097da1c1"}, + {file = "coredis-5.3.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:faf00be39a5cfa78f117416479715bd1287f9c80636ba948ec4c265418195297"}, + {file = "coredis-5.3.0-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:ecd00d89005c0eca263d94e7e088f98951c10b95ec82042b46f384e5d4517a4e"}, + {file = "coredis-5.3.0-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:a5539542faf3f7e64b8f62bcc82f79e031e4d9853d0444401bc796dbae0fe3f6"}, + {file = "coredis-5.3.0-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:fd6fa281ab92cf71256f6bcc9bea896a1d17d1b339d8d8d2159f1e6d40e078d1"}, + {file = "coredis-5.3.0-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:673d602d76d2bcb2823ac6a50cff38af859a4435d0b4f61f59f93ed5622887d0"}, + {file = "coredis-5.3.0-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:558b7709c023b7f88c2207fa0741c53a38e7aba2b0ad392153966b481ac9cf29"}, + {file = "coredis-5.3.0-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:75ecfbb6e70b482ad84bd5bb5d2b7a9dccebbfed64d88175b3b83b1b7649ac74"}, + {file = "coredis-5.3.0-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:a98b4a446a3a08b8052bf2f419794d7e6c24f7606eafa1a90b96599603e3a33b"}, + {file = "coredis-5.3.0-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:b734c1021005b76c123fdcf49dda1171629d4ec45b9d3d46aaeda18ffe3860eb"}, + {file = "coredis-5.3.0-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:bd053007b59795e5fdc98a346f217f35d56420943cdf0888b093be13ab2c1b00"}, + {file = "coredis-5.3.0-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:259e427d637d28be4c952ea3dca8a180c1b6ce71f8d5560a3dc8c1e62b5c5783"}, + {file = "coredis-5.3.0.tar.gz", hash = "sha256:a266457b27277a1083033d39d799a3e3bf568c6db0ba75887546b35e006814e0"}, +] + +[package.dependencies] +async-timeout = ">4,<6" beartype = ">=0.20" deprecated = ">=1.2" packaging = ">=21,<26" pympler = ">1,<2" -typing_extensions = ">=4.13" +typing-extensions = ">=4.13" [package.extras] recipes = ["aiobotocore (>=2.15.2)", "asyncache (>=0.3.1)"] [[package]] name = "cryptography" -version = "45.0.5" +version = "46.0.2" description = "cryptography is a package which provides cryptographic recipes and primitives to Python developers." optional = true -python-versions = "!=3.9.0,!=3.9.1,>=3.7" -groups = ["main"] -files = [ - {file = "cryptography-45.0.5-cp311-abi3-macosx_10_9_universal2.whl", hash = "sha256:101ee65078f6dd3e5a028d4f19c07ffa4dd22cce6a20eaa160f8b5219911e7d8"}, - {file = "cryptography-45.0.5-cp311-abi3-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:3a264aae5f7fbb089dbc01e0242d3b67dffe3e6292e1f5182122bdf58e65215d"}, - {file = "cryptography-45.0.5-cp311-abi3-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:e74d30ec9c7cb2f404af331d5b4099a9b322a8a6b25c4632755c8757345baac5"}, - {file = "cryptography-45.0.5-cp311-abi3-manylinux_2_28_aarch64.whl", hash = "sha256:3af26738f2db354aafe492fb3869e955b12b2ef2e16908c8b9cb928128d42c57"}, - {file = "cryptography-45.0.5-cp311-abi3-manylinux_2_28_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:e6c00130ed423201c5bc5544c23359141660b07999ad82e34e7bb8f882bb78e0"}, - {file = "cryptography-45.0.5-cp311-abi3-manylinux_2_28_x86_64.whl", hash = "sha256:dd420e577921c8c2d31289536c386aaa30140b473835e97f83bc71ea9d2baf2d"}, - {file = "cryptography-45.0.5-cp311-abi3-manylinux_2_34_aarch64.whl", hash = "sha256:d05a38884db2ba215218745f0781775806bde4f32e07b135348355fe8e4991d9"}, - {file = "cryptography-45.0.5-cp311-abi3-manylinux_2_34_x86_64.whl", hash = "sha256:ad0caded895a00261a5b4aa9af828baede54638754b51955a0ac75576b831b27"}, - {file = "cryptography-45.0.5-cp311-abi3-musllinux_1_2_aarch64.whl", hash = "sha256:9024beb59aca9d31d36fcdc1604dd9bbeed0a55bface9f1908df19178e2f116e"}, - {file = "cryptography-45.0.5-cp311-abi3-musllinux_1_2_x86_64.whl", hash = "sha256:91098f02ca81579c85f66df8a588c78f331ca19089763d733e34ad359f474174"}, - {file = "cryptography-45.0.5-cp311-abi3-win32.whl", hash = "sha256:926c3ea71a6043921050eaa639137e13dbe7b4ab25800932a8498364fc1abec9"}, - {file = "cryptography-45.0.5-cp311-abi3-win_amd64.whl", hash = "sha256:b85980d1e345fe769cfc57c57db2b59cff5464ee0c045d52c0df087e926fbe63"}, - {file = "cryptography-45.0.5-cp37-abi3-macosx_10_9_universal2.whl", hash = "sha256:f3562c2f23c612f2e4a6964a61d942f891d29ee320edb62ff48ffb99f3de9ae8"}, - {file = "cryptography-45.0.5-cp37-abi3-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:3fcfbefc4a7f332dece7272a88e410f611e79458fab97b5efe14e54fe476f4fd"}, - {file = "cryptography-45.0.5-cp37-abi3-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:460f8c39ba66af7db0545a8c6f2eabcbc5a5528fc1cf6c3fa9a1e44cec33385e"}, - {file = "cryptography-45.0.5-cp37-abi3-manylinux_2_28_aarch64.whl", hash = "sha256:9b4cf6318915dccfe218e69bbec417fdd7c7185aa7aab139a2c0beb7468c89f0"}, - {file = "cryptography-45.0.5-cp37-abi3-manylinux_2_28_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:2089cc8f70a6e454601525e5bf2779e665d7865af002a5dec8d14e561002e135"}, - {file = "cryptography-45.0.5-cp37-abi3-manylinux_2_28_x86_64.whl", hash = "sha256:0027d566d65a38497bc37e0dd7c2f8ceda73597d2ac9ba93810204f56f52ebc7"}, - {file = "cryptography-45.0.5-cp37-abi3-manylinux_2_34_aarch64.whl", hash = "sha256:be97d3a19c16a9be00edf79dca949c8fa7eff621763666a145f9f9535a5d7f42"}, - {file = "cryptography-45.0.5-cp37-abi3-manylinux_2_34_x86_64.whl", hash = "sha256:7760c1c2e1a7084153a0f68fab76e754083b126a47d0117c9ed15e69e2103492"}, - {file = "cryptography-45.0.5-cp37-abi3-musllinux_1_2_aarch64.whl", hash = "sha256:6ff8728d8d890b3dda5765276d1bc6fb099252915a2cd3aff960c4c195745dd0"}, - {file = "cryptography-45.0.5-cp37-abi3-musllinux_1_2_x86_64.whl", hash = "sha256:7259038202a47fdecee7e62e0fd0b0738b6daa335354396c6ddebdbe1206af2a"}, - {file = "cryptography-45.0.5-cp37-abi3-win32.whl", hash = "sha256:1e1da5accc0c750056c556a93c3e9cb828970206c68867712ca5805e46dc806f"}, - {file = "cryptography-45.0.5-cp37-abi3-win_amd64.whl", hash = "sha256:90cb0a7bb35959f37e23303b7eed0a32280510030daba3f7fdfbb65defde6a97"}, - {file = "cryptography-45.0.5-pp310-pypy310_pp73-macosx_10_9_x86_64.whl", hash = "sha256:206210d03c1193f4e1ff681d22885181d47efa1ab3018766a7b32a7b3d6e6afd"}, - {file = "cryptography-45.0.5-pp310-pypy310_pp73-manylinux_2_28_aarch64.whl", hash = "sha256:c648025b6840fe62e57107e0a25f604db740e728bd67da4f6f060f03017d5097"}, - {file = "cryptography-45.0.5-pp310-pypy310_pp73-manylinux_2_28_x86_64.whl", hash = "sha256:b8fa8b0a35a9982a3c60ec79905ba5bb090fc0b9addcfd3dc2dd04267e45f25e"}, - {file = "cryptography-45.0.5-pp310-pypy310_pp73-manylinux_2_34_aarch64.whl", hash = "sha256:14d96584701a887763384f3c47f0ca7c1cce322aa1c31172680eb596b890ec30"}, - {file = "cryptography-45.0.5-pp310-pypy310_pp73-manylinux_2_34_x86_64.whl", hash = "sha256:57c816dfbd1659a367831baca4b775b2a5b43c003daf52e9d57e1d30bc2e1b0e"}, - {file = "cryptography-45.0.5-pp310-pypy310_pp73-win_amd64.whl", hash = "sha256:b9e38e0a83cd51e07f5a48ff9691cae95a79bea28fe4ded168a8e5c6c77e819d"}, - {file = "cryptography-45.0.5-pp311-pypy311_pp73-macosx_10_9_x86_64.whl", hash = "sha256:8c4a6ff8a30e9e3d38ac0539e9a9e02540ab3f827a3394f8852432f6b0ea152e"}, - {file = "cryptography-45.0.5-pp311-pypy311_pp73-manylinux_2_28_aarch64.whl", hash = "sha256:bd4c45986472694e5121084c6ebbd112aa919a25e783b87eb95953c9573906d6"}, - {file = "cryptography-45.0.5-pp311-pypy311_pp73-manylinux_2_28_x86_64.whl", hash = "sha256:982518cd64c54fcada9d7e5cf28eabd3ee76bd03ab18e08a48cad7e8b6f31b18"}, - {file = "cryptography-45.0.5-pp311-pypy311_pp73-manylinux_2_34_aarch64.whl", hash = "sha256:12e55281d993a793b0e883066f590c1ae1e802e3acb67f8b442e721e475e6463"}, - {file = "cryptography-45.0.5-pp311-pypy311_pp73-manylinux_2_34_x86_64.whl", hash = "sha256:5aa1e32983d4443e310f726ee4b071ab7569f58eedfdd65e9675484a4eb67bd1"}, - {file = "cryptography-45.0.5-pp311-pypy311_pp73-win_amd64.whl", hash = "sha256:e357286c1b76403dd384d938f93c46b2b058ed4dfcdce64a770f0537ed3feb6f"}, - {file = "cryptography-45.0.5.tar.gz", hash = "sha256:72e76caa004ab63accdf26023fccd1d087f6d90ec6048ff33ad0445abf7f605a"}, -] - -[package.dependencies] -cffi = {version = ">=1.14", markers = "platform_python_implementation != \"PyPy\""} - -[package.extras] -docs = ["sphinx (>=5.3.0)", "sphinx-inline-tabs ; python_full_version >= \"3.8.0\"", "sphinx-rtd-theme (>=3.0.0) ; python_full_version >= \"3.8.0\""] +python-versions = "!=3.9.0,!=3.9.1,>=3.8" +groups = ["main"] +files = [ + {file = "cryptography-46.0.2-cp311-abi3-macosx_10_9_universal2.whl", hash = "sha256:f3e32ab7dd1b1ef67b9232c4cf5e2ee4cd517d4316ea910acaaa9c5712a1c663"}, + {file = "cryptography-46.0.2-cp311-abi3-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:1fd1a69086926b623ef8126b4c33d5399ce9e2f3fac07c9c734c2a4ec38b6d02"}, + {file = "cryptography-46.0.2-cp311-abi3-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:bb7fb9cd44c2582aa5990cf61a4183e6f54eea3172e54963787ba47287edd135"}, + {file = "cryptography-46.0.2-cp311-abi3-manylinux_2_28_aarch64.whl", hash = "sha256:9066cfd7f146f291869a9898b01df1c9b0e314bfa182cef432043f13fc462c92"}, + {file = "cryptography-46.0.2-cp311-abi3-manylinux_2_28_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:97e83bf4f2f2c084d8dd792d13841d0a9b241643151686010866bbd076b19659"}, + {file = "cryptography-46.0.2-cp311-abi3-manylinux_2_28_ppc64le.whl", hash = "sha256:4a766d2a5d8127364fd936572c6e6757682fc5dfcbdba1632d4554943199f2fa"}, + {file = "cryptography-46.0.2-cp311-abi3-manylinux_2_28_x86_64.whl", hash = "sha256:fab8f805e9675e61ed8538f192aad70500fa6afb33a8803932999b1049363a08"}, + {file = "cryptography-46.0.2-cp311-abi3-manylinux_2_34_aarch64.whl", hash = "sha256:1e3b6428a3d56043bff0bb85b41c535734204e599c1c0977e1d0f261b02f3ad5"}, + {file = "cryptography-46.0.2-cp311-abi3-manylinux_2_34_ppc64le.whl", hash = "sha256:1a88634851d9b8de8bb53726f4300ab191d3b2f42595e2581a54b26aba71b7cc"}, + {file = "cryptography-46.0.2-cp311-abi3-manylinux_2_34_x86_64.whl", hash = "sha256:be939b99d4e091eec9a2bcf41aaf8f351f312cd19ff74b5c83480f08a8a43e0b"}, + {file = "cryptography-46.0.2-cp311-abi3-musllinux_1_2_aarch64.whl", hash = "sha256:9f13b040649bc18e7eb37936009b24fd31ca095a5c647be8bb6aaf1761142bd1"}, + {file = "cryptography-46.0.2-cp311-abi3-musllinux_1_2_x86_64.whl", hash = "sha256:9bdc25e4e01b261a8fda4e98618f1c9515febcecebc9566ddf4a70c63967043b"}, + {file = "cryptography-46.0.2-cp311-abi3-win32.whl", hash = "sha256:8b9bf67b11ef9e28f4d78ff88b04ed0929fcd0e4f70bb0f704cfc32a5c6311ee"}, + {file = "cryptography-46.0.2-cp311-abi3-win_amd64.whl", hash = "sha256:758cfc7f4c38c5c5274b55a57ef1910107436f4ae842478c4989abbd24bd5acb"}, + {file = "cryptography-46.0.2-cp311-abi3-win_arm64.whl", hash = "sha256:218abd64a2e72f8472c2102febb596793347a3e65fafbb4ad50519969da44470"}, + {file = "cryptography-46.0.2-cp314-cp314t-macosx_10_9_universal2.whl", hash = "sha256:bda55e8dbe8533937956c996beaa20266a8eca3570402e52ae52ed60de1faca8"}, + {file = "cryptography-46.0.2-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:e7155c0b004e936d381b15425273aee1cebc94f879c0ce82b0d7fecbf755d53a"}, + {file = "cryptography-46.0.2-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:a61c154cc5488272a6c4b86e8d5beff4639cdb173d75325ce464d723cda0052b"}, + {file = "cryptography-46.0.2-cp314-cp314t-manylinux_2_28_aarch64.whl", hash = "sha256:9ec3f2e2173f36a9679d3b06d3d01121ab9b57c979de1e6a244b98d51fea1b20"}, + {file = "cryptography-46.0.2-cp314-cp314t-manylinux_2_28_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:2fafb6aa24e702bbf74de4cb23bfa2c3beb7ab7683a299062b69724c92e0fa73"}, + {file = "cryptography-46.0.2-cp314-cp314t-manylinux_2_28_ppc64le.whl", hash = "sha256:0c7ffe8c9b1fcbb07a26d7c9fa5e857c2fe80d72d7b9e0353dcf1d2180ae60ee"}, + {file = "cryptography-46.0.2-cp314-cp314t-manylinux_2_28_x86_64.whl", hash = "sha256:5840f05518caa86b09d23f8b9405a7b6d5400085aa14a72a98fdf5cf1568c0d2"}, + {file = "cryptography-46.0.2-cp314-cp314t-manylinux_2_34_aarch64.whl", hash = "sha256:27c53b4f6a682a1b645fbf1cd5058c72cf2f5aeba7d74314c36838c7cbc06e0f"}, + {file = "cryptography-46.0.2-cp314-cp314t-manylinux_2_34_ppc64le.whl", hash = "sha256:512c0250065e0a6b286b2db4bbcc2e67d810acd53eb81733e71314340366279e"}, + {file = "cryptography-46.0.2-cp314-cp314t-manylinux_2_34_x86_64.whl", hash = "sha256:07c0eb6657c0e9cca5891f4e35081dbf985c8131825e21d99b4f440a8f496f36"}, + {file = "cryptography-46.0.2-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:48b983089378f50cba258f7f7aa28198c3f6e13e607eaf10472c26320332ca9a"}, + {file = "cryptography-46.0.2-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:e6f6775eaaa08c0eec73e301f7592f4367ccde5e4e4df8e58320f2ebf161ea2c"}, + {file = "cryptography-46.0.2-cp314-cp314t-win32.whl", hash = "sha256:e8633996579961f9b5a3008683344c2558d38420029d3c0bc7ff77c17949a4e1"}, + {file = "cryptography-46.0.2-cp314-cp314t-win_amd64.whl", hash = "sha256:48c01988ecbb32979bb98731f5c2b2f79042a6c58cc9a319c8c2f9987c7f68f9"}, + {file = "cryptography-46.0.2-cp314-cp314t-win_arm64.whl", hash = "sha256:8e2ad4d1a5899b7caa3a450e33ee2734be7cc0689010964703a7c4bcc8dd4fd0"}, + {file = "cryptography-46.0.2-cp38-abi3-macosx_10_9_universal2.whl", hash = "sha256:a08e7401a94c002e79dc3bc5231b6558cd4b2280ee525c4673f650a37e2c7685"}, + {file = "cryptography-46.0.2-cp38-abi3-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:d30bc11d35743bf4ddf76674a0a369ec8a21f87aaa09b0661b04c5f6c46e8d7b"}, + {file = "cryptography-46.0.2-cp38-abi3-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:bca3f0ce67e5a2a2cf524e86f44697c4323a86e0fd7ba857de1c30d52c11ede1"}, + {file = "cryptography-46.0.2-cp38-abi3-manylinux_2_28_aarch64.whl", hash = "sha256:ff798ad7a957a5021dcbab78dfff681f0cf15744d0e6af62bd6746984d9c9e9c"}, + {file = "cryptography-46.0.2-cp38-abi3-manylinux_2_28_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:cb5e8daac840e8879407acbe689a174f5ebaf344a062f8918e526824eb5d97af"}, + {file = "cryptography-46.0.2-cp38-abi3-manylinux_2_28_ppc64le.whl", hash = "sha256:3f37aa12b2d91e157827d90ce78f6180f0c02319468a0aea86ab5a9566da644b"}, + {file = "cryptography-46.0.2-cp38-abi3-manylinux_2_28_x86_64.whl", hash = "sha256:5e38f203160a48b93010b07493c15f2babb4e0f2319bbd001885adb3f3696d21"}, + {file = "cryptography-46.0.2-cp38-abi3-manylinux_2_34_aarch64.whl", hash = "sha256:d19f5f48883752b5ab34cff9e2f7e4a7f216296f33714e77d1beb03d108632b6"}, + {file = "cryptography-46.0.2-cp38-abi3-manylinux_2_34_ppc64le.whl", hash = "sha256:04911b149eae142ccd8c9a68892a70c21613864afb47aba92d8c7ed9cc001023"}, + {file = "cryptography-46.0.2-cp38-abi3-manylinux_2_34_x86_64.whl", hash = "sha256:8b16c1ede6a937c291d41176934268e4ccac2c6521c69d3f5961c5a1e11e039e"}, + {file = "cryptography-46.0.2-cp38-abi3-musllinux_1_2_aarch64.whl", hash = "sha256:747b6f4a4a23d5a215aadd1d0b12233b4119c4313df83ab4137631d43672cc90"}, + {file = "cryptography-46.0.2-cp38-abi3-musllinux_1_2_x86_64.whl", hash = "sha256:6b275e398ab3a7905e168c036aad54b5969d63d3d9099a0a66cc147a3cc983be"}, + {file = "cryptography-46.0.2-cp38-abi3-win32.whl", hash = "sha256:0b507c8e033307e37af61cb9f7159b416173bdf5b41d11c4df2e499a1d8e007c"}, + {file = "cryptography-46.0.2-cp38-abi3-win_amd64.whl", hash = "sha256:f9b2dc7668418fb6f221e4bf701f716e05e8eadb4f1988a2487b11aedf8abe62"}, + {file = "cryptography-46.0.2-cp38-abi3-win_arm64.whl", hash = "sha256:91447f2b17e83c9e0c89f133119d83f94ce6e0fb55dd47da0a959316e6e9cfa1"}, + {file = "cryptography-46.0.2-pp310-pypy310_pp73-macosx_10_9_x86_64.whl", hash = "sha256:f25a41f5b34b371a06dad3f01799706631331adc7d6c05253f5bca22068c7a34"}, + {file = "cryptography-46.0.2-pp310-pypy310_pp73-win_amd64.whl", hash = "sha256:e12b61e0b86611e3f4c1756686d9086c1d36e6fd15326f5658112ad1f1cc8807"}, + {file = "cryptography-46.0.2-pp311-pypy311_pp73-macosx_10_9_x86_64.whl", hash = "sha256:1d3b3edd145953832e09607986f2bd86f85d1dc9c48ced41808b18009d9f30e5"}, + {file = "cryptography-46.0.2-pp311-pypy311_pp73-manylinux_2_28_aarch64.whl", hash = "sha256:fe245cf4a73c20592f0f48da39748b3513db114465be78f0a36da847221bd1b4"}, + {file = "cryptography-46.0.2-pp311-pypy311_pp73-manylinux_2_28_x86_64.whl", hash = "sha256:2b9cad9cf71d0c45566624ff76654e9bae5f8a25970c250a26ccfc73f8553e2d"}, + {file = "cryptography-46.0.2-pp311-pypy311_pp73-manylinux_2_34_aarch64.whl", hash = "sha256:9bd26f2f75a925fdf5e0a446c0de2714f17819bf560b44b7480e4dd632ad6c46"}, + {file = "cryptography-46.0.2-pp311-pypy311_pp73-manylinux_2_34_x86_64.whl", hash = "sha256:7282d8f092b5be7172d6472f29b0631f39f18512a3642aefe52c3c0e0ccfad5a"}, + {file = "cryptography-46.0.2-pp311-pypy311_pp73-win_amd64.whl", hash = "sha256:c4b93af7920cdf80f71650769464ccf1fb49a4b56ae0024173c24c48eb6b1612"}, + {file = "cryptography-46.0.2.tar.gz", hash = "sha256:21b6fc8c71a3f9a604f028a329e5560009cc4a3a828bfea5fcba8eb7647d88fe"}, +] + +[package.dependencies] +cffi = {version = ">=2.0.0", markers = "python_full_version >= \"3.9.0\" and platform_python_implementation != \"PyPy\""} + +[package.extras] +docs = ["sphinx (>=5.3.0)", "sphinx-inline-tabs", "sphinx-rtd-theme (>=3.0.0)"] docstest = ["pyenchant (>=3)", "readme-renderer (>=30.0)", "sphinxcontrib-spelling (>=7.3.1)"] -nox = ["nox (>=2024.4.15)", "nox[uv] (>=2024.3.2) ; python_full_version >= \"3.8.0\""] -pep8test = ["check-sdist ; python_full_version >= \"3.8.0\"", "click (>=8.0.1)", "mypy (>=1.4)", "ruff (>=0.3.6)"] +nox = ["nox[uv] (>=2024.4.15)"] +pep8test = ["check-sdist", "click (>=8.0.1)", "mypy (>=1.14)", "ruff (>=0.11.11)"] sdist = ["build (>=1.0.0)"] ssh = ["bcrypt (>=3.1.5)"] -test = ["certifi (>=2024)", "cryptography-vectors (==45.0.5)", "pretend (>=0.7)", "pytest (>=7.4.0)", "pytest-benchmark (>=4.0)", "pytest-cov (>=2.10.1)", "pytest-xdist (>=3.5.0)"] +test = ["certifi (>=2024)", "cryptography-vectors (==46.0.2)", "pretend (>=0.7)", "pytest (>=7.4.0)", "pytest-benchmark (>=4.0)", "pytest-cov (>=2.10.1)", "pytest-xdist (>=3.5.0)"] test-randomorder = ["pytest-randomly"] [[package]] @@ -1340,19 +1453,18 @@ test = ["pytest", "ruff"] [[package]] name = "curies" -version = "0.10.19" +version = "0.12.1" description = "Idiomatic conversion between URIs and compact URIs (CURIEs)" optional = false -python-versions = ">=3.9" +python-versions = ">=3.10" groups = ["main"] files = [ - {file = "curies-0.10.19-py3-none-any.whl", hash = "sha256:8f34e945c5101f6ba0916bc73c1e1e244da5412adf35eabcf0e596acb47460d6"}, - {file = "curies-0.10.19.tar.gz", hash = "sha256:aeae5e7cbb7aee6c5144376fcb69e15a0d3c0557a12f9edff809bd0ce5004ea2"}, + {file = "curies-0.12.1-py3-none-any.whl", hash = "sha256:fb72295b807bdb782495b4997ad01e509bff2a5acf3c44f2610c2a14aaf53458"}, + {file = "curies-0.12.1.tar.gz", hash = "sha256:58be363c67dc686766d5630fffdc43d4855bc17aecb7edd282f8bdbc3580133b"}, ] [package.dependencies] pydantic = ">=2.0" -pytrie = "*" typing-extensions = "*" [package.extras] @@ -1361,6 +1473,8 @@ fastapi = ["defusedxml", "fastapi", "httpx", "python-multipart", "uvicorn"] flask = ["defusedxml", "flask"] pandas = ["pandas"] rdflib = ["rdflib"] +sqlalchemy = ["sqlalchemy"] +sqlmodel = ["sqlmodel"] tests = ["coverage[toml]", "pytest", "requests"] [[package]] @@ -1450,24 +1564,24 @@ files = [ [[package]] name = "dnspython" -version = "2.7.0" +version = "2.8.0" description = "DNS toolkit" optional = false -python-versions = ">=3.9" +python-versions = ">=3.10" groups = ["main"] files = [ - {file = "dnspython-2.7.0-py3-none-any.whl", hash = "sha256:b4c34b7d10b51bcc3a5071e7b8dee77939f1e878477eeecc965e9835f63c6c86"}, - {file = "dnspython-2.7.0.tar.gz", hash = "sha256:ce9c432eda0dc91cf618a5cedf1a4e142651196bbcd2c80e89ed5a907e5cfaf1"}, + {file = "dnspython-2.8.0-py3-none-any.whl", hash = "sha256:01d9bbc4a2d76bf0db7c1f729812ded6d912bd318d3b1cf81d30c0f845dbf3af"}, + {file = "dnspython-2.8.0.tar.gz", hash = "sha256:181d3c6996452cb1189c4046c61599b84a5a86e099562ffde77d26984ff26d0f"}, ] [package.extras] -dev = ["black (>=23.1.0)", "coverage (>=7.0)", "flake8 (>=7)", "hypercorn (>=0.16.0)", "mypy (>=1.8)", "pylint (>=3)", "pytest (>=7.4)", "pytest-cov (>=4.1.0)", "quart-trio (>=0.11.0)", "sphinx (>=7.2.0)", "sphinx-rtd-theme (>=2.0.0)", "twine (>=4.0.0)", "wheel (>=0.42.0)"] -dnssec = ["cryptography (>=43)"] -doh = ["h2 (>=4.1.0)", "httpcore (>=1.0.0)", "httpx (>=0.26.0)"] -doq = ["aioquic (>=1.0.0)"] -idna = ["idna (>=3.7)"] -trio = ["trio (>=0.23)"] -wmi = ["wmi (>=1.5.1)"] +dev = ["black (>=25.1.0)", "coverage (>=7.0)", "flake8 (>=7)", "hypercorn (>=0.17.0)", "mypy (>=1.17)", "pylint (>=3)", "pytest (>=8.4)", "pytest-cov (>=6.2.0)", "quart-trio (>=0.12.0)", "sphinx (>=8.2.0)", "sphinx-rtd-theme (>=3.0.0)", "twine (>=6.1.0)", "wheel (>=0.45.0)"] +dnssec = ["cryptography (>=45)"] +doh = ["h2 (>=4.2.0)", "httpcore (>=1.0.0)", "httpx (>=0.28.0)"] +doq = ["aioquic (>=1.2.0)"] +idna = ["idna (>=3.10)"] +trio = ["trio (>=0.30)"] +wmi = ["wmi (>=1.5.1) ; platform_system == \"Windows\""] [[package]] name = "docstring-parser" @@ -1500,49 +1614,47 @@ files = [ [[package]] name = "duckdb" -version = "1.3.2" +version = "1.4.1" description = "DuckDB in-process database" optional = false -python-versions = ">=3.7.0" -groups = ["main"] -files = [ - {file = "duckdb-1.3.2-cp310-cp310-macosx_12_0_arm64.whl", hash = "sha256:14676651b86f827ea10bf965eec698b18e3519fdc6266d4ca849f5af7a8c315e"}, - {file = "duckdb-1.3.2-cp310-cp310-macosx_12_0_universal2.whl", hash = "sha256:e584f25892450757919639b148c2410402b17105bd404017a57fa9eec9c98919"}, - {file = "duckdb-1.3.2-cp310-cp310-macosx_12_0_x86_64.whl", hash = "sha256:84a19f185ee0c5bc66d95908c6be19103e184b743e594e005dee6f84118dc22c"}, - {file = "duckdb-1.3.2-cp310-cp310-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:186fc3f98943e97f88a1e501d5720b11214695571f2c74745d6e300b18bef80e"}, - {file = "duckdb-1.3.2-cp310-cp310-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:6b7e6bb613b73745f03bff4bb412f362d4a1e158bdcb3946f61fd18e9e1a8ddf"}, - {file = "duckdb-1.3.2-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:1c90646b52a0eccda1f76b10ac98b502deb9017569e84073da00a2ab97763578"}, - {file = "duckdb-1.3.2-cp310-cp310-win_amd64.whl", hash = "sha256:4cdffb1e60defbfa75407b7f2ccc322f535fd462976940731dfd1644146f90c6"}, - {file = "duckdb-1.3.2-cp311-cp311-macosx_12_0_arm64.whl", hash = "sha256:e1872cf63aae28c3f1dc2e19b5e23940339fc39fb3425a06196c5d00a8d01040"}, - {file = "duckdb-1.3.2-cp311-cp311-macosx_12_0_universal2.whl", hash = "sha256:db256c206056468ae6a9e931776bdf7debaffc58e19a0ff4fa9e7e1e82d38b3b"}, - {file = "duckdb-1.3.2-cp311-cp311-macosx_12_0_x86_64.whl", hash = "sha256:1d57df2149d6e4e0bd5198689316c5e2ceec7f6ac0a9ec11bc2b216502a57b34"}, - {file = "duckdb-1.3.2-cp311-cp311-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:54f76c8b1e2a19dfe194027894209ce9ddb073fd9db69af729a524d2860e4680"}, - {file = "duckdb-1.3.2-cp311-cp311-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:45bea70b3e93c6bf766ce2f80fc3876efa94c4ee4de72036417a7bd1e32142fe"}, - {file = "duckdb-1.3.2-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:003f7d36f0d8a430cb0e00521f18b7d5ee49ec98aaa541914c6d0e008c306f1a"}, - {file = "duckdb-1.3.2-cp311-cp311-win_amd64.whl", hash = "sha256:0eb210cedf08b067fa90c666339688f1c874844a54708562282bc54b0189aac6"}, - {file = "duckdb-1.3.2-cp312-cp312-macosx_12_0_arm64.whl", hash = "sha256:2455b1ffef4e3d3c7ef8b806977c0e3973c10ec85aa28f08c993ab7f2598e8dd"}, - {file = "duckdb-1.3.2-cp312-cp312-macosx_12_0_universal2.whl", hash = "sha256:9d0ae509713da3461c000af27496d5413f839d26111d2a609242d9d17b37d464"}, - {file = "duckdb-1.3.2-cp312-cp312-macosx_12_0_x86_64.whl", hash = "sha256:72ca6143d23c0bf6426396400f01fcbe4785ad9ceec771bd9a4acc5b5ef9a075"}, - {file = "duckdb-1.3.2-cp312-cp312-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b49a11afba36b98436db83770df10faa03ebded06514cb9b180b513d8be7f392"}, - {file = "duckdb-1.3.2-cp312-cp312-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:36abdfe0d1704fe09b08d233165f312dad7d7d0ecaaca5fb3bb869f4838a2d0b"}, - {file = "duckdb-1.3.2-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:3380aae1c4f2af3f37b0bf223fabd62077dd0493c84ef441e69b45167188e7b6"}, - {file = "duckdb-1.3.2-cp312-cp312-win_amd64.whl", hash = "sha256:11af73963ae174aafd90ea45fb0317f1b2e28a7f1d9902819d47c67cc957d49c"}, - {file = "duckdb-1.3.2-cp313-cp313-macosx_12_0_arm64.whl", hash = "sha256:a3418c973b06ac4e97f178f803e032c30c9a9f56a3e3b43a866f33223dfbf60b"}, - {file = "duckdb-1.3.2-cp313-cp313-macosx_12_0_universal2.whl", hash = "sha256:2a741eae2cf110fd2223eeebe4151e22c0c02803e1cfac6880dbe8a39fecab6a"}, - {file = "duckdb-1.3.2-cp313-cp313-macosx_12_0_x86_64.whl", hash = "sha256:51e62541341ea1a9e31f0f1ade2496a39b742caf513bebd52396f42ddd6525a0"}, - {file = "duckdb-1.3.2-cp313-cp313-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b3e519de5640e5671f1731b3ae6b496e0ed7e4de4a1c25c7a2f34c991ab64d71"}, - {file = "duckdb-1.3.2-cp313-cp313-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:4732fb8cc60566b60e7e53b8c19972cb5ed12d285147a3063b16cc64a79f6d9f"}, - {file = "duckdb-1.3.2-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:97f7a22dcaa1cca889d12c3dc43a999468375cdb6f6fe56edf840e062d4a8293"}, - {file = "duckdb-1.3.2-cp313-cp313-win_amd64.whl", hash = "sha256:cd3d717bf9c49ef4b1016c2216517572258fa645c2923e91c5234053defa3fb5"}, - {file = "duckdb-1.3.2-cp39-cp39-macosx_12_0_arm64.whl", hash = "sha256:18862e3b8a805f2204543d42d5f103b629cb7f7f2e69f5188eceb0b8a023f0af"}, - {file = "duckdb-1.3.2-cp39-cp39-macosx_12_0_universal2.whl", hash = "sha256:75ed129761b6159f0b8eca4854e496a3c4c416e888537ec47ff8eb35fda2b667"}, - {file = "duckdb-1.3.2-cp39-cp39-macosx_12_0_x86_64.whl", hash = "sha256:875193ae9f718bc80ab5635435de5b313e3de3ec99420a9b25275ddc5c45ff58"}, - {file = "duckdb-1.3.2-cp39-cp39-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:09b5fd8a112301096668903781ad5944c3aec2af27622bd80eae54149de42b42"}, - {file = "duckdb-1.3.2-cp39-cp39-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:10cb87ad964b989175e7757d7ada0b1a7264b401a79be2f828cf8f7c366f7f95"}, - {file = "duckdb-1.3.2-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:4389fc3812e26977034fe3ff08d1f7dbfe6d2d8337487b4686f2b50e254d7ee3"}, - {file = "duckdb-1.3.2-cp39-cp39-win_amd64.whl", hash = "sha256:07952ec6f45dd3c7db0f825d231232dc889f1f2490b97a4e9b7abb6830145a19"}, - {file = "duckdb-1.3.2.tar.gz", hash = "sha256:c658df8a1bc78704f702ad0d954d82a1edd4518d7a04f00027ec53e40f591ff5"}, -] +python-versions = ">=3.9.0" +groups = ["main"] +files = [ + {file = "duckdb-1.4.1-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:296b4fff3908fb4c47b0aa1d77bd1933375e75401009d2dc81af8e7a0b8a05b4"}, + {file = "duckdb-1.4.1-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:0b4182800092115feee5d71a8691efb283d3c9f5eb0b36362b308ef007a12222"}, + {file = "duckdb-1.4.1-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:67cc3b6c7f7ba07a69e9331b8ccea7a60cbcd4204bb473e5da9b71588bd2eca9"}, + {file = "duckdb-1.4.1-cp310-cp310-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:0cef0cee7030b561640cb9af718f8841b19cdd2aa020d53561057b5743bea90b"}, + {file = "duckdb-1.4.1-cp310-cp310-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:2bf93347f37a46bacce6ac859d651dbf5731e2c94a64ab358300425b09e3de23"}, + {file = "duckdb-1.4.1-cp310-cp310-win_amd64.whl", hash = "sha256:2e60d2361f978908a3d96eebaf1f4b346f283afcc467351aae50ea45ca293a2b"}, + {file = "duckdb-1.4.1-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:605d563c1d5203ca992497cd33fb386ac3d533deca970f9dcf539f62a34e22a9"}, + {file = "duckdb-1.4.1-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:d3305c7c4b70336171de7adfdb50431f23671c000f11839b580c4201d9ce6ef5"}, + {file = "duckdb-1.4.1-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:a063d6febbe34b32f1ad2e68822db4d0e4b1102036f49aaeeb22b844427a75df"}, + {file = "duckdb-1.4.1-cp311-cp311-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:d1ffcaaf74f7d1df3684b54685cbf8d3ce732781c541def8e1ced304859733ae"}, + {file = "duckdb-1.4.1-cp311-cp311-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:685d3d1599dc08160e0fa0cf09e93ac4ff8b8ed399cb69f8b5391cd46b5b207c"}, + {file = "duckdb-1.4.1-cp311-cp311-win_amd64.whl", hash = "sha256:78f1d28a15ae73bd449c43f80233732adffa49be1840a32de8f1a6bb5b286764"}, + {file = "duckdb-1.4.1-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:cd1765a7d180b7482874586859fc23bc9969d7d6c96ced83b245e6c6f49cde7f"}, + {file = "duckdb-1.4.1-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:8ed7a86725185470953410823762956606693c0813bb64e09c7d44dbd9253a64"}, + {file = "duckdb-1.4.1-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:8a189bdfc64cfb9cc1adfbe4f2dcfde0a4992ec08505ad8ce33c886e4813f0bf"}, + {file = "duckdb-1.4.1-cp312-cp312-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:a9090089b6486f7319c92acdeed8acda022d4374032d78a465956f50fc52fabf"}, + {file = "duckdb-1.4.1-cp312-cp312-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:142552ea3e768048e0e8c832077a545ca07792631c59edaee925e3e67401c2a0"}, + {file = "duckdb-1.4.1-cp312-cp312-win_amd64.whl", hash = "sha256:567f3b3a785a9e8650612461893c49ca799661d2345a6024dda48324ece89ded"}, + {file = "duckdb-1.4.1-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:46496a2518752ae0c6c5d75d4cdecf56ea23dd098746391176dd8e42cf157791"}, + {file = "duckdb-1.4.1-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:1c65ae7e9b541cea07d8075343bcfebdecc29a3c0481aa6078ee63d51951cfcd"}, + {file = "duckdb-1.4.1-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:598d1a314e34b65d9399ddd066ccce1eeab6a60a2ef5885a84ce5ed62dbaf729"}, + {file = "duckdb-1.4.1-cp313-cp313-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:e2f16b8def782d484a9f035fc422bb6f06941ed0054b4511ddcdc514a7fb6a75"}, + {file = "duckdb-1.4.1-cp313-cp313-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:a5a7d0aed068a5c33622a8848857947cab5cfb3f2a315b1251849bac2c74c492"}, + {file = "duckdb-1.4.1-cp313-cp313-win_amd64.whl", hash = "sha256:280fd663dacdd12bb3c3bf41f3e5b2e5b95e00b88120afabb8b8befa5f335c6f"}, + {file = "duckdb-1.4.1-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:04a31b3cf84d77ef02c9914567b5d63a43fc791b144655ee99581cd9f4949e63"}, + {file = "duckdb-1.4.1-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:c01c5f9d0657a26938d640aa8d8effa91cacf66195ed4787824e6d5537bcaf21"}, + {file = "duckdb-1.4.1-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:80c12239abb2a063abcd75dc052e9884b41060615735a532a6e3e8390eee7f70"}, + {file = "duckdb-1.4.1-cp39-cp39-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:4b96d16a10256d05d818b34903243681764b6afc98f7d50b1ae60d23aa1f1f9e"}, + {file = "duckdb-1.4.1-cp39-cp39-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:e8aa4a4298a6a627599f6606c7bedfe77309c1fb05a606af48e0e72333861ef4"}, + {file = "duckdb-1.4.1-cp39-cp39-win_amd64.whl", hash = "sha256:09d152dd4ab24a5984cd289b553e142980b3f029292cdda29e34303c75138de6"}, + {file = "duckdb-1.4.1.tar.gz", hash = "sha256:f903882f045d057ebccad12ac69975952832edfe133697694854bb784b8d6c76"}, +] + +[package.extras] +all = ["adbc-driver-manager", "fsspec", "ipython", "numpy", "pandas", "pyarrow"] [[package]] name = "duckdb-engine" @@ -1630,14 +1742,14 @@ tests = ["pytest"] [[package]] name = "executing" -version = "2.2.0" +version = "2.2.1" description = "Get the currently executing AST node of a frame, and other information" optional = false python-versions = ">=3.8" groups = ["main"] files = [ - {file = "executing-2.2.0-py2.py3-none-any.whl", hash = "sha256:11387150cad388d62750327a53d3339fad4888b39a6fe233c3afbb54ecffd3aa"}, - {file = "executing-2.2.0.tar.gz", hash = "sha256:5d108c028108fe2551d1a7b2e8b713341e2cb4fc0aa7dcf966fa4327a5226755"}, + {file = "executing-2.2.1-py2.py3-none-any.whl", hash = "sha256:760643d3452b4d777d295bb167ccc74c64a81df23fb5e08eff250c425a4b2017"}, + {file = "executing-2.2.1.tar.gz", hash = "sha256:3632cc370565f6648cc328b32435bd120a1e4ebb20c77e3fdde9a13cd1e533c4"}, ] [package.extras] @@ -1645,72 +1757,82 @@ tests = ["asttokens (>=2.1.0)", "coverage", "coverage-enable-subprocess", "ipyth [[package]] name = "fastapi" -version = "0.116.1" +version = "0.119.0" description = "FastAPI framework, high performance, easy to learn, fast to code, ready for production" optional = false python-versions = ">=3.8" groups = ["main"] markers = "extra == \"gradio\"" files = [ - {file = "fastapi-0.116.1-py3-none-any.whl", hash = "sha256:c46ac7c312df840f0c9e220f7964bada936781bc4e2e6eb71f1c4d7553786565"}, - {file = "fastapi-0.116.1.tar.gz", hash = "sha256:ed52cbf946abfd70c5a0dccb24673f0670deeb517a88b3544d03c2a6bf283143"}, + {file = "fastapi-0.119.0-py3-none-any.whl", hash = "sha256:90a2e49ed19515320abb864df570dd766be0662c5d577688f1600170f7f73cf2"}, + {file = "fastapi-0.119.0.tar.gz", hash = "sha256:451082403a2c1f0b99c6bd57c09110ed5463856804c8078d38e5a1f1035dbbb7"}, ] [package.dependencies] pydantic = ">=1.7.4,<1.8 || >1.8,<1.8.1 || >1.8.1,<2.0.0 || >2.0.0,<2.0.1 || >2.0.1,<2.1.0 || >2.1.0,<3.0.0" -starlette = ">=0.40.0,<0.48.0" +starlette = ">=0.40.0,<0.49.0" typing-extensions = ">=4.8.0" [package.extras] -all = ["email-validator (>=2.0.0)", "fastapi-cli[standard] (>=0.0.8)", "httpx (>=0.23.0)", "itsdangerous (>=1.1.0)", "jinja2 (>=3.1.5)", "orjson (>=3.2.1)", "pydantic-extra-types (>=2.0.0)", "pydantic-settings (>=2.0.0)", "python-multipart (>=0.0.18)", "pyyaml (>=5.3.1)", "ujson (>=4.0.1,!=4.0.2,!=4.1.0,!=4.2.0,!=4.3.0,!=5.0.0,!=5.1.0)", "uvicorn[standard] (>=0.12.0)"] -standard = ["email-validator (>=2.0.0)", "fastapi-cli[standard] (>=0.0.8)", "httpx (>=0.23.0)", "jinja2 (>=3.1.5)", "python-multipart (>=0.0.18)", "uvicorn[standard] (>=0.12.0)"] -standard-no-fastapi-cloud-cli = ["email-validator (>=2.0.0)", "fastapi-cli[standard-no-fastapi-cloud-cli] (>=0.0.8)", "httpx (>=0.23.0)", "jinja2 (>=3.1.5)", "python-multipart (>=0.0.18)", "uvicorn[standard] (>=0.12.0)"] +all = ["email-validator (>=2.0.0)", "fastapi-cli[standard] (>=0.0.8)", "httpx (>=0.23.0,<1.0.0)", "itsdangerous (>=1.1.0)", "jinja2 (>=3.1.5)", "orjson (>=3.2.1)", "pydantic-extra-types (>=2.0.0)", "pydantic-settings (>=2.0.0)", "python-multipart (>=0.0.18)", "pyyaml (>=5.3.1)", "ujson (>=4.0.1,!=4.0.2,!=4.1.0,!=4.2.0,!=4.3.0,!=5.0.0,!=5.1.0)", "uvicorn[standard] (>=0.12.0)"] +standard = ["email-validator (>=2.0.0)", "fastapi-cli[standard] (>=0.0.8)", "httpx (>=0.23.0,<1.0.0)", "jinja2 (>=3.1.5)", "python-multipart (>=0.0.18)", "uvicorn[standard] (>=0.12.0)"] +standard-no-fastapi-cloud-cli = ["email-validator (>=2.0.0)", "fastapi-cli[standard-no-fastapi-cloud-cli] (>=0.0.8)", "httpx (>=0.23.0,<1.0.0)", "jinja2 (>=3.1.5)", "python-multipart (>=0.0.18)", "uvicorn[standard] (>=0.12.0)"] [[package]] name = "fastavro" -version = "1.11.1" +version = "1.12.1" description = "Fast read/write of AVRO files" optional = false python-versions = ">=3.9" groups = ["main"] markers = "platform_system != \"Emscripten\"" files = [ - {file = "fastavro-1.11.1-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:603aa1c1d1be21fb4bcb63e1efb0711a9ddb337de81391c32dac95c6e0dacfcc"}, - {file = "fastavro-1.11.1-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:45653b312d4ce297e2bd802ea3ffd17ecbe718e5e8b6e2ae04cd72cb50bb99d5"}, - {file = "fastavro-1.11.1-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:998a53fc552e6bee9acda32af258f02557313c85fb5b48becba5b71ec82f421e"}, - {file = "fastavro-1.11.1-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:9f878c9ad819467120cb066f1c73496c42eb24ecdd7c992ec996f465ef4cedad"}, - {file = "fastavro-1.11.1-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:da9e4c231ac4951092c2230ca423d8a3f2966718f072ac1e2c5d2d44c70b2a50"}, - {file = "fastavro-1.11.1-cp310-cp310-win_amd64.whl", hash = "sha256:7423bfad3199567eeee7ad6816402c7c0ee1658b959e8c10540cfbc60ce96c2a"}, - {file = "fastavro-1.11.1-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:3573340e4564e8962e22f814ac937ffe0d4be5eabbd2250f77738dc47e3c8fe9"}, - {file = "fastavro-1.11.1-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:7291cf47735b8bd6ff5d9b33120e6e0974f52fd5dff90cd24151b22018e7fd29"}, - {file = "fastavro-1.11.1-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:bf3bb065d657d5bac8b2cb39945194aa086a9b3354f2da7f89c30e4dc20e08e2"}, - {file = "fastavro-1.11.1-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:8758317c85296b848698132efb13bc44a4fbd6017431cc0f26eaeb0d6fa13d35"}, - {file = "fastavro-1.11.1-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:ad99d57228f83bf3e2214d183fbf6e2fda97fd649b2bdaf8e9110c36cbb02624"}, - {file = "fastavro-1.11.1-cp311-cp311-win_amd64.whl", hash = "sha256:9134090178bdbf9eefd467717ced3dc151e27a7e7bfc728260ce512697efe5a4"}, - {file = "fastavro-1.11.1-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:e8bc238f2637cd5d15238adbe8fb8c58d2e6f1870e0fb28d89508584670bae4b"}, - {file = "fastavro-1.11.1-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:b403933081c83fc4d8a012ee64b86e560a024b1280e3711ee74f2abc904886e8"}, - {file = "fastavro-1.11.1-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:3f6ecb4b5f77aa756d973b7dd1c2fb4e4c95b4832a3c98b059aa96c61870c709"}, - {file = "fastavro-1.11.1-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:059893df63ef823b0231b485c9d43016c7e32850cae7bf69f4e9d46dd41c28f2"}, - {file = "fastavro-1.11.1-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:5120ffc9a200699218e01777e695a2f08afb3547ba818184198c757dc39417bd"}, - {file = "fastavro-1.11.1-cp312-cp312-win_amd64.whl", hash = "sha256:7bb9d0d2233f33a52908b6ea9b376fe0baf1144bdfdfb3c6ad326e200a8b56b0"}, - {file = "fastavro-1.11.1-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:f963b8ddaf179660e814ab420850c1b4ea33e2ad2de8011549d958b21f77f20a"}, - {file = "fastavro-1.11.1-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:0253e5b6a3c9b62fae9fc3abd8184c5b64a833322b6af7d666d3db266ad879b5"}, - {file = "fastavro-1.11.1-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:ca637b150e1f4c0e8e564fad40a16bd922bcb7ffd1a6e4836e6084f2c4f4e8db"}, - {file = "fastavro-1.11.1-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:76af1709031621828ca6ce7f027f7711fa33ac23e8269e7a5733996ff8d318da"}, - {file = "fastavro-1.11.1-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:8224e6d8d9864d4e55dafbe88920d6a1b8c19cc3006acfac6aa4f494a6af3450"}, - {file = "fastavro-1.11.1-cp313-cp313-win_amd64.whl", hash = "sha256:cde7ed91b52ff21f0f9f157329760ba7251508ca3e9618af3ffdac986d9faaa2"}, - {file = "fastavro-1.11.1-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:e5ed1325c1c414dd954e7a2c5074daefe1eceb672b8c727aa030ba327aa00693"}, - {file = "fastavro-1.11.1-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:8cd3c95baeec37188899824faf44a5ee94dfc4d8667b05b2f867070c7eb174c4"}, - {file = "fastavro-1.11.1-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:2e0babcd81acceb4c60110af9efa25d890dbb68f7de880f806dadeb1e70fe413"}, - {file = "fastavro-1.11.1-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:b2c0cb8063c7208b53b6867983dc6ae7cc80b91116b51d435d2610a5db2fc52f"}, - {file = "fastavro-1.11.1-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:1bc2824e9969c04ab6263d269a1e0e5d40b9bd16ade6b70c29d6ffbc4f3cc102"}, - {file = "fastavro-1.11.1-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:8b579bab31ff87fcb5ef9f6f13baaf99f189b92ed287af60348777583628c327"}, - {file = "fastavro-1.11.1-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:5c646f07c7827fea7425b6936a27f67f356a2a80ac19e6100ed6d3bb0610cc3d"}, - {file = "fastavro-1.11.1-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:2915324e1edb0e06f0be0c18279c60f4cff49f6fe01626594707eb75cd9952fc"}, - {file = "fastavro-1.11.1-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:8fd87ee1e9101b45172fb3cff21b56ce08270d9474eec1d436393677daa95938"}, - {file = "fastavro-1.11.1-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:88876568ef387996fbfc6b193a5b9830de3c0497af7d07e5c839a70b86bb47e7"}, - {file = "fastavro-1.11.1-cp39-cp39-win_amd64.whl", hash = "sha256:cebb7433b860d9b13090d0e53f6db075e4e2042aeb2c577f515e73d2b9c98075"}, - {file = "fastavro-1.11.1.tar.gz", hash = "sha256:bf6acde5ee633a29fb8dfd6dfea13b164722bc3adc05a0e055df080549c1c2f8"}, + {file = "fastavro-1.12.1-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:00650ca533907361edda22e6ffe8cf87ab2091c5d8aee5c8000b0f2dcdda7ed3"}, + {file = "fastavro-1.12.1-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:ac76d6d95f909c72ee70d314b460b7e711d928845771531d823eb96a10952d26"}, + {file = "fastavro-1.12.1-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:1f55eef18c41d4476bd32a82ed5dd86aabc3f614e1b66bdb09ffa291612e1670"}, + {file = "fastavro-1.12.1-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:81563e1f93570e6565487cdb01ba241a36a00e58cff9c5a0614af819d1155d8f"}, + {file = "fastavro-1.12.1-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:bec207360f76f0b3de540758a297193c5390e8e081c43c3317f610b1414d8c8f"}, + {file = "fastavro-1.12.1-cp310-cp310-win_amd64.whl", hash = "sha256:c0390bfe4a9f8056a75ac6785fbbff8f5e317f5356481d2e29ec980877d2314b"}, + {file = "fastavro-1.12.1-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:6b632b713bc5d03928a87d811fa4a11d5f25cd43e79c161e291c7d3f7aa740fd"}, + {file = "fastavro-1.12.1-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:eaa7ab3769beadcebb60f0539054c7755f63bd9cf7666e2c15e615ab605f89a8"}, + {file = "fastavro-1.12.1-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:123fb221df3164abd93f2d042c82f538a1d5a43ce41375f12c91ce1355a9141e"}, + {file = "fastavro-1.12.1-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:632a4e3ff223f834ddb746baae0cc7cee1068eb12c32e4d982c2fee8a5b483d0"}, + {file = "fastavro-1.12.1-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:83e6caf4e7a8717d932a3b1ff31595ad169289bbe1128a216be070d3a8391671"}, + {file = "fastavro-1.12.1-cp311-cp311-win_amd64.whl", hash = "sha256:b91a0fe5a173679a6c02d53ca22dcaad0a2c726b74507e0c1c2e71a7c3f79ef9"}, + {file = "fastavro-1.12.1-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:509818cb24b98a804fc80be9c5fed90f660310ae3d59382fc811bfa187122167"}, + {file = "fastavro-1.12.1-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:089e155c0c76e0d418d7e79144ce000524dd345eab3bc1e9c5ae69d500f71b14"}, + {file = "fastavro-1.12.1-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:44cbff7518901c91a82aab476fcab13d102e4999499df219d481b9e15f61af34"}, + {file = "fastavro-1.12.1-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:a275e48df0b1701bb764b18a8a21900b24cf882263cb03d35ecdba636bbc830b"}, + {file = "fastavro-1.12.1-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:2de72d786eb38be6b16d556b27232b1bf1b2797ea09599507938cdb7a9fe3e7c"}, + {file = "fastavro-1.12.1-cp312-cp312-win_amd64.whl", hash = "sha256:9090f0dee63fe022ee9cc5147483366cc4171c821644c22da020d6b48f576b4f"}, + {file = "fastavro-1.12.1-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:78df838351e4dff9edd10a1c41d1324131ffecbadefb9c297d612ef5363c049a"}, + {file = "fastavro-1.12.1-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:780476c23175d2ae457c52f45b9ffa9d504593499a36cd3c1929662bf5b7b14b"}, + {file = "fastavro-1.12.1-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:0714b285160fcd515eb0455540f40dd6dac93bdeacdb03f24e8eac3d8aa51f8d"}, + {file = "fastavro-1.12.1-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:a8bc2dcec5843d499f2489bfe0747999108f78c5b29295d877379f1972a3d41a"}, + {file = "fastavro-1.12.1-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:3b1921ac35f3d89090a5816b626cf46e67dbecf3f054131f84d56b4e70496f45"}, + {file = "fastavro-1.12.1-cp313-cp313-win_amd64.whl", hash = "sha256:5aa777b8ee595b50aa084104cd70670bf25a7bbb9fd8bb5d07524b0785ee1699"}, + {file = "fastavro-1.12.1-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:c3d67c47f177e486640404a56f2f50b165fe892cc343ac3a34673b80cc7f1dd6"}, + {file = "fastavro-1.12.1-cp313-cp313t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:5217f773492bac43dae15ff2931432bce2d7a80be7039685a78d3fab7df910bd"}, + {file = "fastavro-1.12.1-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:469fecb25cba07f2e1bfa4c8d008477cd6b5b34a59d48715e1b1a73f6160097d"}, + {file = "fastavro-1.12.1-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:d71c8aa841ef65cfab709a22bb887955f42934bced3ddb571e98fdbdade4c609"}, + {file = "fastavro-1.12.1-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:b81fc04e85dfccf7c028e0580c606e33aa8472370b767ef058aae2c674a90746"}, + {file = "fastavro-1.12.1-cp314-cp314-macosx_10_15_universal2.whl", hash = "sha256:9445da127751ba65975d8e4bdabf36bfcfdad70fc35b2d988e3950cce0ec0e7c"}, + {file = "fastavro-1.12.1-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:ed924233272719b5d5a6a0b4d80ef3345fc7e84fc7a382b6232192a9112d38a6"}, + {file = "fastavro-1.12.1-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:3616e2f0e1c9265e92954fa099db79c6e7817356d3ff34f4bcc92699ae99697c"}, + {file = "fastavro-1.12.1-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:cb0337b42fd3c047fcf0e9b7597bd6ad25868de719f29da81eabb6343f08d399"}, + {file = "fastavro-1.12.1-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:64961ab15b74b7c168717bbece5660e0f3d457837c3cc9d9145181d011199fa7"}, + {file = "fastavro-1.12.1-cp314-cp314-win_amd64.whl", hash = "sha256:792356d320f6e757e89f7ac9c22f481e546c886454a6709247f43c0dd7058004"}, + {file = "fastavro-1.12.1-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:120aaf82ac19d60a1016afe410935fe94728752d9c2d684e267e5b7f0e70f6d9"}, + {file = "fastavro-1.12.1-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:b6a3462934b20a74f9ece1daa49c2e4e749bd9a35fa2657b53bf62898fba80f5"}, + {file = "fastavro-1.12.1-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:1f81011d54dd47b12437b51dd93a70a9aa17b61307abf26542fc3c13efbc6c51"}, + {file = "fastavro-1.12.1-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:43ded16b3f4a9f1a42f5970c2aa618acb23ea59c4fcaa06680bdf470b255e5a8"}, + {file = "fastavro-1.12.1-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:02281432dcb11c78b3280da996eff61ee0eff39c5de06c6e0fbf19275093e6d4"}, + {file = "fastavro-1.12.1-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:4128978b930aaf930332db4b3acc290783183f3be06a241ae4a482f3ed8ce892"}, + {file = "fastavro-1.12.1-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:546ffffda6610fca672f0ed41149808e106d8272bb246aa7539fa8bb6f117f17"}, + {file = "fastavro-1.12.1-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:a7d840ccd9aacada3ddc80fbcc4ea079b658107fe62e9d289a0de9d54e95d366"}, + {file = "fastavro-1.12.1-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:3100ad643e7fa658469a2a2db229981c1a000ff16b8037c0b58ce3ec4d2107e8"}, + {file = "fastavro-1.12.1-cp39-cp39-win_amd64.whl", hash = "sha256:a38607444281619eda3a9c1be9f5397634012d1b237142eee1540e810b30ac8b"}, + {file = "fastavro-1.12.1.tar.gz", hash = "sha256:2f285be49e45bc047ab2f6bed040bb349da85db3f3c87880e4b92595ea093b2b"}, ] [package.extras] @@ -1766,15 +1888,15 @@ files = [ [[package]] name = "ffmpy" -version = "0.6.0" +version = "0.6.3" description = "A simple Python wrapper for FFmpeg" optional = false python-versions = ">=3.9" groups = ["main"] markers = "extra == \"gradio\"" files = [ - {file = "ffmpy-0.6.0-py3-none-any.whl", hash = "sha256:c8369bf45f8bd5285ebad94c4a789a79e7af86eded74c1f8c36eccf57aaea58c"}, - {file = "ffmpy-0.6.0.tar.gz", hash = "sha256:332dd93198a162db61e527e866a04578d3713e577bfe68f2ed26ba9d09dbc948"}, + {file = "ffmpy-0.6.3-py3-none-any.whl", hash = "sha256:f7b25c85a4075bf5e68f8b4eb0e332cb8f1584dfc2e444ff590851eaef09b286"}, + {file = "ffmpy-0.6.3.tar.gz", hash = "sha256:306f3e9070e11a3da1aee3241d3a6bd19316ff7284716e15a1bc98d7a1939eaf"}, ] [package.extras] @@ -1782,60 +1904,62 @@ psutil = ["psutil (>=5.8.0)"] [[package]] name = "fhaviary" -version = "0.22.0" +version = "0.25.0" description = "Gymnasium framework for training language model agents on constructive tasks" optional = false python-versions = ">=3.11" groups = ["main"] files = [ - {file = "fhaviary-0.22.0-py3-none-any.whl", hash = "sha256:51589101a6598f9dbd9a9409762fd0ba624f39ff1f028b4d3e32d75826a93838"}, - {file = "fhaviary-0.22.0.tar.gz", hash = "sha256:9d27b7b41ab740d14f11b745afc829acf097a52ada6ceed6e76660a155940714"}, + {file = "fhaviary-0.25.0-py3-none-any.whl", hash = "sha256:762092aa2b49867ab9cd1e8d6dab87c04c70b4b72cb85b7331cb472a0703c61d"}, + {file = "fhaviary-0.25.0.tar.gz", hash = "sha256:be220cfca973a4f38ad249de8bff12572f0a1fb7da87f6dcf25dd96e18c95ded"}, ] [package.dependencies] docstring_parser = ">=0.16" fhlmi = {version = "*", optional = true, markers = "extra == \"llm\""} httpx = "*" +httpx-aiohttp = "*" litellm = {version = ">=1.49.1", optional = true, markers = "extra == \"llm\""} packaging = {version = "*", optional = true, markers = "extra == \"llm\""} pydantic = ">=2.0,<3.0" [package.extras] cloud = ["boto3"] -dev = ["aviary.gsm8k[typing]", "aviary.hotpotqa", "aviary.lfrqa", "aviary.litqa", "fhaviary[image,llm,server,typing,xml]", "ipython (>=8)", "jupyter (>=1.0.0)", "litellm (>=1.65.5,<1.71)", "mypy (>=1.8)", "numpy (>=1)", "pre-commit (>=3.4)", "pydantic (>=2.9,<3.0)", "pylint (>=3.3.3)", "pylint-pydantic", "pytest (>=8)", "pytest-asyncio", "pytest-recording", "pytest-subtests", "pytest-sugar", "pytest-timer[colorama]", "pytest-xdist", "refurb (>=2)", "tantivy (<=0.22.0)", "typeguard", "vcrpy (>=6)"] +dev = ["aviary.gsm8k[typing]", "aviary.hotpotqa", "aviary.lfrqa", "aviary.litqa[dev]", "aviary.notebook[dev]", "fhaviary[image,llm,server,typing,xml]", "ipython (>=8)", "jupyter (>=1.0.0)", "litellm (>=1.71)", "mypy (>=1.8)", "numpy (>=1)", "prek", "pydantic (>=2.9,<3.0)", "pylint (>=3.3.3)", "pylint-pydantic", "pytest (>=8)", "pytest-asyncio", "pytest-recording", "pytest-rerunfailures", "pytest-subtests", "pytest-sugar", "pytest-timer[colorama]", "pytest-xdist", "refurb (>=2)", "tantivy (<=0.22.0)", "tenacity", "typeguard", "vcrpy (>=6)"] gsm8k = ["aviary.gsm8k"] hotpotqa = ["aviary.hotpotqa"] image = ["Pillow"] lfrqa = ["aviary.lfrqa"] litqa = ["aviary.litqa"] llm = ["fhlmi", "litellm (>=1.49.1)", "packaging"] +notebook = ["aviary.notebook"] server = ["click", "cloudpickle", "fastapi", "uvicorn"] typing = ["boto3-stubs[s3]", "numpy", "pandas-stubs", "types-Pillow"] xml = ["dicttoxml"] [[package]] name = "fhlmi" -version = "0.30.0" +version = "0.38.0" description = "A client to provide LLM responses for FutureHouse applications." optional = false python-versions = ">=3.11" groups = ["main"] files = [ - {file = "fhlmi-0.30.0-py3-none-any.whl", hash = "sha256:13303bc06f88cfff92645309128e5ea7a7d2946353f48b30c864ac6f29882bbe"}, - {file = "fhlmi-0.30.0.tar.gz", hash = "sha256:2bba2e39a93b0d222896b141668377d54659adb675cc56a42f2af0a6c67abae6"}, + {file = "fhlmi-0.38.0-py3-none-any.whl", hash = "sha256:3cd8065ed88ce515b82ad58b42a7947b25e579b3f6f7fe04f334542565b00d4c"}, + {file = "fhlmi-0.38.0.tar.gz", hash = "sha256:4d9ddd19bfc1e4b54d45a9eb2f42a7542eb18e79a02eda1fee1480ec6efa68f0"}, ] [package.dependencies] coredis = "*" fhaviary = ">=0.14.0" limits = ">=4.8" -litellm = ">=1.63.5" +litellm = ">=1.63.5,<1.75" pydantic = ">=2.10.1,<3.0" tiktoken = ">=0.4.0" typing-extensions = {version = "*", markers = "python_version <= \"3.11\""} [package.extras] -dev = ["fhaviary[xml]", "fhlmi[local,progress,typing,vcr]", "ipython (>=8)", "litellm (>=1.68,<1.71)", "mypy (>=1.8)", "pre-commit (>=3.4)", "pylint-pydantic", "pytest (>=8)", "pytest-asyncio", "pytest-recording", "pytest-rerunfailures", "pytest-subtests", "pytest-sugar", "pytest-timer[colorama]", "pytest-xdist", "python-dotenv", "refurb (>=2)", "typeguard"] +dev = ["fhaviary[xml]", "fhlmi[local,progress,typing,vcr]", "httpx-aiohttp", "ipython (>=8)", "litellm (>=1.71)", "mypy (>=1.8)", "pre-commit (>=3.4)", "pylint-pydantic", "pytest (>=8)", "pytest-asyncio", "pytest-recording", "pytest-rerunfailures", "pytest-subtests", "pytest-sugar", "pytest-timer[colorama]", "pytest-xdist", "python-dotenv", "refurb (>=2)", "typeguard"] local = ["numpy", "sentence-transformers"] progress = ["tqdm"] typing = ["types-tqdm"] @@ -1843,83 +1967,94 @@ vcr = ["vcrpy (>=6)"] [[package]] name = "filelock" -version = "3.18.0" +version = "3.20.0" description = "A platform independent file lock." optional = false -python-versions = ">=3.9" +python-versions = ">=3.10" groups = ["main", "dev"] files = [ - {file = "filelock-3.18.0-py3-none-any.whl", hash = "sha256:c401f4f8377c4464e6db25fff06205fd89bdd83b65eb0488ed1b160f780e21de"}, - {file = "filelock-3.18.0.tar.gz", hash = "sha256:adbc88eabb99d2fec8c9c1b229b171f18afa655400173ddc653d5d01501fb9f2"}, + {file = "filelock-3.20.0-py3-none-any.whl", hash = "sha256:339b4732ffda5cd79b13f4e2711a31b0365ce445d95d243bb996273d072546a2"}, + {file = "filelock-3.20.0.tar.gz", hash = "sha256:711e943b4ec6be42e1d4e6690b48dc175c822967466bb31c0c293f34334c13f4"}, ] -[package.extras] -docs = ["furo (>=2024.8.6)", "sphinx (>=8.1.3)", "sphinx-autodoc-typehints (>=3)"] -testing = ["covdefaults (>=2.3)", "coverage (>=7.6.10)", "diff-cover (>=9.2.1)", "pytest (>=8.3.4)", "pytest-asyncio (>=0.25.2)", "pytest-cov (>=6)", "pytest-mock (>=3.14)", "pytest-timeout (>=2.3.1)", "virtualenv (>=20.28.1)"] -typing = ["typing-extensions (>=4.12.2) ; python_version < \"3.11\""] - [[package]] name = "flatbuffers" -version = "25.2.10" +version = "25.9.23" description = "The FlatBuffers serialization format for Python" optional = false python-versions = "*" groups = ["main"] files = [ - {file = "flatbuffers-25.2.10-py2.py3-none-any.whl", hash = "sha256:ebba5f4d5ea615af3f7fd70fc310636fbb2bbd1f566ac0a23d98dd412de50051"}, - {file = "flatbuffers-25.2.10.tar.gz", hash = "sha256:97e451377a41262f8d9bd4295cc836133415cc03d8cb966410a4af92eb00d26e"}, + {file = "flatbuffers-25.9.23-py2.py3-none-any.whl", hash = "sha256:255538574d6cb6d0a79a17ec8bc0d30985913b87513a01cce8bcdb6b4c44d0e2"}, + {file = "flatbuffers-25.9.23.tar.gz", hash = "sha256:676f9fa62750bb50cf531b42a0a2a118ad8f7f797a511eda12881c016f093b12"}, ] [[package]] name = "fonttools" -version = "4.59.0" +version = "4.60.1" description = "Tools to manipulate font files" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "fonttools-4.59.0-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:524133c1be38445c5c0575eacea42dbd44374b310b1ffc4b60ff01d881fabb96"}, - {file = "fonttools-4.59.0-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:21e606b2d38fed938dde871c5736822dd6bda7a4631b92e509a1f5cd1b90c5df"}, - {file = "fonttools-4.59.0-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:e93df708c69a193fc7987192f94df250f83f3851fda49413f02ba5dded639482"}, - {file = "fonttools-4.59.0-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:62224a9bb85b4b66d1b46d45cbe43d71cbf8f527d332b177e3b96191ffbc1e64"}, - {file = "fonttools-4.59.0-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:b8974b2a266b54c96709bd5e239979cddfd2dbceed331aa567ea1d7c4a2202db"}, - {file = "fonttools-4.59.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:209b75943d158f610b78320eacb5539aa9e920bee2c775445b2846c65d20e19d"}, - {file = "fonttools-4.59.0-cp310-cp310-win32.whl", hash = "sha256:4c908a7036f0f3677f8afa577bcd973e3e20ddd2f7c42a33208d18bee95cdb6f"}, - {file = "fonttools-4.59.0-cp310-cp310-win_amd64.whl", hash = "sha256:8b4309a2775e4feee7356e63b163969a215d663399cce1b3d3b65e7ec2d9680e"}, - {file = "fonttools-4.59.0-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:841b2186adce48903c0fef235421ae21549020eca942c1da773ac380b056ab3c"}, - {file = "fonttools-4.59.0-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:9bcc1e77fbd1609198966ded6b2a9897bd6c6bcbd2287a2fc7d75f1a254179c5"}, - {file = "fonttools-4.59.0-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:37c377f7cb2ab2eca8a0b319c68146d34a339792f9420fca6cd49cf28d370705"}, - {file = "fonttools-4.59.0-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:fa39475eaccb98f9199eccfda4298abaf35ae0caec676ffc25b3a5e224044464"}, - {file = "fonttools-4.59.0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:d3972b13148c1d1fbc092b27678a33b3080d1ac0ca305742b0119b75f9e87e38"}, - {file = "fonttools-4.59.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:a408c3c51358c89b29cfa5317cf11518b7ce5de1717abb55c5ae2d2921027de6"}, - {file = "fonttools-4.59.0-cp311-cp311-win32.whl", hash = "sha256:6770d7da00f358183d8fd5c4615436189e4f683bdb6affb02cad3d221d7bb757"}, - {file = "fonttools-4.59.0-cp311-cp311-win_amd64.whl", hash = "sha256:84fc186980231a287b28560d3123bd255d3c6b6659828c642b4cf961e2b923d0"}, - {file = "fonttools-4.59.0-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:f9b3a78f69dcbd803cf2fb3f972779875b244c1115481dfbdd567b2c22b31f6b"}, - {file = "fonttools-4.59.0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:57bb7e26928573ee7c6504f54c05860d867fd35e675769f3ce01b52af38d48e2"}, - {file = "fonttools-4.59.0-cp312-cp312-manylinux1_x86_64.manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:4536f2695fe5c1ffb528d84a35a7d3967e5558d2af58b4775e7ab1449d65767b"}, - {file = "fonttools-4.59.0-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:885bde7d26e5b40e15c47bd5def48b38cbd50830a65f98122a8fb90962af7cd1"}, - {file = "fonttools-4.59.0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:6801aeddb6acb2c42eafa45bc1cb98ba236871ae6f33f31e984670b749a8e58e"}, - {file = "fonttools-4.59.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:31003b6a10f70742a63126b80863ab48175fb8272a18ca0846c0482968f0588e"}, - {file = "fonttools-4.59.0-cp312-cp312-win32.whl", hash = "sha256:fbce6dae41b692a5973d0f2158f782b9ad05babc2c2019a970a1094a23909b1b"}, - {file = "fonttools-4.59.0-cp312-cp312-win_amd64.whl", hash = "sha256:332bfe685d1ac58ca8d62b8d6c71c2e52a6c64bc218dc8f7825c9ea51385aa01"}, - {file = "fonttools-4.59.0-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:78813b49d749e1bb4db1c57f2d4d7e6db22c253cb0a86ad819f5dc197710d4b2"}, - {file = "fonttools-4.59.0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:401b1941ce37e78b8fd119b419b617277c65ae9417742a63282257434fd68ea2"}, - {file = "fonttools-4.59.0-cp313-cp313-manylinux1_x86_64.manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:efd7e6660674e234e29937bc1481dceb7e0336bfae75b856b4fb272b5093c5d4"}, - {file = "fonttools-4.59.0-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:51ab1ff33c19e336c02dee1e9fd1abd974a4ca3d8f7eef2a104d0816a241ce97"}, - {file = "fonttools-4.59.0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:a9bf8adc9e1f3012edc8f09b08336272aec0c55bc677422273e21280db748f7c"}, - {file = "fonttools-4.59.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:37e01c6ec0c98599778c2e688350d624fa4770fbd6144551bd5e032f1199171c"}, - {file = "fonttools-4.59.0-cp313-cp313-win32.whl", hash = "sha256:70d6b3ceaa9cc5a6ac52884f3b3d9544e8e231e95b23f138bdb78e6d4dc0eae3"}, - {file = "fonttools-4.59.0-cp313-cp313-win_amd64.whl", hash = "sha256:26731739daa23b872643f0e4072d5939960237d540c35c14e6a06d47d71ca8fe"}, - {file = "fonttools-4.59.0-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:8d77f92438daeaddc05682f0f3dac90c5b9829bcac75b57e8ce09cb67786073c"}, - {file = "fonttools-4.59.0-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:60f6665579e909b618282f3c14fa0b80570fbf1ee0e67678b9a9d43aa5d67a37"}, - {file = "fonttools-4.59.0-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:169b99a2553a227f7b5fea8d9ecd673aa258617f466b2abc6091fe4512a0dcd0"}, - {file = "fonttools-4.59.0-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:052444a5d0151878e87e3e512a1aa1a0ab35ee4c28afde0a778e23b0ace4a7de"}, - {file = "fonttools-4.59.0-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:d40dcf533ca481355aa7b682e9e079f766f35715defa4929aeb5597f9604272e"}, - {file = "fonttools-4.59.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:b818db35879d2edf7f46c7e729c700a0bce03b61b9412f5a7118406687cb151d"}, - {file = "fonttools-4.59.0-cp39-cp39-win32.whl", hash = "sha256:2e7cf8044ce2598bb87e44ba1d2c6e45d7a8decf56055b92906dc53f67c76d64"}, - {file = "fonttools-4.59.0-cp39-cp39-win_amd64.whl", hash = "sha256:902425f5afe28572d65d2bf9c33edd5265c612ff82c69e6f83ea13eafc0dcbea"}, - {file = "fonttools-4.59.0-py3-none-any.whl", hash = "sha256:241313683afd3baacb32a6bd124d0bce7404bc5280e12e291bae1b9bba28711d"}, - {file = "fonttools-4.59.0.tar.gz", hash = "sha256:be392ec3529e2f57faa28709d60723a763904f71a2b63aabe14fee6648fe3b14"}, + {file = "fonttools-4.60.1-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:9a52f254ce051e196b8fe2af4634c2d2f02c981756c6464dc192f1b6050b4e28"}, + {file = "fonttools-4.60.1-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:c7420a2696a44650120cdd269a5d2e56a477e2bfa9d95e86229059beb1c19e15"}, + {file = "fonttools-4.60.1-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:ee0c0b3b35b34f782afc673d503167157094a16f442ace7c6c5e0ca80b08f50c"}, + {file = "fonttools-4.60.1-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:282dafa55f9659e8999110bd8ed422ebe1c8aecd0dc396550b038e6c9a08b8ea"}, + {file = "fonttools-4.60.1-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:4ba4bd646e86de16160f0fb72e31c3b9b7d0721c3e5b26b9fa2fc931dfdb2652"}, + {file = "fonttools-4.60.1-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:0b0835ed15dd5b40d726bb61c846a688f5b4ce2208ec68779bc81860adb5851a"}, + {file = "fonttools-4.60.1-cp310-cp310-win32.whl", hash = "sha256:1525796c3ffe27bb6268ed2a1bb0dcf214d561dfaf04728abf01489eb5339dce"}, + {file = "fonttools-4.60.1-cp310-cp310-win_amd64.whl", hash = "sha256:268ecda8ca6cb5c4f044b1fb9b3b376e8cd1b361cef275082429dc4174907038"}, + {file = "fonttools-4.60.1-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:7b4c32e232a71f63a5d00259ca3d88345ce2a43295bb049d21061f338124246f"}, + {file = "fonttools-4.60.1-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:3630e86c484263eaac71d117085d509cbcf7b18f677906824e4bace598fb70d2"}, + {file = "fonttools-4.60.1-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:5c1015318e4fec75dd4943ad5f6a206d9727adf97410d58b7e32ab644a807914"}, + {file = "fonttools-4.60.1-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:e6c58beb17380f7c2ea181ea11e7db8c0ceb474c9dd45f48e71e2cb577d146a1"}, + {file = "fonttools-4.60.1-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:ec3681a0cb34c255d76dd9d865a55f260164adb9fa02628415cdc2d43ee2c05d"}, + {file = "fonttools-4.60.1-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:f4b5c37a5f40e4d733d3bbaaef082149bee5a5ea3156a785ff64d949bd1353fa"}, + {file = "fonttools-4.60.1-cp311-cp311-win32.whl", hash = "sha256:398447f3d8c0c786cbf1209711e79080a40761eb44b27cdafffb48f52bcec258"}, + {file = "fonttools-4.60.1-cp311-cp311-win_amd64.whl", hash = "sha256:d066ea419f719ed87bc2c99a4a4bfd77c2e5949cb724588b9dd58f3fd90b92bf"}, + {file = "fonttools-4.60.1-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:7b0c6d57ab00dae9529f3faf187f2254ea0aa1e04215cf2f1a8ec277c96661bc"}, + {file = "fonttools-4.60.1-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:839565cbf14645952d933853e8ade66a463684ed6ed6c9345d0faf1f0e868877"}, + {file = "fonttools-4.60.1-cp312-cp312-manylinux1_x86_64.manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:8177ec9676ea6e1793c8a084a90b65a9f778771998eb919d05db6d4b1c0b114c"}, + {file = "fonttools-4.60.1-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:996a4d1834524adbb423385d5a629b868ef9d774670856c63c9a0408a3063401"}, + {file = "fonttools-4.60.1-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:a46b2f450bc79e06ef3b6394f0c68660529ed51692606ad7f953fc2e448bc903"}, + {file = "fonttools-4.60.1-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:6ec722ee589e89a89f5b7574f5c45604030aa6ae24cb2c751e2707193b466fed"}, + {file = "fonttools-4.60.1-cp312-cp312-win32.whl", hash = "sha256:b2cf105cee600d2de04ca3cfa1f74f1127f8455b71dbad02b9da6ec266e116d6"}, + {file = "fonttools-4.60.1-cp312-cp312-win_amd64.whl", hash = "sha256:992775c9fbe2cf794786fa0ffca7f09f564ba3499b8fe9f2f80bd7197db60383"}, + {file = "fonttools-4.60.1-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:6f68576bb4bbf6060c7ab047b1574a1ebe5c50a17de62830079967b211059ebb"}, + {file = "fonttools-4.60.1-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:eedacb5c5d22b7097482fa834bda0dafa3d914a4e829ec83cdea2a01f8c813c4"}, + {file = "fonttools-4.60.1-cp313-cp313-manylinux1_x86_64.manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:b33a7884fabd72bdf5f910d0cf46be50dce86a0362a65cfc746a4168c67eb96c"}, + {file = "fonttools-4.60.1-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:2409d5fb7b55fd70f715e6d34e7a6e4f7511b8ad29a49d6df225ee76da76dd77"}, + {file = "fonttools-4.60.1-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:c8651e0d4b3bdeda6602b85fdc2abbefc1b41e573ecb37b6779c4ca50753a199"}, + {file = "fonttools-4.60.1-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:145daa14bf24824b677b9357c5e44fd8895c2a8f53596e1b9ea3496081dc692c"}, + {file = "fonttools-4.60.1-cp313-cp313-win32.whl", hash = "sha256:2299df884c11162617a66b7c316957d74a18e3758c0274762d2cc87df7bc0272"}, + {file = "fonttools-4.60.1-cp313-cp313-win_amd64.whl", hash = "sha256:a3db56f153bd4c5c2b619ab02c5db5192e222150ce5a1bc10f16164714bc39ac"}, + {file = "fonttools-4.60.1-cp314-cp314-macosx_10_13_universal2.whl", hash = "sha256:a884aef09d45ba1206712c7dbda5829562d3fea7726935d3289d343232ecb0d3"}, + {file = "fonttools-4.60.1-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:8a44788d9d91df72d1a5eac49b31aeb887a5f4aab761b4cffc4196c74907ea85"}, + {file = "fonttools-4.60.1-cp314-cp314-manylinux1_x86_64.manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:e852d9dda9f93ad3651ae1e3bb770eac544ec93c3807888798eccddf84596537"}, + {file = "fonttools-4.60.1-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:154cb6ee417e417bf5f7c42fe25858c9140c26f647c7347c06f0cc2d47eff003"}, + {file = "fonttools-4.60.1-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:5664fd1a9ea7f244487ac8f10340c4e37664675e8667d6fee420766e0fb3cf08"}, + {file = "fonttools-4.60.1-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:583b7f8e3c49486e4d489ad1deacfb8d5be54a8ef34d6df824f6a171f8511d99"}, + {file = "fonttools-4.60.1-cp314-cp314-win32.whl", hash = "sha256:66929e2ea2810c6533a5184f938502cfdaea4bc3efb7130d8cc02e1c1b4108d6"}, + {file = "fonttools-4.60.1-cp314-cp314-win_amd64.whl", hash = "sha256:f3d5be054c461d6a2268831f04091dc82753176f6ea06dc6047a5e168265a987"}, + {file = "fonttools-4.60.1-cp314-cp314t-macosx_10_13_universal2.whl", hash = "sha256:b6379e7546ba4ae4b18f8ae2b9bc5960936007a1c0e30b342f662577e8bc3299"}, + {file = "fonttools-4.60.1-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:9d0ced62b59e0430b3690dbc5373df1c2aa7585e9a8ce38eff87f0fd993c5b01"}, + {file = "fonttools-4.60.1-cp314-cp314t-manylinux1_x86_64.manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:875cb7764708b3132637f6c5fb385b16eeba0f7ac9fa45a69d35e09b47045801"}, + {file = "fonttools-4.60.1-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:a184b2ea57b13680ab6d5fbde99ccef152c95c06746cb7718c583abd8f945ccc"}, + {file = "fonttools-4.60.1-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:026290e4ec76583881763fac284aca67365e0be9f13a7fb137257096114cb3bc"}, + {file = "fonttools-4.60.1-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:f0e8817c7d1a0c2eedebf57ef9a9896f3ea23324769a9a2061a80fe8852705ed"}, + {file = "fonttools-4.60.1-cp314-cp314t-win32.whl", hash = "sha256:1410155d0e764a4615774e5c2c6fc516259fe3eca5882f034eb9bfdbee056259"}, + {file = "fonttools-4.60.1-cp314-cp314t-win_amd64.whl", hash = "sha256:022beaea4b73a70295b688f817ddc24ed3e3418b5036ffcd5658141184ef0d0c"}, + {file = "fonttools-4.60.1-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:122e1a8ada290423c493491d002f622b1992b1ab0b488c68e31c413390dc7eb2"}, + {file = "fonttools-4.60.1-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:a140761c4ff63d0cb9256ac752f230460ee225ccef4ad8f68affc723c88e2036"}, + {file = "fonttools-4.60.1-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:0eae96373e4b7c9e45d099d7a523444e3554360927225c1cdae221a58a45b856"}, + {file = "fonttools-4.60.1-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:596ecaca36367027d525b3b426d8a8208169d09edcf8c7506aceb3a38bfb55c7"}, + {file = "fonttools-4.60.1-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:2ee06fc57512144d8b0445194c2da9f190f61ad51e230f14836286470c99f854"}, + {file = "fonttools-4.60.1-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:b42d86938e8dda1cd9a1a87a6d82f1818eaf933348429653559a458d027446da"}, + {file = "fonttools-4.60.1-cp39-cp39-win32.whl", hash = "sha256:8b4eb332f9501cb1cd3d4d099374a1e1306783ff95489a1026bde9eb02ccc34a"}, + {file = "fonttools-4.60.1-cp39-cp39-win_amd64.whl", hash = "sha256:7473a8ed9ed09aeaa191301244a5a9dbe46fe0bf54f9d6cd21d83044c3321217"}, + {file = "fonttools-4.60.1-py3-none-any.whl", hash = "sha256:906306ac7afe2156fcf0042173d6ebbb05416af70f6b370967b47f8f00103bbb"}, + {file = "fonttools-4.60.1.tar.gz", hash = "sha256:ef00af0439ebfee806b25f24c8f92109157ff3fac5731dc7867957812e87b8d9"}, ] [package.extras] @@ -1949,128 +2084,154 @@ files = [ [[package]] name = "frozenlist" -version = "1.7.0" +version = "1.8.0" description = "A list-like structure which implements collections.abc.MutableSequence" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "frozenlist-1.7.0-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:cc4df77d638aa2ed703b878dd093725b72a824c3c546c076e8fdf276f78ee84a"}, - {file = "frozenlist-1.7.0-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:716a9973a2cc963160394f701964fe25012600f3d311f60c790400b00e568b61"}, - {file = "frozenlist-1.7.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:a0fd1bad056a3600047fb9462cff4c5322cebc59ebf5d0a3725e0ee78955001d"}, - {file = "frozenlist-1.7.0-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:3789ebc19cb811163e70fe2bd354cea097254ce6e707ae42e56f45e31e96cb8e"}, - {file = "frozenlist-1.7.0-cp310-cp310-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:af369aa35ee34f132fcfad5be45fbfcde0e3a5f6a1ec0712857f286b7d20cca9"}, - {file = "frozenlist-1.7.0-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:ac64b6478722eeb7a3313d494f8342ef3478dff539d17002f849101b212ef97c"}, - {file = "frozenlist-1.7.0-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:f89f65d85774f1797239693cef07ad4c97fdd0639544bad9ac4b869782eb1981"}, - {file = "frozenlist-1.7.0-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:1073557c941395fdfcfac13eb2456cb8aad89f9de27bae29fabca8e563b12615"}, - {file = "frozenlist-1.7.0-cp310-cp310-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:1ed8d2fa095aae4bdc7fdd80351009a48d286635edffee66bf865e37a9125c50"}, - {file = "frozenlist-1.7.0-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:24c34bea555fe42d9f928ba0a740c553088500377448febecaa82cc3e88aa1fa"}, - {file = "frozenlist-1.7.0-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:69cac419ac6a6baad202c85aaf467b65ac860ac2e7f2ac1686dc40dbb52f6577"}, - {file = "frozenlist-1.7.0-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:960d67d0611f4c87da7e2ae2eacf7ea81a5be967861e0c63cf205215afbfac59"}, - {file = "frozenlist-1.7.0-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:41be2964bd4b15bf575e5daee5a5ce7ed3115320fb3c2b71fca05582ffa4dc9e"}, - {file = "frozenlist-1.7.0-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:46d84d49e00c9429238a7ce02dc0be8f6d7cd0cd405abd1bebdc991bf27c15bd"}, - {file = "frozenlist-1.7.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:15900082e886edb37480335d9d518cec978afc69ccbc30bd18610b7c1b22a718"}, - {file = "frozenlist-1.7.0-cp310-cp310-win32.whl", hash = "sha256:400ddd24ab4e55014bba442d917203c73b2846391dd42ca5e38ff52bb18c3c5e"}, - {file = "frozenlist-1.7.0-cp310-cp310-win_amd64.whl", hash = "sha256:6eb93efb8101ef39d32d50bce242c84bcbddb4f7e9febfa7b524532a239b4464"}, - {file = "frozenlist-1.7.0-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:aa51e147a66b2d74de1e6e2cf5921890de6b0f4820b257465101d7f37b49fb5a"}, - {file = "frozenlist-1.7.0-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:9b35db7ce1cd71d36ba24f80f0c9e7cff73a28d7a74e91fe83e23d27c7828750"}, - {file = "frozenlist-1.7.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:34a69a85e34ff37791e94542065c8416c1afbf820b68f720452f636d5fb990cd"}, - {file = "frozenlist-1.7.0-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:4a646531fa8d82c87fe4bb2e596f23173caec9185bfbca5d583b4ccfb95183e2"}, - {file = "frozenlist-1.7.0-cp311-cp311-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:79b2ffbba483f4ed36a0f236ccb85fbb16e670c9238313709638167670ba235f"}, - {file = "frozenlist-1.7.0-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:a26f205c9ca5829cbf82bb2a84b5c36f7184c4316617d7ef1b271a56720d6b30"}, - {file = "frozenlist-1.7.0-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:bcacfad3185a623fa11ea0e0634aac7b691aa925d50a440f39b458e41c561d98"}, - {file = "frozenlist-1.7.0-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:72c1b0fe8fe451b34f12dce46445ddf14bd2a5bcad7e324987194dc8e3a74c86"}, - {file = "frozenlist-1.7.0-cp311-cp311-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:61d1a5baeaac6c0798ff6edfaeaa00e0e412d49946c53fae8d4b8e8b3566c4ae"}, - {file = "frozenlist-1.7.0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:7edf5c043c062462f09b6820de9854bf28cc6cc5b6714b383149745e287181a8"}, - {file = "frozenlist-1.7.0-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:d50ac7627b3a1bd2dcef6f9da89a772694ec04d9a61b66cf87f7d9446b4a0c31"}, - {file = "frozenlist-1.7.0-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:ce48b2fece5aeb45265bb7a58259f45027db0abff478e3077e12b05b17fb9da7"}, - {file = "frozenlist-1.7.0-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:fe2365ae915a1fafd982c146754e1de6ab3478def8a59c86e1f7242d794f97d5"}, - {file = "frozenlist-1.7.0-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:45a6f2fdbd10e074e8814eb98b05292f27bad7d1883afbe009d96abdcf3bc898"}, - {file = "frozenlist-1.7.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:21884e23cffabb157a9dd7e353779077bf5b8f9a58e9b262c6caad2ef5f80a56"}, - {file = "frozenlist-1.7.0-cp311-cp311-win32.whl", hash = "sha256:284d233a8953d7b24f9159b8a3496fc1ddc00f4db99c324bd5fb5f22d8698ea7"}, - {file = "frozenlist-1.7.0-cp311-cp311-win_amd64.whl", hash = "sha256:387cbfdcde2f2353f19c2f66bbb52406d06ed77519ac7ee21be0232147c2592d"}, - {file = "frozenlist-1.7.0-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:3dbf9952c4bb0e90e98aec1bd992b3318685005702656bc6f67c1a32b76787f2"}, - {file = "frozenlist-1.7.0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:1f5906d3359300b8a9bb194239491122e6cf1444c2efb88865426f170c262cdb"}, - {file = "frozenlist-1.7.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:3dabd5a8f84573c8d10d8859a50ea2dec01eea372031929871368c09fa103478"}, - {file = "frozenlist-1.7.0-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:aa57daa5917f1738064f302bf2626281a1cb01920c32f711fbc7bc36111058a8"}, - {file = "frozenlist-1.7.0-cp312-cp312-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:c193dda2b6d49f4c4398962810fa7d7c78f032bf45572b3e04dd5249dff27e08"}, - {file = "frozenlist-1.7.0-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:bfe2b675cf0aaa6d61bf8fbffd3c274b3c9b7b1623beb3809df8a81399a4a9c4"}, - {file = "frozenlist-1.7.0-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:8fc5d5cda37f62b262405cf9652cf0856839c4be8ee41be0afe8858f17f4c94b"}, - {file = "frozenlist-1.7.0-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:b0d5ce521d1dd7d620198829b87ea002956e4319002ef0bc8d3e6d045cb4646e"}, - {file = "frozenlist-1.7.0-cp312-cp312-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:488d0a7d6a0008ca0db273c542098a0fa9e7dfaa7e57f70acef43f32b3f69dca"}, - {file = "frozenlist-1.7.0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:15a7eaba63983d22c54d255b854e8108e7e5f3e89f647fc854bd77a237e767df"}, - {file = "frozenlist-1.7.0-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:1eaa7e9c6d15df825bf255649e05bd8a74b04a4d2baa1ae46d9c2d00b2ca2cb5"}, - {file = "frozenlist-1.7.0-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:e4389e06714cfa9d47ab87f784a7c5be91d3934cd6e9a7b85beef808297cc025"}, - {file = "frozenlist-1.7.0-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:73bd45e1488c40b63fe5a7df892baf9e2a4d4bb6409a2b3b78ac1c6236178e01"}, - {file = "frozenlist-1.7.0-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:99886d98e1643269760e5fe0df31e5ae7050788dd288947f7f007209b8c33f08"}, - {file = "frozenlist-1.7.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:290a172aae5a4c278c6da8a96222e6337744cd9c77313efe33d5670b9f65fc43"}, - {file = "frozenlist-1.7.0-cp312-cp312-win32.whl", hash = "sha256:426c7bc70e07cfebc178bc4c2bf2d861d720c4fff172181eeb4a4c41d4ca2ad3"}, - {file = "frozenlist-1.7.0-cp312-cp312-win_amd64.whl", hash = "sha256:563b72efe5da92e02eb68c59cb37205457c977aa7a449ed1b37e6939e5c47c6a"}, - {file = "frozenlist-1.7.0-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:ee80eeda5e2a4e660651370ebffd1286542b67e268aa1ac8d6dbe973120ef7ee"}, - {file = "frozenlist-1.7.0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:d1a81c85417b914139e3a9b995d4a1c84559afc839a93cf2cb7f15e6e5f6ed2d"}, - {file = "frozenlist-1.7.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:cbb65198a9132ebc334f237d7b0df163e4de83fb4f2bdfe46c1e654bdb0c5d43"}, - {file = "frozenlist-1.7.0-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:dab46c723eeb2c255a64f9dc05b8dd601fde66d6b19cdb82b2e09cc6ff8d8b5d"}, - {file = "frozenlist-1.7.0-cp313-cp313-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:6aeac207a759d0dedd2e40745575ae32ab30926ff4fa49b1635def65806fddee"}, - {file = "frozenlist-1.7.0-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:bd8c4e58ad14b4fa7802b8be49d47993182fdd4023393899632c88fd8cd994eb"}, - {file = "frozenlist-1.7.0-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:04fb24d104f425da3540ed83cbfc31388a586a7696142004c577fa61c6298c3f"}, - {file = "frozenlist-1.7.0-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:6a5c505156368e4ea6b53b5ac23c92d7edc864537ff911d2fb24c140bb175e60"}, - {file = "frozenlist-1.7.0-cp313-cp313-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:8bd7eb96a675f18aa5c553eb7ddc24a43c8c18f22e1f9925528128c052cdbe00"}, - {file = "frozenlist-1.7.0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:05579bf020096fe05a764f1f84cd104a12f78eaab68842d036772dc6d4870b4b"}, - {file = "frozenlist-1.7.0-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:376b6222d114e97eeec13d46c486facd41d4f43bab626b7c3f6a8b4e81a5192c"}, - {file = "frozenlist-1.7.0-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:0aa7e176ebe115379b5b1c95b4096fb1c17cce0847402e227e712c27bdb5a949"}, - {file = "frozenlist-1.7.0-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:3fbba20e662b9c2130dc771e332a99eff5da078b2b2648153a40669a6d0e36ca"}, - {file = "frozenlist-1.7.0-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:f3f4410a0a601d349dd406b5713fec59b4cee7e71678d5b17edda7f4655a940b"}, - {file = "frozenlist-1.7.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:e2cdfaaec6a2f9327bf43c933c0319a7c429058e8537c508964a133dffee412e"}, - {file = "frozenlist-1.7.0-cp313-cp313-win32.whl", hash = "sha256:5fc4df05a6591c7768459caba1b342d9ec23fa16195e744939ba5914596ae3e1"}, - {file = "frozenlist-1.7.0-cp313-cp313-win_amd64.whl", hash = "sha256:52109052b9791a3e6b5d1b65f4b909703984b770694d3eb64fad124c835d7cba"}, - {file = "frozenlist-1.7.0-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:a6f86e4193bb0e235ef6ce3dde5cbabed887e0b11f516ce8a0f4d3b33078ec2d"}, - {file = "frozenlist-1.7.0-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:82d664628865abeb32d90ae497fb93df398a69bb3434463d172b80fc25b0dd7d"}, - {file = "frozenlist-1.7.0-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:912a7e8375a1c9a68325a902f3953191b7b292aa3c3fb0d71a216221deca460b"}, - {file = "frozenlist-1.7.0-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:9537c2777167488d539bc5de2ad262efc44388230e5118868e172dd4a552b146"}, - {file = "frozenlist-1.7.0-cp313-cp313t-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:f34560fb1b4c3e30ba35fa9a13894ba39e5acfc5f60f57d8accde65f46cc5e74"}, - {file = "frozenlist-1.7.0-cp313-cp313t-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:acd03d224b0175f5a850edc104ac19040d35419eddad04e7cf2d5986d98427f1"}, - {file = "frozenlist-1.7.0-cp313-cp313t-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:f2038310bc582f3d6a09b3816ab01737d60bf7b1ec70f5356b09e84fb7408ab1"}, - {file = "frozenlist-1.7.0-cp313-cp313t-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:b8c05e4c8e5f36e5e088caa1bf78a687528f83c043706640a92cb76cd6999384"}, - {file = "frozenlist-1.7.0-cp313-cp313t-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:765bb588c86e47d0b68f23c1bee323d4b703218037765dcf3f25c838c6fecceb"}, - {file = "frozenlist-1.7.0-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:32dc2e08c67d86d0969714dd484fd60ff08ff81d1a1e40a77dd34a387e6ebc0c"}, - {file = "frozenlist-1.7.0-cp313-cp313t-musllinux_1_2_armv7l.whl", hash = "sha256:c0303e597eb5a5321b4de9c68e9845ac8f290d2ab3f3e2c864437d3c5a30cd65"}, - {file = "frozenlist-1.7.0-cp313-cp313t-musllinux_1_2_i686.whl", hash = "sha256:a47f2abb4e29b3a8d0b530f7c3598badc6b134562b1a5caee867f7c62fee51e3"}, - {file = "frozenlist-1.7.0-cp313-cp313t-musllinux_1_2_ppc64le.whl", hash = "sha256:3d688126c242a6fabbd92e02633414d40f50bb6002fa4cf995a1d18051525657"}, - {file = "frozenlist-1.7.0-cp313-cp313t-musllinux_1_2_s390x.whl", hash = "sha256:4e7e9652b3d367c7bd449a727dc79d5043f48b88d0cbfd4f9f1060cf2b414104"}, - {file = "frozenlist-1.7.0-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:1a85e345b4c43db8b842cab1feb41be5cc0b10a1830e6295b69d7310f99becaf"}, - {file = "frozenlist-1.7.0-cp313-cp313t-win32.whl", hash = "sha256:3a14027124ddb70dfcee5148979998066897e79f89f64b13328595c4bdf77c81"}, - {file = "frozenlist-1.7.0-cp313-cp313t-win_amd64.whl", hash = "sha256:3bf8010d71d4507775f658e9823210b7427be36625b387221642725b515dcf3e"}, - {file = "frozenlist-1.7.0-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:cea3dbd15aea1341ea2de490574a4a37ca080b2ae24e4b4f4b51b9057b4c3630"}, - {file = "frozenlist-1.7.0-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:7d536ee086b23fecc36c2073c371572374ff50ef4db515e4e503925361c24f71"}, - {file = "frozenlist-1.7.0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:dfcebf56f703cb2e346315431699f00db126d158455e513bd14089d992101e44"}, - {file = "frozenlist-1.7.0-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:974c5336e61d6e7eb1ea5b929cb645e882aadab0095c5a6974a111e6479f8878"}, - {file = "frozenlist-1.7.0-cp39-cp39-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:c70db4a0ab5ab20878432c40563573229a7ed9241506181bba12f6b7d0dc41cb"}, - {file = "frozenlist-1.7.0-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:1137b78384eebaf70560a36b7b229f752fb64d463d38d1304939984d5cb887b6"}, - {file = "frozenlist-1.7.0-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:e793a9f01b3e8b5c0bc646fb59140ce0efcc580d22a3468d70766091beb81b35"}, - {file = "frozenlist-1.7.0-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:74739ba8e4e38221d2c5c03d90a7e542cb8ad681915f4ca8f68d04f810ee0a87"}, - {file = "frozenlist-1.7.0-cp39-cp39-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:1e63344c4e929b1a01e29bc184bbb5fd82954869033765bfe8d65d09e336a677"}, - {file = "frozenlist-1.7.0-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:2ea2a7369eb76de2217a842f22087913cdf75f63cf1307b9024ab82dfb525938"}, - {file = "frozenlist-1.7.0-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:836b42f472a0e006e02499cef9352ce8097f33df43baaba3e0a28a964c26c7d2"}, - {file = "frozenlist-1.7.0-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:e22b9a99741294b2571667c07d9f8cceec07cb92aae5ccda39ea1b6052ed4319"}, - {file = "frozenlist-1.7.0-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:9a19e85cc503d958abe5218953df722748d87172f71b73cf3c9257a91b999890"}, - {file = "frozenlist-1.7.0-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:f22dac33bb3ee8fe3e013aa7b91dc12f60d61d05b7fe32191ffa84c3aafe77bd"}, - {file = "frozenlist-1.7.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:9ccec739a99e4ccf664ea0775149f2749b8a6418eb5b8384b4dc0a7d15d304cb"}, - {file = "frozenlist-1.7.0-cp39-cp39-win32.whl", hash = "sha256:b3950f11058310008a87757f3eee16a8e1ca97979833239439586857bc25482e"}, - {file = "frozenlist-1.7.0-cp39-cp39-win_amd64.whl", hash = "sha256:43a82fce6769c70f2f5a06248b614a7d268080a9d20f7457ef10ecee5af82b63"}, - {file = "frozenlist-1.7.0-py3-none-any.whl", hash = "sha256:9a5af342e34f7e97caf8c995864c7a396418ae2859cc6fdf1b1073020d516a7e"}, - {file = "frozenlist-1.7.0.tar.gz", hash = "sha256:2e310d81923c2437ea8670467121cc3e9b0f76d3043cc1d2331d56c7fb7a3a8f"}, + {file = "frozenlist-1.8.0-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:b37f6d31b3dcea7deb5e9696e529a6aa4a898adc33db82da12e4c60a7c4d2011"}, + {file = "frozenlist-1.8.0-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:ef2b7b394f208233e471abc541cc6991f907ffd47dc72584acee3147899d6565"}, + {file = "frozenlist-1.8.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:a88f062f072d1589b7b46e951698950e7da00442fc1cacbe17e19e025dc327ad"}, + {file = "frozenlist-1.8.0-cp310-cp310-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:f57fb59d9f385710aa7060e89410aeb5058b99e62f4d16b08b91986b9a2140c2"}, + {file = "frozenlist-1.8.0-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:799345ab092bee59f01a915620b5d014698547afd011e691a208637312db9186"}, + {file = "frozenlist-1.8.0-cp310-cp310-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:c23c3ff005322a6e16f71bf8692fcf4d5a304aaafe1e262c98c6d4adc7be863e"}, + {file = "frozenlist-1.8.0-cp310-cp310-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:8a76ea0f0b9dfa06f254ee06053d93a600865b3274358ca48a352ce4f0798450"}, + {file = "frozenlist-1.8.0-cp310-cp310-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:c7366fe1418a6133d5aa824ee53d406550110984de7637d65a178010f759c6ef"}, + {file = "frozenlist-1.8.0-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:13d23a45c4cebade99340c4165bd90eeb4a56c6d8a9d8aa49568cac19a6d0dc4"}, + {file = "frozenlist-1.8.0-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:e4a3408834f65da56c83528fb52ce7911484f0d1eaf7b761fc66001db1646eff"}, + {file = "frozenlist-1.8.0-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:42145cd2748ca39f32801dad54aeea10039da6f86e303659db90db1c4b614c8c"}, + {file = "frozenlist-1.8.0-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:e2de870d16a7a53901e41b64ffdf26f2fbb8917b3e6ebf398098d72c5b20bd7f"}, + {file = "frozenlist-1.8.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:20e63c9493d33ee48536600d1a5c95eefc870cd71e7ab037763d1fbb89cc51e7"}, + {file = "frozenlist-1.8.0-cp310-cp310-win32.whl", hash = "sha256:adbeebaebae3526afc3c96fad434367cafbfd1b25d72369a9e5858453b1bb71a"}, + {file = "frozenlist-1.8.0-cp310-cp310-win_amd64.whl", hash = "sha256:667c3777ca571e5dbeb76f331562ff98b957431df140b54c85fd4d52eea8d8f6"}, + {file = "frozenlist-1.8.0-cp310-cp310-win_arm64.whl", hash = "sha256:80f85f0a7cc86e7a54c46d99c9e1318ff01f4687c172ede30fd52d19d1da1c8e"}, + {file = "frozenlist-1.8.0-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:09474e9831bc2b2199fad6da3c14c7b0fbdd377cce9d3d77131be28906cb7d84"}, + {file = "frozenlist-1.8.0-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:17c883ab0ab67200b5f964d2b9ed6b00971917d5d8a92df149dc2c9779208ee9"}, + {file = "frozenlist-1.8.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:fa47e444b8ba08fffd1c18e8cdb9a75db1b6a27f17507522834ad13ed5922b93"}, + {file = "frozenlist-1.8.0-cp311-cp311-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:2552f44204b744fba866e573be4c1f9048d6a324dfe14475103fd51613eb1d1f"}, + {file = "frozenlist-1.8.0-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:957e7c38f250991e48a9a73e6423db1bb9dd14e722a10f6b8bb8e16a0f55f695"}, + {file = "frozenlist-1.8.0-cp311-cp311-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:8585e3bb2cdea02fc88ffa245069c36555557ad3609e83be0ec71f54fd4abb52"}, + {file = "frozenlist-1.8.0-cp311-cp311-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:edee74874ce20a373d62dc28b0b18b93f645633c2943fd90ee9d898550770581"}, + {file = "frozenlist-1.8.0-cp311-cp311-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:c9a63152fe95756b85f31186bddf42e4c02c6321207fd6601a1c89ebac4fe567"}, + {file = "frozenlist-1.8.0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:b6db2185db9be0a04fecf2f241c70b63b1a242e2805be291855078f2b404dd6b"}, + {file = "frozenlist-1.8.0-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:f4be2e3d8bc8aabd566f8d5b8ba7ecc09249d74ba3c9ed52e54dc23a293f0b92"}, + {file = "frozenlist-1.8.0-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:c8d1634419f39ea6f5c427ea2f90ca85126b54b50837f31497f3bf38266e853d"}, + {file = "frozenlist-1.8.0-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:1a7fa382a4a223773ed64242dbe1c9c326ec09457e6b8428efb4118c685c3dfd"}, + {file = "frozenlist-1.8.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:11847b53d722050808926e785df837353bd4d75f1d494377e59b23594d834967"}, + {file = "frozenlist-1.8.0-cp311-cp311-win32.whl", hash = "sha256:27c6e8077956cf73eadd514be8fb04d77fc946a7fe9f7fe167648b0b9085cc25"}, + {file = "frozenlist-1.8.0-cp311-cp311-win_amd64.whl", hash = "sha256:ac913f8403b36a2c8610bbfd25b8013488533e71e62b4b4adce9c86c8cea905b"}, + {file = "frozenlist-1.8.0-cp311-cp311-win_arm64.whl", hash = "sha256:d4d3214a0f8394edfa3e303136d0575eece0745ff2b47bd2cb2e66dd92d4351a"}, + {file = "frozenlist-1.8.0-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:78f7b9e5d6f2fdb88cdde9440dc147259b62b9d3b019924def9f6478be254ac1"}, + {file = "frozenlist-1.8.0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:229bf37d2e4acdaf808fd3f06e854a4a7a3661e871b10dc1f8f1896a3b05f18b"}, + {file = "frozenlist-1.8.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:f833670942247a14eafbb675458b4e61c82e002a148f49e68257b79296e865c4"}, + {file = "frozenlist-1.8.0-cp312-cp312-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:494a5952b1c597ba44e0e78113a7266e656b9794eec897b19ead706bd7074383"}, + {file = "frozenlist-1.8.0-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:96f423a119f4777a4a056b66ce11527366a8bb92f54e541ade21f2374433f6d4"}, + {file = "frozenlist-1.8.0-cp312-cp312-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:3462dd9475af2025c31cc61be6652dfa25cbfb56cbbf52f4ccfe029f38decaf8"}, + {file = "frozenlist-1.8.0-cp312-cp312-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:c4c800524c9cd9bac5166cd6f55285957fcfc907db323e193f2afcd4d9abd69b"}, + {file = "frozenlist-1.8.0-cp312-cp312-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:d6a5df73acd3399d893dafc71663ad22534b5aa4f94e8a2fabfe856c3c1b6a52"}, + {file = "frozenlist-1.8.0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:405e8fe955c2280ce66428b3ca55e12b3c4e9c336fb2103a4937e891c69a4a29"}, + {file = "frozenlist-1.8.0-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:908bd3f6439f2fef9e85031b59fd4f1297af54415fb60e4254a95f75b3cab3f3"}, + {file = "frozenlist-1.8.0-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:294e487f9ec720bd8ffcebc99d575f7eff3568a08a253d1ee1a0378754b74143"}, + {file = "frozenlist-1.8.0-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:74c51543498289c0c43656701be6b077f4b265868fa7f8a8859c197006efb608"}, + {file = "frozenlist-1.8.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:776f352e8329135506a1d6bf16ac3f87bc25b28e765949282dcc627af36123aa"}, + {file = "frozenlist-1.8.0-cp312-cp312-win32.whl", hash = "sha256:433403ae80709741ce34038da08511d4a77062aa924baf411ef73d1146e74faf"}, + {file = "frozenlist-1.8.0-cp312-cp312-win_amd64.whl", hash = "sha256:34187385b08f866104f0c0617404c8eb08165ab1272e884abc89c112e9c00746"}, + {file = "frozenlist-1.8.0-cp312-cp312-win_arm64.whl", hash = "sha256:fe3c58d2f5db5fbd18c2987cba06d51b0529f52bc3a6cdc33d3f4eab725104bd"}, + {file = "frozenlist-1.8.0-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:8d92f1a84bb12d9e56f818b3a746f3efba93c1b63c8387a73dde655e1e42282a"}, + {file = "frozenlist-1.8.0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:96153e77a591c8adc2ee805756c61f59fef4cf4073a9275ee86fe8cba41241f7"}, + {file = "frozenlist-1.8.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:f21f00a91358803399890ab167098c131ec2ddd5f8f5fd5fe9c9f2c6fcd91e40"}, + {file = "frozenlist-1.8.0-cp313-cp313-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:fb30f9626572a76dfe4293c7194a09fb1fe93ba94c7d4f720dfae3b646b45027"}, + {file = "frozenlist-1.8.0-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:eaa352d7047a31d87dafcacbabe89df0aa506abb5b1b85a2fb91bc3faa02d822"}, + {file = "frozenlist-1.8.0-cp313-cp313-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:03ae967b4e297f58f8c774c7eabcce57fe3c2434817d4385c50661845a058121"}, + {file = "frozenlist-1.8.0-cp313-cp313-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:f6292f1de555ffcc675941d65fffffb0a5bcd992905015f85d0592201793e0e5"}, + {file = "frozenlist-1.8.0-cp313-cp313-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:29548f9b5b5e3460ce7378144c3010363d8035cea44bc0bf02d57f5a685e084e"}, + {file = "frozenlist-1.8.0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:ec3cc8c5d4084591b4237c0a272cc4f50a5b03396a47d9caaf76f5d7b38a4f11"}, + {file = "frozenlist-1.8.0-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:517279f58009d0b1f2e7c1b130b377a349405da3f7621ed6bfae50b10adf20c1"}, + {file = "frozenlist-1.8.0-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:db1e72ede2d0d7ccb213f218df6a078a9c09a7de257c2fe8fcef16d5925230b1"}, + {file = "frozenlist-1.8.0-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:b4dec9482a65c54a5044486847b8a66bf10c9cb4926d42927ec4e8fd5db7fed8"}, + {file = "frozenlist-1.8.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:21900c48ae04d13d416f0e1e0c4d81f7931f73a9dfa0b7a8746fb2fe7dd970ed"}, + {file = "frozenlist-1.8.0-cp313-cp313-win32.whl", hash = "sha256:8b7b94a067d1c504ee0b16def57ad5738701e4ba10cec90529f13fa03c833496"}, + {file = "frozenlist-1.8.0-cp313-cp313-win_amd64.whl", hash = "sha256:878be833caa6a3821caf85eb39c5ba92d28e85df26d57afb06b35b2efd937231"}, + {file = "frozenlist-1.8.0-cp313-cp313-win_arm64.whl", hash = "sha256:44389d135b3ff43ba8cc89ff7f51f5a0bb6b63d829c8300f79a2fe4fe61bcc62"}, + {file = "frozenlist-1.8.0-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:e25ac20a2ef37e91c1b39938b591457666a0fa835c7783c3a8f33ea42870db94"}, + {file = "frozenlist-1.8.0-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:07cdca25a91a4386d2e76ad992916a85038a9b97561bf7a3fd12d5d9ce31870c"}, + {file = "frozenlist-1.8.0-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:4e0c11f2cc6717e0a741f84a527c52616140741cd812a50422f83dc31749fb52"}, + {file = "frozenlist-1.8.0-cp313-cp313t-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:b3210649ee28062ea6099cfda39e147fa1bc039583c8ee4481cb7811e2448c51"}, + {file = "frozenlist-1.8.0-cp313-cp313t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:581ef5194c48035a7de2aefc72ac6539823bb71508189e5de01d60c9dcd5fa65"}, + {file = "frozenlist-1.8.0-cp313-cp313t-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:3ef2d026f16a2b1866e1d86fc4e1291e1ed8a387b2c333809419a2f8b3a77b82"}, + {file = "frozenlist-1.8.0-cp313-cp313t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:5500ef82073f599ac84d888e3a8c1f77ac831183244bfd7f11eaa0289fb30714"}, + {file = "frozenlist-1.8.0-cp313-cp313t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:50066c3997d0091c411a66e710f4e11752251e6d2d73d70d8d5d4c76442a199d"}, + {file = "frozenlist-1.8.0-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:5c1c8e78426e59b3f8005e9b19f6ff46e5845895adbde20ece9218319eca6506"}, + {file = "frozenlist-1.8.0-cp313-cp313t-musllinux_1_2_armv7l.whl", hash = "sha256:eefdba20de0d938cec6a89bd4d70f346a03108a19b9df4248d3cf0d88f1b0f51"}, + {file = "frozenlist-1.8.0-cp313-cp313t-musllinux_1_2_ppc64le.whl", hash = "sha256:cf253e0e1c3ceb4aaff6df637ce033ff6535fb8c70a764a8f46aafd3d6ab798e"}, + {file = "frozenlist-1.8.0-cp313-cp313t-musllinux_1_2_s390x.whl", hash = "sha256:032efa2674356903cd0261c4317a561a6850f3ac864a63fc1583147fb05a79b0"}, + {file = "frozenlist-1.8.0-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:6da155091429aeba16851ecb10a9104a108bcd32f6c1642867eadaee401c1c41"}, + {file = "frozenlist-1.8.0-cp313-cp313t-win32.whl", hash = "sha256:0f96534f8bfebc1a394209427d0f8a63d343c9779cda6fc25e8e121b5fd8555b"}, + {file = "frozenlist-1.8.0-cp313-cp313t-win_amd64.whl", hash = "sha256:5d63a068f978fc69421fb0e6eb91a9603187527c86b7cd3f534a5b77a592b888"}, + {file = "frozenlist-1.8.0-cp313-cp313t-win_arm64.whl", hash = "sha256:bf0a7e10b077bf5fb9380ad3ae8ce20ef919a6ad93b4552896419ac7e1d8e042"}, + {file = "frozenlist-1.8.0-cp314-cp314-macosx_10_13_universal2.whl", hash = "sha256:cee686f1f4cadeb2136007ddedd0aaf928ab95216e7691c63e50a8ec066336d0"}, + {file = "frozenlist-1.8.0-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:119fb2a1bd47307e899c2fac7f28e85b9a543864df47aa7ec9d3c1b4545f096f"}, + {file = "frozenlist-1.8.0-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:4970ece02dbc8c3a92fcc5228e36a3e933a01a999f7094ff7c23fbd2beeaa67c"}, + {file = "frozenlist-1.8.0-cp314-cp314-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:cba69cb73723c3f329622e34bdbf5ce1f80c21c290ff04256cff1cd3c2036ed2"}, + {file = "frozenlist-1.8.0-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:778a11b15673f6f1df23d9586f83c4846c471a8af693a22e066508b77d201ec8"}, + {file = "frozenlist-1.8.0-cp314-cp314-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:0325024fe97f94c41c08872db482cf8ac4800d80e79222c6b0b7b162d5b13686"}, + {file = "frozenlist-1.8.0-cp314-cp314-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:97260ff46b207a82a7567b581ab4190bd4dfa09f4db8a8b49d1a958f6aa4940e"}, + {file = "frozenlist-1.8.0-cp314-cp314-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:54b2077180eb7f83dd52c40b2750d0a9f175e06a42e3213ce047219de902717a"}, + {file = "frozenlist-1.8.0-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:2f05983daecab868a31e1da44462873306d3cbfd76d1f0b5b69c473d21dbb128"}, + {file = "frozenlist-1.8.0-cp314-cp314-musllinux_1_2_armv7l.whl", hash = "sha256:33f48f51a446114bc5d251fb2954ab0164d5be02ad3382abcbfe07e2531d650f"}, + {file = "frozenlist-1.8.0-cp314-cp314-musllinux_1_2_ppc64le.whl", hash = "sha256:154e55ec0655291b5dd1b8731c637ecdb50975a2ae70c606d100750a540082f7"}, + {file = "frozenlist-1.8.0-cp314-cp314-musllinux_1_2_s390x.whl", hash = "sha256:4314debad13beb564b708b4a496020e5306c7333fa9a3ab90374169a20ffab30"}, + {file = "frozenlist-1.8.0-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:073f8bf8becba60aa931eb3bc420b217bb7d5b8f4750e6f8b3be7f3da85d38b7"}, + {file = "frozenlist-1.8.0-cp314-cp314-win32.whl", hash = "sha256:bac9c42ba2ac65ddc115d930c78d24ab8d4f465fd3fc473cdedfccadb9429806"}, + {file = "frozenlist-1.8.0-cp314-cp314-win_amd64.whl", hash = "sha256:3e0761f4d1a44f1d1a47996511752cf3dcec5bbdd9cc2b4fe595caf97754b7a0"}, + {file = "frozenlist-1.8.0-cp314-cp314-win_arm64.whl", hash = "sha256:d1eaff1d00c7751b7c6662e9c5ba6eb2c17a2306ba5e2a37f24ddf3cc953402b"}, + {file = "frozenlist-1.8.0-cp314-cp314t-macosx_10_13_universal2.whl", hash = "sha256:d3bb933317c52d7ea5004a1c442eef86f426886fba134ef8cf4226ea6ee1821d"}, + {file = "frozenlist-1.8.0-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:8009897cdef112072f93a0efdce29cd819e717fd2f649ee3016efd3cd885a7ed"}, + {file = "frozenlist-1.8.0-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:2c5dcbbc55383e5883246d11fd179782a9d07a986c40f49abe89ddf865913930"}, + {file = "frozenlist-1.8.0-cp314-cp314t-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:39ecbc32f1390387d2aa4f5a995e465e9e2f79ba3adcac92d68e3e0afae6657c"}, + {file = "frozenlist-1.8.0-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:92db2bf818d5cc8d9c1f1fc56b897662e24ea5adb36ad1f1d82875bd64e03c24"}, + {file = "frozenlist-1.8.0-cp314-cp314t-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:2dc43a022e555de94c3b68a4ef0b11c4f747d12c024a520c7101709a2144fb37"}, + {file = "frozenlist-1.8.0-cp314-cp314t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:cb89a7f2de3602cfed448095bab3f178399646ab7c61454315089787df07733a"}, + {file = "frozenlist-1.8.0-cp314-cp314t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:33139dc858c580ea50e7e60a1b0ea003efa1fd42e6ec7fdbad78fff65fad2fd2"}, + {file = "frozenlist-1.8.0-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:168c0969a329b416119507ba30b9ea13688fafffac1b7822802537569a1cb0ef"}, + {file = "frozenlist-1.8.0-cp314-cp314t-musllinux_1_2_armv7l.whl", hash = "sha256:28bd570e8e189d7f7b001966435f9dac6718324b5be2990ac496cf1ea9ddb7fe"}, + {file = "frozenlist-1.8.0-cp314-cp314t-musllinux_1_2_ppc64le.whl", hash = "sha256:b2a095d45c5d46e5e79ba1e5b9cb787f541a8dee0433836cea4b96a2c439dcd8"}, + {file = "frozenlist-1.8.0-cp314-cp314t-musllinux_1_2_s390x.whl", hash = "sha256:eab8145831a0d56ec9c4139b6c3e594c7a83c2c8be25d5bcf2d86136a532287a"}, + {file = "frozenlist-1.8.0-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:974b28cf63cc99dfb2188d8d222bc6843656188164848c4f679e63dae4b0708e"}, + {file = "frozenlist-1.8.0-cp314-cp314t-win32.whl", hash = "sha256:342c97bf697ac5480c0a7ec73cd700ecfa5a8a40ac923bd035484616efecc2df"}, + {file = "frozenlist-1.8.0-cp314-cp314t-win_amd64.whl", hash = "sha256:06be8f67f39c8b1dc671f5d83aaefd3358ae5cdcf8314552c57e7ed3e6475bdd"}, + {file = "frozenlist-1.8.0-cp314-cp314t-win_arm64.whl", hash = "sha256:102e6314ca4da683dca92e3b1355490fed5f313b768500084fbe6371fddfdb79"}, + {file = "frozenlist-1.8.0-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:d8b7138e5cd0647e4523d6685b0eac5d4be9a184ae9634492f25c6eb38c12a47"}, + {file = "frozenlist-1.8.0-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:a6483e309ca809f1efd154b4d37dc6d9f61037d6c6a81c2dc7a15cb22c8c5dca"}, + {file = "frozenlist-1.8.0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:1b9290cf81e95e93fdf90548ce9d3c1211cf574b8e3f4b3b7cb0537cf2227068"}, + {file = "frozenlist-1.8.0-cp39-cp39-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:59a6a5876ca59d1b63af8cd5e7ffffb024c3dc1e9cf9301b21a2e76286505c95"}, + {file = "frozenlist-1.8.0-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:6dc4126390929823e2d2d9dc79ab4046ed74680360fc5f38b585c12c66cdf459"}, + {file = "frozenlist-1.8.0-cp39-cp39-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:332db6b2563333c5671fecacd085141b5800cb866be16d5e3eb15a2086476675"}, + {file = "frozenlist-1.8.0-cp39-cp39-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:9ff15928d62a0b80bb875655c39bf517938c7d589554cbd2669be42d97c2cb61"}, + {file = "frozenlist-1.8.0-cp39-cp39-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:7bf6cdf8e07c8151fba6fe85735441240ec7f619f935a5205953d58009aef8c6"}, + {file = "frozenlist-1.8.0-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:48e6d3f4ec5c7273dfe83ff27c91083c6c9065af655dc2684d2c200c94308bb5"}, + {file = "frozenlist-1.8.0-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:1a7607e17ad33361677adcd1443edf6f5da0ce5e5377b798fba20fae194825f3"}, + {file = "frozenlist-1.8.0-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:5a3a935c3a4e89c733303a2d5a7c257ea44af3a56c8202df486b7f5de40f37e1"}, + {file = "frozenlist-1.8.0-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:940d4a017dbfed9daf46a3b086e1d2167e7012ee297fef9e1c545c4d022f5178"}, + {file = "frozenlist-1.8.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:b9be22a69a014bc47e78072d0ecae716f5eb56c15238acca0f43d6eb8e4a5bda"}, + {file = "frozenlist-1.8.0-cp39-cp39-win32.whl", hash = "sha256:1aa77cb5697069af47472e39612976ed05343ff2e84a3dcf15437b232cbfd087"}, + {file = "frozenlist-1.8.0-cp39-cp39-win_amd64.whl", hash = "sha256:7398c222d1d405e796970320036b1b563892b65809d9e5261487bb2c7f7b5c6a"}, + {file = "frozenlist-1.8.0-cp39-cp39-win_arm64.whl", hash = "sha256:b4f3b365f31c6cd4af24545ca0a244a53688cad8834e32f56831c4923b50a103"}, + {file = "frozenlist-1.8.0-py3-none-any.whl", hash = "sha256:0c18a16eab41e82c295618a77502e17b195883241c563b00f0aa5106fc4eaa0d"}, + {file = "frozenlist-1.8.0.tar.gz", hash = "sha256:3ede829ed8d842f6cd48fc7081d7a41001a56f1f38603f9d49bf3020d59a31ad"}, ] [[package]] name = "fsspec" -version = "2025.7.0" +version = "2025.9.0" description = "File-system specification" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "fsspec-2025.7.0-py3-none-any.whl", hash = "sha256:8b012e39f63c7d5f10474de957f3ab793b47b45ae7d39f2fb735f8bbe25c0e21"}, - {file = "fsspec-2025.7.0.tar.gz", hash = "sha256:786120687ffa54b8283d942929540d8bc5ccfa820deb555a2b5d0ed2b737bf58"}, + {file = "fsspec-2025.9.0-py3-none-any.whl", hash = "sha256:530dc2a2af60a414a832059574df4a6e10cce927f6f4a78209390fe38955cfb7"}, + {file = "fsspec-2025.9.0.tar.gz", hash = "sha256:19fd429483d25d28b65ec68f9f4adc16c17ea2c7c7bf54ec61360d478fb19c19"}, ] [package.extras] @@ -2141,18 +2302,18 @@ dev = ["flake8", "markdown", "twine", "wheel"] [[package]] name = "google-auth" -version = "2.40.3" +version = "2.41.1" description = "Google Authentication Library" optional = false python-versions = ">=3.7" groups = ["main"] files = [ - {file = "google_auth-2.40.3-py2.py3-none-any.whl", hash = "sha256:1370d4593e86213563547f97a92752fc658456fe4514c809544f330fed45a7ca"}, - {file = "google_auth-2.40.3.tar.gz", hash = "sha256:500c3a29adedeb36ea9cf24b8d10858e152f2412e3ca37829b3fa18e33d63b77"}, + {file = "google_auth-2.41.1-py2.py3-none-any.whl", hash = "sha256:754843be95575b9a19c604a848a41be03f7f2afd8c019f716dc1f51ee41c639d"}, + {file = "google_auth-2.41.1.tar.gz", hash = "sha256:b76b7b1f9e61f0cb7e88870d14f6a94aeef248959ef6992670efee37709cbfd2"}, ] [package.dependencies] -cachetools = ">=2.0.0,<6.0" +cachetools = ">=2.0.0,<7.0" pyasn1-modules = ">=0.2.1" rsa = ">=3.1.4,<5" @@ -2163,7 +2324,7 @@ pyjwt = ["cryptography (<39.0.0) ; python_version < \"3.8\"", "cryptography (>=3 pyopenssl = ["cryptography (<39.0.0) ; python_version < \"3.8\"", "cryptography (>=38.0.3)", "pyopenssl (>=20.0.0)"] reauth = ["pyu2f (>=0.1.5)"] requests = ["requests (>=2.20.0,<3.0.0)"] -testing = ["aiohttp (<3.10.0)", "aiohttp (>=3.6.2,<4.0.0)", "aioresponses", "cryptography (<39.0.0) ; python_version < \"3.8\"", "cryptography (>=38.0.3)", "flask", "freezegun", "grpcio", "mock", "oauth2client", "packaging", "pyjwt (>=2.0)", "pyopenssl (<24.3.0)", "pyopenssl (>=20.0.0)", "pytest", "pytest-asyncio", "pytest-cov", "pytest-localserver", "pyu2f (>=0.1.5)", "requests (>=2.20.0,<3.0.0)", "responses", "urllib3"] +testing = ["aiohttp (<3.10.0)", "aiohttp (>=3.6.2,<4.0.0)", "aioresponses", "cryptography (<39.0.0) ; python_version < \"3.8\"", "cryptography (<39.0.0) ; python_version < \"3.8\"", "cryptography (>=38.0.3)", "cryptography (>=38.0.3)", "flask", "freezegun", "grpcio", "mock", "oauth2client", "packaging", "pyjwt (>=2.0)", "pyopenssl (<24.3.0)", "pyopenssl (>=20.0.0)", "pytest", "pytest-asyncio", "pytest-cov", "pytest-localserver", "pyu2f (>=0.1.5)", "requests (>=2.20.0,<3.0.0)", "responses", "urllib3"] urllib3 = ["packaging", "urllib3"] [[package]] @@ -2186,15 +2347,15 @@ grpc = ["grpcio (>=1.44.0,<2.0.0)"] [[package]] name = "gradio" -version = "5.38.0" +version = "5.49.1" description = "Python library for easily interacting with trained machine learning models" optional = false python-versions = ">=3.10" groups = ["main"] markers = "extra == \"gradio\"" files = [ - {file = "gradio-5.38.0-py3-none-any.whl", hash = "sha256:d0ddd19986f66c91c07ba5706aeb74c83764c58e6892a363b249da1047cf4d9a"}, - {file = "gradio-5.38.0.tar.gz", hash = "sha256:448f395bce46ae103da237647c5a44b2581570b5876957f8d2544b3b1351e495"}, + {file = "gradio-5.49.1-py3-none-any.whl", hash = "sha256:1b19369387801a26a6ba7fd2f74d46c5b0e2ac9ddef14f24ddc0d11fb19421b7"}, + {file = "gradio-5.49.1.tar.gz", hash = "sha256:c06faa324ae06c3892c8b4b4e73c706c4520d380f6b9e52a3c02dc53a7627ba9"}, ] [package.dependencies] @@ -2204,10 +2365,10 @@ audioop-lts = {version = "<1.0", markers = "python_version >= \"3.13\""} brotli = ">=1.1.0" fastapi = ">=0.115.2,<1.0" ffmpy = "*" -gradio-client = "1.11.0" +gradio-client = "1.13.3" groovy = ">=0.1,<1.0" httpx = ">=0.24.1,<1.0" -huggingface-hub = ">=0.28.1" +huggingface-hub = ">=0.33.5,<2.0" jinja2 = "<4.0" markupsafe = ">=2.0,<4.0" numpy = ">=1.0,<3.0" @@ -2219,40 +2380,39 @@ pydantic = ">=2.0,<2.12" pydub = "*" python-multipart = ">=0.0.18" pyyaml = ">=5.0,<7.0" -ruff = {version = ">=0.9.3", markers = "sys_platform != \"emscripten\""} +ruff = ">=0.9.3" safehttpx = ">=0.1.6,<0.2.0" semantic-version = ">=2.0,<3.0" -starlette = {version = ">=0.40.0,<1.0", markers = "sys_platform != \"emscripten\""} +starlette = ">=0.40.0,<1.0" tomlkit = ">=0.12.0,<0.14.0" -typer = {version = ">=0.12,<1.0", markers = "sys_platform != \"emscripten\""} +typer = ">=0.12,<1.0" typing-extensions = ">=4.0,<5.0" -urllib3 = {version = ">=2.0,<3.0", markers = "sys_platform == \"emscripten\""} -uvicorn = {version = ">=0.14.0", markers = "sys_platform != \"emscripten\""} +uvicorn = ">=0.14.0" [package.extras] -mcp = ["mcp (==1.10.1)", "pydantic (>=2.11) ; sys_platform != \"emscripten\""] +mcp = ["mcp (==1.10.1)", "pydantic (>=2.11)"] oauth = ["authlib", "itsdangerous"] [[package]] name = "gradio-client" -version = "1.11.0" +version = "1.13.3" description = "Python library for easily interacting with trained machine learning models" optional = false python-versions = ">=3.10" groups = ["main"] markers = "extra == \"gradio\"" files = [ - {file = "gradio_client-1.11.0-py3-none-any.whl", hash = "sha256:afb714aea50224f6f04679fe2ce79c1be75011012d0dc3b3ee575610a0dc8eb2"}, - {file = "gradio_client-1.11.0.tar.gz", hash = "sha256:377c31d8082173663b230dad341614b127b2460fe24d5fd72ed456fb3f0b3a9e"}, + {file = "gradio_client-1.13.3-py3-none-any.whl", hash = "sha256:3f63e4d33a2899c1a12b10fe3cf77b82a6919ff1a1fb6391f6aa225811aa390c"}, + {file = "gradio_client-1.13.3.tar.gz", hash = "sha256:869b3e67e0f7a0f40df8c48c94de99183265cf4b7b1d9bd4623e336d219ffbe7"}, ] [package.dependencies] fsspec = "*" httpx = ">=0.24.1" -huggingface-hub = ">=0.19.3" +huggingface-hub = ">=0.19.3,<2.0" packaging = "*" typing-extensions = ">=4.0,<5.0" -websockets = ">=10.0,<16.0" +websockets = ">=13.0,<16.0" [[package]] name = "graphviz" @@ -2273,83 +2433,83 @@ test = ["coverage", "pytest (>=7,<8.1)", "pytest-cov", "pytest-mock (>=3)"] [[package]] name = "greenlet" -version = "3.2.3" +version = "3.2.4" description = "Lightweight in-process concurrent programming" optional = false python-versions = ">=3.9" groups = ["main"] -markers = "python_version < \"3.14\" and (platform_machine == \"aarch64\" or platform_machine == \"ppc64le\" or platform_machine == \"x86_64\" or platform_machine == \"amd64\" or platform_machine == \"AMD64\" or platform_machine == \"win32\" or platform_machine == \"WIN32\")" -files = [ - {file = "greenlet-3.2.3-cp310-cp310-macosx_11_0_universal2.whl", hash = "sha256:1afd685acd5597349ee6d7a88a8bec83ce13c106ac78c196ee9dde7c04fe87be"}, - {file = "greenlet-3.2.3-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:761917cac215c61e9dc7324b2606107b3b292a8349bdebb31503ab4de3f559ac"}, - {file = "greenlet-3.2.3-cp310-cp310-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:a433dbc54e4a37e4fff90ef34f25a8c00aed99b06856f0119dcf09fbafa16392"}, - {file = "greenlet-3.2.3-cp310-cp310-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:72e77ed69312bab0434d7292316d5afd6896192ac4327d44f3d613ecb85b037c"}, - {file = "greenlet-3.2.3-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:68671180e3849b963649254a882cd544a3c75bfcd2c527346ad8bb53494444db"}, - {file = "greenlet-3.2.3-cp310-cp310-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:49c8cfb18fb419b3d08e011228ef8a25882397f3a859b9fe1436946140b6756b"}, - {file = "greenlet-3.2.3-cp310-cp310-musllinux_1_1_aarch64.whl", hash = "sha256:efc6dc8a792243c31f2f5674b670b3a95d46fa1c6a912b8e310d6f542e7b0712"}, - {file = "greenlet-3.2.3-cp310-cp310-musllinux_1_1_x86_64.whl", hash = "sha256:731e154aba8e757aedd0781d4b240f1225b075b4409f1bb83b05ff410582cf00"}, - {file = "greenlet-3.2.3-cp310-cp310-win_amd64.whl", hash = "sha256:96c20252c2f792defe9a115d3287e14811036d51e78b3aaddbee23b69b216302"}, - {file = "greenlet-3.2.3-cp311-cp311-macosx_11_0_universal2.whl", hash = "sha256:784ae58bba89fa1fa5733d170d42486580cab9decda3484779f4759345b29822"}, - {file = "greenlet-3.2.3-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:0921ac4ea42a5315d3446120ad48f90c3a6b9bb93dd9b3cf4e4d84a66e42de83"}, - {file = "greenlet-3.2.3-cp311-cp311-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:d2971d93bb99e05f8c2c0c2f4aa9484a18d98c4c3bd3c62b65b7e6ae33dfcfaf"}, - {file = "greenlet-3.2.3-cp311-cp311-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:c667c0bf9d406b77a15c924ef3285e1e05250948001220368e039b6aa5b5034b"}, - {file = "greenlet-3.2.3-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:592c12fb1165be74592f5de0d70f82bc5ba552ac44800d632214b76089945147"}, - {file = "greenlet-3.2.3-cp311-cp311-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:29e184536ba333003540790ba29829ac14bb645514fbd7e32af331e8202a62a5"}, - {file = "greenlet-3.2.3-cp311-cp311-musllinux_1_1_aarch64.whl", hash = "sha256:93c0bb79844a367782ec4f429d07589417052e621aa39a5ac1fb99c5aa308edc"}, - {file = "greenlet-3.2.3-cp311-cp311-musllinux_1_1_x86_64.whl", hash = "sha256:751261fc5ad7b6705f5f76726567375bb2104a059454e0226e1eef6c756748ba"}, - {file = "greenlet-3.2.3-cp311-cp311-win_amd64.whl", hash = "sha256:83a8761c75312361aa2b5b903b79da97f13f556164a7dd2d5448655425bd4c34"}, - {file = "greenlet-3.2.3-cp312-cp312-macosx_11_0_universal2.whl", hash = "sha256:25ad29caed5783d4bd7a85c9251c651696164622494c00802a139c00d639242d"}, - {file = "greenlet-3.2.3-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:88cd97bf37fe24a6710ec6a3a7799f3f81d9cd33317dcf565ff9950c83f55e0b"}, - {file = "greenlet-3.2.3-cp312-cp312-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:baeedccca94880d2f5666b4fa16fc20ef50ba1ee353ee2d7092b383a243b0b0d"}, - {file = "greenlet-3.2.3-cp312-cp312-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:be52af4b6292baecfa0f397f3edb3c6092ce071b499dd6fe292c9ac9f2c8f264"}, - {file = "greenlet-3.2.3-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:0cc73378150b8b78b0c9fe2ce56e166695e67478550769536a6742dca3651688"}, - {file = "greenlet-3.2.3-cp312-cp312-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:706d016a03e78df129f68c4c9b4c4f963f7d73534e48a24f5f5a7101ed13dbbb"}, - {file = "greenlet-3.2.3-cp312-cp312-musllinux_1_1_aarch64.whl", hash = "sha256:419e60f80709510c343c57b4bb5a339d8767bf9aef9b8ce43f4f143240f88b7c"}, - {file = "greenlet-3.2.3-cp312-cp312-musllinux_1_1_x86_64.whl", hash = "sha256:93d48533fade144203816783373f27a97e4193177ebaaf0fc396db19e5d61163"}, - {file = "greenlet-3.2.3-cp312-cp312-win_amd64.whl", hash = "sha256:7454d37c740bb27bdeddfc3f358f26956a07d5220818ceb467a483197d84f849"}, - {file = "greenlet-3.2.3-cp313-cp313-macosx_11_0_universal2.whl", hash = "sha256:500b8689aa9dd1ab26872a34084503aeddefcb438e2e7317b89b11eaea1901ad"}, - {file = "greenlet-3.2.3-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:a07d3472c2a93117af3b0136f246b2833fdc0b542d4a9799ae5f41c28323faef"}, - {file = "greenlet-3.2.3-cp313-cp313-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:8704b3768d2f51150626962f4b9a9e4a17d2e37c8a8d9867bbd9fa4eb938d3b3"}, - {file = "greenlet-3.2.3-cp313-cp313-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:5035d77a27b7c62db6cf41cf786cfe2242644a7a337a0e155c80960598baab95"}, - {file = "greenlet-3.2.3-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:2d8aa5423cd4a396792f6d4580f88bdc6efcb9205891c9d40d20f6e670992efb"}, - {file = "greenlet-3.2.3-cp313-cp313-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:2c724620a101f8170065d7dded3f962a2aea7a7dae133a009cada42847e04a7b"}, - {file = "greenlet-3.2.3-cp313-cp313-musllinux_1_1_aarch64.whl", hash = "sha256:873abe55f134c48e1f2a6f53f7d1419192a3d1a4e873bace00499a4e45ea6af0"}, - {file = "greenlet-3.2.3-cp313-cp313-musllinux_1_1_x86_64.whl", hash = "sha256:024571bbce5f2c1cfff08bf3fbaa43bbc7444f580ae13b0099e95d0e6e67ed36"}, - {file = "greenlet-3.2.3-cp313-cp313-win_amd64.whl", hash = "sha256:5195fb1e75e592dd04ce79881c8a22becdfa3e6f500e7feb059b1e6fdd54d3e3"}, - {file = "greenlet-3.2.3-cp314-cp314-macosx_11_0_universal2.whl", hash = "sha256:3d04332dddb10b4a211b68111dabaee2e1a073663d117dc10247b5b1642bac86"}, - {file = "greenlet-3.2.3-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:8186162dffde068a465deab08fc72c767196895c39db26ab1c17c0b77a6d8b97"}, - {file = "greenlet-3.2.3-cp314-cp314-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:f4bfbaa6096b1b7a200024784217defedf46a07c2eee1a498e94a1b5f8ec5728"}, - {file = "greenlet-3.2.3-cp314-cp314-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:ed6cfa9200484d234d8394c70f5492f144b20d4533f69262d530a1a082f6ee9a"}, - {file = "greenlet-3.2.3-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:02b0df6f63cd15012bed5401b47829cfd2e97052dc89da3cfaf2c779124eb892"}, - {file = "greenlet-3.2.3-cp314-cp314-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:86c2d68e87107c1792e2e8d5399acec2487a4e993ab76c792408e59394d52141"}, - {file = "greenlet-3.2.3-cp314-cp314-win_amd64.whl", hash = "sha256:8c47aae8fbbfcf82cc13327ae802ba13c9c36753b67e760023fd116bc124a62a"}, - {file = "greenlet-3.2.3-cp39-cp39-macosx_11_0_universal2.whl", hash = "sha256:42efc522c0bd75ffa11a71e09cd8a399d83fafe36db250a87cf1dacfaa15dc64"}, - {file = "greenlet-3.2.3-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:d760f9bdfe79bff803bad32b4d8ffb2c1d2ce906313fc10a83976ffb73d64ca7"}, - {file = "greenlet-3.2.3-cp39-cp39-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:8324319cbd7b35b97990090808fdc99c27fe5338f87db50514959f8059999805"}, - {file = "greenlet-3.2.3-cp39-cp39-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:8c37ef5b3787567d322331d5250e44e42b58c8c713859b8a04c6065f27efbf72"}, - {file = "greenlet-3.2.3-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:ce539fb52fb774d0802175d37fcff5c723e2c7d249c65916257f0a940cee8904"}, - {file = "greenlet-3.2.3-cp39-cp39-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:003c930e0e074db83559edc8705f3a2d066d4aa8c2f198aff1e454946efd0f26"}, - {file = "greenlet-3.2.3-cp39-cp39-musllinux_1_1_aarch64.whl", hash = "sha256:7e70ea4384b81ef9e84192e8a77fb87573138aa5d4feee541d8014e452b434da"}, - {file = "greenlet-3.2.3-cp39-cp39-musllinux_1_1_x86_64.whl", hash = "sha256:22eb5ba839c4b2156f18f76768233fe44b23a31decd9cc0d4cc8141c211fd1b4"}, - {file = "greenlet-3.2.3-cp39-cp39-win32.whl", hash = "sha256:4532f0d25df67f896d137431b13f4cdce89f7e3d4a96387a41290910df4d3a57"}, - {file = "greenlet-3.2.3-cp39-cp39-win_amd64.whl", hash = "sha256:aaa7aae1e7f75eaa3ae400ad98f8644bb81e1dc6ba47ce8a93d3f17274e08322"}, - {file = "greenlet-3.2.3.tar.gz", hash = "sha256:8b0dd8ae4c0d6f5e54ee55ba935eeb3d735a9b58a8a1e5b5cbab64e01a39f365"}, +markers = "platform_machine == \"aarch64\" or platform_machine == \"ppc64le\" or platform_machine == \"x86_64\" or platform_machine == \"amd64\" or platform_machine == \"AMD64\" or platform_machine == \"win32\" or platform_machine == \"WIN32\"" +files = [ + {file = "greenlet-3.2.4-cp310-cp310-macosx_11_0_universal2.whl", hash = "sha256:8c68325b0d0acf8d91dde4e6f930967dd52a5302cd4062932a6b2e7c2969f47c"}, + {file = "greenlet-3.2.4-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:94385f101946790ae13da500603491f04a76b6e4c059dab271b3ce2e283b2590"}, + {file = "greenlet-3.2.4-cp310-cp310-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:f10fd42b5ee276335863712fa3da6608e93f70629c631bf77145021600abc23c"}, + {file = "greenlet-3.2.4-cp310-cp310-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:c8c9e331e58180d0d83c5b7999255721b725913ff6bc6cf39fa2a45841a4fd4b"}, + {file = "greenlet-3.2.4-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:58b97143c9cc7b86fc458f215bd0932f1757ce649e05b640fea2e79b54cedb31"}, + {file = "greenlet-3.2.4-cp310-cp310-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:c2ca18a03a8cfb5b25bc1cbe20f3d9a4c80d8c3b13ba3df49ac3961af0b1018d"}, + {file = "greenlet-3.2.4-cp310-cp310-musllinux_1_1_aarch64.whl", hash = "sha256:9fe0a28a7b952a21e2c062cd5756d34354117796c6d9215a87f55e38d15402c5"}, + {file = "greenlet-3.2.4-cp310-cp310-musllinux_1_1_x86_64.whl", hash = "sha256:8854167e06950ca75b898b104b63cc646573aa5fef1353d4508ecdd1ee76254f"}, + {file = "greenlet-3.2.4-cp310-cp310-win_amd64.whl", hash = "sha256:73f49b5368b5359d04e18d15828eecc1806033db5233397748f4ca813ff1056c"}, + {file = "greenlet-3.2.4-cp311-cp311-macosx_11_0_universal2.whl", hash = "sha256:96378df1de302bc38e99c3a9aa311967b7dc80ced1dcc6f171e99842987882a2"}, + {file = "greenlet-3.2.4-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:1ee8fae0519a337f2329cb78bd7a8e128ec0f881073d43f023c7b8d4831d5246"}, + {file = "greenlet-3.2.4-cp311-cp311-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:94abf90142c2a18151632371140b3dba4dee031633fe614cb592dbb6c9e17bc3"}, + {file = "greenlet-3.2.4-cp311-cp311-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:4d1378601b85e2e5171b99be8d2dc85f594c79967599328f95c1dc1a40f1c633"}, + {file = "greenlet-3.2.4-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:0db5594dce18db94f7d1650d7489909b57afde4c580806b8d9203b6e79cdc079"}, + {file = "greenlet-3.2.4-cp311-cp311-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:2523e5246274f54fdadbce8494458a2ebdcdbc7b802318466ac5606d3cded1f8"}, + {file = "greenlet-3.2.4-cp311-cp311-musllinux_1_1_aarch64.whl", hash = "sha256:1987de92fec508535687fb807a5cea1560f6196285a4cde35c100b8cd632cc52"}, + {file = "greenlet-3.2.4-cp311-cp311-musllinux_1_1_x86_64.whl", hash = "sha256:55e9c5affaa6775e2c6b67659f3a71684de4c549b3dd9afca3bc773533d284fa"}, + {file = "greenlet-3.2.4-cp311-cp311-win_amd64.whl", hash = "sha256:9c40adce87eaa9ddb593ccb0fa6a07caf34015a29bf8d344811665b573138db9"}, + {file = "greenlet-3.2.4-cp312-cp312-macosx_11_0_universal2.whl", hash = "sha256:3b67ca49f54cede0186854a008109d6ee71f66bd57bb36abd6d0a0267b540cdd"}, + {file = "greenlet-3.2.4-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:ddf9164e7a5b08e9d22511526865780a576f19ddd00d62f8a665949327fde8bb"}, + {file = "greenlet-3.2.4-cp312-cp312-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:f28588772bb5fb869a8eb331374ec06f24a83a9c25bfa1f38b6993afe9c1e968"}, + {file = "greenlet-3.2.4-cp312-cp312-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:5c9320971821a7cb77cfab8d956fa8e39cd07ca44b6070db358ceb7f8797c8c9"}, + {file = "greenlet-3.2.4-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:c60a6d84229b271d44b70fb6e5fa23781abb5d742af7b808ae3f6efd7c9c60f6"}, + {file = "greenlet-3.2.4-cp312-cp312-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:3b3812d8d0c9579967815af437d96623f45c0f2ae5f04e366de62a12d83a8fb0"}, + {file = "greenlet-3.2.4-cp312-cp312-musllinux_1_1_aarch64.whl", hash = "sha256:abbf57b5a870d30c4675928c37278493044d7c14378350b3aa5d484fa65575f0"}, + {file = "greenlet-3.2.4-cp312-cp312-musllinux_1_1_x86_64.whl", hash = "sha256:20fb936b4652b6e307b8f347665e2c615540d4b42b3b4c8a321d8286da7e520f"}, + {file = "greenlet-3.2.4-cp312-cp312-win_amd64.whl", hash = "sha256:a7d4e128405eea3814a12cc2605e0e6aedb4035bf32697f72deca74de4105e02"}, + {file = "greenlet-3.2.4-cp313-cp313-macosx_11_0_universal2.whl", hash = "sha256:1a921e542453fe531144e91e1feedf12e07351b1cf6c9e8a3325ea600a715a31"}, + {file = "greenlet-3.2.4-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:cd3c8e693bff0fff6ba55f140bf390fa92c994083f838fece0f63be121334945"}, + {file = "greenlet-3.2.4-cp313-cp313-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:710638eb93b1fa52823aa91bf75326f9ecdfd5e0466f00789246a5280f4ba0fc"}, + {file = "greenlet-3.2.4-cp313-cp313-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:c5111ccdc9c88f423426df3fd1811bfc40ed66264d35aa373420a34377efc98a"}, + {file = "greenlet-3.2.4-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:d76383238584e9711e20ebe14db6c88ddcedc1829a9ad31a584389463b5aa504"}, + {file = "greenlet-3.2.4-cp313-cp313-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:23768528f2911bcd7e475210822ffb5254ed10d71f4028387e5a99b4c6699671"}, + {file = "greenlet-3.2.4-cp313-cp313-musllinux_1_1_aarch64.whl", hash = "sha256:00fadb3fedccc447f517ee0d3fd8fe49eae949e1cd0f6a611818f4f6fb7dc83b"}, + {file = "greenlet-3.2.4-cp313-cp313-musllinux_1_1_x86_64.whl", hash = "sha256:d25c5091190f2dc0eaa3f950252122edbbadbb682aa7b1ef2f8af0f8c0afefae"}, + {file = "greenlet-3.2.4-cp313-cp313-win_amd64.whl", hash = "sha256:554b03b6e73aaabec3745364d6239e9e012d64c68ccd0b8430c64ccc14939a8b"}, + {file = "greenlet-3.2.4-cp314-cp314-macosx_11_0_universal2.whl", hash = "sha256:49a30d5fda2507ae77be16479bdb62a660fa51b1eb4928b524975b3bde77b3c0"}, + {file = "greenlet-3.2.4-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:299fd615cd8fc86267b47597123e3f43ad79c9d8a22bebdce535e53550763e2f"}, + {file = "greenlet-3.2.4-cp314-cp314-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:c17b6b34111ea72fc5a4e4beec9711d2226285f0386ea83477cbb97c30a3f3a5"}, + {file = "greenlet-3.2.4-cp314-cp314-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:b4a1870c51720687af7fa3e7cda6d08d801dae660f75a76f3845b642b4da6ee1"}, + {file = "greenlet-3.2.4-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:061dc4cf2c34852b052a8620d40f36324554bc192be474b9e9770e8c042fd735"}, + {file = "greenlet-3.2.4-cp314-cp314-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:44358b9bf66c8576a9f57a590d5f5d6e72fa4228b763d0e43fee6d3b06d3a337"}, + {file = "greenlet-3.2.4-cp314-cp314-win_amd64.whl", hash = "sha256:e37ab26028f12dbb0ff65f29a8d3d44a765c61e729647bf2ddfbbed621726f01"}, + {file = "greenlet-3.2.4-cp39-cp39-macosx_11_0_universal2.whl", hash = "sha256:b6a7c19cf0d2742d0809a4c05975db036fdff50cd294a93632d6a310bf9ac02c"}, + {file = "greenlet-3.2.4-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:27890167f55d2387576d1f41d9487ef171849ea0359ce1510ca6e06c8bece11d"}, + {file = "greenlet-3.2.4-cp39-cp39-manylinux2014_ppc64le.manylinux_2_17_ppc64le.whl", hash = "sha256:18d9260df2b5fbf41ae5139e1be4e796d99655f023a636cd0e11e6406cca7d58"}, + {file = "greenlet-3.2.4-cp39-cp39-manylinux2014_s390x.manylinux_2_17_s390x.whl", hash = "sha256:671df96c1f23c4a0d4077a325483c1503c96a1b7d9db26592ae770daa41233d4"}, + {file = "greenlet-3.2.4-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:16458c245a38991aa19676900d48bd1a6f2ce3e16595051a4db9d012154e8433"}, + {file = "greenlet-3.2.4-cp39-cp39-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:c9913f1a30e4526f432991f89ae263459b1c64d1608c0d22a5c79c287b3c70df"}, + {file = "greenlet-3.2.4-cp39-cp39-musllinux_1_1_aarch64.whl", hash = "sha256:b90654e092f928f110e0007f572007c9727b5265f7632c2fa7415b4689351594"}, + {file = "greenlet-3.2.4-cp39-cp39-musllinux_1_1_x86_64.whl", hash = "sha256:81701fd84f26330f0d5f4944d4e92e61afe6319dcd9775e39396e39d7c3e5f98"}, + {file = "greenlet-3.2.4-cp39-cp39-win32.whl", hash = "sha256:65458b409c1ed459ea899e939f0e1cdb14f58dbc803f2f93c5eab5694d32671b"}, + {file = "greenlet-3.2.4-cp39-cp39-win_amd64.whl", hash = "sha256:d2e685ade4dafd447ede19c31277a224a239a0a1a4eca4e6390efedf20260cfb"}, + {file = "greenlet-3.2.4.tar.gz", hash = "sha256:0dca0d95ff849f9a364385f36ab49f50065d76964944638be9691e1832e9f86d"}, ] [package.extras] docs = ["Sphinx", "furo"] -test = ["objgraph", "psutil"] +test = ["objgraph", "psutil", "setuptools"] [[package]] name = "griffe" -version = "1.7.3" +version = "1.14.0" description = "Signatures for entire Python programs. Extract the structure, the frame, the skeleton of your project, to generate API documentation or find breaking changes in your API." optional = false python-versions = ">=3.9" groups = ["main", "docs"] files = [ - {file = "griffe-1.7.3-py3-none-any.whl", hash = "sha256:c6b3ee30c2f0f17f30bcdef5068d6ab7a2a4f1b8bf1a3e74b56fffd21e1c5f75"}, - {file = "griffe-1.7.3.tar.gz", hash = "sha256:52ee893c6a3a968b639ace8015bec9d36594961e156e23315c8e8e51401fa50b"}, + {file = "griffe-1.14.0-py3-none-any.whl", hash = "sha256:0e9d52832cccf0f7188cfe585ba962d2674b241c01916d780925df34873bceb0"}, + {file = "griffe-1.14.0.tar.gz", hash = "sha256:9d2a15c1eca966d68e00517de5d69dd1bc5c9f2335ef6c1775362ba5b8651a13"}, ] [package.dependencies] @@ -2373,14 +2533,14 @@ dev = ["pytest", "ruff (==0.9.3)"] [[package]] name = "groq" -version = "0.30.0" +version = "0.32.0" description = "The official Python library for the groq API" optional = false python-versions = ">=3.8" groups = ["main"] files = [ - {file = "groq-0.30.0-py3-none-any.whl", hash = "sha256:6d9609a7778ba56432f45c1bac21b005f02c6c0aca9c1c094e65536f162c1e83"}, - {file = "groq-0.30.0.tar.gz", hash = "sha256:919466e48fcbebef08fed3f71debb0f96b0ea8d2ec77842c384aa843019f6e2c"}, + {file = "groq-0.32.0-py3-none-any.whl", hash = "sha256:0ed0be290042f8826f851f3a1defaac4f979dcfce86ec4a0681a23af00ec800b"}, + {file = "groq-0.32.0.tar.gz", hash = "sha256:fb1ade61f47a06d1a1c1dc0fab690d269b799ebd57ad1dd867efaeaa7adeb2af"}, ] [package.dependencies] @@ -2392,7 +2552,7 @@ sniffio = "*" typing-extensions = ">=4.10,<5" [package.extras] -aiohttp = ["aiohttp", "httpx-aiohttp (>=0.1.6)"] +aiohttp = ["aiohttp", "httpx-aiohttp (>=0.1.8)"] [[package]] name = "h11" @@ -2420,21 +2580,21 @@ files = [ [[package]] name = "hf-xet" -version = "1.1.5" +version = "1.1.10" description = "Fast transfer of large files with the Hugging Face Hub." optional = false python-versions = ">=3.8" groups = ["main"] markers = "platform_machine == \"x86_64\" or platform_machine == \"amd64\" or platform_machine == \"arm64\" or platform_machine == \"aarch64\"" files = [ - {file = "hf_xet-1.1.5-cp37-abi3-macosx_10_12_x86_64.whl", hash = "sha256:f52c2fa3635b8c37c7764d8796dfa72706cc4eded19d638331161e82b0792e23"}, - {file = "hf_xet-1.1.5-cp37-abi3-macosx_11_0_arm64.whl", hash = "sha256:9fa6e3ee5d61912c4a113e0708eaaef987047616465ac7aa30f7121a48fc1af8"}, - {file = "hf_xet-1.1.5-cp37-abi3-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:fc874b5c843e642f45fd85cda1ce599e123308ad2901ead23d3510a47ff506d1"}, - {file = "hf_xet-1.1.5-cp37-abi3-manylinux_2_28_aarch64.whl", hash = "sha256:dbba1660e5d810bd0ea77c511a99e9242d920790d0e63c0e4673ed36c4022d18"}, - {file = "hf_xet-1.1.5-cp37-abi3-musllinux_1_2_aarch64.whl", hash = "sha256:ab34c4c3104133c495785d5d8bba3b1efc99de52c02e759cf711a91fd39d3a14"}, - {file = "hf_xet-1.1.5-cp37-abi3-musllinux_1_2_x86_64.whl", hash = "sha256:83088ecea236d5113de478acb2339f92c95b4fb0462acaa30621fac02f5a534a"}, - {file = "hf_xet-1.1.5-cp37-abi3-win_amd64.whl", hash = "sha256:73e167d9807d166596b4b2f0b585c6d5bd84a26dea32843665a8b58f6edba245"}, - {file = "hf_xet-1.1.5.tar.gz", hash = "sha256:69ebbcfd9ec44fdc2af73441619eeb06b94ee34511bbcf57cd423820090f5694"}, + {file = "hf_xet-1.1.10-cp37-abi3-macosx_10_12_x86_64.whl", hash = "sha256:686083aca1a6669bc85c21c0563551cbcdaa5cf7876a91f3d074a030b577231d"}, + {file = "hf_xet-1.1.10-cp37-abi3-macosx_11_0_arm64.whl", hash = "sha256:71081925383b66b24eedff3013f8e6bbd41215c3338be4b94ba75fd75b21513b"}, + {file = "hf_xet-1.1.10-cp37-abi3-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:6b6bceb6361c80c1cc42b5a7b4e3efd90e64630bcf11224dcac50ef30a47e435"}, + {file = "hf_xet-1.1.10-cp37-abi3-manylinux_2_28_aarch64.whl", hash = "sha256:eae7c1fc8a664e54753ffc235e11427ca61f4b0477d757cc4eb9ae374b69f09c"}, + {file = "hf_xet-1.1.10-cp37-abi3-musllinux_1_2_aarch64.whl", hash = "sha256:0a0005fd08f002180f7a12d4e13b22be277725bc23ed0529f8add5c7a6309c06"}, + {file = "hf_xet-1.1.10-cp37-abi3-musllinux_1_2_x86_64.whl", hash = "sha256:f900481cf6e362a6c549c61ff77468bd59d6dd082f3170a36acfef2eb6a6793f"}, + {file = "hf_xet-1.1.10-cp37-abi3-win_amd64.whl", hash = "sha256:5f54b19cc347c13235ae7ee98b330c26dd65ef1df47e5316ffb1e87713ca7045"}, + {file = "hf_xet-1.1.10.tar.gz", hash = "sha256:408aef343800a2102374a883f283ff29068055c111f003ff840733d3b715bb97"}, ] [package.extras] @@ -2499,6 +2659,22 @@ http2 = ["h2 (>=3,<5)"] socks = ["socksio (==1.*)"] zstd = ["zstandard (>=0.18.0)"] +[[package]] +name = "httpx-aiohttp" +version = "0.1.8" +description = "Aiohttp transport for HTTPX" +optional = false +python-versions = ">=3.8" +groups = ["main"] +files = [ + {file = "httpx_aiohttp-0.1.8-py3-none-any.whl", hash = "sha256:b7bd958d1331f3759a38a0ba22ad29832cb63ca69498c17735228055bf78fa7e"}, + {file = "httpx_aiohttp-0.1.8.tar.gz", hash = "sha256:756c5e74cdb568c3248ba63fe82bfe8bbe64b928728720f7eaac64b3cf46f308"}, +] + +[package.dependencies] +aiohttp = ">=3.10.0,<4" +httpx = ">=0.27.0" + [[package]] name = "httpx-sse" version = "0.4.0" @@ -2513,14 +2689,14 @@ files = [ [[package]] name = "huggingface-hub" -version = "0.35.1" +version = "0.35.3" description = "Client library to download and publish models, datasets and other repos on the huggingface.co hub" optional = false python-versions = ">=3.8.0" groups = ["main"] files = [ - {file = "huggingface_hub-0.35.1-py3-none-any.whl", hash = "sha256:2f0e2709c711e3040e31d3e0418341f7092910f1462dd00350c4e97af47280a8"}, - {file = "huggingface_hub-0.35.1.tar.gz", hash = "sha256:3585b88c5169c64b7e4214d0e88163d4a709de6d1a502e0cd0459e9ee2c9c572"}, + {file = "huggingface_hub-0.35.3-py3-none-any.whl", hash = "sha256:0e3a01829c19d86d03793e4577816fe3bdfc1602ac62c7fb220d593d351224ba"}, + {file = "huggingface_hub-0.35.3.tar.gz", hash = "sha256:350932eaa5cc6a4747efae85126ee220e4ef1b54e29d31c3b45c5612ddf0b32a"}, ] [package.dependencies] @@ -2567,14 +2743,14 @@ pyreadline3 = {version = "*", markers = "sys_platform == \"win32\" and python_ve [[package]] name = "identify" -version = "2.6.12" +version = "2.6.15" description = "File identification library for Python" optional = false python-versions = ">=3.9" groups = ["dev"] files = [ - {file = "identify-2.6.12-py2.py3-none-any.whl", hash = "sha256:ad9672d5a72e0d2ff7c5c8809b62dfa60458626352fb0eb7b55e69bdc45334a2"}, - {file = "identify-2.6.12.tar.gz", hash = "sha256:d8de45749f1efb108badef65ee8386f0f7bb19a7f26185f74de6367bffbaf0e6"}, + {file = "identify-2.6.15-py2.py3-none-any.whl", hash = "sha256:1181ef7608e00704db228516541eb83a88a9f94433a8c80bb9b5bd54b1d81757"}, + {file = "identify-2.6.15.tar.gz", hash = "sha256:e4f4864b96c6557ef2a1e1c951771838f4edc9df3a72ec7118b338801b11c7bf"}, ] [package.extras] @@ -2582,14 +2758,14 @@ license = ["ukkonen"] [[package]] name = "idna" -version = "3.10" +version = "3.11" description = "Internationalized Domain Names in Applications (IDNA)" optional = false -python-versions = ">=3.6" +python-versions = ">=3.8" groups = ["main", "docs"] files = [ - {file = "idna-3.10-py3-none-any.whl", hash = "sha256:946d195a0d259cbba61165e88e65941f16e9b36ea6ddb97f00452bae8b1287d3"}, - {file = "idna-3.10.tar.gz", hash = "sha256:12f65c9b470abda6dc35cf8e63cc574b1c52b11df2c86030af0ac09b01b13ea9"}, + {file = "idna-3.11-py3-none-any.whl", hash = "sha256:771a87f49d9defaf64091e6e6fe9c18d4833f140bd19464795bc32d966ca37ea"}, + {file = "idna-3.11.tar.gz", hash = "sha256:795dafcc9c04ed0c1fb032c2aa73654d8e8c5023a7df64a53f39190ada629902"}, ] [package.extras] @@ -2597,97 +2773,107 @@ all = ["flake8 (>=7.1.1)", "mypy (>=1.11.2)", "pytest (>=8.3.2)", "ruff (>=0.6.2 [[package]] name = "ijson" -version = "3.4.0" +version = "3.4.0.post0" description = "Iterative JSON parser with standard Python iterator interfaces" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "ijson-3.4.0-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:e27e50f6dcdee648f704abc5d31b976cd2f90b4642ed447cf03296d138433d09"}, - {file = "ijson-3.4.0-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:2a753be681ac930740a4af9c93cfb4edc49a167faed48061ea650dc5b0f406f1"}, - {file = "ijson-3.4.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:a07c47aed534e0ec198e6a2d4360b259d32ac654af59c015afc517ad7973b7fb"}, - {file = "ijson-3.4.0-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:9c55f48181e11c597cd7146fb31edc8058391201ead69f8f40d2ecbb0b3e4fc6"}, - {file = "ijson-3.4.0-cp310-cp310-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:abd5669f96f79d8a2dd5ae81cbd06770a4d42c435fd4a75c74ef28d9913b697d"}, - {file = "ijson-3.4.0-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:3e3ddd46d16b8542c63b1b8af7006c758d4e21cc1b86122c15f8530fae773461"}, - {file = "ijson-3.4.0-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:1504cec7fe04be2bb0cc33b50c9dd3f83f98c0540ad4991d4017373b7853cfe6"}, - {file = "ijson-3.4.0-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:2f2ff456adeb216603e25d7915f10584c1b958b6eafa60038d76d08fc8a5fb06"}, - {file = "ijson-3.4.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:0ab00d75d61613a125fbbb524551658b1ad6919a52271ca16563ca5bc2737bb1"}, - {file = "ijson-3.4.0-cp310-cp310-win32.whl", hash = "sha256:ada421fd59fe2bfa4cfa64ba39aeba3f0753696cdcd4d50396a85f38b1d12b01"}, - {file = "ijson-3.4.0-cp310-cp310-win_amd64.whl", hash = "sha256:8c75e82cec05d00ed3a4af5f4edf08f59d536ed1a86ac7e84044870872d82a33"}, - {file = "ijson-3.4.0-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:9e369bf5a173ca51846c243002ad8025d32032532523b06510881ecc8723ee54"}, - {file = "ijson-3.4.0-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:26e7da0a3cd2a56a1fde1b34231867693f21c528b683856f6691e95f9f39caec"}, - {file = "ijson-3.4.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:1c28c7f604729be22aa453e604e9617b665fa0c24cd25f9f47a970e8130c571a"}, - {file = "ijson-3.4.0-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:0bed8bcb84d3468940f97869da323ba09ae3e6b950df11dea9b62e2b231ca1e3"}, - {file = "ijson-3.4.0-cp311-cp311-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:296bc824f4088f2af814aaf973b0435bc887ce3d9f517b1577cc4e7d1afb1cb7"}, - {file = "ijson-3.4.0-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:8145f8f40617b6a8aa24e28559d0adc8b889e56a203725226a8a60fa3501073f"}, - {file = "ijson-3.4.0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:b674a97bd503ea21bc85103e06b6493b1b2a12da3372950f53e1c664566a33a4"}, - {file = "ijson-3.4.0-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:8bc731cf1c3282b021d3407a601a5a327613da9ad3c4cecb1123232623ae1826"}, - {file = "ijson-3.4.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:42ace5e940e0cf58c9de72f688d6829ddd815096d07927ee7e77df2648006365"}, - {file = "ijson-3.4.0-cp311-cp311-win32.whl", hash = "sha256:5be39a0df4cd3f02b304382ea8885391900ac62e95888af47525a287c50005e9"}, - {file = "ijson-3.4.0-cp311-cp311-win_amd64.whl", hash = "sha256:0b1be1781792291e70d2e177acf564ec672a7907ba74f313583bdf39fe81f9b7"}, - {file = "ijson-3.4.0-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:956b148f88259a80a9027ffbe2d91705fae0c004fbfba3e5a24028fbe72311a9"}, - {file = "ijson-3.4.0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:06b89960f5c721106394c7fba5760b3f67c515b8eb7d80f612388f5eca2f4621"}, - {file = "ijson-3.4.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:9a0bb591cf250dd7e9dfab69d634745a7f3272d31cfe879f9156e0a081fd97ee"}, - {file = "ijson-3.4.0-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:72e92de999977f4c6b660ffcf2b8d59604ccd531edcbfde05b642baf283e0de8"}, - {file = "ijson-3.4.0-cp312-cp312-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:9e9602157a5b869d44b6896e64f502c712a312fcde044c2e586fccb85d3e316e"}, - {file = "ijson-3.4.0-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:b1e83660edb931a425b7ff662eb49db1f10d30ca6d4d350e5630edbed098bc01"}, - {file = "ijson-3.4.0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:49bf8eac1c7b7913073865a859c215488461f7591b4fa6a33c14b51cb73659d0"}, - {file = "ijson-3.4.0-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:160b09273cb42019f1811469508b0a057d19f26434d44752bde6f281da6d3f32"}, - {file = "ijson-3.4.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:2019ff4e6f354aa00c76c8591bd450899111c61f2354ad55cc127e2ce2492c44"}, - {file = "ijson-3.4.0-cp312-cp312-win32.whl", hash = "sha256:931c007bf6bb8330705429989b2deed6838c22b63358a330bf362b6e458ba0bf"}, - {file = "ijson-3.4.0-cp312-cp312-win_amd64.whl", hash = "sha256:71523f2b64cb856a820223e94d23e88369f193017ecc789bb4de198cc9d349eb"}, - {file = "ijson-3.4.0-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:e8d96f88d75196a61c9d9443de2b72c2d4a7ba9456ff117b57ae3bba23a54256"}, - {file = "ijson-3.4.0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:c45906ce2c1d3b62f15645476fc3a6ca279549127f01662a39ca5ed334a00cf9"}, - {file = "ijson-3.4.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:4ab4bc2119b35c4363ea49f29563612237cae9413d2fbe54b223be098b97bc9e"}, - {file = "ijson-3.4.0-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:97b0a9b5a15e61dfb1f14921ea4e0dba39f3a650df6d8f444ddbc2b19b479ff1"}, - {file = "ijson-3.4.0-cp313-cp313-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:e3047bb994dabedf11de11076ed1147a307924b6e5e2df6784fb2599c4ad8c60"}, - {file = "ijson-3.4.0-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:68c83161b052e9f5dc8191acbc862bb1e63f8a35344cb5cd0db1afd3afd487a6"}, - {file = "ijson-3.4.0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:1eebd9b6c20eb1dffde0ae1f0fbb4aeacec2eb7b89adb5c7c0449fc9fd742760"}, - {file = "ijson-3.4.0-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:13fb6d5c35192c541421f3ee81239d91fc15a8d8f26c869250f941f4b346a86c"}, - {file = "ijson-3.4.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:28b7196ff7b37c4897c547a28fa4876919696739fc91c1f347651c9736877c69"}, - {file = "ijson-3.4.0-cp313-cp313-win32.whl", hash = "sha256:3c2691d2da42629522140f77b99587d6f5010440d58d36616f33bc7bdc830cc3"}, - {file = "ijson-3.4.0-cp313-cp313-win_amd64.whl", hash = "sha256:c4554718c275a044c47eb3874f78f2c939f300215d9031e785a6711cc51b83fc"}, - {file = "ijson-3.4.0-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:915a65e3f3c0eee2ea937bc62aaedb6c14cc1e8f0bb9f3f4fb5a9e2bbfa4b480"}, - {file = "ijson-3.4.0-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:afbe9748707684b6c5adc295c4fdcf27765b300aec4d484e14a13dca4e5c0afa"}, - {file = "ijson-3.4.0-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:d823f8f321b4d8d5fa020d0a84f089fec5d52b7c0762430476d9f8bf95bbc1a9"}, - {file = "ijson-3.4.0-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:b8a0a2c54f3becf76881188beefd98b484b1d3bd005769a740d5b433b089fa23"}, - {file = "ijson-3.4.0-cp313-cp313t-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:ced19a83ab09afa16257a0b15bc1aa888dbc555cb754be09d375c7f8d41051f2"}, - {file = "ijson-3.4.0-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:8100f9885eff1f38d35cef80ef759a1bbf5fc946349afa681bd7d0e681b7f1a0"}, - {file = "ijson-3.4.0-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:d7bcc3f7f21b0f703031ecd15209b1284ea51b2a329d66074b5261de3916c1eb"}, - {file = "ijson-3.4.0-cp313-cp313t-musllinux_1_2_i686.whl", hash = "sha256:2dcb190227b09dd171bdcbfe4720fddd574933c66314818dfb3960c8a6246a77"}, - {file = "ijson-3.4.0-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:eda4cfb1d49c6073a901735aaa62e39cb7ab47f3ad7bb184862562f776f1fa8a"}, - {file = "ijson-3.4.0-cp313-cp313t-win32.whl", hash = "sha256:0772638efa1f3b72b51736833404f1cbd2f5beeb9c1a3d392e7d385b9160cba7"}, - {file = "ijson-3.4.0-cp313-cp313t-win_amd64.whl", hash = "sha256:3d8a0d67f36e4fb97c61a724456ef0791504b16ce6f74917a31c2e92309bbeb9"}, - {file = "ijson-3.4.0-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:8a990401dc7350c1739f42187823e68d2ef6964b55040c6e9f3a29461f9929e2"}, - {file = "ijson-3.4.0-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:80f50e0f5da4cd6b65e2d8ff38cb61b26559608a05dd3a3f9cfa6f19848e6f22"}, - {file = "ijson-3.4.0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:2d9ca52f5650d820a2e7aa672dea1c560f609e165337e5b3ed7cf56d696bf309"}, - {file = "ijson-3.4.0-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:940c8c5fd20fb89b56dde9194a4f1c7b779149f1ab26af6d8dc1da51a95d26dd"}, - {file = "ijson-3.4.0-cp39-cp39-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:41dbb525666017ad856ac9b4f0f4b87d3e56b7dfde680d5f6d123556b22e2172"}, - {file = "ijson-3.4.0-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:a9f84f5e2eea5c2d271c97221c382db005534294d1175ddd046a12369617c41c"}, - {file = "ijson-3.4.0-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:c0cd126c11835839bba8ac0baaba568f67d701fc4f717791cf37b10b74a2ebd7"}, - {file = "ijson-3.4.0-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:f9a9d3bbc6d91c24a2524a189d2aca703cb5f7e8eb34ad0aff3c91702404a983"}, - {file = "ijson-3.4.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:56679ee133470d0f1f598a8ad109d760fcfebeef4819531e29335aefb7e4cb1a"}, - {file = "ijson-3.4.0-cp39-cp39-win32.whl", hash = "sha256:583c15ded42ba80104fa1d0fa0dfdd89bb47922f3bb893a931bb843aeb55a3f3"}, - {file = "ijson-3.4.0-cp39-cp39-win_amd64.whl", hash = "sha256:4563e603e56f4451572d96b47311dffef5b933d825f3417881d4d3630c6edac2"}, - {file = "ijson-3.4.0-pp310-pypy310_pp73-macosx_10_15_x86_64.whl", hash = "sha256:54e989c35dba9cf163d532c14bcf0c260897d5f465643f0cd1fba9c908bed7ef"}, - {file = "ijson-3.4.0-pp310-pypy310_pp73-macosx_11_0_arm64.whl", hash = "sha256:494eeb8e87afef22fbb969a4cb81ac2c535f30406f334fb6136e9117b0bb5380"}, - {file = "ijson-3.4.0-pp310-pypy310_pp73-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:81603de95de1688958af65cd2294881a4790edae7de540b70c65c8253c5dc44a"}, - {file = "ijson-3.4.0-pp310-pypy310_pp73-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:8524be12c1773e1be466034cc49c1ecbe3d5b47bb86217bd2a57f73f970a6c19"}, - {file = "ijson-3.4.0-pp310-pypy310_pp73-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:17994696ec895d05e0cfa21b11c68c920c82634b4a3d8b8a1455d6fe9fdee8f7"}, - {file = "ijson-3.4.0-pp310-pypy310_pp73-win_amd64.whl", hash = "sha256:0b67727aaee55d43b2e82b6a866c3cbcb2b66a5e9894212190cbd8773d0d9857"}, - {file = "ijson-3.4.0-pp311-pypy311_pp73-macosx_10_15_x86_64.whl", hash = "sha256:cdc8c5ca0eec789ed99db29c68012dda05027af0860bb360afd28d825238d69d"}, - {file = "ijson-3.4.0-pp311-pypy311_pp73-macosx_11_0_arm64.whl", hash = "sha256:8e6b44b6ec45d5b1a0ee9d97e0e65ab7f62258727004cbbe202bf5f198bc21f7"}, - {file = "ijson-3.4.0-pp311-pypy311_pp73-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:b51e239e4cb537929796e840d349fc731fdc0d58b1a0683ce5465ad725321e0f"}, - {file = "ijson-3.4.0-pp311-pypy311_pp73-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:ed05d43ec02be8ddb1ab59579761f6656b25d241a77fd74f4f0f7ec09074318a"}, - {file = "ijson-3.4.0-pp311-pypy311_pp73-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:cfeca1aaa59d93fd0a3718cbe5f7ef0effff85cf837e0bceb71831a47f39cc14"}, - {file = "ijson-3.4.0-pp311-pypy311_pp73-win_amd64.whl", hash = "sha256:7ca72ca12e9a1dd4252c97d952be34282907f263f7e28fcdff3a01b83981e837"}, - {file = "ijson-3.4.0-pp39-pypy39_pp73-macosx_10_15_x86_64.whl", hash = "sha256:0f79b2cd52bd220fff83b3ee4ef89b54fd897f57cc8564a6d8ab7ac669de3930"}, - {file = "ijson-3.4.0-pp39-pypy39_pp73-macosx_11_0_arm64.whl", hash = "sha256:d16eed737610ad5ad8989b5864fbe09c64133129734e840c29085bb0d497fb03"}, - {file = "ijson-3.4.0-pp39-pypy39_pp73-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:6b3aac1d7a27e1e3bdec5bd0689afe55c34aa499baa06a80852eda31f1ffa6dc"}, - {file = "ijson-3.4.0-pp39-pypy39_pp73-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:784ae654aa9851851e87f323e9429b20b58a5399f83e6a7e348e080f2892081f"}, - {file = "ijson-3.4.0-pp39-pypy39_pp73-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:5d05bd8fa6a8adefb32bbf7b993d2a2f4507db08453dd1a444c281413a6d9685"}, - {file = "ijson-3.4.0-pp39-pypy39_pp73-win_amd64.whl", hash = "sha256:b5a05fd935cc28786b88c16976313086cd96414c6a3eb0a3822c47ab48b1793e"}, - {file = "ijson-3.4.0.tar.gz", hash = "sha256:5f74dcbad9d592c428d3ca3957f7115a42689ee7ee941458860900236ae9bb13"}, + {file = "ijson-3.4.0.post0-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:8f904a405b58a04b6ef0425f1babbc5c65feb66b0a4cc7f214d4ad7de106f77d"}, + {file = "ijson-3.4.0.post0-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:a07dcc1a8a1ddd76131a7c7528cbd12951c2e34eb3c3d63697b905069a2d65b1"}, + {file = "ijson-3.4.0.post0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:ab3be841b8c430c1883b8c0775eb551f21b5500c102c7ee828afa35ddd701bdd"}, + {file = "ijson-3.4.0.post0-cp310-cp310-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:43059ae0d657b11c5ddb11d149bc400c44f9e514fb8663057e9b2ea4d8d44c1f"}, + {file = "ijson-3.4.0.post0-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:0d3e82963096579d1385c06b2559570d7191e225664b7fa049617da838e1a4a4"}, + {file = "ijson-3.4.0.post0-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:461ce4e87a21a261b60c0a68a2ad17c7dd214f0b90a0bec7e559a66b6ae3bd7e"}, + {file = "ijson-3.4.0.post0-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:890cf6610c9554efcb9765a93e368efeb5bb6135f59ce0828d92eaefff07fde5"}, + {file = "ijson-3.4.0.post0-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:6793c29a5728e7751a7df01be58ba7da9b9690c12bf79d32094c70a908fa02b9"}, + {file = "ijson-3.4.0.post0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:a56b6674d7feec0401c91f86c376f4e3d8ff8129128a8ad21ca43ec0b1242f79"}, + {file = "ijson-3.4.0.post0-cp310-cp310-win32.whl", hash = "sha256:01767fcbd75a5fa5a626069787b41f04681216b798510d5f63bcf66884386368"}, + {file = "ijson-3.4.0.post0-cp310-cp310-win_amd64.whl", hash = "sha256:09127c06e5dec753feb9e4b8c5f6a23603d1cd672d098159a17e53a73b898eec"}, + {file = "ijson-3.4.0.post0-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:0b473112e72c0c506da425da3278367b6680f340ecc093084693a1e819d28435"}, + {file = "ijson-3.4.0.post0-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:043f9b7cf9cc744263a78175e769947733710d2412d25180df44b1086b23ebd5"}, + {file = "ijson-3.4.0.post0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:b55e49045f4c8031f3673f56662fd828dc9e8d65bd3b03a9420dda0d370e64ba"}, + {file = "ijson-3.4.0.post0-cp311-cp311-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:11f13b73194ea2a5a8b4a2863f25b0b4624311f10db3a75747b510c4958179b0"}, + {file = "ijson-3.4.0.post0-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:659acb2843433e080c271ecedf7d19c71adde1ee5274fc7faa2fec0a793f9f1c"}, + {file = "ijson-3.4.0.post0-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:deda4cfcaafa72ca3fa845350045b1d0fef9364ec9f413241bb46988afbe6ee6"}, + {file = "ijson-3.4.0.post0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:47352563e8c594360bacee2e0753e97025f0861234722d02faace62b1b6d2b2a"}, + {file = "ijson-3.4.0.post0-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:5a48b9486242d1295abe7fd0fbb6308867da5ca3f69b55c77922a93c2b6847aa"}, + {file = "ijson-3.4.0.post0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:9c0886234d1fae15cf4581a430bdba03d79251c1ab3b07e30aa31b13ef28d01c"}, + {file = "ijson-3.4.0.post0-cp311-cp311-win32.whl", hash = "sha256:fecae19b5187d92900c73debb3a979b0b3290a53f85df1f8f3c5ba7d1e9fb9cb"}, + {file = "ijson-3.4.0.post0-cp311-cp311-win_amd64.whl", hash = "sha256:b39dbf87071f23a23c8077eea2ae7cfeeca9ff9ffec722dfc8b5f352e4dd729c"}, + {file = "ijson-3.4.0.post0-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:b607a500fca26101be47d2baf7cddb457b819ab60a75ce51ed1092a40da8b2f9"}, + {file = "ijson-3.4.0.post0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:4827d9874a6a81625412c59f7ca979a84d01f7f6bfb3c6d4dc4c46d0382b14e0"}, + {file = "ijson-3.4.0.post0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:d4d4afec780881edb2a0d2dd40b1cdbe246e630022d5192f266172a0307986a7"}, + {file = "ijson-3.4.0.post0-cp312-cp312-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:432fb60ffb952926f9438e0539011e2dfcd108f8426ee826ccc6173308c3ff2c"}, + {file = "ijson-3.4.0.post0-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:54a0e3e05d9a0c95ecba73d9579f146cf6d5c5874116c849dba2d39a5f30380e"}, + {file = "ijson-3.4.0.post0-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:05807edc0bcbd222dc6ea32a2b897f0c81dc7f12c8580148bc82f6d7f5e7ec7b"}, + {file = "ijson-3.4.0.post0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:a5269af16f715855d9864937f9dd5c348ca1ac49cee6a2c7a1b7091c159e874f"}, + {file = "ijson-3.4.0.post0-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:b200df83c901f5bfa416d069ac71077aa1608f854a4c50df1b84ced560e9c9ec"}, + {file = "ijson-3.4.0.post0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:6458bd8e679cdff459a0a5e555b107c3bbacb1f382da3fe0f40e392871eb518d"}, + {file = "ijson-3.4.0.post0-cp312-cp312-win32.whl", hash = "sha256:55f7f656b5986326c978cbb3a9eea9e33f3ef6ecc4535b38f1d452c731da39ab"}, + {file = "ijson-3.4.0.post0-cp312-cp312-win_amd64.whl", hash = "sha256:e15833dcf6f6d188fdc624a31cd0520c3ba21b6855dc304bc7c1a8aeca02d4ac"}, + {file = "ijson-3.4.0.post0-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:114ed248166ac06377e87a245a158d6b98019d2bdd3bb93995718e0bd996154f"}, + {file = "ijson-3.4.0.post0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:ffb21203736b08fe27cb30df6a4f802fafb9ef7646c5ff7ef79569b63ea76c57"}, + {file = "ijson-3.4.0.post0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:07f20ecd748602ac7f18c617637e53bd73ded7f3b22260bba3abe401a7fc284e"}, + {file = "ijson-3.4.0.post0-cp313-cp313-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:27aa193d47ffc6bc4e45453896ad98fb089a367e8283b973f1fe5c0198b60b4e"}, + {file = "ijson-3.4.0.post0-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:ccddb2894eb7af162ba43b9475ac5825d15d568832f82eb8783036e5d2aebd42"}, + {file = "ijson-3.4.0.post0-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:61ab0b8c5bf707201dc67e02c116f4b6545c4afd7feb2264b989d242d9c4348a"}, + {file = "ijson-3.4.0.post0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:254cfb8c124af68327a0e7a49b50bbdacafd87c4690a3d62c96eb01020a685ef"}, + {file = "ijson-3.4.0.post0-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:04ac9ca54db20f82aeda6379b5f4f6112fdb150d09ebce04affeab98a17b4ed3"}, + {file = "ijson-3.4.0.post0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:a603d7474bf35e7b3a8e49c8dabfc4751841931301adff3f3318171c4e407f32"}, + {file = "ijson-3.4.0.post0-cp313-cp313-win32.whl", hash = "sha256:ec5bb1520cb212ebead7dba048bb9b70552c3440584f83b01b0abc96862e2a09"}, + {file = "ijson-3.4.0.post0-cp313-cp313-win_amd64.whl", hash = "sha256:3505dff18bdeb8b171eb28af6df34857e2be80dc01e2e3b624e77215ad58897f"}, + {file = "ijson-3.4.0.post0-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:45a0b1c833ed2620eaf8da958f06ac8351c59e5e470e078400d23814670ed708"}, + {file = "ijson-3.4.0.post0-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:7809ec8c8f40228edaaa089f33e811dff4c5b8509702652870d3f286c9682e27"}, + {file = "ijson-3.4.0.post0-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:cf4a34c2cfe852aee75c89c05b0a4531c49dc0be27eeed221afd6fbf9c3e149c"}, + {file = "ijson-3.4.0.post0-cp313-cp313t-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:a39d5d36067604b26b78de70b8951c90e9272450642661fe531a8f7a6936a7fa"}, + {file = "ijson-3.4.0.post0-cp313-cp313t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:83fc738d81c9ea686b452996110b8a6678296c481e0546857db24785bff8da92"}, + {file = "ijson-3.4.0.post0-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:b2a81aee91633868f5b40280e2523f7c5392e920a5082f47c5e991e516b483f6"}, + {file = "ijson-3.4.0.post0-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:56169e298c5a2e7196aaa55da78ddc2415876a74fe6304f81b1eb0d3273346f7"}, + {file = "ijson-3.4.0.post0-cp313-cp313t-musllinux_1_2_i686.whl", hash = "sha256:eeb9540f0b1a575cbb5968166706946458f98c16e7accc6f2fe71efa29864241"}, + {file = "ijson-3.4.0.post0-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:ba3478ff0bb49d7ba88783f491a99b6e3fa929c930ab062d2bb7837e6a38fe88"}, + {file = "ijson-3.4.0.post0-cp313-cp313t-win32.whl", hash = "sha256:b005ce84e82f28b00bf777a464833465dfe3efa43a0a26c77b5ac40723e1a728"}, + {file = "ijson-3.4.0.post0-cp313-cp313t-win_amd64.whl", hash = "sha256:fe9c84c9b1c8798afa407be1cea1603401d99bfc7c34497e19f4f5e5ddc9b441"}, + {file = "ijson-3.4.0.post0-cp314-cp314-macosx_10_13_universal2.whl", hash = "sha256:da6a21b88cbf5ecbc53371283988d22c9643aa71ae2873bbeaefd2dea3b6160b"}, + {file = "ijson-3.4.0.post0-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:cf24a48a1c3ca9d44a04feb59ccefeb9aa52bb49b9cb70ad30518c25cce74bb7"}, + {file = "ijson-3.4.0.post0-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:d14427d366f95f21adcb97d0ed1f6d30f6fdc04d0aa1e4de839152c50c2b8d65"}, + {file = "ijson-3.4.0.post0-cp314-cp314-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:339d49f6c5d24051c85d9226be96d2d56e633cb8b7d09dd8099de8d8b51a97e2"}, + {file = "ijson-3.4.0.post0-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:7206afcb396aaef66c2b066997b4e9d9042c4b7d777f4d994e9cec6d322c2fe6"}, + {file = "ijson-3.4.0.post0-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:c8dd327da225887194fe8b93f2b3c9c256353e14a6b9eefc940ed17fde38f5b8"}, + {file = "ijson-3.4.0.post0-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:4810546e66128af51fd4a0c9a640e84e8508e9c15c4f247d8a3e3253b20e1465"}, + {file = "ijson-3.4.0.post0-cp314-cp314-musllinux_1_2_i686.whl", hash = "sha256:103a0838061297d063bca81d724b0958b616f372bd893bbc278320152252c652"}, + {file = "ijson-3.4.0.post0-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:40007c977e230e04118b27322f25a72ae342a3d61464b2057fcd9b21eeb7427a"}, + {file = "ijson-3.4.0.post0-cp314-cp314-win32.whl", hash = "sha256:f932969fc1fd4449ca141cf5f47ff357656a154a361f28d9ebca0badc5b02297"}, + {file = "ijson-3.4.0.post0-cp314-cp314-win_amd64.whl", hash = "sha256:3ed19b1e4349240773a8ce4a4bfa450892d4a57949c02c515cd6be5a46b7696a"}, + {file = "ijson-3.4.0.post0-cp314-cp314t-macosx_10_13_universal2.whl", hash = "sha256:226447e40ca9340a39ed07d68ea02ee14b52cb4fe649425b256c1f0073531c83"}, + {file = "ijson-3.4.0.post0-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:2c88f0669d45d4b1aa017c9b68d378e7cd15d188dfb6f0209adc78b7f45590a7"}, + {file = "ijson-3.4.0.post0-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:56b3089dc28c12492d92cc4896d2be585a89ecae34e25d08c1df88f21815cb50"}, + {file = "ijson-3.4.0.post0-cp314-cp314t-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:c117321cfa7b749cc1213f9b4c80dc958f0a206df98ec038ae4bcbbdb8463a15"}, + {file = "ijson-3.4.0.post0-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:8311f48db6a33116db5c81682f08b6e2405501a4b4e460193ae69fec3cd1f87a"}, + {file = "ijson-3.4.0.post0-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:91c61a3e63e04da648737e6b4abd537df1b46fb8cdf3219b072e790bb3c1a46b"}, + {file = "ijson-3.4.0.post0-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:1709171023ce82651b2f132575c2e6282e47f64ad67bd3260da476418d0e7895"}, + {file = "ijson-3.4.0.post0-cp314-cp314t-musllinux_1_2_i686.whl", hash = "sha256:5f0a72b1e3c0f78551670c12b2fdc1bf05f2796254d9c2055ba319bec2216020"}, + {file = "ijson-3.4.0.post0-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:b982a3597b0439ce9c8f4cfc929d86c6ed43907908be1e8463a34dc35fe5b258"}, + {file = "ijson-3.4.0.post0-cp314-cp314t-win32.whl", hash = "sha256:4e39bfdc36b0b460ef15a06550a6a385c64c81f7ac205ccff39bd45147918912"}, + {file = "ijson-3.4.0.post0-cp314-cp314t-win_amd64.whl", hash = "sha256:17e45262a5ddef39894013fb1548ee7094e444c8389eb1a97f86708b19bea03e"}, + {file = "ijson-3.4.0.post0-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:35eb2760a42fd9461358b4be131287587b49ff504fc37fa3014dca6c27c343f4"}, + {file = "ijson-3.4.0.post0-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:f82ca7abfb3ef3cf2194c71dad634572bcccd62a5dd466649f78fe73d492c860"}, + {file = "ijson-3.4.0.post0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:97f5ef3d839fc24b0ad47e8b31b4751ae72c5d83606e3ee4c92bb25965c03a4f"}, + {file = "ijson-3.4.0.post0-cp39-cp39-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:a2c873742e9f7e21378516217d81d6fa11d34bae860ed364832c00ab1dbf37ed"}, + {file = "ijson-3.4.0.post0-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:2f8b9ffa2c2dfe3289da9aec4e5ab52684fa2b2da2c853c7891b360ec46fba07"}, + {file = "ijson-3.4.0.post0-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:0634b21188c67e5cf471cc1d30d193d19f521d89e2125ab1fb602aa8ae61e050"}, + {file = "ijson-3.4.0.post0-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:3752dd6f51ef58a71799de745649deff293e959700f1b7f5b1989618da366f24"}, + {file = "ijson-3.4.0.post0-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:57db77f4ea3eca09f519f627d9f9c76eb862b30edef5d899f031feeed94f05a1"}, + {file = "ijson-3.4.0.post0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:435270a4b75667305f6df3226e5224e83cd6906022d7fdcc9df05caae725f796"}, + {file = "ijson-3.4.0.post0-cp39-cp39-win32.whl", hash = "sha256:742c211b004ab51ccad2b301525d8a6eb2cf68a5fb82d78836f3a351eec44d4e"}, + {file = "ijson-3.4.0.post0-cp39-cp39-win_amd64.whl", hash = "sha256:35aaa979da875fa92bea5dc5969b1541b4912b165091761785459a43f0c20946"}, + {file = "ijson-3.4.0.post0-pp311-pypy311_pp73-macosx_10_15_x86_64.whl", hash = "sha256:add9242f886eae844a7410b84aee2bbb8bdc83c624f227cb1fdb2d0476a96cb1"}, + {file = "ijson-3.4.0.post0-pp311-pypy311_pp73-macosx_11_0_arm64.whl", hash = "sha256:69718ed41710dfcaa7564b0af42abc05875d4f7aaa24627c808867ef32634bc7"}, + {file = "ijson-3.4.0.post0-pp311-pypy311_pp73-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:636b6eca96c6c43c04629c6b37fad0181662eaacf9877c71c698485637f752f9"}, + {file = "ijson-3.4.0.post0-pp311-pypy311_pp73-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:eb5e73028f6e63d27b3d286069fe350ed80a4ccc493b022b590fea4bb086710d"}, + {file = "ijson-3.4.0.post0-pp311-pypy311_pp73-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:461acf4320219459dabe5ed90a45cb86c9ba8cc6d6db9dad0d9427d42f57794c"}, + {file = "ijson-3.4.0.post0-pp311-pypy311_pp73-win_amd64.whl", hash = "sha256:a0fedf09c0f6ffa2a99e7e7fd9c5f3caf74e655c1ee015a0797383e99382ebc3"}, + {file = "ijson-3.4.0.post0.tar.gz", hash = "sha256:9aa02dc70bb245670a6ca7fba737b992aeeb4895360980622f7e568dbf23e41e"}, ] [[package]] @@ -2726,26 +2912,6 @@ perf = ["ipython"] test = ["flufl.flake8", "importlib_resources (>=1.3) ; python_version < \"3.9\"", "jaraco.test (>=5.4)", "packaging", "pyfakefs", "pytest (>=6,!=8.1.*)", "pytest-perf (>=0.9.2)"] type = ["pytest-mypy"] -[[package]] -name = "importlib-resources" -version = "6.5.2" -description = "Read resources from Python packages" -optional = false -python-versions = ">=3.9" -groups = ["main"] -files = [ - {file = "importlib_resources-6.5.2-py3-none-any.whl", hash = "sha256:789cfdc3ed28c78b67a06acb8126751ced69a3d5f79c095a98298cd8a760ccec"}, - {file = "importlib_resources-6.5.2.tar.gz", hash = "sha256:185f87adef5bcc288449d98fb4fba07cea78bc036455dd44c5fc4a2fe78fed2c"}, -] - -[package.extras] -check = ["pytest-checkdocs (>=2.4)", "pytest-ruff (>=0.2.1) ; sys_platform != \"cygwin\""] -cover = ["pytest-cov"] -doc = ["furo", "jaraco.packaging (>=9.3)", "jaraco.tidelift (>=1.4)", "rst.linker (>=1.9)", "sphinx (>=3.5)", "sphinx-lint"] -enabler = ["pytest-enabler (>=2.2)"] -test = ["jaraco.test (>=5.4)", "pytest (>=6,!=8.1.*)", "zipp (>=3.17)"] -type = ["pytest-mypy"] - [[package]] name = "iniconfig" version = "2.1.0" @@ -2760,14 +2926,14 @@ files = [ [[package]] name = "invoke" -version = "2.2.0" +version = "2.2.1" description = "Pythonic task execution" optional = false python-versions = ">=3.6" groups = ["main"] files = [ - {file = "invoke-2.2.0-py3-none-any.whl", hash = "sha256:6ea924cc53d4f78e3d98bc436b08069a03077e6f85ad1ddaa8a116d7dad15820"}, - {file = "invoke-2.2.0.tar.gz", hash = "sha256:ee6cbb101af1a859c7fe84f2a264c059020b0cb7fe3535f9424300ab568f6bd5"}, + {file = "invoke-2.2.1-py3-none-any.whl", hash = "sha256:2413bc441b376e5cd3f55bb5d364f973ad8bdd7bf87e53c79de3c11bf3feecc8"}, + {file = "invoke-2.2.1.tar.gz", hash = "sha256:515bf49b4a48932b79b024590348da22f39c4942dff991ad1fb8b8baea1be707"}, ] [[package]] @@ -2817,89 +2983,90 @@ i18n = ["Babel (>=2.7)"] [[package]] name = "jiter" -version = "0.10.0" +version = "0.11.0" description = "Fast iterable JSON parser." optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "jiter-0.10.0-cp310-cp310-macosx_10_12_x86_64.whl", hash = "sha256:cd2fb72b02478f06a900a5782de2ef47e0396b3e1f7d5aba30daeb1fce66f303"}, - {file = "jiter-0.10.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:32bb468e3af278f095d3fa5b90314728a6916d89ba3d0ffb726dd9bf7367285e"}, - {file = "jiter-0.10.0-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:aa8b3e0068c26ddedc7abc6fac37da2d0af16b921e288a5a613f4b86f050354f"}, - {file = "jiter-0.10.0-cp310-cp310-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:286299b74cc49e25cd42eea19b72aa82c515d2f2ee12d11392c56d8701f52224"}, - {file = "jiter-0.10.0-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:6ed5649ceeaeffc28d87fb012d25a4cd356dcd53eff5acff1f0466b831dda2a7"}, - {file = "jiter-0.10.0-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:b2ab0051160cb758a70716448908ef14ad476c3774bd03ddce075f3c1f90a3d6"}, - {file = "jiter-0.10.0-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:03997d2f37f6b67d2f5c475da4412be584e1cec273c1cfc03d642c46db43f8cf"}, - {file = "jiter-0.10.0-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:c404a99352d839fed80d6afd6c1d66071f3bacaaa5c4268983fc10f769112e90"}, - {file = "jiter-0.10.0-cp310-cp310-musllinux_1_1_aarch64.whl", hash = "sha256:66e989410b6666d3ddb27a74c7e50d0829704ede652fd4c858e91f8d64b403d0"}, - {file = "jiter-0.10.0-cp310-cp310-musllinux_1_1_x86_64.whl", hash = "sha256:b532d3af9ef4f6374609a3bcb5e05a1951d3bf6190dc6b176fdb277c9bbf15ee"}, - {file = "jiter-0.10.0-cp310-cp310-win32.whl", hash = "sha256:da9be20b333970e28b72edc4dff63d4fec3398e05770fb3205f7fb460eb48dd4"}, - {file = "jiter-0.10.0-cp310-cp310-win_amd64.whl", hash = "sha256:f59e533afed0c5b0ac3eba20d2548c4a550336d8282ee69eb07b37ea526ee4e5"}, - {file = "jiter-0.10.0-cp311-cp311-macosx_10_12_x86_64.whl", hash = "sha256:3bebe0c558e19902c96e99217e0b8e8b17d570906e72ed8a87170bc290b1e978"}, - {file = "jiter-0.10.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:558cc7e44fd8e507a236bee6a02fa17199ba752874400a0ca6cd6e2196cdb7dc"}, - {file = "jiter-0.10.0-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:4d613e4b379a07d7c8453c5712ce7014e86c6ac93d990a0b8e7377e18505e98d"}, - {file = "jiter-0.10.0-cp311-cp311-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:f62cf8ba0618eda841b9bf61797f21c5ebd15a7a1e19daab76e4e4b498d515b2"}, - {file = "jiter-0.10.0-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:919d139cdfa8ae8945112398511cb7fca58a77382617d279556b344867a37e61"}, - {file = "jiter-0.10.0-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:13ddbc6ae311175a3b03bd8994881bc4635c923754932918e18da841632349db"}, - {file = "jiter-0.10.0-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:4c440ea003ad10927a30521a9062ce10b5479592e8a70da27f21eeb457b4a9c5"}, - {file = "jiter-0.10.0-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:dc347c87944983481e138dea467c0551080c86b9d21de6ea9306efb12ca8f606"}, - {file = "jiter-0.10.0-cp311-cp311-musllinux_1_1_aarch64.whl", hash = "sha256:13252b58c1f4d8c5b63ab103c03d909e8e1e7842d302473f482915d95fefd605"}, - {file = "jiter-0.10.0-cp311-cp311-musllinux_1_1_x86_64.whl", hash = "sha256:7d1bbf3c465de4a24ab12fb7766a0003f6f9bce48b8b6a886158c4d569452dc5"}, - {file = "jiter-0.10.0-cp311-cp311-win32.whl", hash = "sha256:db16e4848b7e826edca4ccdd5b145939758dadf0dc06e7007ad0e9cfb5928ae7"}, - {file = "jiter-0.10.0-cp311-cp311-win_amd64.whl", hash = "sha256:9c9c1d5f10e18909e993f9641f12fe1c77b3e9b533ee94ffa970acc14ded3812"}, - {file = "jiter-0.10.0-cp312-cp312-macosx_10_12_x86_64.whl", hash = "sha256:1e274728e4a5345a6dde2d343c8da018b9d4bd4350f5a472fa91f66fda44911b"}, - {file = "jiter-0.10.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:7202ae396446c988cb2a5feb33a543ab2165b786ac97f53b59aafb803fef0744"}, - {file = "jiter-0.10.0-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:23ba7722d6748b6920ed02a8f1726fb4b33e0fd2f3f621816a8b486c66410ab2"}, - {file = "jiter-0.10.0-cp312-cp312-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:371eab43c0a288537d30e1f0b193bc4eca90439fc08a022dd83e5e07500ed026"}, - {file = "jiter-0.10.0-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:6c675736059020365cebc845a820214765162728b51ab1e03a1b7b3abb70f74c"}, - {file = "jiter-0.10.0-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:0c5867d40ab716e4684858e4887489685968a47e3ba222e44cde6e4a2154f959"}, - {file = "jiter-0.10.0-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:395bb9a26111b60141757d874d27fdea01b17e8fac958b91c20128ba8f4acc8a"}, - {file = "jiter-0.10.0-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:6842184aed5cdb07e0c7e20e5bdcfafe33515ee1741a6835353bb45fe5d1bd95"}, - {file = "jiter-0.10.0-cp312-cp312-musllinux_1_1_aarch64.whl", hash = "sha256:62755d1bcea9876770d4df713d82606c8c1a3dca88ff39046b85a048566d56ea"}, - {file = "jiter-0.10.0-cp312-cp312-musllinux_1_1_x86_64.whl", hash = "sha256:533efbce2cacec78d5ba73a41756beff8431dfa1694b6346ce7af3a12c42202b"}, - {file = "jiter-0.10.0-cp312-cp312-win32.whl", hash = "sha256:8be921f0cadd245e981b964dfbcd6fd4bc4e254cdc069490416dd7a2632ecc01"}, - {file = "jiter-0.10.0-cp312-cp312-win_amd64.whl", hash = "sha256:a7c7d785ae9dda68c2678532a5a1581347e9c15362ae9f6e68f3fdbfb64f2e49"}, - {file = "jiter-0.10.0-cp313-cp313-macosx_10_12_x86_64.whl", hash = "sha256:e0588107ec8e11b6f5ef0e0d656fb2803ac6cf94a96b2b9fc675c0e3ab5e8644"}, - {file = "jiter-0.10.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:cafc4628b616dc32530c20ee53d71589816cf385dd9449633e910d596b1f5c8a"}, - {file = "jiter-0.10.0-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:520ef6d981172693786a49ff5b09eda72a42e539f14788124a07530f785c3ad6"}, - {file = "jiter-0.10.0-cp313-cp313-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:554dedfd05937f8fc45d17ebdf298fe7e0c77458232bcb73d9fbbf4c6455f5b3"}, - {file = "jiter-0.10.0-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:5bc299da7789deacf95f64052d97f75c16d4fc8c4c214a22bf8d859a4288a1c2"}, - {file = "jiter-0.10.0-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:5161e201172de298a8a1baad95eb85db4fb90e902353b1f6a41d64ea64644e25"}, - {file = "jiter-0.10.0-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:2e2227db6ba93cb3e2bf67c87e594adde0609f146344e8207e8730364db27041"}, - {file = "jiter-0.10.0-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:15acb267ea5e2c64515574b06a8bf393fbfee6a50eb1673614aa45f4613c0cca"}, - {file = "jiter-0.10.0-cp313-cp313-musllinux_1_1_aarch64.whl", hash = "sha256:901b92f2e2947dc6dfcb52fd624453862e16665ea909a08398dde19c0731b7f4"}, - {file = "jiter-0.10.0-cp313-cp313-musllinux_1_1_x86_64.whl", hash = "sha256:d0cb9a125d5a3ec971a094a845eadde2db0de85b33c9f13eb94a0c63d463879e"}, - {file = "jiter-0.10.0-cp313-cp313-win32.whl", hash = "sha256:48a403277ad1ee208fb930bdf91745e4d2d6e47253eedc96e2559d1e6527006d"}, - {file = "jiter-0.10.0-cp313-cp313-win_amd64.whl", hash = "sha256:75f9eb72ecb640619c29bf714e78c9c46c9c4eaafd644bf78577ede459f330d4"}, - {file = "jiter-0.10.0-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:28ed2a4c05a1f32ef0e1d24c2611330219fed727dae01789f4a335617634b1ca"}, - {file = "jiter-0.10.0-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:14a4c418b1ec86a195f1ca69da8b23e8926c752b685af665ce30777233dfe070"}, - {file = "jiter-0.10.0-cp313-cp313t-win_amd64.whl", hash = "sha256:d7bfed2fe1fe0e4dda6ef682cee888ba444b21e7a6553e03252e4feb6cf0adca"}, - {file = "jiter-0.10.0-cp314-cp314-macosx_10_12_x86_64.whl", hash = "sha256:5e9251a5e83fab8d87799d3e1a46cb4b7f2919b895c6f4483629ed2446f66522"}, - {file = "jiter-0.10.0-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:023aa0204126fe5b87ccbcd75c8a0d0261b9abdbbf46d55e7ae9f8e22424eeb8"}, - {file = "jiter-0.10.0-cp314-cp314-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:3c189c4f1779c05f75fc17c0c1267594ed918996a231593a21a5ca5438445216"}, - {file = "jiter-0.10.0-cp314-cp314-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:15720084d90d1098ca0229352607cd68256c76991f6b374af96f36920eae13c4"}, - {file = "jiter-0.10.0-cp314-cp314-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:e4f2fb68e5f1cfee30e2b2a09549a00683e0fde4c6a2ab88c94072fc33cb7426"}, - {file = "jiter-0.10.0-cp314-cp314-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:ce541693355fc6da424c08b7edf39a2895f58d6ea17d92cc2b168d20907dee12"}, - {file = "jiter-0.10.0-cp314-cp314-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:31c50c40272e189d50006ad5c73883caabb73d4e9748a688b216e85a9a9ca3b9"}, - {file = "jiter-0.10.0-cp314-cp314-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:fa3402a2ff9815960e0372a47b75c76979d74402448509ccd49a275fa983ef8a"}, - {file = "jiter-0.10.0-cp314-cp314-musllinux_1_1_aarch64.whl", hash = "sha256:1956f934dca32d7bb647ea21d06d93ca40868b505c228556d3373cbd255ce853"}, - {file = "jiter-0.10.0-cp314-cp314-musllinux_1_1_x86_64.whl", hash = "sha256:fcedb049bdfc555e261d6f65a6abe1d5ad68825b7202ccb9692636c70fcced86"}, - {file = "jiter-0.10.0-cp314-cp314-win32.whl", hash = "sha256:ac509f7eccca54b2a29daeb516fb95b6f0bd0d0d8084efaf8ed5dfc7b9f0b357"}, - {file = "jiter-0.10.0-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:5ed975b83a2b8639356151cef5c0d597c68376fc4922b45d0eb384ac058cfa00"}, - {file = "jiter-0.10.0-cp314-cp314t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:3aa96f2abba33dc77f79b4cf791840230375f9534e5fac927ccceb58c5e604a5"}, - {file = "jiter-0.10.0-cp39-cp39-macosx_10_12_x86_64.whl", hash = "sha256:bd6292a43c0fc09ce7c154ec0fa646a536b877d1e8f2f96c19707f65355b5a4d"}, - {file = "jiter-0.10.0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:39de429dcaeb6808d75ffe9effefe96a4903c6a4b376b2f6d08d77c1aaee2f18"}, - {file = "jiter-0.10.0-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:52ce124f13a7a616fad3bb723f2bfb537d78239d1f7f219566dc52b6f2a9e48d"}, - {file = "jiter-0.10.0-cp39-cp39-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:166f3606f11920f9a1746b2eea84fa2c0a5d50fd313c38bdea4edc072000b0af"}, - {file = "jiter-0.10.0-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:28dcecbb4ba402916034fc14eba7709f250c4d24b0c43fc94d187ee0580af181"}, - {file = "jiter-0.10.0-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:86c5aa6910f9bebcc7bc4f8bc461aff68504388b43bfe5e5c0bd21efa33b52f4"}, - {file = "jiter-0.10.0-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:ceeb52d242b315d7f1f74b441b6a167f78cea801ad7c11c36da77ff2d42e8a28"}, - {file = "jiter-0.10.0-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:ff76d8887c8c8ee1e772274fcf8cc1071c2c58590d13e33bd12d02dc9a560397"}, - {file = "jiter-0.10.0-cp39-cp39-musllinux_1_1_aarch64.whl", hash = "sha256:a9be4d0fa2b79f7222a88aa488bd89e2ae0a0a5b189462a12def6ece2faa45f1"}, - {file = "jiter-0.10.0-cp39-cp39-musllinux_1_1_x86_64.whl", hash = "sha256:9ab7fd8738094139b6c1ab1822d6f2000ebe41515c537235fd45dabe13ec9324"}, - {file = "jiter-0.10.0-cp39-cp39-win32.whl", hash = "sha256:5f51e048540dd27f204ff4a87f5d79294ea0aa3aa552aca34934588cf27023cf"}, - {file = "jiter-0.10.0-cp39-cp39-win_amd64.whl", hash = "sha256:1b28302349dc65703a9e4ead16f163b1c339efffbe1049c30a44b001a2a4fff9"}, - {file = "jiter-0.10.0.tar.gz", hash = "sha256:07a7142c38aacc85194391108dc91b5b57093c978a9932bd86a36862759d9500"}, + {file = "jiter-0.11.0-cp310-cp310-macosx_10_12_x86_64.whl", hash = "sha256:3893ce831e1c0094a83eeaf56c635a167d6fa8cc14393cc14298fd6fdc2a2449"}, + {file = "jiter-0.11.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:25c625b9b61b5a8725267fdf867ef2e51b429687f6a4eef211f4612e95607179"}, + {file = "jiter-0.11.0-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:dd4ca85fb6a62cf72e1c7f5e34ddef1b660ce4ed0886ec94a1ef9777d35eaa1f"}, + {file = "jiter-0.11.0-cp310-cp310-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:572208127034725e79c28437b82414028c3562335f2b4f451d98136d0fc5f9cd"}, + {file = "jiter-0.11.0-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:494ba627c7f550ad3dabb21862864b8f2216098dc18ff62f37b37796f2f7c325"}, + {file = "jiter-0.11.0-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:b8da18a99f58bca3ecc2d2bba99cac000a924e115b6c4f0a2b98f752b6fbf39a"}, + {file = "jiter-0.11.0-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:e4ffd3b0fff3fabbb02cc09910c08144db6bb5697a98d227a074401e01ee63dd"}, + {file = "jiter-0.11.0-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:8fe6530aa738a4f7d4e4702aa8f9581425d04036a5f9e25af65ebe1f708f23be"}, + {file = "jiter-0.11.0-cp310-cp310-musllinux_1_1_aarch64.whl", hash = "sha256:e35d66681c133a03d7e974e7eedae89720fe8ca3bd09f01a4909b86a8adf31f5"}, + {file = "jiter-0.11.0-cp310-cp310-musllinux_1_1_x86_64.whl", hash = "sha256:c59459beca2fbc9718b6f1acb7bfb59ebc3eb4294fa4d40e9cb679dafdcc6c60"}, + {file = "jiter-0.11.0-cp310-cp310-win32.whl", hash = "sha256:b7b0178417b0dcfc5f259edbc6db2b1f5896093ed9035ee7bab0f2be8854726d"}, + {file = "jiter-0.11.0-cp310-cp310-win_amd64.whl", hash = "sha256:11df2bf99fb4754abddd7f5d940a48e51f9d11624d6313ca4314145fcad347f0"}, + {file = "jiter-0.11.0-cp311-cp311-macosx_10_12_x86_64.whl", hash = "sha256:cb5d9db02979c3f49071fce51a48f4b4e4cf574175fb2b11c7a535fa4867b222"}, + {file = "jiter-0.11.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:1dc6a123f3471c4730db7ca8ba75f1bb3dcb6faeb8d46dd781083e7dee88b32d"}, + {file = "jiter-0.11.0-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:09858f8d230f031c7b8e557429102bf050eea29c77ad9c34c8fe253c5329acb7"}, + {file = "jiter-0.11.0-cp311-cp311-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:dbe2196c4a0ce760925a74ab4456bf644748ab0979762139626ad138f6dac72d"}, + {file = "jiter-0.11.0-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:5beb56d22b63647bafd0b74979216fdee80c580c0c63410be8c11053860ffd09"}, + {file = "jiter-0.11.0-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:97025d09ef549795d8dc720a824312cee3253c890ac73c621721ddfc75066789"}, + {file = "jiter-0.11.0-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:d50880a6da65d8c23a2cf53c412847d9757e74cc9a3b95c5704a1d1a24667347"}, + {file = "jiter-0.11.0-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:452d80a1c86c095a242007bd9fc5d21b8a8442307193378f891cb8727e469648"}, + {file = "jiter-0.11.0-cp311-cp311-musllinux_1_1_aarch64.whl", hash = "sha256:e84e58198d4894668eec2da660ffff60e0f3e60afa790ecc50cb12b0e02ca1d4"}, + {file = "jiter-0.11.0-cp311-cp311-musllinux_1_1_x86_64.whl", hash = "sha256:df64edcfc5dd5279a791eea52aa113d432c933119a025b0b5739f90d2e4e75f1"}, + {file = "jiter-0.11.0-cp311-cp311-win32.whl", hash = "sha256:144fc21337d21b1d048f7f44bf70881e1586401d405ed3a98c95a114a9994982"}, + {file = "jiter-0.11.0-cp311-cp311-win_amd64.whl", hash = "sha256:b0f32e644d241293b892b1a6dd8f0b9cc029bfd94c97376b2681c36548aabab7"}, + {file = "jiter-0.11.0-cp312-cp312-macosx_10_12_x86_64.whl", hash = "sha256:2fb7b377688cc3850bbe5c192a6bd493562a0bc50cbc8b047316428fbae00ada"}, + {file = "jiter-0.11.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:a1b7cbe3f25bd0d8abb468ba4302a5d45617ee61b2a7a638f63fee1dc086be99"}, + {file = "jiter-0.11.0-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:c0a7f0ec81d5b7588c5cade1eb1925b91436ae6726dc2df2348524aeabad5de6"}, + {file = "jiter-0.11.0-cp312-cp312-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:07630bb46ea2a6b9c6ed986c6e17e35b26148cce2c535454b26ee3f0e8dcaba1"}, + {file = "jiter-0.11.0-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:7764f27d28cd4a9cbc61704dfcd80c903ce3aad106a37902d3270cd6673d17f4"}, + {file = "jiter-0.11.0-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:1d4a6c4a737d486f77f842aeb22807edecb4a9417e6700c7b981e16d34ba7c72"}, + {file = "jiter-0.11.0-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:cf408d2a0abd919b60de8c2e7bc5eeab72d4dafd18784152acc7c9adc3291591"}, + {file = "jiter-0.11.0-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:cdef53eda7d18e799625023e1e250dbc18fbc275153039b873ec74d7e8883e09"}, + {file = "jiter-0.11.0-cp312-cp312-musllinux_1_1_aarch64.whl", hash = "sha256:53933a38ef7b551dd9c7f1064f9d7bb235bb3168d0fa5f14f0798d1b7ea0d9c5"}, + {file = "jiter-0.11.0-cp312-cp312-musllinux_1_1_x86_64.whl", hash = "sha256:11840d2324c9ab5162fc1abba23bc922124fedcff0d7b7f85fffa291e2f69206"}, + {file = "jiter-0.11.0-cp312-cp312-win32.whl", hash = "sha256:4f01a744d24a5f2bb4a11657a1b27b61dc038ae2e674621a74020406e08f749b"}, + {file = "jiter-0.11.0-cp312-cp312-win_amd64.whl", hash = "sha256:29fff31190ab3a26de026da2f187814f4b9c6695361e20a9ac2123e4d4378a4c"}, + {file = "jiter-0.11.0-cp313-cp313-macosx_10_12_x86_64.whl", hash = "sha256:4441a91b80a80249f9a6452c14b2c24708f139f64de959943dfeaa6cb915e8eb"}, + {file = "jiter-0.11.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:ff85fc6d2a431251ad82dbd1ea953affb5a60376b62e7d6809c5cd058bb39471"}, + {file = "jiter-0.11.0-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:c5e86126d64706fd28dfc46f910d496923c6f95b395138c02d0e252947f452bd"}, + {file = "jiter-0.11.0-cp313-cp313-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:4ad8bd82165961867a10f52010590ce0b7a8c53da5ddd8bbb62fef68c181b921"}, + {file = "jiter-0.11.0-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:b42c2cd74273455ce439fd9528db0c6e84b5623cb74572305bdd9f2f2961d3df"}, + {file = "jiter-0.11.0-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:f0062dab98172dd0599fcdbf90214d0dcde070b1ff38a00cc1b90e111f071982"}, + {file = "jiter-0.11.0-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:bb948402821bc76d1f6ef0f9e19b816f9b09f8577844ba7140f0b6afe994bc64"}, + {file = "jiter-0.11.0-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:25a5b1110cca7329fd0daf5060faa1234be5c11e988948e4f1a1923b6a457fe1"}, + {file = "jiter-0.11.0-cp313-cp313-musllinux_1_1_aarch64.whl", hash = "sha256:bf11807e802a214daf6c485037778843fadd3e2ec29377ae17e0706ec1a25758"}, + {file = "jiter-0.11.0-cp313-cp313-musllinux_1_1_x86_64.whl", hash = "sha256:dbb57da40631c267861dd0090461222060960012d70fd6e4c799b0f62d0ba166"}, + {file = "jiter-0.11.0-cp313-cp313-win32.whl", hash = "sha256:8e36924dad32c48d3c5e188d169e71dc6e84d6cb8dedefea089de5739d1d2f80"}, + {file = "jiter-0.11.0-cp313-cp313-win_amd64.whl", hash = "sha256:452d13e4fd59698408087235259cebe67d9d49173b4dacb3e8d35ce4acf385d6"}, + {file = "jiter-0.11.0-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:089f9df9f69532d1339e83142438668f52c97cd22ee2d1195551c2b1a9e6cf33"}, + {file = "jiter-0.11.0-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:29ed1fe69a8c69bf0f2a962d8d706c7b89b50f1332cd6b9fbda014f60bd03a03"}, + {file = "jiter-0.11.0-cp313-cp313t-win_amd64.whl", hash = "sha256:a4d71d7ea6ea8786291423fe209acf6f8d398a0759d03e7f24094acb8ab686ba"}, + {file = "jiter-0.11.0-cp314-cp314-macosx_10_12_x86_64.whl", hash = "sha256:9a6dff27eca70930bdbe4cbb7c1a4ba8526e13b63dc808c0670083d2d51a4a72"}, + {file = "jiter-0.11.0-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:b1ae2a7593a62132c7d4c2abbee80bbbb94fdc6d157e2c6cc966250c564ef774"}, + {file = "jiter-0.11.0-cp314-cp314-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:7b13a431dba4b059e9e43019d3022346d009baf5066c24dcdea321a303cde9f0"}, + {file = "jiter-0.11.0-cp314-cp314-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:af62e84ca3889604ebb645df3b0a3f3bcf6b92babbff642bd214616f57abb93a"}, + {file = "jiter-0.11.0-cp314-cp314-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:c6f3b32bb723246e6b351aecace52aba78adb8eeb4b2391630322dc30ff6c773"}, + {file = "jiter-0.11.0-cp314-cp314-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:adcab442f4a099a358a7f562eaa54ed6456fb866e922c6545a717be51dbed7d7"}, + {file = "jiter-0.11.0-cp314-cp314-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:c9967c2ab338ee2b2c0102fd379ec2693c496abf71ffd47e4d791d1f593b68e2"}, + {file = "jiter-0.11.0-cp314-cp314-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:e7d0bed3b187af8b47a981d9742ddfc1d9b252a7235471ad6078e7e4e5fe75c2"}, + {file = "jiter-0.11.0-cp314-cp314-musllinux_1_1_aarch64.whl", hash = "sha256:f6fe0283e903ebc55f1a6cc569b8c1f3bf4abd026fed85e3ff8598a9e6f982f0"}, + {file = "jiter-0.11.0-cp314-cp314-musllinux_1_1_x86_64.whl", hash = "sha256:4ee5821e3d66606b29ae5b497230b304f1376f38137d69e35f8d2bd5f310ff73"}, + {file = "jiter-0.11.0-cp314-cp314-win32.whl", hash = "sha256:c2d13ba7567ca8799f17c76ed56b1d49be30df996eb7fa33e46b62800562a5e2"}, + {file = "jiter-0.11.0-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:fb4790497369d134a07fc763cc88888c46f734abdd66f9fdf7865038bf3a8f40"}, + {file = "jiter-0.11.0-cp314-cp314t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:6e2bbf24f16ba5ad4441a9845e40e4ea0cb9eed00e76ba94050664ef53ef4406"}, + {file = "jiter-0.11.0-cp39-cp39-macosx_10_12_x86_64.whl", hash = "sha256:719891c2fb7628a41adff4f2f54c19380a27e6fdfdb743c24680ef1a54c67bd0"}, + {file = "jiter-0.11.0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:df7f1927cbdf34cb91262a5418ca06920fd42f1cf733936d863aeb29b45a14ef"}, + {file = "jiter-0.11.0-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:e71ae6d969d0c9bab336c5e9e2fabad31e74d823f19e3604eaf96d9a97f463df"}, + {file = "jiter-0.11.0-cp39-cp39-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:5661469a7b2be25ade3a4bb6c21ffd1e142e13351a0759f264dfdd3ad99af1ab"}, + {file = "jiter-0.11.0-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:76c15ef0d3d02f8b389066fa4c410a0b89e9cc6468a1f0674c5925d2f3c3e890"}, + {file = "jiter-0.11.0-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:63782a1350917a27817030716566ed3d5b3c731500fd42d483cbd7094e2c5b25"}, + {file = "jiter-0.11.0-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:5a7092b699646a1ddc03a7b112622d9c066172627c7382659befb0d2996f1659"}, + {file = "jiter-0.11.0-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:f637b8e818f6d75540f350a6011ce21252573c0998ea1b4365ee54b7672c23c5"}, + {file = "jiter-0.11.0-cp39-cp39-musllinux_1_1_aarch64.whl", hash = "sha256:a624d87719e1b5d09c15286eaee7e1532a40c692a096ea7ca791121365f548c1"}, + {file = "jiter-0.11.0-cp39-cp39-musllinux_1_1_x86_64.whl", hash = "sha256:a9d0146d8d9b3995821bb586fc8256636258947c2f39da5bab709f3a28fb1a0b"}, + {file = "jiter-0.11.0-cp39-cp39-win32.whl", hash = "sha256:d067655a7cf0831eb8ec3e39cbd752995e9b69a2206df3535b3a067fac23b032"}, + {file = "jiter-0.11.0-cp39-cp39-win_amd64.whl", hash = "sha256:f05d03775a11aaf132c447436983169958439f1219069abf24662a672851f94e"}, + {file = "jiter-0.11.0-graalpy311-graalpy242_311_native-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:902b43386c04739229076bd1c4c69de5d115553d982ab442a8ae82947c72ede7"}, + {file = "jiter-0.11.0.tar.gz", hash = "sha256:1d9637eaf8c1d6a63d6562f2a6e5ab3af946c66037eb1b894e8fad75422266e4"}, ] [[package]] @@ -2916,14 +3083,14 @@ files = [ [[package]] name = "joblib" -version = "1.5.1" +version = "1.5.2" description = "Lightweight pipelining with Python functions" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "joblib-1.5.1-py3-none-any.whl", hash = "sha256:4719a31f054c7d766948dcd83e9613686b27114f190f717cec7eaa2084f8a74a"}, - {file = "joblib-1.5.1.tar.gz", hash = "sha256:f4f86e351f39fe3d0d32a9f2c3d8af1ee4cec285aafcb27003dda5205576b444"}, + {file = "joblib-1.5.2-py3-none-any.whl", hash = "sha256:4e1f0bdbb987e6d843c70cf43714cb276623def372df3c22fe5266b2670bc241"}, + {file = "joblib-1.5.2.tar.gz", hash = "sha256:3faa5c39054b2f03ca547da9b2f52fde67c06240c31853f306aea97f13647b55"}, ] [[package]] @@ -3029,14 +3196,14 @@ files = [ [[package]] name = "jsonschema" -version = "4.25.0" +version = "4.25.1" description = "An implementation of JSON Schema validation for Python" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "jsonschema-4.25.0-py3-none-any.whl", hash = "sha256:24c2e8da302de79c8b9382fee3e76b355e44d2a4364bb207159ce10b517bd716"}, - {file = "jsonschema-4.25.0.tar.gz", hash = "sha256:e63acf5c11762c0e6672ffb61482bdf57f0876684d8d249c0fe2d730d48bc55f"}, + {file = "jsonschema-4.25.1-py3-none-any.whl", hash = "sha256:3fba0169e345c7175110351d456342c364814cfcf3b964ba4587f22915230a63"}, + {file = "jsonschema-4.25.1.tar.gz", hash = "sha256:e4a9655ce0da0c0b67a085847e00a3a51449e1157f4f75e9fb5aa545e122eb85"}, ] [package.dependencies] @@ -3059,14 +3226,14 @@ format-nongpl = ["fqdn", "idna", "isoduration", "jsonpointer (>1.13)", "rfc3339- [[package]] name = "jsonschema-specifications" -version = "2025.4.1" +version = "2025.9.1" description = "The JSON Schema meta-schemas and vocabularies, exposed as a Registry" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "jsonschema_specifications-2025.4.1-py3-none-any.whl", hash = "sha256:4653bffbd6584f7de83a67e0d620ef16900b390ddc7939d56684d6c81e33f1af"}, - {file = "jsonschema_specifications-2025.4.1.tar.gz", hash = "sha256:630159c9f4dbea161a6a2205c3011cc4f18ff381b189fff48bb39b9bf26ae608"}, + {file = "jsonschema_specifications-2025.9.1-py3-none-any.whl", hash = "sha256:98802fee3a11ee76ecaca44429fda8a41bff98b00a0f2838151b113f210cc6fe"}, + {file = "jsonschema_specifications-2025.9.1.tar.gz", hash = "sha256:b540987f239e745613c7a9176f3edb72b832a4ac465cf02712288397832b5e8d"}, ] [package.dependencies] @@ -3108,104 +3275,125 @@ prefixmaps = ">=0.2.0,<0.3.0" [[package]] name = "kiwisolver" -version = "1.4.8" +version = "1.4.9" description = "A fast implementation of the Cassowary constraint solver" optional = false python-versions = ">=3.10" groups = ["main"] files = [ - {file = "kiwisolver-1.4.8-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:88c6f252f6816a73b1f8c904f7bbe02fd67c09a69f7cb8a0eecdbf5ce78e63db"}, - {file = "kiwisolver-1.4.8-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:c72941acb7b67138f35b879bbe85be0f6c6a70cab78fe3ef6db9c024d9223e5b"}, - {file = "kiwisolver-1.4.8-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:ce2cf1e5688edcb727fdf7cd1bbd0b6416758996826a8be1d958f91880d0809d"}, - {file = "kiwisolver-1.4.8-cp310-cp310-manylinux_2_12_i686.manylinux2010_i686.whl", hash = "sha256:c8bf637892dc6e6aad2bc6d4d69d08764166e5e3f69d469e55427b6ac001b19d"}, - {file = "kiwisolver-1.4.8-cp310-cp310-manylinux_2_12_x86_64.manylinux2010_x86_64.whl", hash = "sha256:034d2c891f76bd3edbdb3ea11140d8510dca675443da7304205a2eaa45d8334c"}, - {file = "kiwisolver-1.4.8-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:d47b28d1dfe0793d5e96bce90835e17edf9a499b53969b03c6c47ea5985844c3"}, - {file = "kiwisolver-1.4.8-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:eb158fe28ca0c29f2260cca8c43005329ad58452c36f0edf298204de32a9a3ed"}, - {file = "kiwisolver-1.4.8-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:d5536185fce131780ebd809f8e623bf4030ce1b161353166c49a3c74c287897f"}, - {file = "kiwisolver-1.4.8-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:369b75d40abedc1da2c1f4de13f3482cb99e3237b38726710f4a793432b1c5ff"}, - {file = "kiwisolver-1.4.8-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:641f2ddf9358c80faa22e22eb4c9f54bd3f0e442e038728f500e3b978d00aa7d"}, - {file = "kiwisolver-1.4.8-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:d561d2d8883e0819445cfe58d7ddd673e4015c3c57261d7bdcd3710d0d14005c"}, - {file = "kiwisolver-1.4.8-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:1732e065704b47c9afca7ffa272f845300a4eb959276bf6970dc07265e73b605"}, - {file = "kiwisolver-1.4.8-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:bcb1ebc3547619c3b58a39e2448af089ea2ef44b37988caf432447374941574e"}, - {file = "kiwisolver-1.4.8-cp310-cp310-win_amd64.whl", hash = "sha256:89c107041f7b27844179ea9c85d6da275aa55ecf28413e87624d033cf1f6b751"}, - {file = "kiwisolver-1.4.8-cp310-cp310-win_arm64.whl", hash = "sha256:b5773efa2be9eb9fcf5415ea3ab70fc785d598729fd6057bea38d539ead28271"}, - {file = "kiwisolver-1.4.8-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:a4d3601908c560bdf880f07d94f31d734afd1bb71e96585cace0e38ef44c6d84"}, - {file = "kiwisolver-1.4.8-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:856b269c4d28a5c0d5e6c1955ec36ebfd1651ac00e1ce0afa3e28da95293b561"}, - {file = "kiwisolver-1.4.8-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:c2b9a96e0f326205af81a15718a9073328df1173a2619a68553decb7097fd5d7"}, - {file = "kiwisolver-1.4.8-cp311-cp311-manylinux_2_12_i686.manylinux2010_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:c5020c83e8553f770cb3b5fc13faac40f17e0b205bd237aebd21d53d733adb03"}, - {file = "kiwisolver-1.4.8-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:dace81d28c787956bfbfbbfd72fdcef014f37d9b48830829e488fdb32b49d954"}, - {file = "kiwisolver-1.4.8-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:11e1022b524bd48ae56c9b4f9296bce77e15a2e42a502cceba602f804b32bb79"}, - {file = "kiwisolver-1.4.8-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:3b9b4d2892fefc886f30301cdd80debd8bb01ecdf165a449eb6e78f79f0fabd6"}, - {file = "kiwisolver-1.4.8-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:3a96c0e790ee875d65e340ab383700e2b4891677b7fcd30a699146f9384a2bb0"}, - {file = "kiwisolver-1.4.8-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:23454ff084b07ac54ca8be535f4174170c1094a4cff78fbae4f73a4bcc0d4dab"}, - {file = "kiwisolver-1.4.8-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:87b287251ad6488e95b4f0b4a79a6d04d3ea35fde6340eb38fbd1ca9cd35bbbc"}, - {file = "kiwisolver-1.4.8-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:b21dbe165081142b1232a240fc6383fd32cdd877ca6cc89eab93e5f5883e1c25"}, - {file = "kiwisolver-1.4.8-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:768cade2c2df13db52475bd28d3a3fac8c9eff04b0e9e2fda0f3760f20b3f7fc"}, - {file = "kiwisolver-1.4.8-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:d47cfb2650f0e103d4bf68b0b5804c68da97272c84bb12850d877a95c056bd67"}, - {file = "kiwisolver-1.4.8-cp311-cp311-win_amd64.whl", hash = "sha256:ed33ca2002a779a2e20eeb06aea7721b6e47f2d4b8a8ece979d8ba9e2a167e34"}, - {file = "kiwisolver-1.4.8-cp311-cp311-win_arm64.whl", hash = "sha256:16523b40aab60426ffdebe33ac374457cf62863e330a90a0383639ce14bf44b2"}, - {file = "kiwisolver-1.4.8-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:d6af5e8815fd02997cb6ad9bbed0ee1e60014438ee1a5c2444c96f87b8843502"}, - {file = "kiwisolver-1.4.8-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:bade438f86e21d91e0cf5dd7c0ed00cda0f77c8c1616bd83f9fc157fa6760d31"}, - {file = "kiwisolver-1.4.8-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:b83dc6769ddbc57613280118fb4ce3cd08899cc3369f7d0e0fab518a7cf37fdb"}, - {file = "kiwisolver-1.4.8-cp312-cp312-manylinux_2_12_i686.manylinux2010_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:111793b232842991be367ed828076b03d96202c19221b5ebab421ce8bcad016f"}, - {file = "kiwisolver-1.4.8-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:257af1622860e51b1a9d0ce387bf5c2c4f36a90594cb9514f55b074bcc787cfc"}, - {file = "kiwisolver-1.4.8-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:69b5637c3f316cab1ec1c9a12b8c5f4750a4c4b71af9157645bf32830e39c03a"}, - {file = "kiwisolver-1.4.8-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:782bb86f245ec18009890e7cb8d13a5ef54dcf2ebe18ed65f795e635a96a1c6a"}, - {file = "kiwisolver-1.4.8-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:cc978a80a0db3a66d25767b03688f1147a69e6237175c0f4ffffaaedf744055a"}, - {file = "kiwisolver-1.4.8-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:36dbbfd34838500a31f52c9786990d00150860e46cd5041386f217101350f0d3"}, - {file = "kiwisolver-1.4.8-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:eaa973f1e05131de5ff3569bbba7f5fd07ea0595d3870ed4a526d486fe57fa1b"}, - {file = "kiwisolver-1.4.8-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:a66f60f8d0c87ab7f59b6fb80e642ebb29fec354a4dfad687ca4092ae69d04f4"}, - {file = "kiwisolver-1.4.8-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:858416b7fb777a53f0c59ca08190ce24e9abbd3cffa18886a5781b8e3e26f65d"}, - {file = "kiwisolver-1.4.8-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:085940635c62697391baafaaeabdf3dd7a6c3643577dde337f4d66eba021b2b8"}, - {file = "kiwisolver-1.4.8-cp312-cp312-win_amd64.whl", hash = "sha256:01c3d31902c7db5fb6182832713d3b4122ad9317c2c5877d0539227d96bb2e50"}, - {file = "kiwisolver-1.4.8-cp312-cp312-win_arm64.whl", hash = "sha256:a3c44cb68861de93f0c4a8175fbaa691f0aa22550c331fefef02b618a9dcb476"}, - {file = "kiwisolver-1.4.8-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:1c8ceb754339793c24aee1c9fb2485b5b1f5bb1c2c214ff13368431e51fc9a09"}, - {file = "kiwisolver-1.4.8-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:54a62808ac74b5e55a04a408cda6156f986cefbcf0ada13572696b507cc92fa1"}, - {file = "kiwisolver-1.4.8-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:68269e60ee4929893aad82666821aaacbd455284124817af45c11e50a4b42e3c"}, - {file = "kiwisolver-1.4.8-cp313-cp313-manylinux_2_12_i686.manylinux2010_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:34d142fba9c464bc3bbfeff15c96eab0e7310343d6aefb62a79d51421fcc5f1b"}, - {file = "kiwisolver-1.4.8-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:3ddc373e0eef45b59197de815b1b28ef89ae3955e7722cc9710fb91cd77b7f47"}, - {file = "kiwisolver-1.4.8-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:77e6f57a20b9bd4e1e2cedda4d0b986ebd0216236f0106e55c28aea3d3d69b16"}, - {file = "kiwisolver-1.4.8-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:08e77738ed7538f036cd1170cbed942ef749137b1311fa2bbe2a7fda2f6bf3cc"}, - {file = "kiwisolver-1.4.8-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:a5ce1e481a74b44dd5e92ff03ea0cb371ae7a0268318e202be06c8f04f4f1246"}, - {file = "kiwisolver-1.4.8-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:fc2ace710ba7c1dfd1a3b42530b62b9ceed115f19a1656adefce7b1782a37794"}, - {file = "kiwisolver-1.4.8-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:3452046c37c7692bd52b0e752b87954ef86ee2224e624ef7ce6cb21e8c41cc1b"}, - {file = "kiwisolver-1.4.8-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:7e9a60b50fe8b2ec6f448fe8d81b07e40141bfced7f896309df271a0b92f80f3"}, - {file = "kiwisolver-1.4.8-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:918139571133f366e8362fa4a297aeba86c7816b7ecf0bc79168080e2bd79957"}, - {file = "kiwisolver-1.4.8-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:e063ef9f89885a1d68dd8b2e18f5ead48653176d10a0e324e3b0030e3a69adeb"}, - {file = "kiwisolver-1.4.8-cp313-cp313-win_amd64.whl", hash = "sha256:a17b7c4f5b2c51bb68ed379defd608a03954a1845dfed7cc0117f1cc8a9b7fd2"}, - {file = "kiwisolver-1.4.8-cp313-cp313-win_arm64.whl", hash = "sha256:3cd3bc628b25f74aedc6d374d5babf0166a92ff1317f46267f12d2ed54bc1d30"}, - {file = "kiwisolver-1.4.8-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:370fd2df41660ed4e26b8c9d6bbcad668fbe2560462cba151a721d49e5b6628c"}, - {file = "kiwisolver-1.4.8-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:84a2f830d42707de1d191b9490ac186bf7997a9495d4e9072210a1296345f7dc"}, - {file = "kiwisolver-1.4.8-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:7a3ad337add5148cf51ce0b55642dc551c0b9d6248458a757f98796ca7348712"}, - {file = "kiwisolver-1.4.8-cp313-cp313t-manylinux_2_12_i686.manylinux2010_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:7506488470f41169b86d8c9aeff587293f530a23a23a49d6bc64dab66bedc71e"}, - {file = "kiwisolver-1.4.8-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:2f0121b07b356a22fb0414cec4666bbe36fd6d0d759db3d37228f496ed67c880"}, - {file = "kiwisolver-1.4.8-cp313-cp313t-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:d6d6bd87df62c27d4185de7c511c6248040afae67028a8a22012b010bc7ad062"}, - {file = "kiwisolver-1.4.8-cp313-cp313t-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:291331973c64bb9cce50bbe871fb2e675c4331dab4f31abe89f175ad7679a4d7"}, - {file = "kiwisolver-1.4.8-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:893f5525bb92d3d735878ec00f781b2de998333659507d29ea4466208df37bed"}, - {file = "kiwisolver-1.4.8-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:b47a465040146981dc9db8647981b8cb96366fbc8d452b031e4f8fdffec3f26d"}, - {file = "kiwisolver-1.4.8-cp313-cp313t-musllinux_1_2_i686.whl", hash = "sha256:99cea8b9dd34ff80c521aef46a1dddb0dcc0283cf18bde6d756f1e6f31772165"}, - {file = "kiwisolver-1.4.8-cp313-cp313t-musllinux_1_2_ppc64le.whl", hash = "sha256:151dffc4865e5fe6dafce5480fab84f950d14566c480c08a53c663a0020504b6"}, - {file = "kiwisolver-1.4.8-cp313-cp313t-musllinux_1_2_s390x.whl", hash = "sha256:577facaa411c10421314598b50413aa1ebcf5126f704f1e5d72d7e4e9f020d90"}, - {file = "kiwisolver-1.4.8-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:be4816dc51c8a471749d664161b434912eee82f2ea66bd7628bd14583a833e85"}, - {file = "kiwisolver-1.4.8-pp310-pypy310_pp73-macosx_10_15_x86_64.whl", hash = "sha256:e7a019419b7b510f0f7c9dceff8c5eae2392037eae483a7f9162625233802b0a"}, - {file = "kiwisolver-1.4.8-pp310-pypy310_pp73-macosx_11_0_arm64.whl", hash = "sha256:286b18e86682fd2217a48fc6be6b0f20c1d0ed10958d8dc53453ad58d7be0bf8"}, - {file = "kiwisolver-1.4.8-pp310-pypy310_pp73-manylinux_2_12_i686.manylinux2010_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:4191ee8dfd0be1c3666ccbac178c5a05d5f8d689bbe3fc92f3c4abec817f8fe0"}, - {file = "kiwisolver-1.4.8-pp310-pypy310_pp73-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:7cd2785b9391f2873ad46088ed7599a6a71e762e1ea33e87514b1a441ed1da1c"}, - {file = "kiwisolver-1.4.8-pp310-pypy310_pp73-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:c07b29089b7ba090b6f1a669f1411f27221c3662b3a1b7010e67b59bb5a6f10b"}, - {file = "kiwisolver-1.4.8-pp310-pypy310_pp73-win_amd64.whl", hash = "sha256:65ea09a5a3faadd59c2ce96dc7bf0f364986a315949dc6374f04396b0d60e09b"}, - {file = "kiwisolver-1.4.8.tar.gz", hash = "sha256:23d5f023bdc8c7e54eb65f03ca5d5bb25b601eac4d7f1a042888a1f45237987e"}, + {file = "kiwisolver-1.4.9-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:b4b4d74bda2b8ebf4da5bd42af11d02d04428b2c32846e4c2c93219df8a7987b"}, + {file = "kiwisolver-1.4.9-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:fb3b8132019ea572f4611d770991000d7f58127560c4889729248eb5852a102f"}, + {file = "kiwisolver-1.4.9-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:84fd60810829c27ae375114cd379da1fa65e6918e1da405f356a775d49a62bcf"}, + {file = "kiwisolver-1.4.9-cp310-cp310-manylinux_2_12_x86_64.manylinux2010_x86_64.whl", hash = "sha256:b78efa4c6e804ecdf727e580dbb9cba85624d2e1c6b5cb059c66290063bd99a9"}, + {file = "kiwisolver-1.4.9-cp310-cp310-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:d4efec7bcf21671db6a3294ff301d2fc861c31faa3c8740d1a94689234d1b415"}, + {file = "kiwisolver-1.4.9-cp310-cp310-manylinux_2_24_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:90f47e70293fc3688b71271100a1a5453aa9944a81d27ff779c108372cf5567b"}, + {file = "kiwisolver-1.4.9-cp310-cp310-manylinux_2_24_s390x.manylinux_2_28_s390x.whl", hash = "sha256:8fdca1def57a2e88ef339de1737a1449d6dbf5fab184c54a1fca01d541317154"}, + {file = "kiwisolver-1.4.9-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:9cf554f21be770f5111a1690d42313e140355e687e05cf82cb23d0a721a64a48"}, + {file = "kiwisolver-1.4.9-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:fc1795ac5cd0510207482c3d1d3ed781143383b8cfd36f5c645f3897ce066220"}, + {file = "kiwisolver-1.4.9-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:ccd09f20ccdbbd341b21a67ab50a119b64a403b09288c27481575105283c1586"}, + {file = "kiwisolver-1.4.9-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:540c7c72324d864406a009d72f5d6856f49693db95d1fbb46cf86febef873634"}, + {file = "kiwisolver-1.4.9-cp310-cp310-win_amd64.whl", hash = "sha256:ede8c6d533bc6601a47ad4046080d36b8fc99f81e6f1c17b0ac3c2dc91ac7611"}, + {file = "kiwisolver-1.4.9-cp310-cp310-win_arm64.whl", hash = "sha256:7b4da0d01ac866a57dd61ac258c5607b4cd677f63abaec7b148354d2b2cdd536"}, + {file = "kiwisolver-1.4.9-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:eb14a5da6dc7642b0f3a18f13654847cd8b7a2550e2645a5bda677862b03ba16"}, + {file = "kiwisolver-1.4.9-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:39a219e1c81ae3b103643d2aedb90f1ef22650deb266ff12a19e7773f3e5f089"}, + {file = "kiwisolver-1.4.9-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:2405a7d98604b87f3fc28b1716783534b1b4b8510d8142adca34ee0bc3c87543"}, + {file = "kiwisolver-1.4.9-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:dc1ae486f9abcef254b5618dfb4113dd49f94c68e3e027d03cf0143f3f772b61"}, + {file = "kiwisolver-1.4.9-cp311-cp311-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:8a1f570ce4d62d718dce3f179ee78dac3b545ac16c0c04bb363b7607a949c0d1"}, + {file = "kiwisolver-1.4.9-cp311-cp311-manylinux_2_24_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:cb27e7b78d716c591e88e0a09a2139c6577865d7f2e152488c2cc6257f460872"}, + {file = "kiwisolver-1.4.9-cp311-cp311-manylinux_2_24_s390x.manylinux_2_28_s390x.whl", hash = "sha256:15163165efc2f627eb9687ea5f3a28137217d217ac4024893d753f46bce9de26"}, + {file = "kiwisolver-1.4.9-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:bdee92c56a71d2b24c33a7d4c2856bd6419d017e08caa7802d2963870e315028"}, + {file = "kiwisolver-1.4.9-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:412f287c55a6f54b0650bd9b6dce5aceddb95864a1a90c87af16979d37c89771"}, + {file = "kiwisolver-1.4.9-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:2c93f00dcba2eea70af2be5f11a830a742fe6b579a1d4e00f47760ef13be247a"}, + {file = "kiwisolver-1.4.9-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:f117e1a089d9411663a3207ba874f31be9ac8eaa5b533787024dc07aeb74f464"}, + {file = "kiwisolver-1.4.9-cp311-cp311-win_amd64.whl", hash = "sha256:be6a04e6c79819c9a8c2373317d19a96048e5a3f90bec587787e86a1153883c2"}, + {file = "kiwisolver-1.4.9-cp311-cp311-win_arm64.whl", hash = "sha256:0ae37737256ba2de764ddc12aed4956460277f00c4996d51a197e72f62f5eec7"}, + {file = "kiwisolver-1.4.9-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:ac5a486ac389dddcc5bef4f365b6ae3ffff2c433324fb38dd35e3fab7c957999"}, + {file = "kiwisolver-1.4.9-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:f2ba92255faa7309d06fe44c3a4a97efe1c8d640c2a79a5ef728b685762a6fd2"}, + {file = "kiwisolver-1.4.9-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:4a2899935e724dd1074cb568ce7ac0dce28b2cd6ab539c8e001a8578eb106d14"}, + {file = "kiwisolver-1.4.9-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:f6008a4919fdbc0b0097089f67a1eb55d950ed7e90ce2cc3e640abadd2757a04"}, + {file = "kiwisolver-1.4.9-cp312-cp312-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:67bb8b474b4181770f926f7b7d2f8c0248cbcb78b660fdd41a47054b28d2a752"}, + {file = "kiwisolver-1.4.9-cp312-cp312-manylinux_2_24_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:2327a4a30d3ee07d2fbe2e7933e8a37c591663b96ce42a00bc67461a87d7df77"}, + {file = "kiwisolver-1.4.9-cp312-cp312-manylinux_2_24_s390x.manylinux_2_28_s390x.whl", hash = "sha256:7a08b491ec91b1d5053ac177afe5290adacf1f0f6307d771ccac5de30592d198"}, + {file = "kiwisolver-1.4.9-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:d8fc5c867c22b828001b6a38d2eaeb88160bf5783c6cb4a5e440efc981ce286d"}, + {file = "kiwisolver-1.4.9-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:3b3115b2581ea35bb6d1f24a4c90af37e5d9b49dcff267eeed14c3893c5b86ab"}, + {file = "kiwisolver-1.4.9-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:858e4c22fb075920b96a291928cb7dea5644e94c0ee4fcd5af7e865655e4ccf2"}, + {file = "kiwisolver-1.4.9-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:ed0fecd28cc62c54b262e3736f8bb2512d8dcfdc2bcf08be5f47f96bf405b145"}, + {file = "kiwisolver-1.4.9-cp312-cp312-win_amd64.whl", hash = "sha256:f68208a520c3d86ea51acf688a3e3002615a7f0238002cccc17affecc86a8a54"}, + {file = "kiwisolver-1.4.9-cp312-cp312-win_arm64.whl", hash = "sha256:2c1a4f57df73965f3f14df20b80ee29e6a7930a57d2d9e8491a25f676e197c60"}, + {file = "kiwisolver-1.4.9-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:a5d0432ccf1c7ab14f9949eec60c5d1f924f17c037e9f8b33352fa05799359b8"}, + {file = "kiwisolver-1.4.9-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:efb3a45b35622bb6c16dbfab491a8f5a391fe0e9d45ef32f4df85658232ca0e2"}, + {file = "kiwisolver-1.4.9-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:1a12cf6398e8a0a001a059747a1cbf24705e18fe413bc22de7b3d15c67cffe3f"}, + {file = "kiwisolver-1.4.9-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:b67e6efbf68e077dd71d1a6b37e43e1a99d0bff1a3d51867d45ee8908b931098"}, + {file = "kiwisolver-1.4.9-cp313-cp313-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:5656aa670507437af0207645273ccdfee4f14bacd7f7c67a4306d0dcaeaf6eed"}, + {file = "kiwisolver-1.4.9-cp313-cp313-manylinux_2_24_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:bfc08add558155345129c7803b3671cf195e6a56e7a12f3dde7c57d9b417f525"}, + {file = "kiwisolver-1.4.9-cp313-cp313-manylinux_2_24_s390x.manylinux_2_28_s390x.whl", hash = "sha256:40092754720b174e6ccf9e845d0d8c7d8e12c3d71e7fc35f55f3813e96376f78"}, + {file = "kiwisolver-1.4.9-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:497d05f29a1300d14e02e6441cf0f5ee81c1ff5a304b0d9fb77423974684e08b"}, + {file = "kiwisolver-1.4.9-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:bdd1a81a1860476eb41ac4bc1e07b3f07259e6d55bbf739b79c8aaedcf512799"}, + {file = "kiwisolver-1.4.9-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:e6b93f13371d341afee3be9f7c5964e3fe61d5fa30f6a30eb49856935dfe4fc3"}, + {file = "kiwisolver-1.4.9-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:d75aa530ccfaa593da12834b86a0724f58bff12706659baa9227c2ccaa06264c"}, + {file = "kiwisolver-1.4.9-cp313-cp313-win_amd64.whl", hash = "sha256:dd0a578400839256df88c16abddf9ba14813ec5f21362e1fe65022e00c883d4d"}, + {file = "kiwisolver-1.4.9-cp313-cp313-win_arm64.whl", hash = "sha256:d4188e73af84ca82468f09cadc5ac4db578109e52acb4518d8154698d3a87ca2"}, + {file = "kiwisolver-1.4.9-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:5a0f2724dfd4e3b3ac5a82436a8e6fd16baa7d507117e4279b660fe8ca38a3a1"}, + {file = "kiwisolver-1.4.9-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:1b11d6a633e4ed84fc0ddafd4ebfd8ea49b3f25082c04ad12b8315c11d504dc1"}, + {file = "kiwisolver-1.4.9-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:61874cdb0a36016354853593cffc38e56fc9ca5aa97d2c05d3dcf6922cd55a11"}, + {file = "kiwisolver-1.4.9-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:60c439763a969a6af93b4881db0eed8fadf93ee98e18cbc35bc8da868d0c4f0c"}, + {file = "kiwisolver-1.4.9-cp313-cp313t-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:92a2f997387a1b79a75e7803aa7ded2cfbe2823852ccf1ba3bcf613b62ae3197"}, + {file = "kiwisolver-1.4.9-cp313-cp313t-manylinux_2_24_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:a31d512c812daea6d8b3be3b2bfcbeb091dbb09177706569bcfc6240dcf8b41c"}, + {file = "kiwisolver-1.4.9-cp313-cp313t-manylinux_2_24_s390x.manylinux_2_28_s390x.whl", hash = "sha256:52a15b0f35dad39862d376df10c5230155243a2c1a436e39eb55623ccbd68185"}, + {file = "kiwisolver-1.4.9-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:a30fd6fdef1430fd9e1ba7b3398b5ee4e2887783917a687d86ba69985fb08748"}, + {file = "kiwisolver-1.4.9-cp313-cp313t-musllinux_1_2_ppc64le.whl", hash = "sha256:cc9617b46837c6468197b5945e196ee9ca43057bb7d9d1ae688101e4e1dddf64"}, + {file = "kiwisolver-1.4.9-cp313-cp313t-musllinux_1_2_s390x.whl", hash = "sha256:0ab74e19f6a2b027ea4f845a78827969af45ce790e6cb3e1ebab71bdf9f215ff"}, + {file = "kiwisolver-1.4.9-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:dba5ee5d3981160c28d5490f0d1b7ed730c22470ff7f6cc26cfcfaacb9896a07"}, + {file = "kiwisolver-1.4.9-cp313-cp313t-win_arm64.whl", hash = "sha256:0749fd8f4218ad2e851e11cc4dc05c7cbc0cbc4267bdfdb31782e65aace4ee9c"}, + {file = "kiwisolver-1.4.9-cp314-cp314-macosx_10_13_universal2.whl", hash = "sha256:9928fe1eb816d11ae170885a74d074f57af3a0d65777ca47e9aeb854a1fba386"}, + {file = "kiwisolver-1.4.9-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:d0005b053977e7b43388ddec89fa567f43d4f6d5c2c0affe57de5ebf290dc552"}, + {file = "kiwisolver-1.4.9-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:2635d352d67458b66fd0667c14cb1d4145e9560d503219034a18a87e971ce4f3"}, + {file = "kiwisolver-1.4.9-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:767c23ad1c58c9e827b649a9ab7809fd5fd9db266a9cf02b0e926ddc2c680d58"}, + {file = "kiwisolver-1.4.9-cp314-cp314-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:72d0eb9fba308b8311685c2268cf7d0a0639a6cd027d8128659f72bdd8a024b4"}, + {file = "kiwisolver-1.4.9-cp314-cp314-manylinux_2_24_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:f68e4f3eeca8fb22cc3d731f9715a13b652795ef657a13df1ad0c7dc0e9731df"}, + {file = "kiwisolver-1.4.9-cp314-cp314-manylinux_2_24_s390x.manylinux_2_28_s390x.whl", hash = "sha256:d84cd4061ae292d8ac367b2c3fa3aad11cb8625a95d135fe93f286f914f3f5a6"}, + {file = "kiwisolver-1.4.9-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:a60ea74330b91bd22a29638940d115df9dc00af5035a9a2a6ad9399ffb4ceca5"}, + {file = "kiwisolver-1.4.9-cp314-cp314-musllinux_1_2_ppc64le.whl", hash = "sha256:ce6a3a4e106cf35c2d9c4fa17c05ce0b180db622736845d4315519397a77beaf"}, + {file = "kiwisolver-1.4.9-cp314-cp314-musllinux_1_2_s390x.whl", hash = "sha256:77937e5e2a38a7b48eef0585114fe7930346993a88060d0bf886086d2aa49ef5"}, + {file = "kiwisolver-1.4.9-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:24c175051354f4a28c5d6a31c93906dc653e2bf234e8a4bbfb964892078898ce"}, + {file = "kiwisolver-1.4.9-cp314-cp314-win_amd64.whl", hash = "sha256:0763515d4df10edf6d06a3c19734e2566368980d21ebec439f33f9eb936c07b7"}, + {file = "kiwisolver-1.4.9-cp314-cp314-win_arm64.whl", hash = "sha256:0e4e2bf29574a6a7b7f6cb5fa69293b9f96c928949ac4a53ba3f525dffb87f9c"}, + {file = "kiwisolver-1.4.9-cp314-cp314t-macosx_10_13_universal2.whl", hash = "sha256:d976bbb382b202f71c67f77b0ac11244021cfa3f7dfd9e562eefcea2df711548"}, + {file = "kiwisolver-1.4.9-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:2489e4e5d7ef9a1c300a5e0196e43d9c739f066ef23270607d45aba368b91f2d"}, + {file = "kiwisolver-1.4.9-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:e2ea9f7ab7fbf18fffb1b5434ce7c69a07582f7acc7717720f1d69f3e806f90c"}, + {file = "kiwisolver-1.4.9-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:b34e51affded8faee0dfdb705416153819d8ea9250bbbf7ea1b249bdeb5f1122"}, + {file = "kiwisolver-1.4.9-cp314-cp314t-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:d8aacd3d4b33b772542b2e01beb50187536967b514b00003bdda7589722d2a64"}, + {file = "kiwisolver-1.4.9-cp314-cp314t-manylinux_2_24_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:7cf974dd4e35fa315563ac99d6287a1024e4dc2077b8a7d7cd3d2fb65d283134"}, + {file = "kiwisolver-1.4.9-cp314-cp314t-manylinux_2_24_s390x.manylinux_2_28_s390x.whl", hash = "sha256:85bd218b5ecfbee8c8a82e121802dcb519a86044c9c3b2e4aef02fa05c6da370"}, + {file = "kiwisolver-1.4.9-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:0856e241c2d3df4efef7c04a1e46b1936b6120c9bcf36dd216e3acd84bc4fb21"}, + {file = "kiwisolver-1.4.9-cp314-cp314t-musllinux_1_2_ppc64le.whl", hash = "sha256:9af39d6551f97d31a4deebeac6f45b156f9755ddc59c07b402c148f5dbb6482a"}, + {file = "kiwisolver-1.4.9-cp314-cp314t-musllinux_1_2_s390x.whl", hash = "sha256:bb4ae2b57fc1d8cbd1cf7b1d9913803681ffa903e7488012be5b76dedf49297f"}, + {file = "kiwisolver-1.4.9-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:aedff62918805fb62d43a4aa2ecd4482c380dc76cd31bd7c8878588a61bd0369"}, + {file = "kiwisolver-1.4.9-cp314-cp314t-win_amd64.whl", hash = "sha256:1fa333e8b2ce4d9660f2cda9c0e1b6bafcfb2457a9d259faa82289e73ec24891"}, + {file = "kiwisolver-1.4.9-cp314-cp314t-win_arm64.whl", hash = "sha256:4a48a2ce79d65d363597ef7b567ce3d14d68783d2b2263d98db3d9477805ba32"}, + {file = "kiwisolver-1.4.9-pp310-pypy310_pp73-macosx_10_15_x86_64.whl", hash = "sha256:4d1d9e582ad4d63062d34077a9a1e9f3c34088a2ec5135b1f7190c07cf366527"}, + {file = "kiwisolver-1.4.9-pp310-pypy310_pp73-macosx_11_0_arm64.whl", hash = "sha256:deed0c7258ceb4c44ad5ec7d9918f9f14fd05b2be86378d86cf50e63d1e7b771"}, + {file = "kiwisolver-1.4.9-pp310-pypy310_pp73-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:0a590506f303f512dff6b7f75fd2fd18e16943efee932008fe7140e5fa91d80e"}, + {file = "kiwisolver-1.4.9-pp310-pypy310_pp73-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:e09c2279a4d01f099f52d5c4b3d9e208e91edcbd1a175c9662a8b16e000fece9"}, + {file = "kiwisolver-1.4.9-pp310-pypy310_pp73-win_amd64.whl", hash = "sha256:c9e7cdf45d594ee04d5be1b24dd9d49f3d1590959b2271fb30b5ca2b262c00fb"}, + {file = "kiwisolver-1.4.9-pp311-pypy311_pp73-macosx_10_15_x86_64.whl", hash = "sha256:720e05574713db64c356e86732c0f3c5252818d05f9df320f0ad8380641acea5"}, + {file = "kiwisolver-1.4.9-pp311-pypy311_pp73-macosx_11_0_arm64.whl", hash = "sha256:17680d737d5335b552994a2008fab4c851bcd7de33094a82067ef3a576ff02fa"}, + {file = "kiwisolver-1.4.9-pp311-pypy311_pp73-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:85b5352f94e490c028926ea567fc569c52ec79ce131dadb968d3853e809518c2"}, + {file = "kiwisolver-1.4.9-pp311-pypy311_pp73-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:464415881e4801295659462c49461a24fb107c140de781d55518c4b80cb6790f"}, + {file = "kiwisolver-1.4.9-pp311-pypy311_pp73-win_amd64.whl", hash = "sha256:fb940820c63a9590d31d88b815e7a3aa5915cad3ce735ab45f0c730b39547de1"}, + {file = "kiwisolver-1.4.9.tar.gz", hash = "sha256:c3b22c26c6fd6811b0ae8363b95ca8ce4ea3c202d3d0975b2914310ceb1bcc4d"}, ] [[package]] name = "lark" -version = "1.2.2" +version = "1.3.0" description = "a modern parsing library" optional = false python-versions = ">=3.8" groups = ["main"] files = [ - {file = "lark-1.2.2-py3-none-any.whl", hash = "sha256:c2276486b02f0f1b90be155f2c8ba4a8e194d42775786db622faccd652d8e80c"}, - {file = "lark-1.2.2.tar.gz", hash = "sha256:ca807d0162cd16cef15a8feecb862d7319e7a09bdb13aef927968e45040fed80"}, + {file = "lark-1.3.0-py3-none-any.whl", hash = "sha256:80661f261fb2584a9828a097a2432efd575af27d20be0fd35d17f0fe37253831"}, + {file = "lark-1.3.0.tar.gz", hash = "sha256:9a3839d0ca5e1faf7cfa3460e420e859b66bcbde05b634e73c369c8244c5fa48"}, ] [package.extras] @@ -3228,43 +3416,42 @@ files = [ [[package]] name = "limits" -version = "5.4.0" +version = "5.6.0" description = "Rate limiting utilities" optional = false python-versions = ">=3.10" groups = ["main"] files = [ - {file = "limits-5.4.0-py3-none-any.whl", hash = "sha256:1afb03c0624cf004085532aa9524953f2565cf8b0a914e48dda89d172c13ceb7"}, - {file = "limits-5.4.0.tar.gz", hash = "sha256:27ebf55118e3c9045f0dbc476f4559b26d42f4b043db670afb8963f36cf07fd9"}, + {file = "limits-5.6.0-py3-none-any.whl", hash = "sha256:b585c2104274528536a5b68864ec3835602b3c4a802cd6aa0b07419798394021"}, + {file = "limits-5.6.0.tar.gz", hash = "sha256:807fac75755e73912e894fdd61e2838de574c5721876a19f7ab454ae1fffb4b5"}, ] [package.dependencies] deprecated = ">=1.2" -packaging = ">=21,<26" -typing_extensions = "*" +packaging = ">=21" +typing-extensions = "*" [package.extras] -all = ["coredis (>=3.4.0,<5)", "memcachio (>=0.3)", "motor (>=3,<4)", "pymemcache (>3,<5.0.0)", "pymongo (>4.1,<5)", "redis (>3,!=4.5.2,!=4.5.3,<6.0.0)", "redis (>=4.2.0,!=4.5.2,!=4.5.3)", "valkey (>=6)", "valkey (>=6)"] async-memcached = ["memcachio (>=0.3)"] async-mongodb = ["motor (>=3,<4)"] -async-redis = ["coredis (>=3.4.0,<5)"] +async-redis = ["coredis (>=3.4.0,<6)"] async-valkey = ["valkey (>=6)"] memcached = ["pymemcache (>3,<5.0.0)"] mongodb = ["pymongo (>4.1,<5)"] -redis = ["redis (>3,!=4.5.2,!=4.5.3,<6.0.0)"] +redis = ["redis (>3,!=4.5.2,!=4.5.3,<7.0.0)"] rediscluster = ["redis (>=4.2.0,!=4.5.2,!=4.5.3)"] valkey = ["valkey (>=6)"] [[package]] name = "linkml" -version = "1.9.2" +version = "1.9.3" description = "Linked Open Data Modeling Language" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "linkml-1.9.2-py3-none-any.whl", hash = "sha256:4c9cf217948367df8a20cdf68e8f6da24ba23ab97a551f8ae32e9d4264e702cc"}, - {file = "linkml-1.9.2.tar.gz", hash = "sha256:2f9141d2bc8a93bfe1d4b86a015ad0acbb94c2af099177f5687a50d3331d2b34"}, + {file = "linkml-1.9.3-py3-none-any.whl", hash = "sha256:77f2e566ce03f897bc0a9dc49d4d933a859d2a78ef56f080c9a0f8415becb884"}, + {file = "linkml-1.9.3.tar.gz", hash = "sha256:96de208001dae5bde43092ce0f3fab61df4c85231939476dc3f93d0b5b0d4590"}, ] [package.dependencies] @@ -3276,7 +3463,7 @@ isodate = ">=0.6.0" jinja2 = ">=3.1.0" jsonasobj2 = ">=1.0.3,<2.0.0" jsonschema = {version = ">=4.0.0", extras = ["format"]} -linkml-runtime = ">=1.9.2,<2.0.0" +linkml-runtime = ">=1.9.4,<2.0.0" openpyxl = "*" parse = "*" prefixcommons = ">=0.1.7" @@ -3322,14 +3509,14 @@ pydantic = "*" [[package]] name = "linkml-runtime" -version = "1.9.4" +version = "1.9.5" description = "Runtime environment for LinkML, the Linked open data modeling language" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "linkml_runtime-1.9.4-py3-none-any.whl", hash = "sha256:df54f38ea836da97a7f7e61375241d898f37f18a7a4b1f890c181dcf03998e90"}, - {file = "linkml_runtime-1.9.4.tar.gz", hash = "sha256:ac8f01aa4f92eb32ca377bf15ce42dad63fc2d2201e08e2b955896e34016075b"}, + {file = "linkml_runtime-1.9.5-py3-none-any.whl", hash = "sha256:fece3e8aa25a4246165c6528b6a7fe83a929b985d2ce1951cc8a0f4da1a30b90"}, + {file = "linkml_runtime-1.9.5.tar.gz", hash = "sha256:78dc1383adf11ad5f20bb11b6adde56ed566fbd2429a292d57699ad4596c738a"}, ] [package.dependencies] @@ -3401,14 +3588,13 @@ validation = ["linkml (>=1.8.0)"] [[package]] name = "litellm" -version = "1.74.7" +version = "1.74.15.post2" description = "Library to easily interface with LLM API providers" optional = false python-versions = "!=2.7.*,!=3.0.*,!=3.1.*,!=3.2.*,!=3.3.*,!=3.4.*,!=3.5.*,!=3.6.*,!=3.7.*,>=3.8" groups = ["main"] files = [ - {file = "litellm-1.74.7-py3-none-any.whl", hash = "sha256:d630785faf07813cf0d5e9fb0bb84aaa18aa728297858c58c56f34c0b9190df1"}, - {file = "litellm-1.74.7.tar.gz", hash = "sha256:53b809a342154d8543ea96422cf962cd5ea9df293f83dab0cc63b27baadf0ece"}, + {file = "litellm-1.74.15.post2.tar.gz", hash = "sha256:8eddb1c8a6a5a7048f8ba16e652aba23d6ca996dd87cb853c874ba375aa32479"}, ] [package.dependencies] @@ -3427,19 +3613,21 @@ tokenizers = "*" [package.extras] caching = ["diskcache (>=5.6.1,<6.0.0)"] extra-proxy = ["azure-identity (>=1.15.0,<2.0.0)", "azure-keyvault-secrets (>=4.8.0,<5.0.0)", "google-cloud-kms (>=2.21.3,<3.0.0)", "prisma (==0.11.0)", "redisvl (>=0.4.1,<0.5.0) ; python_version >= \"3.9\" and python_version < \"3.14\"", "resend (>=0.8.0,<0.9.0)"] -proxy = ["PyJWT (>=2.8.0,<3.0.0)", "apscheduler (>=3.10.4,<4.0.0)", "azure-identity (>=1.15.0,<2.0.0)", "azure-storage-blob (>=12.25.1,<13.0.0)", "backoff", "boto3 (==1.34.34)", "cryptography (>=43.0.1,<44.0.0)", "fastapi (>=0.115.5,<0.116.0)", "fastapi-sso (>=0.16.0,<0.17.0)", "gunicorn (>=23.0.0,<24.0.0)", "litellm-enterprise (==0.1.15)", "litellm-proxy-extras (==0.2.11)", "mcp (==1.10.0) ; python_version >= \"3.10\"", "orjson (>=3.9.7,<4.0.0)", "pynacl (>=1.5.0,<2.0.0)", "python-multipart (>=0.0.18,<0.0.19)", "pyyaml (>=6.0.1,<7.0.0)", "rich (==13.7.1)", "rq", "uvicorn (>=0.29.0,<0.30.0)", "uvloop (>=0.21.0,<0.22.0) ; sys_platform != \"win32\"", "websockets (>=13.1.0,<14.0.0)"] +mlflow = ["mlflow (>3.1.4) ; python_version >= \"3.10\""] +proxy = ["PyJWT (>=2.8.0,<3.0.0)", "apscheduler (>=3.10.4,<4.0.0)", "azure-identity (>=1.15.0,<2.0.0)", "azure-storage-blob (>=12.25.1,<13.0.0)", "backoff", "boto3 (==1.34.34)", "cryptography (>=43.0.1,<44.0.0)", "fastapi (>=0.115.5,<0.116.0)", "fastapi-sso (>=0.16.0,<0.17.0)", "gunicorn (>=23.0.0,<24.0.0)", "litellm-enterprise (==0.1.16)", "litellm-proxy-extras (==0.2.16)", "mcp (>=1.10.0,<2.0.0) ; python_version >= \"3.10\"", "orjson (>=3.9.7,<4.0.0)", "polars (>=1.31.0,<2.0.0) ; python_version >= \"3.10\"", "pynacl (>=1.5.0,<2.0.0)", "python-multipart (>=0.0.18,<0.0.19)", "pyyaml (>=6.0.1,<7.0.0)", "rich (==13.7.1)", "rq", "uvicorn (>=0.29.0,<0.30.0)", "uvloop (>=0.21.0,<0.22.0) ; sys_platform != \"win32\"", "websockets (>=13.1.0,<14.0.0)"] +semantic-router = ["semantic-router ; python_version >= \"3.9\""] utils = ["numpydoc"] [[package]] name = "llm" -version = "0.26" +version = "0.27.1" description = "CLI utility and Python library for interacting with Large Language Models from organizations like OpenAI, Anthropic and Gemini plus local models installed on your own machine." optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "llm-0.26-py3-none-any.whl", hash = "sha256:93dc331facbfb909f946df8812fb1d627ec9ce764aab2ebd29f9011ed647339c"}, - {file = "llm-0.26.tar.gz", hash = "sha256:c2e9ddbc582da10c61112c0f983383fa0dc7bee3ca7d6f2ade1a2d003771eb1b"}, + {file = "llm-0.27.1-py3-none-any.whl", hash = "sha256:a884a575062fbea8c2b129708a80e146fa9682bd1c444d8d7b028196107de727"}, + {file = "llm-0.27.1.tar.gz", hash = "sha256:02b0b393e31cf0e0ee1f2a6006c451c74ec18c7ec3973218de56e76fd72baa80"}, ] [package.dependencies] @@ -3463,21 +3651,21 @@ test = ["black (>=25.1.0)", "build", "click (<8.2.0)", "cogapp", "llm-echo (==0. [[package]] name = "logfire" -version = "3.25.0" +version = "4.13.2" description = "The best Python observability tool! 🪵🔥" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "logfire-3.25.0-py3-none-any.whl", hash = "sha256:d3cb8c078f3000923be347191466f47d836e9be7a47caedecd07527870ebc7ec"}, - {file = "logfire-3.25.0.tar.gz", hash = "sha256:3d0b88c0c5a7f4fc27b7591341d4467af499c464c70e7a3784f1fa2751bf5151"}, + {file = "logfire-4.13.2-py3-none-any.whl", hash = "sha256:887e99897a1818864aa5bfc595b02c93264ce23d1860866369eff6b6e2dde1c6"}, + {file = "logfire-4.13.2.tar.gz", hash = "sha256:4e756e140c3b8fd25653d20437ebcb75734975f5382de6ae28be775c75575d95"}, ] [package.dependencies] executing = ">=2.0.1" -opentelemetry-exporter-otlp-proto-http = ">=1.21.0,<1.36.0" +opentelemetry-exporter-otlp-proto-http = ">=1.35.0,<1.38.0" opentelemetry-instrumentation = ">=0.41b0" -opentelemetry-sdk = ">=1.21.0,<1.36.0" +opentelemetry-sdk = ">=1.35.0,<1.38.0" protobuf = ">=4.23.4" rich = ">=13.4.2" typing-extensions = ">=4.1.0" @@ -3493,7 +3681,9 @@ celery = ["opentelemetry-instrumentation-celery (>=0.42b0)"] django = ["opentelemetry-instrumentation-asgi (>=0.42b0)", "opentelemetry-instrumentation-django (>=0.42b0)"] fastapi = ["opentelemetry-instrumentation-fastapi (>=0.42b0)"] flask = ["opentelemetry-instrumentation-flask (>=0.42b0)"] +google-genai = ["opentelemetry-instrumentation-google-genai (>=0)"] httpx = ["opentelemetry-instrumentation-httpx (>=0.42b0)"] +litellm = ["openinference-instrumentation-litellm (>=0)"] mysql = ["opentelemetry-instrumentation-mysql (>=0.42b0)"] psycopg = ["opentelemetry-instrumentation-psycopg (>=0.42b0)", "packaging"] psycopg2 = ["opentelemetry-instrumentation-psycopg2 (>=0.42b0)", "packaging"] @@ -3508,118 +3698,164 @@ wsgi = ["opentelemetry-instrumentation-wsgi (>=0.42b0)"] [[package]] name = "logfire-api" -version = "3.25.0" +version = "4.13.2" description = "Shim for the Logfire SDK which does nothing unless Logfire is installed" optional = false python-versions = ">=3.8" groups = ["main"] files = [ - {file = "logfire_api-3.25.0-py3-none-any.whl", hash = "sha256:cc1c2482d6a738e15cd165c483577f8ef7a8a4c462eafa0f6129aa9077676a8d"}, - {file = "logfire_api-3.25.0.tar.gz", hash = "sha256:d6aeeeb246cc8d7aeb14a503523422292047db5e7be35d47c8979f70b0962bb0"}, + {file = "logfire_api-4.13.2-py3-none-any.whl", hash = "sha256:e79182e25cb12545939cb40446df27daed99bc8ada05664e32a3aea793b499a4"}, + {file = "logfire_api-4.13.2.tar.gz", hash = "sha256:4540686d2781ac9e6563306d3449ea7980518cdc2df2ac5315ddc24b91458f8d"}, ] [[package]] name = "lxml" -version = "6.0.0" +version = "6.0.2" description = "Powerful and Pythonic XML processing library combining libxml2/libxslt with the ElementTree API." optional = false python-versions = ">=3.8" groups = ["main"] files = [ - {file = "lxml-6.0.0-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:35bc626eec405f745199200ccb5c6b36f202675d204aa29bb52e27ba2b71dea8"}, - {file = "lxml-6.0.0-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:246b40f8a4aec341cbbf52617cad8ab7c888d944bfe12a6abd2b1f6cfb6f6082"}, - {file = "lxml-6.0.0-cp310-cp310-manylinux2010_i686.manylinux2014_i686.manylinux_2_12_i686.manylinux_2_17_i686.whl", hash = "sha256:2793a627e95d119e9f1e19720730472f5543a6d84c50ea33313ce328d870f2dd"}, - {file = "lxml-6.0.0-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:46b9ed911f36bfeb6338e0b482e7fe7c27d362c52fde29f221fddbc9ee2227e7"}, - {file = "lxml-6.0.0-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:2b4790b558bee331a933e08883c423f65bbcd07e278f91b2272489e31ab1e2b4"}, - {file = "lxml-6.0.0-cp310-cp310-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:e2030956cf4886b10be9a0285c6802e078ec2391e1dd7ff3eb509c2c95a69b76"}, - {file = "lxml-6.0.0-cp310-cp310-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:4d23854ecf381ab1facc8f353dcd9adeddef3652268ee75297c1164c987c11dc"}, - {file = "lxml-6.0.0-cp310-cp310-manylinux_2_31_armv7l.whl", hash = "sha256:43fe5af2d590bf4691531b1d9a2495d7aab2090547eaacd224a3afec95706d76"}, - {file = "lxml-6.0.0-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:74e748012f8c19b47f7d6321ac929a9a94ee92ef12bc4298c47e8b7219b26541"}, - {file = "lxml-6.0.0-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:43cfbb7db02b30ad3926e8fceaef260ba2fb7df787e38fa2df890c1ca7966c3b"}, - {file = "lxml-6.0.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:34190a1ec4f1e84af256495436b2d196529c3f2094f0af80202947567fdbf2e7"}, - {file = "lxml-6.0.0-cp310-cp310-win32.whl", hash = "sha256:5967fe415b1920a3877a4195e9a2b779249630ee49ece22021c690320ff07452"}, - {file = "lxml-6.0.0-cp310-cp310-win_amd64.whl", hash = "sha256:f3389924581d9a770c6caa4df4e74b606180869043b9073e2cec324bad6e306e"}, - {file = "lxml-6.0.0-cp310-cp310-win_arm64.whl", hash = "sha256:522fe7abb41309e9543b0d9b8b434f2b630c5fdaf6482bee642b34c8c70079c8"}, - {file = "lxml-6.0.0-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:4ee56288d0df919e4aac43b539dd0e34bb55d6a12a6562038e8d6f3ed07f9e36"}, - {file = "lxml-6.0.0-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:b8dd6dd0e9c1992613ccda2bcb74fc9d49159dbe0f0ca4753f37527749885c25"}, - {file = "lxml-6.0.0-cp311-cp311-manylinux2010_i686.manylinux2014_i686.manylinux_2_12_i686.manylinux_2_17_i686.whl", hash = "sha256:d7ae472f74afcc47320238b5dbfd363aba111a525943c8a34a1b657c6be934c3"}, - {file = "lxml-6.0.0-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:5592401cdf3dc682194727c1ddaa8aa0f3ddc57ca64fd03226a430b955eab6f6"}, - {file = "lxml-6.0.0-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:58ffd35bd5425c3c3b9692d078bf7ab851441434531a7e517c4984d5634cd65b"}, - {file = "lxml-6.0.0-cp311-cp311-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:f720a14aa102a38907c6d5030e3d66b3b680c3e6f6bc95473931ea3c00c59967"}, - {file = "lxml-6.0.0-cp311-cp311-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:c2a5e8d207311a0170aca0eb6b160af91adc29ec121832e4ac151a57743a1e1e"}, - {file = "lxml-6.0.0-cp311-cp311-manylinux_2_31_armv7l.whl", hash = "sha256:2dd1cc3ea7e60bfb31ff32cafe07e24839df573a5e7c2d33304082a5019bcd58"}, - {file = "lxml-6.0.0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:2cfcf84f1defed7e5798ef4f88aa25fcc52d279be731ce904789aa7ccfb7e8d2"}, - {file = "lxml-6.0.0-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:a52a4704811e2623b0324a18d41ad4b9fabf43ce5ff99b14e40a520e2190c851"}, - {file = "lxml-6.0.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:c16304bba98f48a28ae10e32a8e75c349dd742c45156f297e16eeb1ba9287a1f"}, - {file = "lxml-6.0.0-cp311-cp311-win32.whl", hash = "sha256:f8d19565ae3eb956d84da3ef367aa7def14a2735d05bd275cd54c0301f0d0d6c"}, - {file = "lxml-6.0.0-cp311-cp311-win_amd64.whl", hash = "sha256:b2d71cdefda9424adff9a3607ba5bbfc60ee972d73c21c7e3c19e71037574816"}, - {file = "lxml-6.0.0-cp311-cp311-win_arm64.whl", hash = "sha256:8a2e76efbf8772add72d002d67a4c3d0958638696f541734304c7f28217a9cab"}, - {file = "lxml-6.0.0-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:78718d8454a6e928470d511bf8ac93f469283a45c354995f7d19e77292f26108"}, - {file = "lxml-6.0.0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:84ef591495ffd3f9dcabffd6391db7bb70d7230b5c35ef5148354a134f56f2be"}, - {file = "lxml-6.0.0-cp312-cp312-manylinux2010_i686.manylinux2014_i686.manylinux_2_12_i686.manylinux_2_17_i686.whl", hash = "sha256:2930aa001a3776c3e2601cb8e0a15d21b8270528d89cc308be4843ade546b9ab"}, - {file = "lxml-6.0.0-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:219e0431ea8006e15005767f0351e3f7f9143e793e58519dc97fe9e07fae5563"}, - {file = "lxml-6.0.0-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:bd5913b4972681ffc9718bc2d4c53cde39ef81415e1671ff93e9aa30b46595e7"}, - {file = "lxml-6.0.0-cp312-cp312-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:390240baeb9f415a82eefc2e13285016f9c8b5ad71ec80574ae8fa9605093cd7"}, - {file = "lxml-6.0.0-cp312-cp312-manylinux_2_27_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:d6e200909a119626744dd81bae409fc44134389e03fbf1d68ed2a55a2fb10991"}, - {file = "lxml-6.0.0-cp312-cp312-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:ca50bd612438258a91b5b3788c6621c1f05c8c478e7951899f492be42defc0da"}, - {file = "lxml-6.0.0-cp312-cp312-manylinux_2_31_armv7l.whl", hash = "sha256:c24b8efd9c0f62bad0439283c2c795ef916c5a6b75f03c17799775c7ae3c0c9e"}, - {file = "lxml-6.0.0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:afd27d8629ae94c5d863e32ab0e1d5590371d296b87dae0a751fb22bf3685741"}, - {file = "lxml-6.0.0-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:54c4855eabd9fc29707d30141be99e5cd1102e7d2258d2892314cf4c110726c3"}, - {file = "lxml-6.0.0-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:c907516d49f77f6cd8ead1322198bdfd902003c3c330c77a1c5f3cc32a0e4d16"}, - {file = "lxml-6.0.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:36531f81c8214e293097cd2b7873f178997dae33d3667caaae8bdfb9666b76c0"}, - {file = "lxml-6.0.0-cp312-cp312-win32.whl", hash = "sha256:690b20e3388a7ec98e899fd54c924e50ba6693874aa65ef9cb53de7f7de9d64a"}, - {file = "lxml-6.0.0-cp312-cp312-win_amd64.whl", hash = "sha256:310b719b695b3dd442cdfbbe64936b2f2e231bb91d998e99e6f0daf991a3eba3"}, - {file = "lxml-6.0.0-cp312-cp312-win_arm64.whl", hash = "sha256:8cb26f51c82d77483cdcd2b4a53cda55bbee29b3c2f3ddeb47182a2a9064e4eb"}, - {file = "lxml-6.0.0-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:6da7cd4f405fd7db56e51e96bff0865b9853ae70df0e6720624049da76bde2da"}, - {file = "lxml-6.0.0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:b34339898bb556a2351a1830f88f751679f343eabf9cf05841c95b165152c9e7"}, - {file = "lxml-6.0.0-cp313-cp313-manylinux2010_i686.manylinux2014_i686.manylinux_2_12_i686.manylinux_2_17_i686.whl", hash = "sha256:51a5e4c61a4541bd1cd3ba74766d0c9b6c12d6a1a4964ef60026832aac8e79b3"}, - {file = "lxml-6.0.0-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:d18a25b19ca7307045581b18b3ec9ead2b1db5ccd8719c291f0cd0a5cec6cb81"}, - {file = "lxml-6.0.0-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:d4f0c66df4386b75d2ab1e20a489f30dc7fd9a06a896d64980541506086be1f1"}, - {file = "lxml-6.0.0-cp313-cp313-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:9f4b481b6cc3a897adb4279216695150bbe7a44c03daba3c894f49d2037e0a24"}, - {file = "lxml-6.0.0-cp313-cp313-manylinux_2_27_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:8a78d6c9168f5bcb20971bf3329c2b83078611fbe1f807baadc64afc70523b3a"}, - {file = "lxml-6.0.0-cp313-cp313-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:2ae06fbab4f1bb7db4f7c8ca9897dc8db4447d1a2b9bee78474ad403437bcc29"}, - {file = "lxml-6.0.0-cp313-cp313-manylinux_2_31_armv7l.whl", hash = "sha256:1fa377b827ca2023244a06554c6e7dc6828a10aaf74ca41965c5d8a4925aebb4"}, - {file = "lxml-6.0.0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:1676b56d48048a62ef77a250428d1f31f610763636e0784ba67a9740823988ca"}, - {file = "lxml-6.0.0-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:0e32698462aacc5c1cf6bdfebc9c781821b7e74c79f13e5ffc8bfe27c42b1abf"}, - {file = "lxml-6.0.0-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:4d6036c3a296707357efb375cfc24bb64cd955b9ec731abf11ebb1e40063949f"}, - {file = "lxml-6.0.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:7488a43033c958637b1a08cddc9188eb06d3ad36582cebc7d4815980b47e27ef"}, - {file = "lxml-6.0.0-cp313-cp313-win32.whl", hash = "sha256:5fcd7d3b1d8ecb91445bd71b9c88bdbeae528fefee4f379895becfc72298d181"}, - {file = "lxml-6.0.0-cp313-cp313-win_amd64.whl", hash = "sha256:2f34687222b78fff795feeb799a7d44eca2477c3d9d3a46ce17d51a4f383e32e"}, - {file = "lxml-6.0.0-cp313-cp313-win_arm64.whl", hash = "sha256:21db1ec5525780fd07251636eb5f7acb84003e9382c72c18c542a87c416ade03"}, - {file = "lxml-6.0.0-cp38-cp38-macosx_10_9_x86_64.whl", hash = "sha256:4eb114a0754fd00075c12648d991ec7a4357f9cb873042cc9a77bf3a7e30c9db"}, - {file = "lxml-6.0.0-cp38-cp38-manylinux2010_i686.manylinux2014_i686.manylinux_2_12_i686.manylinux_2_17_i686.whl", hash = "sha256:7da298e1659e45d151b4028ad5c7974917e108afb48731f4ed785d02b6818994"}, - {file = "lxml-6.0.0-cp38-cp38-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:7bf61bc4345c1895221357af8f3e89f8c103d93156ef326532d35c707e2fb19d"}, - {file = "lxml-6.0.0-cp38-cp38-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:63b634facdfbad421d4b61c90735688465d4ab3a8853ac22c76ccac2baf98d97"}, - {file = "lxml-6.0.0-cp38-cp38-musllinux_1_2_x86_64.whl", hash = "sha256:e380e85b93f148ad28ac15f8117e2fd8e5437aa7732d65e260134f83ce67911b"}, - {file = "lxml-6.0.0-cp38-cp38-win32.whl", hash = "sha256:185efc2fed89cdd97552585c624d3c908f0464090f4b91f7d92f8ed2f3b18f54"}, - {file = "lxml-6.0.0-cp38-cp38-win_amd64.whl", hash = "sha256:f97487996a39cb18278ca33f7be98198f278d0bc3c5d0fd4d7b3d63646ca3c8a"}, - {file = "lxml-6.0.0-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:85b14a4689d5cff426c12eefe750738648706ea2753b20c2f973b2a000d3d261"}, - {file = "lxml-6.0.0-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:f64ccf593916e93b8d36ed55401bb7fe9c7d5de3180ce2e10b08f82a8f397316"}, - {file = "lxml-6.0.0-cp39-cp39-manylinux2010_i686.manylinux2014_i686.manylinux_2_12_i686.manylinux_2_17_i686.whl", hash = "sha256:b372d10d17a701b0945f67be58fae4664fd056b85e0ff0fbc1e6c951cdbc0512"}, - {file = "lxml-6.0.0-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:a674c0948789e9136d69065cc28009c1b1874c6ea340253db58be7622ce6398f"}, - {file = "lxml-6.0.0-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:edf6e4c8fe14dfe316939711e3ece3f9a20760aabf686051b537a7562f4da91a"}, - {file = "lxml-6.0.0-cp39-cp39-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:048a930eb4572829604982e39a0c7289ab5dc8abc7fc9f5aabd6fbc08c154e93"}, - {file = "lxml-6.0.0-cp39-cp39-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:c0b5fa5eda84057a4f1bbb4bb77a8c28ff20ae7ce211588d698ae453e13c6281"}, - {file = "lxml-6.0.0-cp39-cp39-manylinux_2_31_armv7l.whl", hash = "sha256:c352fc8f36f7e9727db17adbf93f82499457b3d7e5511368569b4c5bd155a922"}, - {file = "lxml-6.0.0-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:8db5dc617cb937ae17ff3403c3a70a7de9df4852a046f93e71edaec678f721d0"}, - {file = "lxml-6.0.0-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:2181e4b1d07dde53986023482673c0f1fba5178ef800f9ab95ad791e8bdded6a"}, - {file = "lxml-6.0.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:b3c98d5b24c6095e89e03d65d5c574705be3d49c0d8ca10c17a8a4b5201b72f5"}, - {file = "lxml-6.0.0-cp39-cp39-win32.whl", hash = "sha256:04d67ceee6db4bcb92987ccb16e53bef6b42ced872509f333c04fb58a3315256"}, - {file = "lxml-6.0.0-cp39-cp39-win_amd64.whl", hash = "sha256:e0b1520ef900e9ef62e392dd3d7ae4f5fa224d1dd62897a792cf353eb20b6cae"}, - {file = "lxml-6.0.0-cp39-cp39-win_arm64.whl", hash = "sha256:e35e8aaaf3981489f42884b59726693de32dabfc438ac10ef4eb3409961fd402"}, - {file = "lxml-6.0.0-pp310-pypy310_pp73-macosx_10_15_x86_64.whl", hash = "sha256:dbdd7679a6f4f08152818043dbb39491d1af3332128b3752c3ec5cebc0011a72"}, - {file = "lxml-6.0.0-pp310-pypy310_pp73-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:40442e2a4456e9910875ac12951476d36c0870dcb38a68719f8c4686609897c4"}, - {file = "lxml-6.0.0-pp310-pypy310_pp73-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:db0efd6bae1c4730b9c863fc4f5f3c0fa3e8f05cae2c44ae141cb9dfc7d091dc"}, - {file = "lxml-6.0.0-pp310-pypy310_pp73-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:9ab542c91f5a47aaa58abdd8ea84b498e8e49fe4b883d67800017757a3eb78e8"}, - {file = "lxml-6.0.0-pp310-pypy310_pp73-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:013090383863b72c62a702d07678b658fa2567aa58d373d963cca245b017e065"}, - {file = "lxml-6.0.0-pp310-pypy310_pp73-win_amd64.whl", hash = "sha256:c86df1c9af35d903d2b52d22ea3e66db8058d21dc0f59842ca5deb0595921141"}, - {file = "lxml-6.0.0-pp39-pypy39_pp73-macosx_10_15_x86_64.whl", hash = "sha256:4337e4aec93b7c011f7ee2e357b0d30562edd1955620fdd4aeab6aacd90d43c5"}, - {file = "lxml-6.0.0-pp39-pypy39_pp73-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:ae74f7c762270196d2dda56f8dd7309411f08a4084ff2dfcc0b095a218df2e06"}, - {file = "lxml-6.0.0-pp39-pypy39_pp73-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:059c4cbf3973a621b62ea3132934ae737da2c132a788e6cfb9b08d63a0ef73f9"}, - {file = "lxml-6.0.0-pp39-pypy39_pp73-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:17f090a9bc0ce8da51a5632092f98a7e7f84bca26f33d161a98b57f7fb0004ca"}, - {file = "lxml-6.0.0-pp39-pypy39_pp73-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:9da022c14baeec36edfcc8daf0e281e2f55b950249a455776f0d1adeeada4734"}, - {file = "lxml-6.0.0-pp39-pypy39_pp73-win_amd64.whl", hash = "sha256:a55da151d0b0c6ab176b4e761670ac0e2667817a1e0dadd04a01d0561a219349"}, - {file = "lxml-6.0.0.tar.gz", hash = "sha256:032e65120339d44cdc3efc326c9f660f5f7205f3a535c1fdbf898b29ea01fb72"}, + {file = "lxml-6.0.2-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:e77dd455b9a16bbd2a5036a63ddbd479c19572af81b624e79ef422f929eef388"}, + {file = "lxml-6.0.2-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:5d444858b9f07cefff6455b983aea9a67f7462ba1f6cbe4a21e8bf6791bf2153"}, + {file = "lxml-6.0.2-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:f952dacaa552f3bb8834908dddd500ba7d508e6ea6eb8c52eb2d28f48ca06a31"}, + {file = "lxml-6.0.2-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:71695772df6acea9f3c0e59e44ba8ac50c4f125217e84aab21074a1a55e7e5c9"}, + {file = "lxml-6.0.2-cp310-cp310-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:17f68764f35fd78d7c4cc4ef209a184c38b65440378013d24b8aecd327c3e0c8"}, + {file = "lxml-6.0.2-cp310-cp310-manylinux_2_26_i686.manylinux_2_28_i686.whl", hash = "sha256:058027e261afed589eddcfe530fcc6f3402d7fd7e89bfd0532df82ebc1563dba"}, + {file = "lxml-6.0.2-cp310-cp310-manylinux_2_26_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:a8ffaeec5dfea5881d4c9d8913a32d10cfe3923495386106e4a24d45300ef79c"}, + {file = "lxml-6.0.2-cp310-cp310-manylinux_2_31_armv7l.whl", hash = "sha256:f2e3b1a6bb38de0bc713edd4d612969dd250ca8b724be8d460001a387507021c"}, + {file = "lxml-6.0.2-cp310-cp310-manylinux_2_38_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:d6690ec5ec1cce0385cb20896b16be35247ac8c2046e493d03232f1c2414d321"}, + {file = "lxml-6.0.2-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:f2a50c3c1d11cad0ebebbac357a97b26aa79d2bcaf46f256551152aa85d3a4d1"}, + {file = "lxml-6.0.2-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:3efe1b21c7801ffa29a1112fab3b0f643628c30472d507f39544fd48e9549e34"}, + {file = "lxml-6.0.2-cp310-cp310-musllinux_1_2_riscv64.whl", hash = "sha256:59c45e125140b2c4b33920d21d83681940ca29f0b83f8629ea1a2196dc8cfe6a"}, + {file = "lxml-6.0.2-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:452b899faa64f1805943ec1c0c9ebeaece01a1af83e130b69cdefeda180bb42c"}, + {file = "lxml-6.0.2-cp310-cp310-win32.whl", hash = "sha256:1e786a464c191ca43b133906c6903a7e4d56bef376b75d97ccbb8ec5cf1f0a4b"}, + {file = "lxml-6.0.2-cp310-cp310-win_amd64.whl", hash = "sha256:dacf3c64ef3f7440e3167aa4b49aa9e0fb99e0aa4f9ff03795640bf94531bcb0"}, + {file = "lxml-6.0.2-cp310-cp310-win_arm64.whl", hash = "sha256:45f93e6f75123f88d7f0cfd90f2d05f441b808562bf0bc01070a00f53f5028b5"}, + {file = "lxml-6.0.2-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:13e35cbc684aadf05d8711a5d1b5857c92e5e580efa9a0d2be197199c8def607"}, + {file = "lxml-6.0.2-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:3b1675e096e17c6fe9c0e8c81434f5736c0739ff9ac6123c87c2d452f48fc938"}, + {file = "lxml-6.0.2-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:8ac6e5811ae2870953390452e3476694196f98d447573234592d30488147404d"}, + {file = "lxml-6.0.2-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:5aa0fc67ae19d7a64c3fe725dc9a1bb11f80e01f78289d05c6f62545affec438"}, + {file = "lxml-6.0.2-cp311-cp311-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:de496365750cc472b4e7902a485d3f152ecf57bd3ba03ddd5578ed8ceb4c5964"}, + {file = "lxml-6.0.2-cp311-cp311-manylinux_2_26_i686.manylinux_2_28_i686.whl", hash = "sha256:200069a593c5e40b8f6fc0d84d86d970ba43138c3e68619ffa234bc9bb806a4d"}, + {file = "lxml-6.0.2-cp311-cp311-manylinux_2_26_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:7d2de809c2ee3b888b59f995625385f74629707c9355e0ff856445cdcae682b7"}, + {file = "lxml-6.0.2-cp311-cp311-manylinux_2_31_armv7l.whl", hash = "sha256:b2c3da8d93cf5db60e8858c17684c47d01fee6405e554fb55018dd85fc23b178"}, + {file = "lxml-6.0.2-cp311-cp311-manylinux_2_38_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:442de7530296ef5e188373a1ea5789a46ce90c4847e597856570439621d9c553"}, + {file = "lxml-6.0.2-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:2593c77efde7bfea7f6389f1ab249b15ed4aa5bc5cb5131faa3b843c429fbedb"}, + {file = "lxml-6.0.2-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:3e3cb08855967a20f553ff32d147e14329b3ae70ced6edc2f282b94afbc74b2a"}, + {file = "lxml-6.0.2-cp311-cp311-musllinux_1_2_riscv64.whl", hash = "sha256:2ed6c667fcbb8c19c6791bbf40b7268ef8ddf5a96940ba9404b9f9a304832f6c"}, + {file = "lxml-6.0.2-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:b8f18914faec94132e5b91e69d76a5c1d7b0c73e2489ea8929c4aaa10b76bbf7"}, + {file = "lxml-6.0.2-cp311-cp311-win32.whl", hash = "sha256:6605c604e6daa9e0d7f0a2137bdc47a2e93b59c60a65466353e37f8272f47c46"}, + {file = "lxml-6.0.2-cp311-cp311-win_amd64.whl", hash = "sha256:e5867f2651016a3afd8dd2c8238baa66f1e2802f44bc17e236f547ace6647078"}, + {file = "lxml-6.0.2-cp311-cp311-win_arm64.whl", hash = "sha256:4197fb2534ee05fd3e7afaab5d8bfd6c2e186f65ea7f9cd6a82809c887bd1285"}, + {file = "lxml-6.0.2-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:a59f5448ba2ceccd06995c95ea59a7674a10de0810f2ce90c9006f3cbc044456"}, + {file = "lxml-6.0.2-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:e8113639f3296706fbac34a30813929e29247718e88173ad849f57ca59754924"}, + {file = "lxml-6.0.2-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:a8bef9b9825fa8bc816a6e641bb67219489229ebc648be422af695f6e7a4fa7f"}, + {file = "lxml-6.0.2-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:65ea18d710fd14e0186c2f973dc60bb52039a275f82d3c44a0e42b43440ea534"}, + {file = "lxml-6.0.2-cp312-cp312-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:c371aa98126a0d4c739ca93ceffa0fd7a5d732e3ac66a46e74339acd4d334564"}, + {file = "lxml-6.0.2-cp312-cp312-manylinux_2_26_i686.manylinux_2_28_i686.whl", hash = "sha256:700efd30c0fa1a3581d80a748157397559396090a51d306ea59a70020223d16f"}, + {file = "lxml-6.0.2-cp312-cp312-manylinux_2_26_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:c33e66d44fe60e72397b487ee92e01da0d09ba2d66df8eae42d77b6d06e5eba0"}, + {file = "lxml-6.0.2-cp312-cp312-manylinux_2_26_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:90a345bbeaf9d0587a3aaffb7006aa39ccb6ff0e96a57286c0cb2fd1520ea192"}, + {file = "lxml-6.0.2-cp312-cp312-manylinux_2_31_armv7l.whl", hash = "sha256:064fdadaf7a21af3ed1dcaa106b854077fbeada827c18f72aec9346847cd65d0"}, + {file = "lxml-6.0.2-cp312-cp312-manylinux_2_38_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:fbc74f42c3525ac4ffa4b89cbdd00057b6196bcefe8bce794abd42d33a018092"}, + {file = "lxml-6.0.2-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:6ddff43f702905a4e32bc24f3f2e2edfe0f8fde3277d481bffb709a4cced7a1f"}, + {file = "lxml-6.0.2-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:6da5185951d72e6f5352166e3da7b0dc27aa70bd1090b0eb3f7f7212b53f1bb8"}, + {file = "lxml-6.0.2-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:57a86e1ebb4020a38d295c04fc79603c7899e0df71588043eb218722dabc087f"}, + {file = "lxml-6.0.2-cp312-cp312-musllinux_1_2_riscv64.whl", hash = "sha256:2047d8234fe735ab77802ce5f2297e410ff40f5238aec569ad7c8e163d7b19a6"}, + {file = "lxml-6.0.2-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:6f91fd2b2ea15a6800c8e24418c0775a1694eefc011392da73bc6cef2623b322"}, + {file = "lxml-6.0.2-cp312-cp312-win32.whl", hash = "sha256:3ae2ce7d6fedfb3414a2b6c5e20b249c4c607f72cb8d2bb7cc9c6ec7c6f4e849"}, + {file = "lxml-6.0.2-cp312-cp312-win_amd64.whl", hash = "sha256:72c87e5ee4e58a8354fb9c7c84cbf95a1c8236c127a5d1b7683f04bed8361e1f"}, + {file = "lxml-6.0.2-cp312-cp312-win_arm64.whl", hash = "sha256:61cb10eeb95570153e0c0e554f58df92ecf5109f75eacad4a95baa709e26c3d6"}, + {file = "lxml-6.0.2-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:9b33d21594afab46f37ae58dfadd06636f154923c4e8a4d754b0127554eb2e77"}, + {file = "lxml-6.0.2-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:6c8963287d7a4c5c9a432ff487c52e9c5618667179c18a204bdedb27310f022f"}, + {file = "lxml-6.0.2-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:1941354d92699fb5ffe6ed7b32f9649e43c2feb4b97205f75866f7d21aa91452"}, + {file = "lxml-6.0.2-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:bb2f6ca0ae2d983ded09357b84af659c954722bbf04dea98030064996d156048"}, + {file = "lxml-6.0.2-cp313-cp313-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:eb2a12d704f180a902d7fa778c6d71f36ceb7b0d317f34cdc76a5d05aa1dd1df"}, + {file = "lxml-6.0.2-cp313-cp313-manylinux_2_26_i686.manylinux_2_28_i686.whl", hash = "sha256:6ec0e3f745021bfed19c456647f0298d60a24c9ff86d9d051f52b509663feeb1"}, + {file = "lxml-6.0.2-cp313-cp313-manylinux_2_26_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:846ae9a12d54e368933b9759052d6206a9e8b250291109c48e350c1f1f49d916"}, + {file = "lxml-6.0.2-cp313-cp313-manylinux_2_26_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:ef9266d2aa545d7374938fb5c484531ef5a2ec7f2d573e62f8ce722c735685fd"}, + {file = "lxml-6.0.2-cp313-cp313-manylinux_2_31_armv7l.whl", hash = "sha256:4077b7c79f31755df33b795dc12119cb557a0106bfdab0d2c2d97bd3cf3dffa6"}, + {file = "lxml-6.0.2-cp313-cp313-manylinux_2_38_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:a7c5d5e5f1081955358533be077166ee97ed2571d6a66bdba6ec2f609a715d1a"}, + {file = "lxml-6.0.2-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:8f8d0cbd0674ee89863a523e6994ac25fd5be9c8486acfc3e5ccea679bad2679"}, + {file = "lxml-6.0.2-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:2cbcbf6d6e924c28f04a43f3b6f6e272312a090f269eff68a2982e13e5d57659"}, + {file = "lxml-6.0.2-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:dfb874cfa53340009af6bdd7e54ebc0d21012a60a4e65d927c2e477112e63484"}, + {file = "lxml-6.0.2-cp313-cp313-musllinux_1_2_riscv64.whl", hash = "sha256:fb8dae0b6b8b7f9e96c26fdd8121522ce5de9bb5538010870bd538683d30e9a2"}, + {file = "lxml-6.0.2-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:358d9adae670b63e95bc59747c72f4dc97c9ec58881d4627fe0120da0f90d314"}, + {file = "lxml-6.0.2-cp313-cp313-win32.whl", hash = "sha256:e8cd2415f372e7e5a789d743d133ae474290a90b9023197fd78f32e2dc6873e2"}, + {file = "lxml-6.0.2-cp313-cp313-win_amd64.whl", hash = "sha256:b30d46379644fbfc3ab81f8f82ae4de55179414651f110a1514f0b1f8f6cb2d7"}, + {file = "lxml-6.0.2-cp313-cp313-win_arm64.whl", hash = "sha256:13dcecc9946dca97b11b7c40d29fba63b55ab4170d3c0cf8c0c164343b9bfdcf"}, + {file = "lxml-6.0.2-cp314-cp314-macosx_10_13_universal2.whl", hash = "sha256:b0c732aa23de8f8aec23f4b580d1e52905ef468afb4abeafd3fec77042abb6fe"}, + {file = "lxml-6.0.2-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:4468e3b83e10e0317a89a33d28f7aeba1caa4d1a6fd457d115dd4ffe90c5931d"}, + {file = "lxml-6.0.2-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:abd44571493973bad4598a3be7e1d807ed45aa2adaf7ab92ab7c62609569b17d"}, + {file = "lxml-6.0.2-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:370cd78d5855cfbffd57c422851f7d3864e6ae72d0da615fca4dad8c45d375a5"}, + {file = "lxml-6.0.2-cp314-cp314-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:901e3b4219fa04ef766885fb40fa516a71662a4c61b80c94d25336b4934b71c0"}, + {file = "lxml-6.0.2-cp314-cp314-manylinux_2_26_i686.manylinux_2_28_i686.whl", hash = "sha256:a4bf42d2e4cf52c28cc1812d62426b9503cdb0c87a6de81442626aa7d69707ba"}, + {file = "lxml-6.0.2-cp314-cp314-manylinux_2_26_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:b2c7fdaa4d7c3d886a42534adec7cfac73860b89b4e5298752f60aa5984641a0"}, + {file = "lxml-6.0.2-cp314-cp314-manylinux_2_26_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:98a5e1660dc7de2200b00d53fa00bcd3c35a3608c305d45a7bbcaf29fa16e83d"}, + {file = "lxml-6.0.2-cp314-cp314-manylinux_2_31_armv7l.whl", hash = "sha256:dc051506c30b609238d79eda75ee9cab3e520570ec8219844a72a46020901e37"}, + {file = "lxml-6.0.2-cp314-cp314-manylinux_2_38_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:8799481bbdd212470d17513a54d568f44416db01250f49449647b5ab5b5dccb9"}, + {file = "lxml-6.0.2-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:9261bb77c2dab42f3ecd9103951aeca2c40277701eb7e912c545c1b16e0e4917"}, + {file = "lxml-6.0.2-cp314-cp314-musllinux_1_2_armv7l.whl", hash = "sha256:65ac4a01aba353cfa6d5725b95d7aed6356ddc0a3cd734de00124d285b04b64f"}, + {file = "lxml-6.0.2-cp314-cp314-musllinux_1_2_ppc64le.whl", hash = "sha256:b22a07cbb82fea98f8a2fd814f3d1811ff9ed76d0fc6abc84eb21527596e7cc8"}, + {file = "lxml-6.0.2-cp314-cp314-musllinux_1_2_riscv64.whl", hash = "sha256:d759cdd7f3e055d6bc8d9bec3ad905227b2e4c785dc16c372eb5b5e83123f48a"}, + {file = "lxml-6.0.2-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:945da35a48d193d27c188037a05fec5492937f66fb1958c24fc761fb9d40d43c"}, + {file = "lxml-6.0.2-cp314-cp314-win32.whl", hash = "sha256:be3aaa60da67e6153eb15715cc2e19091af5dc75faef8b8a585aea372507384b"}, + {file = "lxml-6.0.2-cp314-cp314-win_amd64.whl", hash = "sha256:fa25afbadead523f7001caf0c2382afd272c315a033a7b06336da2637d92d6ed"}, + {file = "lxml-6.0.2-cp314-cp314-win_arm64.whl", hash = "sha256:063eccf89df5b24e361b123e257e437f9e9878f425ee9aae3144c77faf6da6d8"}, + {file = "lxml-6.0.2-cp314-cp314t-macosx_10_13_universal2.whl", hash = "sha256:6162a86d86893d63084faaf4ff937b3daea233e3682fb4474db07395794fa80d"}, + {file = "lxml-6.0.2-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:414aaa94e974e23a3e92e7ca5b97d10c0cf37b6481f50911032c69eeb3991bba"}, + {file = "lxml-6.0.2-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:48461bd21625458dd01e14e2c38dd0aea69addc3c4f960c30d9f59d7f93be601"}, + {file = "lxml-6.0.2-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:25fcc59afc57d527cfc78a58f40ab4c9b8fd096a9a3f964d2781ffb6eb33f4ed"}, + {file = "lxml-6.0.2-cp314-cp314t-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:5179c60288204e6ddde3f774a93350177e08876eaf3ab78aa3a3649d43eb7d37"}, + {file = "lxml-6.0.2-cp314-cp314t-manylinux_2_26_i686.manylinux_2_28_i686.whl", hash = "sha256:967aab75434de148ec80597b75062d8123cadf2943fb4281f385141e18b21338"}, + {file = "lxml-6.0.2-cp314-cp314t-manylinux_2_26_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:d100fcc8930d697c6561156c6810ab4a508fb264c8b6779e6e61e2ed5e7558f9"}, + {file = "lxml-6.0.2-cp314-cp314t-manylinux_2_26_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:2ca59e7e13e5981175b8b3e4ab84d7da57993eeff53c07764dcebda0d0e64ecd"}, + {file = "lxml-6.0.2-cp314-cp314t-manylinux_2_31_armv7l.whl", hash = "sha256:957448ac63a42e2e49531b9d6c0fa449a1970dbc32467aaad46f11545be9af1d"}, + {file = "lxml-6.0.2-cp314-cp314t-manylinux_2_38_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:b7fc49c37f1786284b12af63152fe1d0990722497e2d5817acfe7a877522f9a9"}, + {file = "lxml-6.0.2-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:e19e0643cc936a22e837f79d01a550678da8377d7d801a14487c10c34ee49c7e"}, + {file = "lxml-6.0.2-cp314-cp314t-musllinux_1_2_armv7l.whl", hash = "sha256:1db01e5cf14345628e0cbe71067204db658e2fb8e51e7f33631f5f4735fefd8d"}, + {file = "lxml-6.0.2-cp314-cp314t-musllinux_1_2_ppc64le.whl", hash = "sha256:875c6b5ab39ad5291588aed6925fac99d0097af0dd62f33c7b43736043d4a2ec"}, + {file = "lxml-6.0.2-cp314-cp314t-musllinux_1_2_riscv64.whl", hash = "sha256:cdcbed9ad19da81c480dfd6dd161886db6096083c9938ead313d94b30aadf272"}, + {file = "lxml-6.0.2-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:80dadc234ebc532e09be1975ff538d154a7fa61ea5031c03d25178855544728f"}, + {file = "lxml-6.0.2-cp314-cp314t-win32.whl", hash = "sha256:da08e7bb297b04e893d91087df19638dc7a6bb858a954b0cc2b9f5053c922312"}, + {file = "lxml-6.0.2-cp314-cp314t-win_amd64.whl", hash = "sha256:252a22982dca42f6155125ac76d3432e548a7625d56f5a273ee78a5057216eca"}, + {file = "lxml-6.0.2-cp314-cp314t-win_arm64.whl", hash = "sha256:bb4c1847b303835d89d785a18801a883436cdfd5dc3d62947f9c49e24f0f5a2c"}, + {file = "lxml-6.0.2-cp38-cp38-macosx_10_9_x86_64.whl", hash = "sha256:a656ca105115f6b766bba324f23a67914d9c728dafec57638e2b92a9dcd76c62"}, + {file = "lxml-6.0.2-cp38-cp38-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:c54d83a2188a10ebdba573f16bd97135d06c9ef60c3dc495315c7a28c80a263f"}, + {file = "lxml-6.0.2-cp38-cp38-manylinux_2_26_i686.manylinux_2_28_i686.whl", hash = "sha256:1ea99340b3c729beea786f78c38f60f4795622f36e305d9c9be402201efdc3b7"}, + {file = "lxml-6.0.2-cp38-cp38-manylinux_2_26_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:af85529ae8d2a453feee4c780d9406a5e3b17cee0dd75c18bd31adcd584debc3"}, + {file = "lxml-6.0.2-cp38-cp38-musllinux_1_2_x86_64.whl", hash = "sha256:fe659f6b5d10fb5a17f00a50eb903eb277a71ee35df4615db573c069bcf967ac"}, + {file = "lxml-6.0.2-cp38-cp38-win32.whl", hash = "sha256:5921d924aa5468c939d95c9814fa9f9b5935a6ff4e679e26aaf2951f74043512"}, + {file = "lxml-6.0.2-cp38-cp38-win_amd64.whl", hash = "sha256:0aa7070978f893954008ab73bb9e3c24a7c56c054e00566a21b553dc18105fca"}, + {file = "lxml-6.0.2-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:2c8458c2cdd29589a8367c09c8f030f1d202be673f0ca224ec18590b3b9fb694"}, + {file = "lxml-6.0.2-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:3fee0851639d06276e6b387f1c190eb9d7f06f7f53514e966b26bae46481ec90"}, + {file = "lxml-6.0.2-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:b2142a376b40b6736dfc214fd2902409e9e3857eff554fed2d3c60f097e62a62"}, + {file = "lxml-6.0.2-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:a6b5b39cc7e2998f968f05309e666103b53e2edd01df8dc51b90d734c0825444"}, + {file = "lxml-6.0.2-cp39-cp39-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:d4aec24d6b72ee457ec665344a29acb2d35937d5192faebe429ea02633151aad"}, + {file = "lxml-6.0.2-cp39-cp39-manylinux_2_26_i686.manylinux_2_28_i686.whl", hash = "sha256:b42f4d86b451c2f9d06ffb4f8bbc776e04df3ba070b9fe2657804b1b40277c48"}, + {file = "lxml-6.0.2-cp39-cp39-manylinux_2_26_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:6cdaefac66e8b8f30e37a9b4768a391e1f8a16a7526d5bc77a7928408ef68e93"}, + {file = "lxml-6.0.2-cp39-cp39-manylinux_2_31_armv7l.whl", hash = "sha256:b738f7e648735714bbb82bdfd030203360cfeab7f6e8a34772b3c8c8b820568c"}, + {file = "lxml-6.0.2-cp39-cp39-manylinux_2_38_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:daf42de090d59db025af61ce6bdb2521f0f102ea0e6ea310f13c17610a97da4c"}, + {file = "lxml-6.0.2-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:66328dabea70b5ba7e53d94aa774b733cf66686535f3bc9250a7aab53a91caaf"}, + {file = "lxml-6.0.2-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:e237b807d68a61fc3b1e845407e27e5eb8ef69bc93fe8505337c1acb4ee300b6"}, + {file = "lxml-6.0.2-cp39-cp39-musllinux_1_2_riscv64.whl", hash = "sha256:ac02dc29fd397608f8eb15ac1610ae2f2f0154b03f631e6d724d9e2ad4ee2c84"}, + {file = "lxml-6.0.2-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:817ef43a0c0b4a77bd166dc9a09a555394105ff3374777ad41f453526e37f9cb"}, + {file = "lxml-6.0.2-cp39-cp39-win32.whl", hash = "sha256:bc532422ff26b304cfb62b328826bd995c96154ffd2bac4544f37dbb95ecaa8f"}, + {file = "lxml-6.0.2-cp39-cp39-win_amd64.whl", hash = "sha256:995e783eb0374c120f528f807443ad5a83a656a8624c467ea73781fc5f8a8304"}, + {file = "lxml-6.0.2-cp39-cp39-win_arm64.whl", hash = "sha256:08b9d5e803c2e4725ae9e8559ee880e5328ed61aa0935244e0515d7d9dbec0aa"}, + {file = "lxml-6.0.2-pp310-pypy310_pp73-macosx_10_15_x86_64.whl", hash = "sha256:e748d4cf8fef2526bb2a589a417eba0c8674e29ffcb570ce2ceca44f1e567bf6"}, + {file = "lxml-6.0.2-pp310-pypy310_pp73-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:4ddb1049fa0579d0cbd00503ad8c58b9ab34d1254c77bc6a5576d96ec7853dba"}, + {file = "lxml-6.0.2-pp310-pypy310_pp73-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:cb233f9c95f83707dae461b12b720c1af9c28c2d19208e1be03387222151daf5"}, + {file = "lxml-6.0.2-pp310-pypy310_pp73-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:bc456d04db0515ce3320d714a1eac7a97774ff0849e7718b492d957da4631dd4"}, + {file = "lxml-6.0.2-pp310-pypy310_pp73-manylinux_2_26_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:2613e67de13d619fd283d58bda40bff0ee07739f624ffee8b13b631abf33083d"}, + {file = "lxml-6.0.2-pp310-pypy310_pp73-win_amd64.whl", hash = "sha256:24a8e756c982c001ca8d59e87c80c4d9dcd4d9b44a4cbeb8d9be4482c514d41d"}, + {file = "lxml-6.0.2-pp311-pypy311_pp73-macosx_10_15_x86_64.whl", hash = "sha256:1c06035eafa8404b5cf475bb37a9f6088b0aca288d4ccc9d69389750d5543700"}, + {file = "lxml-6.0.2-pp311-pypy311_pp73-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:c7d13103045de1bdd6fe5d61802565f1a3537d70cd3abf596aa0af62761921ee"}, + {file = "lxml-6.0.2-pp311-pypy311_pp73-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:0a3c150a95fbe5ac91de323aa756219ef9cf7fde5a3f00e2281e30f33fa5fa4f"}, + {file = "lxml-6.0.2-pp311-pypy311_pp73-manylinux_2_26_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:60fa43be34f78bebb27812ed90f1925ec99560b0fa1decdb7d12b84d857d31e9"}, + {file = "lxml-6.0.2-pp311-pypy311_pp73-manylinux_2_26_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:21c73b476d3cfe836be731225ec3421fa2f048d84f6df6a8e70433dff1376d5a"}, + {file = "lxml-6.0.2-pp311-pypy311_pp73-win_amd64.whl", hash = "sha256:27220da5be049e936c3aca06f174e8827ca6445a4353a1995584311487fc4e3e"}, + {file = "lxml-6.0.2.tar.gz", hash = "sha256:cd79f3367bd74b317dda655dc8fcfa304d9eb6e4fb06b7168c5cf27f96e0cd62"}, ] [package.extras] @@ -3655,14 +3891,14 @@ python-dotenv = ">=1.0.1" [[package]] name = "markdown" -version = "3.8.2" +version = "3.9" description = "Python implementation of John Gruber's Markdown." optional = false python-versions = ">=3.9" groups = ["docs"] files = [ - {file = "markdown-3.8.2-py3-none-any.whl", hash = "sha256:5c83764dbd4e00bdd94d85a19b8d55ccca20fe35b2e678a1422b380324dd5f24"}, - {file = "markdown-3.8.2.tar.gz", hash = "sha256:247b9a70dd12e27f67431ce62523e675b866d254f900c4fe75ce3dda62237c45"}, + {file = "markdown-3.9-py3-none-any.whl", hash = "sha256:9f4d91ed810864ea88a6f32c07ba8bee1346c0cc1f6b1f9f6c822f2a9667d280"}, + {file = "markdown-3.9.tar.gz", hash = "sha256:d2900fe1782bd33bdbbd56859defef70c2e78fc46668f8eb9df3128138f2cb6a"}, ] [package.extras] @@ -3671,14 +3907,14 @@ testing = ["coverage", "pyyaml"] [[package]] name = "markdown-it-py" -version = "3.0.0" +version = "4.0.0" description = "Python port of markdown-it. Markdown parsing, done right!" optional = false -python-versions = ">=3.8" +python-versions = ">=3.10" groups = ["main"] files = [ - {file = "markdown-it-py-3.0.0.tar.gz", hash = "sha256:e3f60a94fa066dc52ec76661e37c851cb232d92f9886b15cb560aaada2df8feb"}, - {file = "markdown_it_py-3.0.0-py3-none-any.whl", hash = "sha256:355216845c60bd96232cd8d8c40e8f9765cc86f46880e43a8fd22dc1a1a8cab1"}, + {file = "markdown_it_py-4.0.0-py3-none-any.whl", hash = "sha256:87327c59b172c5011896038353a81343b6754500a08cd7a4973bb48c6d578147"}, + {file = "markdown_it_py-4.0.0.tar.gz", hash = "sha256:cb0a2b4aa34f932c007117b194e945bd74e0ec24133ceb5bac59009cda1cb9f3"}, ] [package.dependencies] @@ -3686,24 +3922,23 @@ mdurl = ">=0.1,<1.0" [package.extras] benchmarking = ["psutil", "pytest", "pytest-benchmark"] -code-style = ["pre-commit (>=3.0,<4.0)"] -compare = ["commonmark (>=0.9,<1.0)", "markdown (>=3.4,<4.0)", "mistletoe (>=1.0,<2.0)", "mistune (>=2.0,<3.0)", "panflute (>=2.3,<3.0)"] +compare = ["commonmark (>=0.9,<1.0)", "markdown (>=3.4,<4.0)", "markdown-it-pyrs", "mistletoe (>=1.0,<2.0)", "mistune (>=3.0,<4.0)", "panflute (>=2.3,<3.0)"] linkify = ["linkify-it-py (>=1,<3)"] -plugins = ["mdit-py-plugins"] +plugins = ["mdit-py-plugins (>=0.5.0)"] profiling = ["gprof2dot"] -rtd = ["jupyter_sphinx", "mdit-py-plugins", "myst-parser", "pyyaml", "sphinx", "sphinx-copybutton", "sphinx-design", "sphinx_book_theme"] -testing = ["coverage", "pytest", "pytest-cov", "pytest-regressions"] +rtd = ["ipykernel", "jupyter_sphinx", "mdit-py-plugins (>=0.5.0)", "myst-parser", "pyyaml", "sphinx", "sphinx-book-theme (>=1.0,<2.0)", "sphinx-copybutton", "sphinx-design"] +testing = ["coverage", "pytest", "pytest-cov", "pytest-regressions", "requests"] [[package]] name = "markdownify" -version = "1.1.0" +version = "1.2.0" description = "Convert HTML to markdown." optional = false python-versions = "*" groups = ["main"] files = [ - {file = "markdownify-1.1.0-py3-none-any.whl", hash = "sha256:32a5a08e9af02c8a6528942224c91b933b4bd2c7d078f9012943776fc313eeef"}, - {file = "markdownify-1.1.0.tar.gz", hash = "sha256:449c0bbbf1401c5112379619524f33b63490a8fa479456d41de9dc9e37560ebd"}, + {file = "markdownify-1.2.0-py3-none-any.whl", hash = "sha256:48e150a1c4993d4d50f282f725c0111bd9eb25645d41fa2f543708fd44161351"}, + {file = "markdownify-1.2.0.tar.gz", hash = "sha256:f6c367c54eb24ee953921804dfe6d6575c5e5b42c643955e7242034435de634c"}, ] [package.dependencies] @@ -3712,14 +3947,14 @@ six = ">=1.15,<2" [[package]] name = "markitdown" -version = "0.1.2" +version = "0.1.3" description = "Utility tool for converting various files to Markdown" optional = false python-versions = ">=3.10" groups = ["main"] files = [ - {file = "markitdown-0.1.2-py3-none-any.whl", hash = "sha256:4881f0768794ffccb52d09dd86498813a6896ba9639b4fc15512817f56ed9d74"}, - {file = "markitdown-0.1.2.tar.gz", hash = "sha256:85fe108a92bd18f317e75a36cf567a6fa812072612a898abf8c156d5d74c13c4"}, + {file = "markitdown-0.1.3-py3-none-any.whl", hash = "sha256:08d9a25770979d78f60dcc0afcb868de6799608e4db65342b2e03304fb091251"}, + {file = "markitdown-0.1.3.tar.gz", hash = "sha256:b0d9127c3373a68274dede6af6c9bb0684b78ce364c727c4c304da97a20d6fd9"}, ] [package.dependencies] @@ -3728,10 +3963,11 @@ charset-normalizer = "*" defusedxml = "*" magika = ">=0.6.1,<0.7.0" markdownify = "*" +onnxruntime = {version = "<=1.20.1", markers = "sys_platform == \"win32\""} requests = "*" [package.extras] -all = ["azure-ai-documentintelligence", "azure-identity", "lxml", "mammoth", "olefile", "openpyxl", "pandas", "pdfminer-six", "pydub", "python-pptx", "speechrecognition", "xlrd", "youtube-transcript-api (>=1.0.0,<1.1.0)"] +all = ["azure-ai-documentintelligence", "azure-identity", "lxml", "mammoth (>=1.10.0,<1.11.0)", "olefile", "openpyxl", "pandas", "pdfminer-six", "pydub", "python-pptx", "speechrecognition", "xlrd", "youtube-transcript-api (>=1.0.0,<1.1.0)"] audio-transcription = ["pydub", "speechrecognition"] az-doc-intel = ["azure-ai-documentintelligence", "azure-identity"] docx = ["lxml", "mammoth"] @@ -3744,117 +3980,166 @@ youtube-transcription = ["youtube-transcript-api"] [[package]] name = "markupsafe" -version = "3.0.2" +version = "3.0.3" description = "Safely add untrusted strings to HTML/XML markup." optional = false python-versions = ">=3.9" groups = ["main", "docs"] files = [ - {file = "MarkupSafe-3.0.2-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:7e94c425039cde14257288fd61dcfb01963e658efbc0ff54f5306b06054700f8"}, - {file = "MarkupSafe-3.0.2-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:9e2d922824181480953426608b81967de705c3cef4d1af983af849d7bd619158"}, - {file = "MarkupSafe-3.0.2-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:38a9ef736c01fccdd6600705b09dc574584b89bea478200c5fbf112a6b0d5579"}, - {file = "MarkupSafe-3.0.2-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:bbcb445fa71794da8f178f0f6d66789a28d7319071af7a496d4d507ed566270d"}, - {file = "MarkupSafe-3.0.2-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:57cb5a3cf367aeb1d316576250f65edec5bb3be939e9247ae594b4bcbc317dfb"}, - {file = "MarkupSafe-3.0.2-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:3809ede931876f5b2ec92eef964286840ed3540dadf803dd570c3b7e13141a3b"}, - {file = "MarkupSafe-3.0.2-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:e07c3764494e3776c602c1e78e298937c3315ccc9043ead7e685b7f2b8d47b3c"}, - {file = "MarkupSafe-3.0.2-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:b424c77b206d63d500bcb69fa55ed8d0e6a3774056bdc4839fc9298a7edca171"}, - {file = "MarkupSafe-3.0.2-cp310-cp310-win32.whl", hash = "sha256:fcabf5ff6eea076f859677f5f0b6b5c1a51e70a376b0579e0eadef8db48c6b50"}, - {file = "MarkupSafe-3.0.2-cp310-cp310-win_amd64.whl", hash = "sha256:6af100e168aa82a50e186c82875a5893c5597a0c1ccdb0d8b40240b1f28b969a"}, - {file = "MarkupSafe-3.0.2-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:9025b4018f3a1314059769c7bf15441064b2207cb3f065e6ea1e7359cb46db9d"}, - {file = "MarkupSafe-3.0.2-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:93335ca3812df2f366e80509ae119189886b0f3c2b81325d39efdb84a1e2ae93"}, - {file = "MarkupSafe-3.0.2-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:2cb8438c3cbb25e220c2ab33bb226559e7afb3baec11c4f218ffa7308603c832"}, - {file = "MarkupSafe-3.0.2-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:a123e330ef0853c6e822384873bef7507557d8e4a082961e1defa947aa59ba84"}, - {file = "MarkupSafe-3.0.2-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:1e084f686b92e5b83186b07e8a17fc09e38fff551f3602b249881fec658d3eca"}, - {file = "MarkupSafe-3.0.2-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:d8213e09c917a951de9d09ecee036d5c7d36cb6cb7dbaece4c71a60d79fb9798"}, - {file = "MarkupSafe-3.0.2-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:5b02fb34468b6aaa40dfc198d813a641e3a63b98c2b05a16b9f80b7ec314185e"}, - {file = "MarkupSafe-3.0.2-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:0bff5e0ae4ef2e1ae4fdf2dfd5b76c75e5c2fa4132d05fc1b0dabcd20c7e28c4"}, - {file = "MarkupSafe-3.0.2-cp311-cp311-win32.whl", hash = "sha256:6c89876f41da747c8d3677a2b540fb32ef5715f97b66eeb0c6b66f5e3ef6f59d"}, - {file = "MarkupSafe-3.0.2-cp311-cp311-win_amd64.whl", hash = "sha256:70a87b411535ccad5ef2f1df5136506a10775d267e197e4cf531ced10537bd6b"}, - {file = "MarkupSafe-3.0.2-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:9778bd8ab0a994ebf6f84c2b949e65736d5575320a17ae8984a77fab08db94cf"}, - {file = "MarkupSafe-3.0.2-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:846ade7b71e3536c4e56b386c2a47adf5741d2d8b94ec9dc3e92e5e1ee1e2225"}, - {file = "MarkupSafe-3.0.2-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:1c99d261bd2d5f6b59325c92c73df481e05e57f19837bdca8413b9eac4bd8028"}, - {file = "MarkupSafe-3.0.2-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:e17c96c14e19278594aa4841ec148115f9c7615a47382ecb6b82bd8fea3ab0c8"}, - {file = "MarkupSafe-3.0.2-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:88416bd1e65dcea10bc7569faacb2c20ce071dd1f87539ca2ab364bf6231393c"}, - {file = "MarkupSafe-3.0.2-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:2181e67807fc2fa785d0592dc2d6206c019b9502410671cc905d132a92866557"}, - {file = "MarkupSafe-3.0.2-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:52305740fe773d09cffb16f8ed0427942901f00adedac82ec8b67752f58a1b22"}, - {file = "MarkupSafe-3.0.2-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:ad10d3ded218f1039f11a75f8091880239651b52e9bb592ca27de44eed242a48"}, - {file = "MarkupSafe-3.0.2-cp312-cp312-win32.whl", hash = "sha256:0f4ca02bea9a23221c0182836703cbf8930c5e9454bacce27e767509fa286a30"}, - {file = "MarkupSafe-3.0.2-cp312-cp312-win_amd64.whl", hash = "sha256:8e06879fc22a25ca47312fbe7c8264eb0b662f6db27cb2d3bbbc74b1df4b9b87"}, - {file = "MarkupSafe-3.0.2-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:ba9527cdd4c926ed0760bc301f6728ef34d841f405abf9d4f959c478421e4efd"}, - {file = "MarkupSafe-3.0.2-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:f8b3d067f2e40fe93e1ccdd6b2e1d16c43140e76f02fb1319a05cf2b79d99430"}, - {file = "MarkupSafe-3.0.2-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:569511d3b58c8791ab4c2e1285575265991e6d8f8700c7be0e88f86cb0672094"}, - {file = "MarkupSafe-3.0.2-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:15ab75ef81add55874e7ab7055e9c397312385bd9ced94920f2802310c930396"}, - {file = "MarkupSafe-3.0.2-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:f3818cb119498c0678015754eba762e0d61e5b52d34c8b13d770f0719f7b1d79"}, - {file = "MarkupSafe-3.0.2-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:cdb82a876c47801bb54a690c5ae105a46b392ac6099881cdfb9f6e95e4014c6a"}, - {file = "MarkupSafe-3.0.2-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:cabc348d87e913db6ab4aa100f01b08f481097838bdddf7c7a84b7575b7309ca"}, - {file = "MarkupSafe-3.0.2-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:444dcda765c8a838eaae23112db52f1efaf750daddb2d9ca300bcae1039adc5c"}, - {file = "MarkupSafe-3.0.2-cp313-cp313-win32.whl", hash = "sha256:bcf3e58998965654fdaff38e58584d8937aa3096ab5354d493c77d1fdd66d7a1"}, - {file = "MarkupSafe-3.0.2-cp313-cp313-win_amd64.whl", hash = "sha256:e6a2a455bd412959b57a172ce6328d2dd1f01cb2135efda2e4576e8a23fa3b0f"}, - {file = "MarkupSafe-3.0.2-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:b5a6b3ada725cea8a5e634536b1b01c30bcdcd7f9c6fff4151548d5bf6b3a36c"}, - {file = "MarkupSafe-3.0.2-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:a904af0a6162c73e3edcb969eeeb53a63ceeb5d8cf642fade7d39e7963a22ddb"}, - {file = "MarkupSafe-3.0.2-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:4aa4e5faecf353ed117801a068ebab7b7e09ffb6e1d5e412dc852e0da018126c"}, - {file = "MarkupSafe-3.0.2-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:c0ef13eaeee5b615fb07c9a7dadb38eac06a0608b41570d8ade51c56539e509d"}, - {file = "MarkupSafe-3.0.2-cp313-cp313t-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:d16a81a06776313e817c951135cf7340a3e91e8c1ff2fac444cfd75fffa04afe"}, - {file = "MarkupSafe-3.0.2-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:6381026f158fdb7c72a168278597a5e3a5222e83ea18f543112b2662a9b699c5"}, - {file = "MarkupSafe-3.0.2-cp313-cp313t-musllinux_1_2_i686.whl", hash = "sha256:3d79d162e7be8f996986c064d1c7c817f6df3a77fe3d6859f6f9e7be4b8c213a"}, - {file = "MarkupSafe-3.0.2-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:131a3c7689c85f5ad20f9f6fb1b866f402c445b220c19fe4308c0b147ccd2ad9"}, - {file = "MarkupSafe-3.0.2-cp313-cp313t-win32.whl", hash = "sha256:ba8062ed2cf21c07a9e295d5b8a2a5ce678b913b45fdf68c32d95d6c1291e0b6"}, - {file = "MarkupSafe-3.0.2-cp313-cp313t-win_amd64.whl", hash = "sha256:e444a31f8db13eb18ada366ab3cf45fd4b31e4db1236a4448f68778c1d1a5a2f"}, - {file = "MarkupSafe-3.0.2-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:eaa0a10b7f72326f1372a713e73c3f739b524b3af41feb43e4921cb529f5929a"}, - {file = "MarkupSafe-3.0.2-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:48032821bbdf20f5799ff537c7ac3d1fba0ba032cfc06194faffa8cda8b560ff"}, - {file = "MarkupSafe-3.0.2-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:1a9d3f5f0901fdec14d8d2f66ef7d035f2157240a433441719ac9a3fba440b13"}, - {file = "MarkupSafe-3.0.2-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:88b49a3b9ff31e19998750c38e030fc7bb937398b1f78cfa599aaef92d693144"}, - {file = "MarkupSafe-3.0.2-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:cfad01eed2c2e0c01fd0ecd2ef42c492f7f93902e39a42fc9ee1692961443a29"}, - {file = "MarkupSafe-3.0.2-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:1225beacc926f536dc82e45f8a4d68502949dc67eea90eab715dea3a21c1b5f0"}, - {file = "MarkupSafe-3.0.2-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:3169b1eefae027567d1ce6ee7cae382c57fe26e82775f460f0b2778beaad66c0"}, - {file = "MarkupSafe-3.0.2-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:eb7972a85c54febfb25b5c4b4f3af4dcc731994c7da0d8a0b4a6eb0640e1d178"}, - {file = "MarkupSafe-3.0.2-cp39-cp39-win32.whl", hash = "sha256:8c4e8c3ce11e1f92f6536ff07154f9d49677ebaaafc32db9db4620bc11ed480f"}, - {file = "MarkupSafe-3.0.2-cp39-cp39-win_amd64.whl", hash = "sha256:6e296a513ca3d94054c2c881cc913116e90fd030ad1c656b3869762b754f5f8a"}, - {file = "markupsafe-3.0.2.tar.gz", hash = "sha256:ee55d3edf80167e48ea11a923c7386f4669df67d7994554387f84e7d8b0a2bf0"}, + {file = "markupsafe-3.0.3-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:2f981d352f04553a7171b8e44369f2af4055f888dfb147d55e42d29e29e74559"}, + {file = "markupsafe-3.0.3-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:e1c1493fb6e50ab01d20a22826e57520f1284df32f2d8601fdd90b6304601419"}, + {file = "markupsafe-3.0.3-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:1ba88449deb3de88bd40044603fafffb7bc2b055d626a330323a9ed736661695"}, + {file = "markupsafe-3.0.3-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:f42d0984e947b8adf7dd6dde396e720934d12c506ce84eea8476409563607591"}, + {file = "markupsafe-3.0.3-cp310-cp310-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:c0c0b3ade1c0b13b936d7970b1d37a57acde9199dc2aecc4c336773e1d86049c"}, + {file = "markupsafe-3.0.3-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:0303439a41979d9e74d18ff5e2dd8c43ed6c6001fd40e5bf2e43f7bd9bbc523f"}, + {file = "markupsafe-3.0.3-cp310-cp310-musllinux_1_2_riscv64.whl", hash = "sha256:d2ee202e79d8ed691ceebae8e0486bd9a2cd4794cec4824e1c99b6f5009502f6"}, + {file = "markupsafe-3.0.3-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:177b5253b2834fe3678cb4a5f0059808258584c559193998be2601324fdeafb1"}, + {file = "markupsafe-3.0.3-cp310-cp310-win32.whl", hash = "sha256:2a15a08b17dd94c53a1da0438822d70ebcd13f8c3a95abe3a9ef9f11a94830aa"}, + {file = "markupsafe-3.0.3-cp310-cp310-win_amd64.whl", hash = "sha256:c4ffb7ebf07cfe8931028e3e4c85f0357459a3f9f9490886198848f4fa002ec8"}, + {file = "markupsafe-3.0.3-cp310-cp310-win_arm64.whl", hash = "sha256:e2103a929dfa2fcaf9bb4e7c091983a49c9ac3b19c9061b6d5427dd7d14d81a1"}, + {file = "markupsafe-3.0.3-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:1cc7ea17a6824959616c525620e387f6dd30fec8cb44f649e31712db02123dad"}, + {file = "markupsafe-3.0.3-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:4bd4cd07944443f5a265608cc6aab442e4f74dff8088b0dfc8238647b8f6ae9a"}, + {file = "markupsafe-3.0.3-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:6b5420a1d9450023228968e7e6a9ce57f65d148ab56d2313fcd589eee96a7a50"}, + {file = "markupsafe-3.0.3-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:0bf2a864d67e76e5c9a34dc26ec616a66b9888e25e7b9460e1c76d3293bd9dbf"}, + {file = "markupsafe-3.0.3-cp311-cp311-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:bc51efed119bc9cfdf792cdeaa4d67e8f6fcccab66ed4bfdd6bde3e59bfcbb2f"}, + {file = "markupsafe-3.0.3-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:068f375c472b3e7acbe2d5318dea141359e6900156b5b2ba06a30b169086b91a"}, + {file = "markupsafe-3.0.3-cp311-cp311-musllinux_1_2_riscv64.whl", hash = "sha256:7be7b61bb172e1ed687f1754f8e7484f1c8019780f6f6b0786e76bb01c2ae115"}, + {file = "markupsafe-3.0.3-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:f9e130248f4462aaa8e2552d547f36ddadbeaa573879158d721bbd33dfe4743a"}, + {file = "markupsafe-3.0.3-cp311-cp311-win32.whl", hash = "sha256:0db14f5dafddbb6d9208827849fad01f1a2609380add406671a26386cdf15a19"}, + {file = "markupsafe-3.0.3-cp311-cp311-win_amd64.whl", hash = "sha256:de8a88e63464af587c950061a5e6a67d3632e36df62b986892331d4620a35c01"}, + {file = "markupsafe-3.0.3-cp311-cp311-win_arm64.whl", hash = "sha256:3b562dd9e9ea93f13d53989d23a7e775fdfd1066c33494ff43f5418bc8c58a5c"}, + {file = "markupsafe-3.0.3-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:d53197da72cc091b024dd97249dfc7794d6a56530370992a5e1a08983ad9230e"}, + {file = "markupsafe-3.0.3-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:1872df69a4de6aead3491198eaf13810b565bdbeec3ae2dc8780f14458ec73ce"}, + {file = "markupsafe-3.0.3-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:3a7e8ae81ae39e62a41ec302f972ba6ae23a5c5396c8e60113e9066ef893da0d"}, + {file = "markupsafe-3.0.3-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:d6dd0be5b5b189d31db7cda48b91d7e0a9795f31430b7f271219ab30f1d3ac9d"}, + {file = "markupsafe-3.0.3-cp312-cp312-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:94c6f0bb423f739146aec64595853541634bde58b2135f27f61c1ffd1cd4d16a"}, + {file = "markupsafe-3.0.3-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:be8813b57049a7dc738189df53d69395eba14fb99345e0a5994914a3864c8a4b"}, + {file = "markupsafe-3.0.3-cp312-cp312-musllinux_1_2_riscv64.whl", hash = "sha256:83891d0e9fb81a825d9a6d61e3f07550ca70a076484292a70fde82c4b807286f"}, + {file = "markupsafe-3.0.3-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:77f0643abe7495da77fb436f50f8dab76dbc6e5fd25d39589a0f1fe6548bfa2b"}, + {file = "markupsafe-3.0.3-cp312-cp312-win32.whl", hash = "sha256:d88b440e37a16e651bda4c7c2b930eb586fd15ca7406cb39e211fcff3bf3017d"}, + {file = "markupsafe-3.0.3-cp312-cp312-win_amd64.whl", hash = "sha256:26a5784ded40c9e318cfc2bdb30fe164bdb8665ded9cd64d500a34fb42067b1c"}, + {file = "markupsafe-3.0.3-cp312-cp312-win_arm64.whl", hash = "sha256:35add3b638a5d900e807944a078b51922212fb3dedb01633a8defc4b01a3c85f"}, + {file = "markupsafe-3.0.3-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:e1cf1972137e83c5d4c136c43ced9ac51d0e124706ee1c8aa8532c1287fa8795"}, + {file = "markupsafe-3.0.3-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:116bb52f642a37c115f517494ea5feb03889e04df47eeff5b130b1808ce7c219"}, + {file = "markupsafe-3.0.3-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:133a43e73a802c5562be9bbcd03d090aa5a1fe899db609c29e8c8d815c5f6de6"}, + {file = "markupsafe-3.0.3-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:ccfcd093f13f0f0b7fdd0f198b90053bf7b2f02a3927a30e63f3ccc9df56b676"}, + {file = "markupsafe-3.0.3-cp313-cp313-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:509fa21c6deb7a7a273d629cf5ec029bc209d1a51178615ddf718f5918992ab9"}, + {file = "markupsafe-3.0.3-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:a4afe79fb3de0b7097d81da19090f4df4f8d3a2b3adaa8764138aac2e44f3af1"}, + {file = "markupsafe-3.0.3-cp313-cp313-musllinux_1_2_riscv64.whl", hash = "sha256:795e7751525cae078558e679d646ae45574b47ed6e7771863fcc079a6171a0fc"}, + {file = "markupsafe-3.0.3-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:8485f406a96febb5140bfeca44a73e3ce5116b2501ac54fe953e488fb1d03b12"}, + {file = "markupsafe-3.0.3-cp313-cp313-win32.whl", hash = "sha256:bdd37121970bfd8be76c5fb069c7751683bdf373db1ed6c010162b2a130248ed"}, + {file = "markupsafe-3.0.3-cp313-cp313-win_amd64.whl", hash = "sha256:9a1abfdc021a164803f4d485104931fb8f8c1efd55bc6b748d2f5774e78b62c5"}, + {file = "markupsafe-3.0.3-cp313-cp313-win_arm64.whl", hash = "sha256:7e68f88e5b8799aa49c85cd116c932a1ac15caaa3f5db09087854d218359e485"}, + {file = "markupsafe-3.0.3-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:218551f6df4868a8d527e3062d0fb968682fe92054e89978594c28e642c43a73"}, + {file = "markupsafe-3.0.3-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:3524b778fe5cfb3452a09d31e7b5adefeea8c5be1d43c4f810ba09f2ceb29d37"}, + {file = "markupsafe-3.0.3-cp313-cp313t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:4e885a3d1efa2eadc93c894a21770e4bc67899e3543680313b09f139e149ab19"}, + {file = "markupsafe-3.0.3-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:8709b08f4a89aa7586de0aadc8da56180242ee0ada3999749b183aa23df95025"}, + {file = "markupsafe-3.0.3-cp313-cp313t-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:b8512a91625c9b3da6f127803b166b629725e68af71f8184ae7e7d54686a56d6"}, + {file = "markupsafe-3.0.3-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:9b79b7a16f7fedff2495d684f2b59b0457c3b493778c9eed31111be64d58279f"}, + {file = "markupsafe-3.0.3-cp313-cp313t-musllinux_1_2_riscv64.whl", hash = "sha256:12c63dfb4a98206f045aa9563db46507995f7ef6d83b2f68eda65c307c6829eb"}, + {file = "markupsafe-3.0.3-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:8f71bc33915be5186016f675cd83a1e08523649b0e33efdb898db577ef5bb009"}, + {file = "markupsafe-3.0.3-cp313-cp313t-win32.whl", hash = "sha256:69c0b73548bc525c8cb9a251cddf1931d1db4d2258e9599c28c07ef3580ef354"}, + {file = "markupsafe-3.0.3-cp313-cp313t-win_amd64.whl", hash = "sha256:1b4b79e8ebf6b55351f0d91fe80f893b4743f104bff22e90697db1590e47a218"}, + {file = "markupsafe-3.0.3-cp313-cp313t-win_arm64.whl", hash = "sha256:ad2cf8aa28b8c020ab2fc8287b0f823d0a7d8630784c31e9ee5edea20f406287"}, + {file = "markupsafe-3.0.3-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:eaa9599de571d72e2daf60164784109f19978b327a3910d3e9de8c97b5b70cfe"}, + {file = "markupsafe-3.0.3-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:c47a551199eb8eb2121d4f0f15ae0f923d31350ab9280078d1e5f12b249e0026"}, + {file = "markupsafe-3.0.3-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:f34c41761022dd093b4b6896d4810782ffbabe30f2d443ff5f083e0cbbb8c737"}, + {file = "markupsafe-3.0.3-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:457a69a9577064c05a97c41f4e65148652db078a3a509039e64d3467b9e7ef97"}, + {file = "markupsafe-3.0.3-cp314-cp314-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:e8afc3f2ccfa24215f8cb28dcf43f0113ac3c37c2f0f0806d8c70e4228c5cf4d"}, + {file = "markupsafe-3.0.3-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:ec15a59cf5af7be74194f7ab02d0f59a62bdcf1a537677ce67a2537c9b87fcda"}, + {file = "markupsafe-3.0.3-cp314-cp314-musllinux_1_2_riscv64.whl", hash = "sha256:0eb9ff8191e8498cca014656ae6b8d61f39da5f95b488805da4bb029cccbfbaf"}, + {file = "markupsafe-3.0.3-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:2713baf880df847f2bece4230d4d094280f4e67b1e813eec43b4c0e144a34ffe"}, + {file = "markupsafe-3.0.3-cp314-cp314-win32.whl", hash = "sha256:729586769a26dbceff69f7a7dbbf59ab6572b99d94576a5592625d5b411576b9"}, + {file = "markupsafe-3.0.3-cp314-cp314-win_amd64.whl", hash = "sha256:bdc919ead48f234740ad807933cdf545180bfbe9342c2bb451556db2ed958581"}, + {file = "markupsafe-3.0.3-cp314-cp314-win_arm64.whl", hash = "sha256:5a7d5dc5140555cf21a6fefbdbf8723f06fcd2f63ef108f2854de715e4422cb4"}, + {file = "markupsafe-3.0.3-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:1353ef0c1b138e1907ae78e2f6c63ff67501122006b0f9abad68fda5f4ffc6ab"}, + {file = "markupsafe-3.0.3-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:1085e7fbddd3be5f89cc898938f42c0b3c711fdcb37d75221de2666af647c175"}, + {file = "markupsafe-3.0.3-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:1b52b4fb9df4eb9ae465f8d0c228a00624de2334f216f178a995ccdcf82c4634"}, + {file = "markupsafe-3.0.3-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:fed51ac40f757d41b7c48425901843666a6677e3e8eb0abcff09e4ba6e664f50"}, + {file = "markupsafe-3.0.3-cp314-cp314t-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:f190daf01f13c72eac4efd5c430a8de82489d9cff23c364c3ea822545032993e"}, + {file = "markupsafe-3.0.3-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:e56b7d45a839a697b5eb268c82a71bd8c7f6c94d6fd50c3d577fa39a9f1409f5"}, + {file = "markupsafe-3.0.3-cp314-cp314t-musllinux_1_2_riscv64.whl", hash = "sha256:f3e98bb3798ead92273dc0e5fd0f31ade220f59a266ffd8a4f6065e0a3ce0523"}, + {file = "markupsafe-3.0.3-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:5678211cb9333a6468fb8d8be0305520aa073f50d17f089b5b4b477ea6e67fdc"}, + {file = "markupsafe-3.0.3-cp314-cp314t-win32.whl", hash = "sha256:915c04ba3851909ce68ccc2b8e2cd691618c4dc4c4232fb7982bca3f41fd8c3d"}, + {file = "markupsafe-3.0.3-cp314-cp314t-win_amd64.whl", hash = "sha256:4faffd047e07c38848ce017e8725090413cd80cbc23d86e55c587bf979e579c9"}, + {file = "markupsafe-3.0.3-cp314-cp314t-win_arm64.whl", hash = "sha256:32001d6a8fc98c8cb5c947787c5d08b0a50663d139f1305bac5885d98d9b40fa"}, + {file = "markupsafe-3.0.3-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:15d939a21d546304880945ca1ecb8a039db6b4dc49b2c5a400387cdae6a62e26"}, + {file = "markupsafe-3.0.3-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:f71a396b3bf33ecaa1626c255855702aca4d3d9fea5e051b41ac59a9c1c41edc"}, + {file = "markupsafe-3.0.3-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:0f4b68347f8c5eab4a13419215bdfd7f8c9b19f2b25520968adfad23eb0ce60c"}, + {file = "markupsafe-3.0.3-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:e8fc20152abba6b83724d7ff268c249fa196d8259ff481f3b1476383f8f24e42"}, + {file = "markupsafe-3.0.3-cp39-cp39-manylinux_2_31_riscv64.manylinux_2_39_riscv64.whl", hash = "sha256:949b8d66bc381ee8b007cd945914c721d9aba8e27f71959d750a46f7c282b20b"}, + {file = "markupsafe-3.0.3-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:3537e01efc9d4dccdf77221fb1cb3b8e1a38d5428920e0657ce299b20324d758"}, + {file = "markupsafe-3.0.3-cp39-cp39-musllinux_1_2_riscv64.whl", hash = "sha256:591ae9f2a647529ca990bc681daebdd52c8791ff06c2bfa05b65163e28102ef2"}, + {file = "markupsafe-3.0.3-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:a320721ab5a1aba0a233739394eb907f8c8da5c98c9181d1161e77a0c8e36f2d"}, + {file = "markupsafe-3.0.3-cp39-cp39-win32.whl", hash = "sha256:df2449253ef108a379b8b5d6b43f4b1a8e81a061d6537becd5582fba5f9196d7"}, + {file = "markupsafe-3.0.3-cp39-cp39-win_amd64.whl", hash = "sha256:7c3fb7d25180895632e5d3148dbdc29ea38ccb7fd210aa27acbd1201a1902c6e"}, + {file = "markupsafe-3.0.3-cp39-cp39-win_arm64.whl", hash = "sha256:38664109c14ffc9e7437e86b4dceb442b0096dfe3541d7864d9cbe1da4cf36c8"}, + {file = "markupsafe-3.0.3.tar.gz", hash = "sha256:722695808f4b6457b320fdc131280796bdceb04ab50fe1795cd540799ebe1698"}, ] [[package]] name = "matplotlib" -version = "3.10.3" +version = "3.10.7" description = "Python plotting package" optional = false python-versions = ">=3.10" groups = ["main"] files = [ - {file = "matplotlib-3.10.3-cp310-cp310-macosx_10_12_x86_64.whl", hash = "sha256:213fadd6348d106ca7db99e113f1bea1e65e383c3ba76e8556ba4a3054b65ae7"}, - {file = "matplotlib-3.10.3-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:d3bec61cb8221f0ca6313889308326e7bb303d0d302c5cc9e523b2f2e6c73deb"}, - {file = "matplotlib-3.10.3-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:8c21ae75651c0231b3ba014b6d5e08fb969c40cdb5a011e33e99ed0c9ea86ecb"}, - {file = "matplotlib-3.10.3-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:a49e39755580b08e30e3620efc659330eac5d6534ab7eae50fa5e31f53ee4e30"}, - {file = "matplotlib-3.10.3-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:cf4636203e1190871d3a73664dea03d26fb019b66692cbfd642faafdad6208e8"}, - {file = "matplotlib-3.10.3-cp310-cp310-win_amd64.whl", hash = "sha256:fd5641a9bb9d55f4dd2afe897a53b537c834b9012684c8444cc105895c8c16fd"}, - {file = "matplotlib-3.10.3-cp311-cp311-macosx_10_12_x86_64.whl", hash = "sha256:0ef061f74cd488586f552d0c336b2f078d43bc00dc473d2c3e7bfee2272f3fa8"}, - {file = "matplotlib-3.10.3-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:d96985d14dc5f4a736bbea4b9de9afaa735f8a0fc2ca75be2fa9e96b2097369d"}, - {file = "matplotlib-3.10.3-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:7c5f0283da91e9522bdba4d6583ed9d5521566f63729ffb68334f86d0bb98049"}, - {file = "matplotlib-3.10.3-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:fdfa07c0ec58035242bc8b2c8aae37037c9a886370eef6850703d7583e19964b"}, - {file = "matplotlib-3.10.3-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:c0b9849a17bce080a16ebcb80a7b714b5677d0ec32161a2cc0a8e5a6030ae220"}, - {file = "matplotlib-3.10.3-cp311-cp311-win_amd64.whl", hash = "sha256:eef6ed6c03717083bc6d69c2d7ee8624205c29a8e6ea5a31cd3492ecdbaee1e1"}, - {file = "matplotlib-3.10.3-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:0ab1affc11d1f495ab9e6362b8174a25afc19c081ba5b0775ef00533a4236eea"}, - {file = "matplotlib-3.10.3-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:2a818d8bdcafa7ed2eed74487fdb071c09c1ae24152d403952adad11fa3c65b4"}, - {file = "matplotlib-3.10.3-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:748ebc3470c253e770b17d8b0557f0aa85cf8c63fd52f1a61af5b27ec0b7ffee"}, - {file = "matplotlib-3.10.3-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:ed70453fd99733293ace1aec568255bc51c6361cb0da94fa5ebf0649fdb2150a"}, - {file = "matplotlib-3.10.3-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:dbed9917b44070e55640bd13419de83b4c918e52d97561544814ba463811cbc7"}, - {file = "matplotlib-3.10.3-cp312-cp312-win_amd64.whl", hash = "sha256:cf37d8c6ef1a48829443e8ba5227b44236d7fcaf7647caa3178a4ff9f7a5be05"}, - {file = "matplotlib-3.10.3-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:9f2efccc8dcf2b86fc4ee849eea5dcaecedd0773b30f47980dc0cbeabf26ec84"}, - {file = "matplotlib-3.10.3-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:3ddbba06a6c126e3301c3d272a99dcbe7f6c24c14024e80307ff03791a5f294e"}, - {file = "matplotlib-3.10.3-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:748302b33ae9326995b238f606e9ed840bf5886ebafcb233775d946aa8107a15"}, - {file = "matplotlib-3.10.3-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:a80fcccbef63302c0efd78042ea3c2436104c5b1a4d3ae20f864593696364ac7"}, - {file = "matplotlib-3.10.3-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:55e46cbfe1f8586adb34f7587c3e4f7dedc59d5226719faf6cb54fc24f2fd52d"}, - {file = "matplotlib-3.10.3-cp313-cp313-win_amd64.whl", hash = "sha256:151d89cb8d33cb23345cd12490c76fd5d18a56581a16d950b48c6ff19bb2ab93"}, - {file = "matplotlib-3.10.3-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:c26dd9834e74d164d06433dc7be5d75a1e9890b926b3e57e74fa446e1a62c3e2"}, - {file = "matplotlib-3.10.3-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:24853dad5b8c84c8c2390fc31ce4858b6df504156893292ce8092d190ef8151d"}, - {file = "matplotlib-3.10.3-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:68f7878214d369d7d4215e2a9075fef743be38fa401d32e6020bab2dfabaa566"}, - {file = "matplotlib-3.10.3-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:f6929fc618cb6db9cb75086f73b3219bbb25920cb24cee2ea7a12b04971a4158"}, - {file = "matplotlib-3.10.3-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:6c7818292a5cc372a2dc4c795e5c356942eb8350b98ef913f7fda51fe175ac5d"}, - {file = "matplotlib-3.10.3-cp313-cp313t-win_amd64.whl", hash = "sha256:4f23ffe95c5667ef8a2b56eea9b53db7f43910fa4a2d5472ae0f72b64deab4d5"}, - {file = "matplotlib-3.10.3-pp310-pypy310_pp73-macosx_10_15_x86_64.whl", hash = "sha256:86ab63d66bbc83fdb6733471d3bff40897c1e9921cba112accd748eee4bce5e4"}, - {file = "matplotlib-3.10.3-pp310-pypy310_pp73-macosx_11_0_arm64.whl", hash = "sha256:a48f9c08bf7444b5d2391a83e75edb464ccda3c380384b36532a0962593a1751"}, - {file = "matplotlib-3.10.3-pp310-pypy310_pp73-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:cb73d8aa75a237457988f9765e4dfe1c0d2453c5ca4eabc897d4309672c8e014"}, - {file = "matplotlib-3.10.3.tar.gz", hash = "sha256:2f82d2c5bb7ae93aaaa4cd42aca65d76ce6376f83304fa3a630b569aca274df0"}, + {file = "matplotlib-3.10.7-cp310-cp310-macosx_10_12_x86_64.whl", hash = "sha256:7ac81eee3b7c266dd92cee1cd658407b16c57eed08c7421fa354ed68234de380"}, + {file = "matplotlib-3.10.7-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:667ecd5d8d37813a845053d8f5bf110b534c3c9f30e69ebd25d4701385935a6d"}, + {file = "matplotlib-3.10.7-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:cc1c51b846aca49a5a8b44fbba6a92d583a35c64590ad9e1e950dc88940a4297"}, + {file = "matplotlib-3.10.7-cp310-cp310-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:4a11c2e9e72e7de09b7b72e62f3df23317c888299c875e2b778abf1eda8c0a42"}, + {file = "matplotlib-3.10.7-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:f19410b486fdd139885ace124e57f938c1e6a3210ea13dd29cab58f5d4bc12c7"}, + {file = "matplotlib-3.10.7-cp310-cp310-win_amd64.whl", hash = "sha256:b498e9e4022f93de2d5a37615200ca01297ceebbb56fe4c833f46862a490f9e3"}, + {file = "matplotlib-3.10.7-cp311-cp311-macosx_10_12_x86_64.whl", hash = "sha256:53b492410a6cd66c7a471de6c924f6ede976e963c0f3097a3b7abfadddc67d0a"}, + {file = "matplotlib-3.10.7-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:d9749313deb729f08207718d29c86246beb2ea3fdba753595b55901dee5d2fd6"}, + {file = "matplotlib-3.10.7-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:2222c7ba2cbde7fe63032769f6eb7e83ab3227f47d997a8453377709b7fe3a5a"}, + {file = "matplotlib-3.10.7-cp311-cp311-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:e91f61a064c92c307c5a9dc8c05dc9f8a68f0a3be199d9a002a0622e13f874a1"}, + {file = "matplotlib-3.10.7-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:6f1851eab59ca082c95df5a500106bad73672645625e04538b3ad0f69471ffcc"}, + {file = "matplotlib-3.10.7-cp311-cp311-win_amd64.whl", hash = "sha256:6516ce375109c60ceec579e699524e9d504cd7578506f01150f7a6bc174a775e"}, + {file = "matplotlib-3.10.7-cp311-cp311-win_arm64.whl", hash = "sha256:b172db79759f5f9bc13ef1c3ef8b9ee7b37b0247f987fbbbdaa15e4f87fd46a9"}, + {file = "matplotlib-3.10.7-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:7a0edb7209e21840e8361e91ea84ea676658aa93edd5f8762793dec77a4a6748"}, + {file = "matplotlib-3.10.7-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:c380371d3c23e0eadf8ebff114445b9f970aff2010198d498d4ab4c3b41eea4f"}, + {file = "matplotlib-3.10.7-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:d5f256d49fea31f40f166a5e3131235a5d2f4b7f44520b1cf0baf1ce568ccff0"}, + {file = "matplotlib-3.10.7-cp312-cp312-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:11ae579ac83cdf3fb72573bb89f70e0534de05266728740d478f0f818983c695"}, + {file = "matplotlib-3.10.7-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:4c14b6acd16cddc3569a2d515cfdd81c7a68ac5639b76548cfc1a9e48b20eb65"}, + {file = "matplotlib-3.10.7-cp312-cp312-win_amd64.whl", hash = "sha256:0d8c32b7ea6fb80b1aeff5a2ceb3fb9778e2759e899d9beff75584714afcc5ee"}, + {file = "matplotlib-3.10.7-cp312-cp312-win_arm64.whl", hash = "sha256:5f3f6d315dcc176ba7ca6e74c7768fb7e4cf566c49cb143f6bc257b62e634ed8"}, + {file = "matplotlib-3.10.7-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:1d9d3713a237970569156cfb4de7533b7c4eacdd61789726f444f96a0d28f57f"}, + {file = "matplotlib-3.10.7-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:37a1fea41153dd6ee061d21ab69c9cf2cf543160b1b85d89cd3d2e2a7902ca4c"}, + {file = "matplotlib-3.10.7-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:b3c4ea4948d93c9c29dc01c0c23eef66f2101bf75158c291b88de6525c55c3d1"}, + {file = "matplotlib-3.10.7-cp313-cp313-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:22df30ffaa89f6643206cf13877191c63a50e8f800b038bc39bee9d2d4957632"}, + {file = "matplotlib-3.10.7-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:b69676845a0a66f9da30e87f48be36734d6748024b525ec4710be40194282c84"}, + {file = "matplotlib-3.10.7-cp313-cp313-win_amd64.whl", hash = "sha256:744991e0cc863dd669c8dc9136ca4e6e0082be2070b9d793cbd64bec872a6815"}, + {file = "matplotlib-3.10.7-cp313-cp313-win_arm64.whl", hash = "sha256:fba2974df0bf8ce3c995fa84b79cde38326e0f7b5409e7a3a481c1141340bcf7"}, + {file = "matplotlib-3.10.7-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:932c55d1fa7af4423422cb6a492a31cbcbdbe68fd1a9a3f545aa5e7a143b5355"}, + {file = "matplotlib-3.10.7-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:5e38c2d581d62ee729a6e144c47a71b3f42fb4187508dbbf4fe71d5612c3433b"}, + {file = "matplotlib-3.10.7-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:786656bb13c237bbcebcd402f65f44dd61ead60ee3deb045af429d889c8dbc67"}, + {file = "matplotlib-3.10.7-cp313-cp313t-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:09d7945a70ea43bf9248f4b6582734c2fe726723204a76eca233f24cffc7ef67"}, + {file = "matplotlib-3.10.7-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:d0b181e9fa8daf1d9f2d4c547527b167cb8838fc587deabca7b5c01f97199e84"}, + {file = "matplotlib-3.10.7-cp313-cp313t-win_amd64.whl", hash = "sha256:31963603041634ce1a96053047b40961f7a29eb8f9a62e80cc2c0427aa1d22a2"}, + {file = "matplotlib-3.10.7-cp313-cp313t-win_arm64.whl", hash = "sha256:aebed7b50aa6ac698c90f60f854b47e48cd2252b30510e7a1feddaf5a3f72cbf"}, + {file = "matplotlib-3.10.7-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:d883460c43e8c6b173fef244a2341f7f7c0e9725c7fe68306e8e44ed9c8fb100"}, + {file = "matplotlib-3.10.7-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:07124afcf7a6504eafcb8ce94091c5898bbdd351519a1beb5c45f7a38c67e77f"}, + {file = "matplotlib-3.10.7-cp314-cp314-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:c17398b709a6cce3d9fdb1595c33e356d91c098cd9486cb2cc21ea2ea418e715"}, + {file = "matplotlib-3.10.7-cp314-cp314-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:7146d64f561498764561e9cd0ed64fcf582e570fc519e6f521e2d0cfd43365e1"}, + {file = "matplotlib-3.10.7-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:90ad854c0a435da3104c01e2c6f0028d7e719b690998a2333d7218db80950722"}, + {file = "matplotlib-3.10.7-cp314-cp314-win_amd64.whl", hash = "sha256:4645fc5d9d20ffa3a39361fcdbcec731382763b623b72627806bf251b6388866"}, + {file = "matplotlib-3.10.7-cp314-cp314-win_arm64.whl", hash = "sha256:9257be2f2a03415f9105c486d304a321168e61ad450f6153d77c69504ad764bb"}, + {file = "matplotlib-3.10.7-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:1e4bbad66c177a8fdfa53972e5ef8be72a5f27e6a607cec0d8579abd0f3102b1"}, + {file = "matplotlib-3.10.7-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:d8eb7194b084b12feb19142262165832fc6ee879b945491d1c3d4660748020c4"}, + {file = "matplotlib-3.10.7-cp314-cp314t-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b4d41379b05528091f00e1728004f9a8d7191260f3862178b88e8fd770206318"}, + {file = "matplotlib-3.10.7-cp314-cp314t-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:4a74f79fafb2e177f240579bc83f0b60f82cc47d2f1d260f422a0627207008ca"}, + {file = "matplotlib-3.10.7-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:702590829c30aada1e8cef0568ddbffa77ca747b4d6e36c6d173f66e301f89cc"}, + {file = "matplotlib-3.10.7-cp314-cp314t-win_amd64.whl", hash = "sha256:f79d5de970fc90cd5591f60053aecfce1fcd736e0303d9f0bf86be649fa68fb8"}, + {file = "matplotlib-3.10.7-cp314-cp314t-win_arm64.whl", hash = "sha256:cb783436e47fcf82064baca52ce748af71725d0352e1d31564cbe9c95df92b9c"}, + {file = "matplotlib-3.10.7-pp310-pypy310_pp73-macosx_10_15_x86_64.whl", hash = "sha256:5c09cf8f2793f81368f49f118b6f9f937456362bee282eac575cca7f84cda537"}, + {file = "matplotlib-3.10.7-pp310-pypy310_pp73-macosx_11_0_arm64.whl", hash = "sha256:de66744b2bb88d5cd27e80dfc2ec9f0517d0a46d204ff98fe9e5f2864eb67657"}, + {file = "matplotlib-3.10.7-pp310-pypy310_pp73-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:53cc80662dd197ece414dd5b66e07370201515a3eaf52e7c518c68c16814773b"}, + {file = "matplotlib-3.10.7-pp311-pypy311_pp73-macosx_10_15_x86_64.whl", hash = "sha256:15112bcbaef211bd663fa935ec33313b948e214454d949b723998a43357b17b0"}, + {file = "matplotlib-3.10.7-pp311-pypy311_pp73-macosx_11_0_arm64.whl", hash = "sha256:d2a959c640cdeecdd2ec3136e8ea0441da59bcaf58d67e9c590740addba2cb68"}, + {file = "matplotlib-3.10.7-pp311-pypy311_pp73-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:3886e47f64611046bc1db523a09dd0a0a6bed6081e6f90e13806dd1d1d1b5e91"}, + {file = "matplotlib-3.10.7.tar.gz", hash = "sha256:a06ba7e2a2ef9131c79c49e63dad355d2d878413a0376c1727c8b9335ff731c7"}, ] [package.dependencies] @@ -3865,7 +4150,7 @@ kiwisolver = ">=1.3.1" numpy = ">=1.23" packaging = ">=20.0" pillow = ">=8" -pyparsing = ">=2.3.1" +pyparsing = ">=3" python-dateutil = ">=2.7" [package.extras] @@ -3873,14 +4158,14 @@ dev = ["meson-python (>=0.13.1,<0.17.0)", "pybind11 (>=2.13.2,!=2.13.3)", "setup [[package]] name = "mcp" -version = "1.14.1" +version = "1.17.0" description = "Model Context Protocol SDK" optional = false python-versions = ">=3.10" groups = ["main"] files = [ - {file = "mcp-1.14.1-py3-none-any.whl", hash = "sha256:3b7a479e8e5cbf5361bdc1da8bc6d500d795dc3aff44b44077a363a7f7e945a4"}, - {file = "mcp-1.14.1.tar.gz", hash = "sha256:31c4406182ba15e8f30a513042719c3f0a38c615e76188ee5a736aaa89e20134"}, + {file = "mcp-1.17.0-py3-none-any.whl", hash = "sha256:0660ef275cada7a545af154db3082f176cf1d2681d5e35ae63e014faf0a35d40"}, + {file = "mcp-1.17.0.tar.gz", hash = "sha256:1b57fabf3203240ccc48e39859faf3ae1ccb0b571ff798bbedae800c73c6df90"}, ] [package.dependencies] @@ -3929,14 +4214,14 @@ files = [ [[package]] name = "mistralai" -version = "1.9.10" +version = "1.9.11" description = "Python Client SDK for the Mistral AI API." optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "mistralai-1.9.10-py3-none-any.whl", hash = "sha256:cf0a2906e254bb4825209a26e1957e6e0bacbbe61875bd22128dc3d5d51a7b0a"}, - {file = "mistralai-1.9.10.tar.gz", hash = "sha256:a95721276f035bf86c7fdc1373d7fb7d056d83510226f349426e0d522c0c0965"}, + {file = "mistralai-1.9.11-py3-none-any.whl", hash = "sha256:7a3dc2b8ef3fceaa3582220234261b5c4e3e03a972563b07afa150e44a25a6d3"}, + {file = "mistralai-1.9.11.tar.gz", hash = "sha256:3df9e403c31a756ec79e78df25ee73cea3eb15f86693773e16b16adaf59c9b8a"}, ] [package.dependencies] @@ -3985,14 +4270,14 @@ min-versions = ["babel (==2.9.0)", "click (==7.0)", "colorama (==0.4) ; platform [[package]] name = "mkdocs-autorefs" -version = "1.4.2" +version = "1.4.3" description = "Automatically link across pages in MkDocs." optional = false python-versions = ">=3.9" groups = ["docs"] files = [ - {file = "mkdocs_autorefs-1.4.2-py3-none-any.whl", hash = "sha256:83d6d777b66ec3c372a1aad4ae0cf77c243ba5bcda5bf0c6b8a2c5e7a3d89f13"}, - {file = "mkdocs_autorefs-1.4.2.tar.gz", hash = "sha256:e2ebe1abd2b67d597ed19378c0fff84d73d1dbce411fce7a7cc6f161888b6749"}, + {file = "mkdocs_autorefs-1.4.3-py3-none-any.whl", hash = "sha256:469d85eb3114801d08e9cc55d102b3ba65917a869b893403b8987b601cf55dc9"}, + {file = "mkdocs_autorefs-1.4.3.tar.gz", hash = "sha256:beee715b254455c4aa93b6ef3c67579c399ca092259cc41b7d9342573ff1fc75"}, ] [package.dependencies] @@ -4019,14 +4304,14 @@ pyyaml = ">=5.1" [[package]] name = "mkdocs-material" -version = "9.6.15" +version = "9.6.21" description = "Documentation that simply works" optional = false python-versions = ">=3.8" groups = ["docs"] files = [ - {file = "mkdocs_material-9.6.15-py3-none-any.whl", hash = "sha256:ac969c94d4fe5eb7c924b6d2f43d7db41159ea91553d18a9afc4780c34f2717a"}, - {file = "mkdocs_material-9.6.15.tar.gz", hash = "sha256:64adf8fa8dba1a17905b6aee1894a5aafd966d4aeb44a11088519b0f5ca4f1b5"}, + {file = "mkdocs_material-9.6.21-py3-none-any.whl", hash = "sha256:aa6a5ab6fb4f6d381588ac51da8782a4d3757cb3d1b174f81a2ec126e1f22c92"}, + {file = "mkdocs_material-9.6.21.tar.gz", hash = "sha256:b01aa6d2731322438056f360f0e623d3faae981f8f2d8c68b1b973f4f2657870"}, ] [package.dependencies] @@ -4044,7 +4329,7 @@ requests = ">=2.26,<3.0" [package.extras] git = ["mkdocs-git-committers-plugin-2 (>=1.1,<3)", "mkdocs-git-revision-date-localized-plugin (>=1.2.4,<2.0)"] -imaging = ["cairosvg (>=2.6,<3.0)", "pillow (>=10.2,<11.0)"] +imaging = ["cairosvg (>=2.6,<3.0)", "pillow (>=10.2,<12.0)"] recommended = ["mkdocs-minify-plugin (>=0.7,<1.0)", "mkdocs-redirects (>=1.2,<2.0)", "mkdocs-rss-plugin (>=1.6,<2.0)"] [[package]] @@ -4142,122 +4427,158 @@ tests = ["pytest (>=4.6)"] [[package]] name = "multidict" -version = "6.6.3" +version = "6.7.0" description = "multidict implementation" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "multidict-6.6.3-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:a2be5b7b35271f7fff1397204ba6708365e3d773579fe2a30625e16c4b4ce817"}, - {file = "multidict-6.6.3-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:12f4581d2930840295c461764b9a65732ec01250b46c6b2c510d7ee68872b140"}, - {file = "multidict-6.6.3-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:dd7793bab517e706c9ed9d7310b06c8672fd0aeee5781bfad612f56b8e0f7d14"}, - {file = "multidict-6.6.3-cp310-cp310-manylinux1_i686.manylinux2014_i686.manylinux_2_17_i686.manylinux_2_5_i686.whl", hash = "sha256:72d8815f2cd3cf3df0f83cac3f3ef801d908b2d90409ae28102e0553af85545a"}, - {file = "multidict-6.6.3-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:531e331a2ee53543ab32b16334e2deb26f4e6b9b28e41f8e0c87e99a6c8e2d69"}, - {file = "multidict-6.6.3-cp310-cp310-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:42ca5aa9329a63be8dc49040f63817d1ac980e02eeddba763a9ae5b4027b9c9c"}, - {file = "multidict-6.6.3-cp310-cp310-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:208b9b9757060b9faa6f11ab4bc52846e4f3c2fb8b14d5680c8aac80af3dc751"}, - {file = "multidict-6.6.3-cp310-cp310-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:acf6b97bd0884891af6a8b43d0f586ab2fcf8e717cbd47ab4bdddc09e20652d8"}, - {file = "multidict-6.6.3-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:68e9e12ed00e2089725669bdc88602b0b6f8d23c0c95e52b95f0bc69f7fe9b55"}, - {file = "multidict-6.6.3-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:05db2f66c9addb10cfa226e1acb363450fab2ff8a6df73c622fefe2f5af6d4e7"}, - {file = "multidict-6.6.3-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:0db58da8eafb514db832a1b44f8fa7906fdd102f7d982025f816a93ba45e3dcb"}, - {file = "multidict-6.6.3-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:14117a41c8fdb3ee19c743b1c027da0736fdb79584d61a766da53d399b71176c"}, - {file = "multidict-6.6.3-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:877443eaaabcd0b74ff32ebeed6f6176c71850feb7d6a1d2db65945256ea535c"}, - {file = "multidict-6.6.3-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:70b72e749a4f6e7ed8fb334fa8d8496384840319512746a5f42fa0aec79f4d61"}, - {file = "multidict-6.6.3-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:43571f785b86afd02b3855c5ac8e86ec921b760298d6f82ff2a61daf5a35330b"}, - {file = "multidict-6.6.3-cp310-cp310-win32.whl", hash = "sha256:20c5a0c3c13a15fd5ea86c42311859f970070e4e24de5a550e99d7c271d76318"}, - {file = "multidict-6.6.3-cp310-cp310-win_amd64.whl", hash = "sha256:ab0a34a007704c625e25a9116c6770b4d3617a071c8a7c30cd338dfbadfe6485"}, - {file = "multidict-6.6.3-cp310-cp310-win_arm64.whl", hash = "sha256:769841d70ca8bdd140a715746199fc6473414bd02efd678d75681d2d6a8986c5"}, - {file = "multidict-6.6.3-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:18f4eba0cbac3546b8ae31e0bbc55b02c801ae3cbaf80c247fcdd89b456ff58c"}, - {file = "multidict-6.6.3-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:ef43b5dd842382329e4797c46f10748d8c2b6e0614f46b4afe4aee9ac33159df"}, - {file = "multidict-6.6.3-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:bf9bd1fd5eec01494e0f2e8e446a74a85d5e49afb63d75a9934e4a5423dba21d"}, - {file = "multidict-6.6.3-cp311-cp311-manylinux1_i686.manylinux2014_i686.manylinux_2_17_i686.manylinux_2_5_i686.whl", hash = "sha256:5bd8d6f793a787153956cd35e24f60485bf0651c238e207b9a54f7458b16d539"}, - {file = "multidict-6.6.3-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:1bf99b4daf908c73856bd87ee0a2499c3c9a3d19bb04b9c6025e66af3fd07462"}, - {file = "multidict-6.6.3-cp311-cp311-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:0b9e59946b49dafaf990fd9c17ceafa62976e8471a14952163d10a7a630413a9"}, - {file = "multidict-6.6.3-cp311-cp311-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:e2db616467070d0533832d204c54eea6836a5e628f2cb1e6dfd8cd6ba7277cb7"}, - {file = "multidict-6.6.3-cp311-cp311-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:7394888236621f61dcdd25189b2768ae5cc280f041029a5bcf1122ac63df79f9"}, - {file = "multidict-6.6.3-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:f114d8478733ca7388e7c7e0ab34b72547476b97009d643644ac33d4d3fe1821"}, - {file = "multidict-6.6.3-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:cdf22e4db76d323bcdc733514bf732e9fb349707c98d341d40ebcc6e9318ef3d"}, - {file = "multidict-6.6.3-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:e995a34c3d44ab511bfc11aa26869b9d66c2d8c799fa0e74b28a473a692532d6"}, - {file = "multidict-6.6.3-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:766a4a5996f54361d8d5a9050140aa5362fe48ce51c755a50c0bc3706460c430"}, - {file = "multidict-6.6.3-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:3893a0d7d28a7fe6ca7a1f760593bc13038d1d35daf52199d431b61d2660602b"}, - {file = "multidict-6.6.3-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:934796c81ea996e61914ba58064920d6cad5d99140ac3167901eb932150e2e56"}, - {file = "multidict-6.6.3-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:9ed948328aec2072bc00f05d961ceadfd3e9bfc2966c1319aeaf7b7c21219183"}, - {file = "multidict-6.6.3-cp311-cp311-win32.whl", hash = "sha256:9f5b28c074c76afc3e4c610c488e3493976fe0e596dd3db6c8ddfbb0134dcac5"}, - {file = "multidict-6.6.3-cp311-cp311-win_amd64.whl", hash = "sha256:bc7f6fbc61b1c16050a389c630da0b32fc6d4a3d191394ab78972bf5edc568c2"}, - {file = "multidict-6.6.3-cp311-cp311-win_arm64.whl", hash = "sha256:d4e47d8faffaae822fb5cba20937c048d4f734f43572e7079298a6c39fb172cb"}, - {file = "multidict-6.6.3-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:056bebbeda16b2e38642d75e9e5310c484b7c24e3841dc0fb943206a72ec89d6"}, - {file = "multidict-6.6.3-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:e5f481cccb3c5c5e5de5d00b5141dc589c1047e60d07e85bbd7dea3d4580d63f"}, - {file = "multidict-6.6.3-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:10bea2ee839a759ee368b5a6e47787f399b41e70cf0c20d90dfaf4158dfb4e55"}, - {file = "multidict-6.6.3-cp312-cp312-manylinux1_i686.manylinux2014_i686.manylinux_2_17_i686.manylinux_2_5_i686.whl", hash = "sha256:2334cfb0fa9549d6ce2c21af2bfbcd3ac4ec3646b1b1581c88e3e2b1779ec92b"}, - {file = "multidict-6.6.3-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b8fee016722550a2276ca2cb5bb624480e0ed2bd49125b2b73b7010b9090e888"}, - {file = "multidict-6.6.3-cp312-cp312-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:e5511cb35f5c50a2db21047c875eb42f308c5583edf96bd8ebf7d770a9d68f6d"}, - {file = "multidict-6.6.3-cp312-cp312-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:712b348f7f449948e0a6c4564a21c7db965af900973a67db432d724619b3c680"}, - {file = "multidict-6.6.3-cp312-cp312-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:e4e15d2138ee2694e038e33b7c3da70e6b0ad8868b9f8094a72e1414aeda9c1a"}, - {file = "multidict-6.6.3-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:8df25594989aebff8a130f7899fa03cbfcc5d2b5f4a461cf2518236fe6f15961"}, - {file = "multidict-6.6.3-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:159ca68bfd284a8860f8d8112cf0521113bffd9c17568579e4d13d1f1dc76b65"}, - {file = "multidict-6.6.3-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:e098c17856a8c9ade81b4810888c5ad1914099657226283cab3062c0540b0643"}, - {file = "multidict-6.6.3-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:67c92ed673049dec52d7ed39f8cf9ebbadf5032c774058b4406d18c8f8fe7063"}, - {file = "multidict-6.6.3-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:bd0578596e3a835ef451784053cfd327d607fc39ea1a14812139339a18a0dbc3"}, - {file = "multidict-6.6.3-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:346055630a2df2115cd23ae271910b4cae40f4e336773550dca4889b12916e75"}, - {file = "multidict-6.6.3-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:555ff55a359302b79de97e0468e9ee80637b0de1fce77721639f7cd9440b3a10"}, - {file = "multidict-6.6.3-cp312-cp312-win32.whl", hash = "sha256:73ab034fb8d58ff85c2bcbadc470efc3fafeea8affcf8722855fb94557f14cc5"}, - {file = "multidict-6.6.3-cp312-cp312-win_amd64.whl", hash = "sha256:04cbcce84f63b9af41bad04a54d4cc4e60e90c35b9e6ccb130be2d75b71f8c17"}, - {file = "multidict-6.6.3-cp312-cp312-win_arm64.whl", hash = "sha256:0f1130b896ecb52d2a1e615260f3ea2af55fa7dc3d7c3003ba0c3121a759b18b"}, - {file = "multidict-6.6.3-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:540d3c06d48507357a7d57721e5094b4f7093399a0106c211f33540fdc374d55"}, - {file = "multidict-6.6.3-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:9c19cea2a690f04247d43f366d03e4eb110a0dc4cd1bbeee4d445435428ed35b"}, - {file = "multidict-6.6.3-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:7af039820cfd00effec86bda5d8debef711a3e86a1d3772e85bea0f243a4bd65"}, - {file = "multidict-6.6.3-cp313-cp313-manylinux1_i686.manylinux2014_i686.manylinux_2_17_i686.manylinux_2_5_i686.whl", hash = "sha256:500b84f51654fdc3944e936f2922114349bf8fdcac77c3092b03449f0e5bc2b3"}, - {file = "multidict-6.6.3-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:f3fc723ab8a5c5ed6c50418e9bfcd8e6dceba6c271cee6728a10a4ed8561520c"}, - {file = "multidict-6.6.3-cp313-cp313-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:94c47ea3ade005b5976789baaed66d4de4480d0a0bf31cef6edaa41c1e7b56a6"}, - {file = "multidict-6.6.3-cp313-cp313-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:dbc7cf464cc6d67e83e136c9f55726da3a30176f020a36ead246eceed87f1cd8"}, - {file = "multidict-6.6.3-cp313-cp313-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:900eb9f9da25ada070f8ee4a23f884e0ee66fe4e1a38c3af644256a508ad81ca"}, - {file = "multidict-6.6.3-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:7c6df517cf177da5d47ab15407143a89cd1a23f8b335f3a28d57e8b0a3dbb884"}, - {file = "multidict-6.6.3-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:4ef421045f13879e21c994b36e728d8e7d126c91a64b9185810ab51d474f27e7"}, - {file = "multidict-6.6.3-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:6c1e61bb4f80895c081790b6b09fa49e13566df8fbff817da3f85b3a8192e36b"}, - {file = "multidict-6.6.3-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:e5e8523bb12d7623cd8300dbd91b9e439a46a028cd078ca695eb66ba31adee3c"}, - {file = "multidict-6.6.3-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:ef58340cc896219e4e653dade08fea5c55c6df41bcc68122e3be3e9d873d9a7b"}, - {file = "multidict-6.6.3-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:fc9dc435ec8699e7b602b94fe0cd4703e69273a01cbc34409af29e7820f777f1"}, - {file = "multidict-6.6.3-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:9e864486ef4ab07db5e9cb997bad2b681514158d6954dd1958dfb163b83d53e6"}, - {file = "multidict-6.6.3-cp313-cp313-win32.whl", hash = "sha256:5633a82fba8e841bc5c5c06b16e21529573cd654f67fd833650a215520a6210e"}, - {file = "multidict-6.6.3-cp313-cp313-win_amd64.whl", hash = "sha256:e93089c1570a4ad54c3714a12c2cef549dc9d58e97bcded193d928649cab78e9"}, - {file = "multidict-6.6.3-cp313-cp313-win_arm64.whl", hash = "sha256:c60b401f192e79caec61f166da9c924e9f8bc65548d4246842df91651e83d600"}, - {file = "multidict-6.6.3-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:02fd8f32d403a6ff13864b0851f1f523d4c988051eea0471d4f1fd8010f11134"}, - {file = "multidict-6.6.3-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:f3aa090106b1543f3f87b2041eef3c156c8da2aed90c63a2fbed62d875c49c37"}, - {file = "multidict-6.6.3-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:e924fb978615a5e33ff644cc42e6aa241effcf4f3322c09d4f8cebde95aff5f8"}, - {file = "multidict-6.6.3-cp313-cp313t-manylinux1_i686.manylinux2014_i686.manylinux_2_17_i686.manylinux_2_5_i686.whl", hash = "sha256:b9fe5a0e57c6dbd0e2ce81ca66272282c32cd11d31658ee9553849d91289e1c1"}, - {file = "multidict-6.6.3-cp313-cp313t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b24576f208793ebae00280c59927c3b7c2a3b1655e443a25f753c4611bc1c373"}, - {file = "multidict-6.6.3-cp313-cp313t-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:135631cb6c58eac37d7ac0df380294fecdc026b28837fa07c02e459c7fb9c54e"}, - {file = "multidict-6.6.3-cp313-cp313t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:274d416b0df887aef98f19f21578653982cfb8a05b4e187d4a17103322eeaf8f"}, - {file = "multidict-6.6.3-cp313-cp313t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:e252017a817fad7ce05cafbe5711ed40faeb580e63b16755a3a24e66fa1d87c0"}, - {file = "multidict-6.6.3-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:2e4cc8d848cd4fe1cdee28c13ea79ab0ed37fc2e89dd77bac86a2e7959a8c3bc"}, - {file = "multidict-6.6.3-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:9e236a7094b9c4c1b7585f6b9cca34b9d833cf079f7e4c49e6a4a6ec9bfdc68f"}, - {file = "multidict-6.6.3-cp313-cp313t-musllinux_1_2_armv7l.whl", hash = "sha256:e0cb0ab69915c55627c933f0b555a943d98ba71b4d1c57bc0d0a66e2567c7471"}, - {file = "multidict-6.6.3-cp313-cp313t-musllinux_1_2_i686.whl", hash = "sha256:81ef2f64593aba09c5212a3d0f8c906a0d38d710a011f2f42759704d4557d3f2"}, - {file = "multidict-6.6.3-cp313-cp313t-musllinux_1_2_ppc64le.whl", hash = "sha256:b9cbc60010de3562545fa198bfc6d3825df430ea96d2cc509c39bd71e2e7d648"}, - {file = "multidict-6.6.3-cp313-cp313t-musllinux_1_2_s390x.whl", hash = "sha256:70d974eaaa37211390cd02ef93b7e938de564bbffa866f0b08d07e5e65da783d"}, - {file = "multidict-6.6.3-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:3713303e4a6663c6d01d648a68f2848701001f3390a030edaaf3fc949c90bf7c"}, - {file = "multidict-6.6.3-cp313-cp313t-win32.whl", hash = "sha256:639ecc9fe7cd73f2495f62c213e964843826f44505a3e5d82805aa85cac6f89e"}, - {file = "multidict-6.6.3-cp313-cp313t-win_amd64.whl", hash = "sha256:9f97e181f344a0ef3881b573d31de8542cc0dbc559ec68c8f8b5ce2c2e91646d"}, - {file = "multidict-6.6.3-cp313-cp313t-win_arm64.whl", hash = "sha256:ce8b7693da41a3c4fde5871c738a81490cea5496c671d74374c8ab889e1834fb"}, - {file = "multidict-6.6.3-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:c8161b5a7778d3137ea2ee7ae8a08cce0010de3b00ac671c5ebddeaa17cefd22"}, - {file = "multidict-6.6.3-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:1328201ee930f069961ae707d59c6627ac92e351ed5b92397cf534d1336ce557"}, - {file = "multidict-6.6.3-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:b1db4d2093d6b235de76932febf9d50766cf49a5692277b2c28a501c9637f616"}, - {file = "multidict-6.6.3-cp39-cp39-manylinux1_i686.manylinux2014_i686.manylinux_2_17_i686.manylinux_2_5_i686.whl", hash = "sha256:53becb01dd8ebd19d1724bebe369cfa87e4e7f29abbbe5c14c98ce4c383e16cd"}, - {file = "multidict-6.6.3-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:41bb9d1d4c303886e2d85bade86e59885112a7f4277af5ad47ab919a2251f306"}, - {file = "multidict-6.6.3-cp39-cp39-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:775b464d31dac90f23192af9c291dc9f423101857e33e9ebf0020a10bfcf4144"}, - {file = "multidict-6.6.3-cp39-cp39-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:d04d01f0a913202205a598246cf77826fe3baa5a63e9f6ccf1ab0601cf56eca0"}, - {file = "multidict-6.6.3-cp39-cp39-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:d25594d3b38a2e6cabfdcafef339f754ca6e81fbbdb6650ad773ea9775af35ab"}, - {file = "multidict-6.6.3-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:35712f1748d409e0707b165bf49f9f17f9e28ae85470c41615778f8d4f7d9609"}, - {file = "multidict-6.6.3-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:1c8082e5814b662de8589d6a06c17e77940d5539080cbab9fe6794b5241b76d9"}, - {file = "multidict-6.6.3-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:61af8a4b771f1d4d000b3168c12c3120ccf7284502a94aa58c68a81f5afac090"}, - {file = "multidict-6.6.3-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:448e4a9afccbf297577f2eaa586f07067441e7b63c8362a3540ba5a38dc0f14a"}, - {file = "multidict-6.6.3-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:233ad16999afc2bbd3e534ad8dbe685ef8ee49a37dbc2cdc9514e57b6d589ced"}, - {file = "multidict-6.6.3-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:bb933c891cd4da6bdcc9733d048e994e22e1883287ff7540c2a0f3b117605092"}, - {file = "multidict-6.6.3-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:37b09ca60998e87734699e88c2363abfd457ed18cfbf88e4009a4e83788e63ed"}, - {file = "multidict-6.6.3-cp39-cp39-win32.whl", hash = "sha256:f54cb79d26d0cd420637d184af38f0668558f3c4bbe22ab7ad830e67249f2e0b"}, - {file = "multidict-6.6.3-cp39-cp39-win_amd64.whl", hash = "sha256:295adc9c0551e5d5214b45cf29ca23dbc28c2d197a9c30d51aed9e037cb7c578"}, - {file = "multidict-6.6.3-cp39-cp39-win_arm64.whl", hash = "sha256:15332783596f227db50fb261c2c251a58ac3873c457f3a550a95d5c0aa3c770d"}, - {file = "multidict-6.6.3-py3-none-any.whl", hash = "sha256:8db10f29c7541fc5da4defd8cd697e1ca429db743fa716325f236079b96f775a"}, - {file = "multidict-6.6.3.tar.gz", hash = "sha256:798a9eb12dab0a6c2e29c1de6f3468af5cb2da6053a20dfa3344907eed0937cc"}, + {file = "multidict-6.7.0-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:9f474ad5acda359c8758c8accc22032c6abe6dc87a8be2440d097785e27a9349"}, + {file = "multidict-6.7.0-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:4b7a9db5a870f780220e931d0002bbfd88fb53aceb6293251e2c839415c1b20e"}, + {file = "multidict-6.7.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:03ca744319864e92721195fa28c7a3b2bc7b686246b35e4078c1e4d0eb5466d3"}, + {file = "multidict-6.7.0-cp310-cp310-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:f0e77e3c0008bc9316e662624535b88d360c3a5d3f81e15cf12c139a75250046"}, + {file = "multidict-6.7.0-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:08325c9e5367aa379a3496aa9a022fe8837ff22e00b94db256d3a1378c76ab32"}, + {file = "multidict-6.7.0-cp310-cp310-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:e2862408c99f84aa571ab462d25236ef9cb12a602ea959ba9c9009a54902fc73"}, + {file = "multidict-6.7.0-cp310-cp310-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:4d72a9a2d885f5c208b0cb91ff2ed43636bb7e345ec839ff64708e04f69a13cc"}, + {file = "multidict-6.7.0-cp310-cp310-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:478cc36476687bac1514d651cbbaa94b86b0732fb6855c60c673794c7dd2da62"}, + {file = "multidict-6.7.0-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:6843b28b0364dc605f21481c90fadb5f60d9123b442eb8a726bb74feef588a84"}, + {file = "multidict-6.7.0-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:23bfeee5316266e5ee2d625df2d2c602b829435fc3a235c2ba2131495706e4a0"}, + {file = "multidict-6.7.0-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:680878b9f3d45c31e1f730eef731f9b0bc1da456155688c6745ee84eb818e90e"}, + {file = "multidict-6.7.0-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:eb866162ef2f45063acc7a53a88ef6fe8bf121d45c30ea3c9cd87ce7e191a8d4"}, + {file = "multidict-6.7.0-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:df0e3bf7993bdbeca5ac25aa859cf40d39019e015c9c91809ba7093967f7a648"}, + {file = "multidict-6.7.0-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:661709cdcd919a2ece2234f9bae7174e5220c80b034585d7d8a755632d3e2111"}, + {file = "multidict-6.7.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:096f52730c3fb8ed419db2d44391932b63891b2c5ed14850a7e215c0ba9ade36"}, + {file = "multidict-6.7.0-cp310-cp310-win32.whl", hash = "sha256:afa8a2978ec65d2336305550535c9c4ff50ee527914328c8677b3973ade52b85"}, + {file = "multidict-6.7.0-cp310-cp310-win_amd64.whl", hash = "sha256:b15b3afff74f707b9275d5ba6a91ae8f6429c3ffb29bbfd216b0b375a56f13d7"}, + {file = "multidict-6.7.0-cp310-cp310-win_arm64.whl", hash = "sha256:4b73189894398d59131a66ff157837b1fafea9974be486d036bb3d32331fdbf0"}, + {file = "multidict-6.7.0-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:4d409aa42a94c0b3fa617708ef5276dfe81012ba6753a0370fcc9d0195d0a1fc"}, + {file = "multidict-6.7.0-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:14c9e076eede3b54c636f8ce1c9c252b5f057c62131211f0ceeec273810c9721"}, + {file = "multidict-6.7.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:4c09703000a9d0fa3c3404b27041e574cc7f4df4c6563873246d0e11812a94b6"}, + {file = "multidict-6.7.0-cp311-cp311-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:a265acbb7bb33a3a2d626afbe756371dce0279e7b17f4f4eda406459c2b5ff1c"}, + {file = "multidict-6.7.0-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:51cb455de290ae462593e5b1cb1118c5c22ea7f0d3620d9940bf695cea5a4bd7"}, + {file = "multidict-6.7.0-cp311-cp311-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:db99677b4457c7a5c5a949353e125ba72d62b35f74e26da141530fbb012218a7"}, + {file = "multidict-6.7.0-cp311-cp311-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:f470f68adc395e0183b92a2f4689264d1ea4b40504a24d9882c27375e6662bb9"}, + {file = "multidict-6.7.0-cp311-cp311-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:0db4956f82723cc1c270de9c6e799b4c341d327762ec78ef82bb962f79cc07d8"}, + {file = "multidict-6.7.0-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:3e56d780c238f9e1ae66a22d2adf8d16f485381878250db8d496623cd38b22bd"}, + {file = "multidict-6.7.0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:9d14baca2ee12c1a64740d4531356ba50b82543017f3ad6de0deb943c5979abb"}, + {file = "multidict-6.7.0-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:295a92a76188917c7f99cda95858c822f9e4aae5824246bba9b6b44004ddd0a6"}, + {file = "multidict-6.7.0-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:39f1719f57adbb767ef592a50ae5ebb794220d1188f9ca93de471336401c34d2"}, + {file = "multidict-6.7.0-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:0a13fb8e748dfc94749f622de065dd5c1def7e0d2216dba72b1d8069a389c6ff"}, + {file = "multidict-6.7.0-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:e3aa16de190d29a0ea1b48253c57d99a68492c8dd8948638073ab9e74dc9410b"}, + {file = "multidict-6.7.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:a048ce45dcdaaf1defb76b2e684f997fb5abf74437b6cb7b22ddad934a964e34"}, + {file = "multidict-6.7.0-cp311-cp311-win32.whl", hash = "sha256:a90af66facec4cebe4181b9e62a68be65e45ac9b52b67de9eec118701856e7ff"}, + {file = "multidict-6.7.0-cp311-cp311-win_amd64.whl", hash = "sha256:95b5ffa4349df2887518bb839409bcf22caa72d82beec453216802f475b23c81"}, + {file = "multidict-6.7.0-cp311-cp311-win_arm64.whl", hash = "sha256:329aa225b085b6f004a4955271a7ba9f1087e39dcb7e65f6284a988264a63912"}, + {file = "multidict-6.7.0-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:8a3862568a36d26e650a19bb5cbbba14b71789032aebc0423f8cc5f150730184"}, + {file = "multidict-6.7.0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:960c60b5849b9b4f9dcc9bea6e3626143c252c74113df2c1540aebce70209b45"}, + {file = "multidict-6.7.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:2049be98fb57a31b4ccf870bf377af2504d4ae35646a19037ec271e4c07998aa"}, + {file = "multidict-6.7.0-cp312-cp312-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:0934f3843a1860dd465d38895c17fce1f1cb37295149ab05cd1b9a03afacb2a7"}, + {file = "multidict-6.7.0-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b3e34f3a1b8131ba06f1a73adab24f30934d148afcd5f5de9a73565a4404384e"}, + {file = "multidict-6.7.0-cp312-cp312-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:efbb54e98446892590dc2458c19c10344ee9a883a79b5cec4bc34d6656e8d546"}, + {file = "multidict-6.7.0-cp312-cp312-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:a35c5fc61d4f51eb045061e7967cfe3123d622cd500e8868e7c0c592a09fedc4"}, + {file = "multidict-6.7.0-cp312-cp312-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:29fe6740ebccba4175af1b9b87bf553e9c15cd5868ee967e010efcf94e4fd0f1"}, + {file = "multidict-6.7.0-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:123e2a72e20537add2f33a79e605f6191fba2afda4cbb876e35c1a7074298a7d"}, + {file = "multidict-6.7.0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:b284e319754366c1aee2267a2036248b24eeb17ecd5dc16022095e747f2f4304"}, + {file = "multidict-6.7.0-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:803d685de7be4303b5a657b76e2f6d1240e7e0a8aa2968ad5811fa2285553a12"}, + {file = "multidict-6.7.0-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:c04a328260dfd5db8c39538f999f02779012268f54614902d0afc775d44e0a62"}, + {file = "multidict-6.7.0-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:8a19cdb57cd3df4cd865849d93ee14920fb97224300c88501f16ecfa2604b4e0"}, + {file = "multidict-6.7.0-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:9b2fd74c52accced7e75de26023b7dccee62511a600e62311b918ec5c168fc2a"}, + {file = "multidict-6.7.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:3e8bfdd0e487acf992407a140d2589fe598238eaeffa3da8448d63a63cd363f8"}, + {file = "multidict-6.7.0-cp312-cp312-win32.whl", hash = "sha256:dd32a49400a2c3d52088e120ee00c1e3576cbff7e10b98467962c74fdb762ed4"}, + {file = "multidict-6.7.0-cp312-cp312-win_amd64.whl", hash = "sha256:92abb658ef2d7ef22ac9f8bb88e8b6c3e571671534e029359b6d9e845923eb1b"}, + {file = "multidict-6.7.0-cp312-cp312-win_arm64.whl", hash = "sha256:490dab541a6a642ce1a9d61a4781656b346a55c13038f0b1244653828e3a83ec"}, + {file = "multidict-6.7.0-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:bee7c0588aa0076ce77c0ea5d19a68d76ad81fcd9fe8501003b9a24f9d4000f6"}, + {file = "multidict-6.7.0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:7ef6b61cad77091056ce0e7ce69814ef72afacb150b7ac6a3e9470def2198159"}, + {file = "multidict-6.7.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:9c0359b1ec12b1d6849c59f9d319610b7f20ef990a6d454ab151aa0e3b9f78ca"}, + {file = "multidict-6.7.0-cp313-cp313-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:cd240939f71c64bd658f186330603aac1a9a81bf6273f523fca63673cb7378a8"}, + {file = "multidict-6.7.0-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:a60a4d75718a5efa473ebd5ab685786ba0c67b8381f781d1be14da49f1a2dc60"}, + {file = "multidict-6.7.0-cp313-cp313-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:53a42d364f323275126aff81fb67c5ca1b7a04fda0546245730a55c8c5f24bc4"}, + {file = "multidict-6.7.0-cp313-cp313-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:3b29b980d0ddbecb736735ee5bef69bb2ddca56eff603c86f3f29a1128299b4f"}, + {file = "multidict-6.7.0-cp313-cp313-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:f8a93b1c0ed2d04b97a5e9336fd2d33371b9a6e29ab7dd6503d63407c20ffbaf"}, + {file = "multidict-6.7.0-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:9ff96e8815eecacc6645da76c413eb3b3d34cfca256c70b16b286a687d013c32"}, + {file = "multidict-6.7.0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:7516c579652f6a6be0e266aec0acd0db80829ca305c3d771ed898538804c2036"}, + {file = "multidict-6.7.0-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:040f393368e63fb0f3330e70c26bfd336656bed925e5cbe17c9da839a6ab13ec"}, + {file = "multidict-6.7.0-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:b3bc26a951007b1057a1c543af845f1c7e3e71cc240ed1ace7bf4484aa99196e"}, + {file = "multidict-6.7.0-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:7b022717c748dd1992a83e219587aabe45980d88969f01b316e78683e6285f64"}, + {file = "multidict-6.7.0-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:9600082733859f00d79dee64effc7aef1beb26adb297416a4ad2116fd61374bd"}, + {file = "multidict-6.7.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:94218fcec4d72bc61df51c198d098ce2b378e0ccbac41ddbed5ef44092913288"}, + {file = "multidict-6.7.0-cp313-cp313-win32.whl", hash = "sha256:a37bd74c3fa9d00be2d7b8eca074dc56bd8077ddd2917a839bd989612671ed17"}, + {file = "multidict-6.7.0-cp313-cp313-win_amd64.whl", hash = "sha256:30d193c6cc6d559db42b6bcec8a5d395d34d60c9877a0b71ecd7c204fcf15390"}, + {file = "multidict-6.7.0-cp313-cp313-win_arm64.whl", hash = "sha256:ea3334cabe4d41b7ccd01e4d349828678794edbc2d3ae97fc162a3312095092e"}, + {file = "multidict-6.7.0-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:ad9ce259f50abd98a1ca0aa6e490b58c316a0fce0617f609723e40804add2c00"}, + {file = "multidict-6.7.0-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:07f5594ac6d084cbb5de2df218d78baf55ef150b91f0ff8a21cc7a2e3a5a58eb"}, + {file = "multidict-6.7.0-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:0591b48acf279821a579282444814a2d8d0af624ae0bc600aa4d1b920b6e924b"}, + {file = "multidict-6.7.0-cp313-cp313t-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:749a72584761531d2b9467cfbdfd29487ee21124c304c4b6cb760d8777b27f9c"}, + {file = "multidict-6.7.0-cp313-cp313t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:6b4c3d199f953acd5b446bf7c0de1fe25d94e09e79086f8dc2f48a11a129cdf1"}, + {file = "multidict-6.7.0-cp313-cp313t-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:9fb0211dfc3b51efea2f349ec92c114d7754dd62c01f81c3e32b765b70c45c9b"}, + {file = "multidict-6.7.0-cp313-cp313t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:a027ec240fe73a8d6281872690b988eed307cd7d91b23998ff35ff577ca688b5"}, + {file = "multidict-6.7.0-cp313-cp313t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:d1d964afecdf3a8288789df2f5751dc0a8261138c3768d9af117ed384e538fad"}, + {file = "multidict-6.7.0-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:caf53b15b1b7df9fbd0709aa01409000a2b4dd03a5f6f5cc548183c7c8f8b63c"}, + {file = "multidict-6.7.0-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:654030da3197d927f05a536a66186070e98765aa5142794c9904555d3a9d8fb5"}, + {file = "multidict-6.7.0-cp313-cp313t-musllinux_1_2_armv7l.whl", hash = "sha256:2090d3718829d1e484706a2f525e50c892237b2bf9b17a79b059cb98cddc2f10"}, + {file = "multidict-6.7.0-cp313-cp313t-musllinux_1_2_i686.whl", hash = "sha256:2d2cfeec3f6f45651b3d408c4acec0ebf3daa9bc8a112a084206f5db5d05b754"}, + {file = "multidict-6.7.0-cp313-cp313t-musllinux_1_2_ppc64le.whl", hash = "sha256:4ef089f985b8c194d341eb2c24ae6e7408c9a0e2e5658699c92f497437d88c3c"}, + {file = "multidict-6.7.0-cp313-cp313t-musllinux_1_2_s390x.whl", hash = "sha256:e93a0617cd16998784bf4414c7e40f17a35d2350e5c6f0bd900d3a8e02bd3762"}, + {file = "multidict-6.7.0-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:f0feece2ef8ebc42ed9e2e8c78fc4aa3cf455733b507c09ef7406364c94376c6"}, + {file = "multidict-6.7.0-cp313-cp313t-win32.whl", hash = "sha256:19a1d55338ec1be74ef62440ca9e04a2f001a04d0cc49a4983dc320ff0f3212d"}, + {file = "multidict-6.7.0-cp313-cp313t-win_amd64.whl", hash = "sha256:3da4fb467498df97e986af166b12d01f05d2e04f978a9c1c680ea1988e0bc4b6"}, + {file = "multidict-6.7.0-cp313-cp313t-win_arm64.whl", hash = "sha256:b4121773c49a0776461f4a904cdf6264c88e42218aaa8407e803ca8025872792"}, + {file = "multidict-6.7.0-cp314-cp314-macosx_10_13_universal2.whl", hash = "sha256:3bab1e4aff7adaa34410f93b1f8e57c4b36b9af0426a76003f441ee1d3c7e842"}, + {file = "multidict-6.7.0-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:b8512bac933afc3e45fb2b18da8e59b78d4f408399a960339598374d4ae3b56b"}, + {file = "multidict-6.7.0-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:79dcf9e477bc65414ebfea98ffd013cb39552b5ecd62908752e0e413d6d06e38"}, + {file = "multidict-6.7.0-cp314-cp314-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:31bae522710064b5cbeddaf2e9f32b1abab70ac6ac91d42572502299e9953128"}, + {file = "multidict-6.7.0-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:4a0df7ff02397bb63e2fd22af2c87dfa39e8c7f12947bc524dbdc528282c7e34"}, + {file = "multidict-6.7.0-cp314-cp314-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:7a0222514e8e4c514660e182d5156a415c13ef0aabbd71682fc714e327b95e99"}, + {file = "multidict-6.7.0-cp314-cp314-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:2397ab4daaf2698eb51a76721e98db21ce4f52339e535725de03ea962b5a3202"}, + {file = "multidict-6.7.0-cp314-cp314-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:8891681594162635948a636c9fe0ff21746aeb3dd5463f6e25d9bea3a8a39ca1"}, + {file = "multidict-6.7.0-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:18706cc31dbf402a7945916dd5cddf160251b6dab8a2c5f3d6d5a55949f676b3"}, + {file = "multidict-6.7.0-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:f844a1bbf1d207dd311a56f383f7eda2d0e134921d45751842d8235e7778965d"}, + {file = "multidict-6.7.0-cp314-cp314-musllinux_1_2_armv7l.whl", hash = "sha256:d4393e3581e84e5645506923816b9cc81f5609a778c7e7534054091acc64d1c6"}, + {file = "multidict-6.7.0-cp314-cp314-musllinux_1_2_i686.whl", hash = "sha256:fbd18dc82d7bf274b37aa48d664534330af744e03bccf696d6f4c6042e7d19e7"}, + {file = "multidict-6.7.0-cp314-cp314-musllinux_1_2_ppc64le.whl", hash = "sha256:b6234e14f9314731ec45c42fc4554b88133ad53a09092cc48a88e771c125dadb"}, + {file = "multidict-6.7.0-cp314-cp314-musllinux_1_2_s390x.whl", hash = "sha256:08d4379f9744d8f78d98c8673c06e202ffa88296f009c71bbafe8a6bf847d01f"}, + {file = "multidict-6.7.0-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:9fe04da3f79387f450fd0061d4dd2e45a72749d31bf634aecc9e27f24fdc4b3f"}, + {file = "multidict-6.7.0-cp314-cp314-win32.whl", hash = "sha256:fbafe31d191dfa7c4c51f7a6149c9fb7e914dcf9ffead27dcfd9f1ae382b3885"}, + {file = "multidict-6.7.0-cp314-cp314-win_amd64.whl", hash = "sha256:2f67396ec0310764b9222a1728ced1ab638f61aadc6226f17a71dd9324f9a99c"}, + {file = "multidict-6.7.0-cp314-cp314-win_arm64.whl", hash = "sha256:ba672b26069957ee369cfa7fc180dde1fc6f176eaf1e6beaf61fbebbd3d9c000"}, + {file = "multidict-6.7.0-cp314-cp314t-macosx_10_13_universal2.whl", hash = "sha256:c1dcc7524066fa918c6a27d61444d4ee7900ec635779058571f70d042d86ed63"}, + {file = "multidict-6.7.0-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:27e0b36c2d388dc7b6ced3406671b401e84ad7eb0656b8f3a2f46ed0ce483718"}, + {file = "multidict-6.7.0-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:2a7baa46a22e77f0988e3b23d4ede5513ebec1929e34ee9495be535662c0dfe2"}, + {file = "multidict-6.7.0-cp314-cp314t-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:7bf77f54997a9166a2f5675d1201520586439424c2511723a7312bdb4bcc034e"}, + {file = "multidict-6.7.0-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:e011555abada53f1578d63389610ac8a5400fc70ce71156b0aa30d326f1a5064"}, + {file = "multidict-6.7.0-cp314-cp314t-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:28b37063541b897fd6a318007373930a75ca6d6ac7c940dbe14731ffdd8d498e"}, + {file = "multidict-6.7.0-cp314-cp314t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:05047ada7a2fde2631a0ed706f1fd68b169a681dfe5e4cf0f8e4cb6618bbc2cd"}, + {file = "multidict-6.7.0-cp314-cp314t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:716133f7d1d946a4e1b91b1756b23c088881e70ff180c24e864c26192ad7534a"}, + {file = "multidict-6.7.0-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:d1bed1b467ef657f2a0ae62844a607909ef1c6889562de5e1d505f74457d0b96"}, + {file = "multidict-6.7.0-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:ca43bdfa5d37bd6aee89d85e1d0831fb86e25541be7e9d376ead1b28974f8e5e"}, + {file = "multidict-6.7.0-cp314-cp314t-musllinux_1_2_armv7l.whl", hash = "sha256:44b546bd3eb645fd26fb949e43c02a25a2e632e2ca21a35e2e132c8105dc8599"}, + {file = "multidict-6.7.0-cp314-cp314t-musllinux_1_2_i686.whl", hash = "sha256:a6ef16328011d3f468e7ebc326f24c1445f001ca1dec335b2f8e66bed3006394"}, + {file = "multidict-6.7.0-cp314-cp314t-musllinux_1_2_ppc64le.whl", hash = "sha256:5aa873cbc8e593d361ae65c68f85faadd755c3295ea2c12040ee146802f23b38"}, + {file = "multidict-6.7.0-cp314-cp314t-musllinux_1_2_s390x.whl", hash = "sha256:3d7b6ccce016e29df4b7ca819659f516f0bc7a4b3efa3bb2012ba06431b044f9"}, + {file = "multidict-6.7.0-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:171b73bd4ee683d307599b66793ac80981b06f069b62eea1c9e29c9241aa66b0"}, + {file = "multidict-6.7.0-cp314-cp314t-win32.whl", hash = "sha256:b2d7f80c4e1fd010b07cb26820aae86b7e73b681ee4889684fb8d2d4537aab13"}, + {file = "multidict-6.7.0-cp314-cp314t-win_amd64.whl", hash = "sha256:09929cab6fcb68122776d575e03c6cc64ee0b8fca48d17e135474b042ce515cd"}, + {file = "multidict-6.7.0-cp314-cp314t-win_arm64.whl", hash = "sha256:cc41db090ed742f32bd2d2c721861725e6109681eddf835d0a82bd3a5c382827"}, + {file = "multidict-6.7.0-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:363eb68a0a59bd2303216d2346e6c441ba10d36d1f9969fcb6f1ba700de7bb5c"}, + {file = "multidict-6.7.0-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:d874eb056410ca05fed180b6642e680373688efafc7f077b2a2f61811e873a40"}, + {file = "multidict-6.7.0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:8b55d5497b51afdfde55925e04a022f1de14d4f4f25cdfd4f5d9b0aa96166851"}, + {file = "multidict-6.7.0-cp39-cp39-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:f8e5c0031b90ca9ce555e2e8fd5c3b02a25f14989cbc310701823832c99eb687"}, + {file = "multidict-6.7.0-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:9cf41880c991716f3c7cec48e2f19ae4045fc9db5fc9cff27347ada24d710bb5"}, + {file = "multidict-6.7.0-cp39-cp39-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:8cfc12a8630a29d601f48d47787bd7eb730e475e83edb5d6c5084317463373eb"}, + {file = "multidict-6.7.0-cp39-cp39-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:3996b50c3237c4aec17459217c1e7bbdead9a22a0fcd3c365564fbd16439dde6"}, + {file = "multidict-6.7.0-cp39-cp39-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:7f5170993a0dd3ab871c74f45c0a21a4e2c37a2f2b01b5f722a2ad9c6650469e"}, + {file = "multidict-6.7.0-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:ec81878ddf0e98817def1e77d4f50dae5ef5b0e4fe796fae3bd674304172416e"}, + {file = "multidict-6.7.0-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:9281bf5b34f59afbc6b1e477a372e9526b66ca446f4bf62592839c195a718b32"}, + {file = "multidict-6.7.0-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:68af405971779d8b37198726f2b6fe3955db846fee42db7a4286fc542203934c"}, + {file = "multidict-6.7.0-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:3ba3ef510467abb0667421a286dc906e30eb08569365f5cdb131d7aff7c2dd84"}, + {file = "multidict-6.7.0-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:b61189b29081a20c7e4e0b49b44d5d44bb0dc92be3c6d06a11cc043f81bf9329"}, + {file = "multidict-6.7.0-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:fb287618b9c7aa3bf8d825f02d9201b2f13078a5ed3b293c8f4d953917d84d5e"}, + {file = "multidict-6.7.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:521f33e377ff64b96c4c556b81c55d0cfffb96a11c194fd0c3f1e56f3d8dd5a4"}, + {file = "multidict-6.7.0-cp39-cp39-win32.whl", hash = "sha256:ce8fdc2dca699f8dbf055a61d73eaa10482569ad20ee3c36ef9641f69afa8c91"}, + {file = "multidict-6.7.0-cp39-cp39-win_amd64.whl", hash = "sha256:7e73299c99939f089dd9b2120a04a516b95cdf8c1cd2b18c53ebf0de80b1f18f"}, + {file = "multidict-6.7.0-cp39-cp39-win_arm64.whl", hash = "sha256:6bdce131e14b04fd34a809b6380dbfd826065c3e2fe8a50dbae659fa0c390546"}, + {file = "multidict-6.7.0-py3-none-any.whl", hash = "sha256:394fc5c42a333c9ffc3e421a4c85e08580d990e08b99f6bf35b4132114c5dcb3"}, + {file = "multidict-6.7.0.tar.gz", hash = "sha256:c6e99d9a65ca282e578dfea819cfa9c0a62b2499d8677392e09feaf305e9e6f5"}, ] [[package]] @@ -4274,44 +4595,50 @@ files = [ [[package]] name = "mypy" -version = "1.17.0" +version = "1.18.2" description = "Optional static typing for Python" optional = false python-versions = ">=3.9" groups = ["dev"] files = [ - {file = "mypy-1.17.0-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:f8e08de6138043108b3b18f09d3f817a4783912e48828ab397ecf183135d84d6"}, - {file = "mypy-1.17.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:ce4a17920ec144647d448fc43725b5873548b1aae6c603225626747ededf582d"}, - {file = "mypy-1.17.0-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:6ff25d151cc057fdddb1cb1881ef36e9c41fa2a5e78d8dd71bee6e4dcd2bc05b"}, - {file = "mypy-1.17.0-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:93468cf29aa9a132bceb103bd8475f78cacde2b1b9a94fd978d50d4bdf616c9a"}, - {file = "mypy-1.17.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:98189382b310f16343151f65dd7e6867386d3e35f7878c45cfa11383d175d91f"}, - {file = "mypy-1.17.0-cp310-cp310-win_amd64.whl", hash = "sha256:c004135a300ab06a045c1c0d8e3f10215e71d7b4f5bb9a42ab80236364429937"}, - {file = "mypy-1.17.0-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:9d4fe5c72fd262d9c2c91c1117d16aac555e05f5beb2bae6a755274c6eec42be"}, - {file = "mypy-1.17.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:d96b196e5c16f41b4f7736840e8455958e832871990c7ba26bf58175e357ed61"}, - {file = "mypy-1.17.0-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:73a0ff2dd10337ceb521c080d4147755ee302dcde6e1a913babd59473904615f"}, - {file = "mypy-1.17.0-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:24cfcc1179c4447854e9e406d3af0f77736d631ec87d31c6281ecd5025df625d"}, - {file = "mypy-1.17.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:3c56f180ff6430e6373db7a1d569317675b0a451caf5fef6ce4ab365f5f2f6c3"}, - {file = "mypy-1.17.0-cp311-cp311-win_amd64.whl", hash = "sha256:eafaf8b9252734400f9b77df98b4eee3d2eecab16104680d51341c75702cad70"}, - {file = "mypy-1.17.0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:f986f1cab8dbec39ba6e0eaa42d4d3ac6686516a5d3dccd64be095db05ebc6bb"}, - {file = "mypy-1.17.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:51e455a54d199dd6e931cd7ea987d061c2afbaf0960f7f66deef47c90d1b304d"}, - {file = "mypy-1.17.0-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:3204d773bab5ff4ebbd1f8efa11b498027cd57017c003ae970f310e5b96be8d8"}, - {file = "mypy-1.17.0-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:1051df7ec0886fa246a530ae917c473491e9a0ba6938cfd0ec2abc1076495c3e"}, - {file = "mypy-1.17.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:f773c6d14dcc108a5b141b4456b0871df638eb411a89cd1c0c001fc4a9d08fc8"}, - {file = "mypy-1.17.0-cp312-cp312-win_amd64.whl", hash = "sha256:1619a485fd0e9c959b943c7b519ed26b712de3002d7de43154a489a2d0fd817d"}, - {file = "mypy-1.17.0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:2c41aa59211e49d717d92b3bb1238c06d387c9325d3122085113c79118bebb06"}, - {file = "mypy-1.17.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:0e69db1fb65b3114f98c753e3930a00514f5b68794ba80590eb02090d54a5d4a"}, - {file = "mypy-1.17.0-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:03ba330b76710f83d6ac500053f7727270b6b8553b0423348ffb3af6f2f7b889"}, - {file = "mypy-1.17.0-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:037bc0f0b124ce46bfde955c647f3e395c6174476a968c0f22c95a8d2f589bba"}, - {file = "mypy-1.17.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:c38876106cb6132259683632b287238858bd58de267d80defb6f418e9ee50658"}, - {file = "mypy-1.17.0-cp313-cp313-win_amd64.whl", hash = "sha256:d30ba01c0f151998f367506fab31c2ac4527e6a7b2690107c7a7f9e3cb419a9c"}, - {file = "mypy-1.17.0-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:63e751f1b5ab51d6f3d219fe3a2fe4523eaa387d854ad06906c63883fde5b1ab"}, - {file = "mypy-1.17.0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:f7fb09d05e0f1c329a36dcd30e27564a3555717cde87301fae4fb542402ddfad"}, - {file = "mypy-1.17.0-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b72c34ce05ac3a1361ae2ebb50757fb6e3624032d91488d93544e9f82db0ed6c"}, - {file = "mypy-1.17.0-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:434ad499ad8dde8b2f6391ddfa982f41cb07ccda8e3c67781b1bfd4e5f9450a8"}, - {file = "mypy-1.17.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:f105f61a5eff52e137fd73bee32958b2add9d9f0a856f17314018646af838e97"}, - {file = "mypy-1.17.0-cp39-cp39-win_amd64.whl", hash = "sha256:ba06254a5a22729853209550d80f94e28690d5530c661f9416a68ac097b13fc4"}, - {file = "mypy-1.17.0-py3-none-any.whl", hash = "sha256:15d9d0018237ab058e5de3d8fce61b6fa72cc59cc78fd91f1b474bce12abf496"}, - {file = "mypy-1.17.0.tar.gz", hash = "sha256:e5d7ccc08ba089c06e2f5629c660388ef1fee708444f1dee0b9203fa031dee03"}, + {file = "mypy-1.18.2-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:c1eab0cf6294dafe397c261a75f96dc2c31bffe3b944faa24db5def4e2b0f77c"}, + {file = "mypy-1.18.2-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:7a780ca61fc239e4865968ebc5240bb3bf610ef59ac398de9a7421b54e4a207e"}, + {file = "mypy-1.18.2-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:448acd386266989ef11662ce3c8011fd2a7b632e0ec7d61a98edd8e27472225b"}, + {file = "mypy-1.18.2-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:f9e171c465ad3901dc652643ee4bffa8e9fef4d7d0eece23b428908c77a76a66"}, + {file = "mypy-1.18.2-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:592ec214750bc00741af1f80cbf96b5013d81486b7bb24cb052382c19e40b428"}, + {file = "mypy-1.18.2-cp310-cp310-win_amd64.whl", hash = "sha256:7fb95f97199ea11769ebe3638c29b550b5221e997c63b14ef93d2e971606ebed"}, + {file = "mypy-1.18.2-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:807d9315ab9d464125aa9fcf6d84fde6e1dc67da0b6f80e7405506b8ac72bc7f"}, + {file = "mypy-1.18.2-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:776bb00de1778caf4db739c6e83919c1d85a448f71979b6a0edd774ea8399341"}, + {file = "mypy-1.18.2-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:1379451880512ffce14505493bd9fe469e0697543717298242574882cf8cdb8d"}, + {file = "mypy-1.18.2-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:1331eb7fd110d60c24999893320967594ff84c38ac6d19e0a76c5fd809a84c86"}, + {file = "mypy-1.18.2-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:3ca30b50a51e7ba93b00422e486cbb124f1c56a535e20eff7b2d6ab72b3b2e37"}, + {file = "mypy-1.18.2-cp311-cp311-win_amd64.whl", hash = "sha256:664dc726e67fa54e14536f6e1224bcfce1d9e5ac02426d2326e2bb4e081d1ce8"}, + {file = "mypy-1.18.2-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:33eca32dd124b29400c31d7cf784e795b050ace0e1f91b8dc035672725617e34"}, + {file = "mypy-1.18.2-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:a3c47adf30d65e89b2dcd2fa32f3aeb5e94ca970d2c15fcb25e297871c8e4764"}, + {file = "mypy-1.18.2-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:5d6c838e831a062f5f29d11c9057c6009f60cb294fea33a98422688181fe2893"}, + {file = "mypy-1.18.2-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:01199871b6110a2ce984bde85acd481232d17413868c9807e95c1b0739a58914"}, + {file = "mypy-1.18.2-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:a2afc0fa0b0e91b4599ddfe0f91e2c26c2b5a5ab263737e998d6817874c5f7c8"}, + {file = "mypy-1.18.2-cp312-cp312-win_amd64.whl", hash = "sha256:d8068d0afe682c7c4897c0f7ce84ea77f6de953262b12d07038f4d296d547074"}, + {file = "mypy-1.18.2-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:07b8b0f580ca6d289e69209ec9d3911b4a26e5abfde32228a288eb79df129fcc"}, + {file = "mypy-1.18.2-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:ed4482847168439651d3feee5833ccedbf6657e964572706a2adb1f7fa4dfe2e"}, + {file = "mypy-1.18.2-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:c3ad2afadd1e9fea5cf99a45a822346971ede8685cc581ed9cd4d42eaf940986"}, + {file = "mypy-1.18.2-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:a431a6f1ef14cf8c144c6b14793a23ec4eae3db28277c358136e79d7d062f62d"}, + {file = "mypy-1.18.2-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:7ab28cc197f1dd77a67e1c6f35cd1f8e8b73ed2217e4fc005f9e6a504e46e7ba"}, + {file = "mypy-1.18.2-cp313-cp313-win_amd64.whl", hash = "sha256:0e2785a84b34a72ba55fb5daf079a1003a34c05b22238da94fcae2bbe46f3544"}, + {file = "mypy-1.18.2-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:62f0e1e988ad41c2a110edde6c398383a889d95b36b3e60bcf155f5164c4fdce"}, + {file = "mypy-1.18.2-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:8795a039bab805ff0c1dfdb8cd3344642c2b99b8e439d057aba30850b8d3423d"}, + {file = "mypy-1.18.2-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:6ca1e64b24a700ab5ce10133f7ccd956a04715463d30498e64ea8715236f9c9c"}, + {file = "mypy-1.18.2-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:d924eef3795cc89fecf6bedc6ed32b33ac13e8321344f6ddbf8ee89f706c05cb"}, + {file = "mypy-1.18.2-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:20c02215a080e3a2be3aa50506c67242df1c151eaba0dcbc1e4e557922a26075"}, + {file = "mypy-1.18.2-cp314-cp314-win_amd64.whl", hash = "sha256:749b5f83198f1ca64345603118a6f01a4e99ad4bf9d103ddc5a3200cc4614adf"}, + {file = "mypy-1.18.2-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:25a9c8fb67b00599f839cf472713f54249a62efd53a54b565eb61956a7e3296b"}, + {file = "mypy-1.18.2-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:c2b9c7e284ee20e7598d6f42e13ca40b4928e6957ed6813d1ab6348aa3f47133"}, + {file = "mypy-1.18.2-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:d6985ed057513e344e43a26cc1cd815c7a94602fb6a3130a34798625bc2f07b6"}, + {file = "mypy-1.18.2-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:22f27105f1525ec024b5c630c0b9f36d5c1cc4d447d61fe51ff4bd60633f47ac"}, + {file = "mypy-1.18.2-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:030c52d0ea8144e721e49b1f68391e39553d7451f0c3f8a7565b59e19fcb608b"}, + {file = "mypy-1.18.2-cp39-cp39-win_amd64.whl", hash = "sha256:aa5e07ac1a60a253445797e42b8b2963c9675563a94f11291ab40718b016a7a0"}, + {file = "mypy-1.18.2-py3-none-any.whl", hash = "sha256:22a1748707dd62b58d2ae53562ffc4d7f8bcc727e8ac7cbc69c053ddc874d47e"}, + {file = "mypy-1.18.2.tar.gz", hash = "sha256:06a398102a5f203d7477b2923dda3634c36727fa5c237d8f859ef90c42a9924b"}, ] [package.dependencies] @@ -4340,14 +4667,14 @@ files = [ [[package]] name = "ndex2" -version = "3.10.0" +version = "3.11.0" description = "Nice CX Python includes a client and a data model." optional = false python-versions = "*" groups = ["main"] files = [ - {file = "ndex2-3.10.0-py2.py3-none-any.whl", hash = "sha256:fdb8307ccdbdf49044c9119373852242ca24a4926df1c5566e94965e59b70b67"}, - {file = "ndex2-3.10.0.tar.gz", hash = "sha256:7e8cfc3fc940cddfd612810fc8c913ab61e01a43e4f482608e86c6548b81b7e1"}, + {file = "ndex2-3.11.0-py2.py3-none-any.whl", hash = "sha256:cafb2efa38e9faf3f7e47805429d2498cfd127b5a452df020bf3c8e199c9c072"}, + {file = "ndex2-3.11.0.tar.gz", hash = "sha256:3fbf4d96254f0e85a2162c9f77d970687fe5a41622671a553111238e81350512"}, ] [package.dependencies] @@ -4395,63 +4722,86 @@ files = [ [[package]] name = "numpy" -version = "2.3.1" +version = "2.3.3" description = "Fundamental package for array computing in Python" optional = false python-versions = ">=3.11" groups = ["main"] files = [ - {file = "numpy-2.3.1-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:6ea9e48336a402551f52cd8f593343699003d2353daa4b72ce8d34f66b722070"}, - {file = "numpy-2.3.1-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:5ccb7336eaf0e77c1635b232c141846493a588ec9ea777a7c24d7166bb8533ae"}, - {file = "numpy-2.3.1-cp311-cp311-macosx_14_0_arm64.whl", hash = "sha256:0bb3a4a61e1d327e035275d2a993c96fa786e4913aa089843e6a2d9dd205c66a"}, - {file = "numpy-2.3.1-cp311-cp311-macosx_14_0_x86_64.whl", hash = "sha256:e344eb79dab01f1e838ebb67aab09965fb271d6da6b00adda26328ac27d4a66e"}, - {file = "numpy-2.3.1-cp311-cp311-manylinux_2_28_aarch64.whl", hash = "sha256:467db865b392168ceb1ef1ffa6f5a86e62468c43e0cfb4ab6da667ede10e58db"}, - {file = "numpy-2.3.1-cp311-cp311-manylinux_2_28_x86_64.whl", hash = "sha256:afed2ce4a84f6b0fc6c1ce734ff368cbf5a5e24e8954a338f3bdffa0718adffb"}, - {file = "numpy-2.3.1-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:0025048b3c1557a20bc80d06fdeb8cc7fc193721484cca82b2cfa072fec71a93"}, - {file = "numpy-2.3.1-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:a5ee121b60aa509679b682819c602579e1df14a5b07fe95671c8849aad8f2115"}, - {file = "numpy-2.3.1-cp311-cp311-win32.whl", hash = "sha256:a8b740f5579ae4585831b3cf0e3b0425c667274f82a484866d2adf9570539369"}, - {file = "numpy-2.3.1-cp311-cp311-win_amd64.whl", hash = "sha256:d4580adadc53311b163444f877e0789f1c8861e2698f6b2a4ca852fda154f3ff"}, - {file = "numpy-2.3.1-cp311-cp311-win_arm64.whl", hash = "sha256:ec0bdafa906f95adc9a0c6f26a4871fa753f25caaa0e032578a30457bff0af6a"}, - {file = "numpy-2.3.1-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:2959d8f268f3d8ee402b04a9ec4bb7604555aeacf78b360dc4ec27f1d508177d"}, - {file = "numpy-2.3.1-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:762e0c0c6b56bdedfef9a8e1d4538556438288c4276901ea008ae44091954e29"}, - {file = "numpy-2.3.1-cp312-cp312-macosx_14_0_arm64.whl", hash = "sha256:867ef172a0976aaa1f1d1b63cf2090de8b636a7674607d514505fb7276ab08fc"}, - {file = "numpy-2.3.1-cp312-cp312-macosx_14_0_x86_64.whl", hash = "sha256:4e602e1b8682c2b833af89ba641ad4176053aaa50f5cacda1a27004352dde943"}, - {file = "numpy-2.3.1-cp312-cp312-manylinux_2_28_aarch64.whl", hash = "sha256:8e333040d069eba1652fb08962ec5b76af7f2c7bce1df7e1418c8055cf776f25"}, - {file = "numpy-2.3.1-cp312-cp312-manylinux_2_28_x86_64.whl", hash = "sha256:e7cbf5a5eafd8d230a3ce356d892512185230e4781a361229bd902ff403bc660"}, - {file = "numpy-2.3.1-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:5f1b8f26d1086835f442286c1d9b64bb3974b0b1e41bb105358fd07d20872952"}, - {file = "numpy-2.3.1-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:ee8340cb48c9b7a5899d1149eece41ca535513a9698098edbade2a8e7a84da77"}, - {file = "numpy-2.3.1-cp312-cp312-win32.whl", hash = "sha256:e772dda20a6002ef7061713dc1e2585bc1b534e7909b2030b5a46dae8ff077ab"}, - {file = "numpy-2.3.1-cp312-cp312-win_amd64.whl", hash = "sha256:cfecc7822543abdea6de08758091da655ea2210b8ffa1faf116b940693d3df76"}, - {file = "numpy-2.3.1-cp312-cp312-win_arm64.whl", hash = "sha256:7be91b2239af2658653c5bb6f1b8bccafaf08226a258caf78ce44710a0160d30"}, - {file = "numpy-2.3.1-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:25a1992b0a3fdcdaec9f552ef10d8103186f5397ab45e2d25f8ac51b1a6b97e8"}, - {file = "numpy-2.3.1-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:7dea630156d39b02a63c18f508f85010230409db5b2927ba59c8ba4ab3e8272e"}, - {file = "numpy-2.3.1-cp313-cp313-macosx_14_0_arm64.whl", hash = "sha256:bada6058dd886061f10ea15f230ccf7dfff40572e99fef440a4a857c8728c9c0"}, - {file = "numpy-2.3.1-cp313-cp313-macosx_14_0_x86_64.whl", hash = "sha256:a894f3816eb17b29e4783e5873f92faf55b710c2519e5c351767c51f79d8526d"}, - {file = "numpy-2.3.1-cp313-cp313-manylinux_2_28_aarch64.whl", hash = "sha256:18703df6c4a4fee55fd3d6e5a253d01c5d33a295409b03fda0c86b3ca2ff41a1"}, - {file = "numpy-2.3.1-cp313-cp313-manylinux_2_28_x86_64.whl", hash = "sha256:5902660491bd7a48b2ec16c23ccb9124b8abfd9583c5fdfa123fe6b421e03de1"}, - {file = "numpy-2.3.1-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:36890eb9e9d2081137bd78d29050ba63b8dab95dff7912eadf1185e80074b2a0"}, - {file = "numpy-2.3.1-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:a780033466159c2270531e2b8ac063704592a0bc62ec4a1b991c7c40705eb0e8"}, - {file = "numpy-2.3.1-cp313-cp313-win32.whl", hash = "sha256:39bff12c076812595c3a306f22bfe49919c5513aa1e0e70fac756a0be7c2a2b8"}, - {file = "numpy-2.3.1-cp313-cp313-win_amd64.whl", hash = "sha256:8d5ee6eec45f08ce507a6570e06f2f879b374a552087a4179ea7838edbcbfa42"}, - {file = "numpy-2.3.1-cp313-cp313-win_arm64.whl", hash = "sha256:0c4d9e0a8368db90f93bd192bfa771ace63137c3488d198ee21dfb8e7771916e"}, - {file = "numpy-2.3.1-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:b0b5397374f32ec0649dd98c652a1798192042e715df918c20672c62fb52d4b8"}, - {file = "numpy-2.3.1-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:c5bdf2015ccfcee8253fb8be695516ac4457c743473a43290fd36eba6a1777eb"}, - {file = "numpy-2.3.1-cp313-cp313t-macosx_14_0_arm64.whl", hash = "sha256:d70f20df7f08b90a2062c1f07737dd340adccf2068d0f1b9b3d56e2038979fee"}, - {file = "numpy-2.3.1-cp313-cp313t-macosx_14_0_x86_64.whl", hash = "sha256:2fb86b7e58f9ac50e1e9dd1290154107e47d1eef23a0ae9145ded06ea606f992"}, - {file = "numpy-2.3.1-cp313-cp313t-manylinux_2_28_aarch64.whl", hash = "sha256:23ab05b2d241f76cb883ce8b9a93a680752fbfcbd51c50eff0b88b979e471d8c"}, - {file = "numpy-2.3.1-cp313-cp313t-manylinux_2_28_x86_64.whl", hash = "sha256:ce2ce9e5de4703a673e705183f64fd5da5bf36e7beddcb63a25ee2286e71ca48"}, - {file = "numpy-2.3.1-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:c4913079974eeb5c16ccfd2b1f09354b8fed7e0d6f2cab933104a09a6419b1ee"}, - {file = "numpy-2.3.1-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:010ce9b4f00d5c036053ca684c77441f2f2c934fd23bee058b4d6f196efd8280"}, - {file = "numpy-2.3.1-cp313-cp313t-win32.whl", hash = "sha256:6269b9edfe32912584ec496d91b00b6d34282ca1d07eb10e82dfc780907d6c2e"}, - {file = "numpy-2.3.1-cp313-cp313t-win_amd64.whl", hash = "sha256:2a809637460e88a113e186e87f228d74ae2852a2e0c44de275263376f17b5bdc"}, - {file = "numpy-2.3.1-cp313-cp313t-win_arm64.whl", hash = "sha256:eccb9a159db9aed60800187bc47a6d3451553f0e1b08b068d8b277ddfbb9b244"}, - {file = "numpy-2.3.1-pp311-pypy311_pp73-macosx_10_15_x86_64.whl", hash = "sha256:ad506d4b09e684394c42c966ec1527f6ebc25da7f4da4b1b056606ffe446b8a3"}, - {file = "numpy-2.3.1-pp311-pypy311_pp73-macosx_14_0_arm64.whl", hash = "sha256:ebb8603d45bc86bbd5edb0d63e52c5fd9e7945d3a503b77e486bd88dde67a19b"}, - {file = "numpy-2.3.1-pp311-pypy311_pp73-macosx_14_0_x86_64.whl", hash = "sha256:15aa4c392ac396e2ad3d0a2680c0f0dee420f9fed14eef09bdb9450ee6dcb7b7"}, - {file = "numpy-2.3.1-pp311-pypy311_pp73-manylinux_2_28_aarch64.whl", hash = "sha256:c6e0bf9d1a2f50d2b65a7cf56db37c095af17b59f6c132396f7c6d5dd76484df"}, - {file = "numpy-2.3.1-pp311-pypy311_pp73-manylinux_2_28_x86_64.whl", hash = "sha256:eabd7e8740d494ce2b4ea0ff05afa1b7b291e978c0ae075487c51e8bd93c0c68"}, - {file = "numpy-2.3.1-pp311-pypy311_pp73-win_amd64.whl", hash = "sha256:e610832418a2bc09d974cc9fecebfa51e9532d6190223bc5ef6a7402ebf3b5cb"}, - {file = "numpy-2.3.1.tar.gz", hash = "sha256:1ec9ae20a4226da374362cca3c62cd753faf2f951440b0e3b98e93c235441d2b"}, + {file = "numpy-2.3.3-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:0ffc4f5caba7dfcbe944ed674b7eef683c7e94874046454bb79ed7ee0236f59d"}, + {file = "numpy-2.3.3-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:e7e946c7170858a0295f79a60214424caac2ffdb0063d4d79cb681f9aa0aa569"}, + {file = "numpy-2.3.3-cp311-cp311-macosx_14_0_arm64.whl", hash = "sha256:cd4260f64bc794c3390a63bf0728220dd1a68170c169088a1e0dfa2fde1be12f"}, + {file = "numpy-2.3.3-cp311-cp311-macosx_14_0_x86_64.whl", hash = "sha256:f0ddb4b96a87b6728df9362135e764eac3cfa674499943ebc44ce96c478ab125"}, + {file = "numpy-2.3.3-cp311-cp311-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:afd07d377f478344ec6ca2b8d4ca08ae8bd44706763d1efb56397de606393f48"}, + {file = "numpy-2.3.3-cp311-cp311-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:bc92a5dedcc53857249ca51ef29f5e5f2f8c513e22cfb90faeb20343b8c6f7a6"}, + {file = "numpy-2.3.3-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:7af05ed4dc19f308e1d9fc759f36f21921eb7bbfc82843eeec6b2a2863a0aefa"}, + {file = "numpy-2.3.3-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:433bf137e338677cebdd5beac0199ac84712ad9d630b74eceeb759eaa45ddf30"}, + {file = "numpy-2.3.3-cp311-cp311-win32.whl", hash = "sha256:eb63d443d7b4ffd1e873f8155260d7f58e7e4b095961b01c91062935c2491e57"}, + {file = "numpy-2.3.3-cp311-cp311-win_amd64.whl", hash = "sha256:ec9d249840f6a565f58d8f913bccac2444235025bbb13e9a4681783572ee3caa"}, + {file = "numpy-2.3.3-cp311-cp311-win_arm64.whl", hash = "sha256:74c2a948d02f88c11a3c075d9733f1ae67d97c6bdb97f2bb542f980458b257e7"}, + {file = "numpy-2.3.3-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:cfdd09f9c84a1a934cde1eec2267f0a43a7cd44b2cca4ff95b7c0d14d144b0bf"}, + {file = "numpy-2.3.3-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:cb32e3cf0f762aee47ad1ddc6672988f7f27045b0783c887190545baba73aa25"}, + {file = "numpy-2.3.3-cp312-cp312-macosx_14_0_arm64.whl", hash = "sha256:396b254daeb0a57b1fe0ecb5e3cff6fa79a380fa97c8f7781a6d08cd429418fe"}, + {file = "numpy-2.3.3-cp312-cp312-macosx_14_0_x86_64.whl", hash = "sha256:067e3d7159a5d8f8a0b46ee11148fc35ca9b21f61e3c49fbd0a027450e65a33b"}, + {file = "numpy-2.3.3-cp312-cp312-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:1c02d0629d25d426585fb2e45a66154081b9fa677bc92a881ff1d216bc9919a8"}, + {file = "numpy-2.3.3-cp312-cp312-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:d9192da52b9745f7f0766531dcfa978b7763916f158bb63bdb8a1eca0068ab20"}, + {file = "numpy-2.3.3-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:cd7de500a5b66319db419dc3c345244404a164beae0d0937283b907d8152e6ea"}, + {file = "numpy-2.3.3-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:93d4962d8f82af58f0b2eb85daaf1b3ca23fe0a85d0be8f1f2b7bb46034e56d7"}, + {file = "numpy-2.3.3-cp312-cp312-win32.whl", hash = "sha256:5534ed6b92f9b7dca6c0a19d6df12d41c68b991cef051d108f6dbff3babc4ebf"}, + {file = "numpy-2.3.3-cp312-cp312-win_amd64.whl", hash = "sha256:497d7cad08e7092dba36e3d296fe4c97708c93daf26643a1ae4b03f6294d30eb"}, + {file = "numpy-2.3.3-cp312-cp312-win_arm64.whl", hash = "sha256:ca0309a18d4dfea6fc6262a66d06c26cfe4640c3926ceec90e57791a82b6eee5"}, + {file = "numpy-2.3.3-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:f5415fb78995644253370985342cd03572ef8620b934da27d77377a2285955bf"}, + {file = "numpy-2.3.3-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:d00de139a3324e26ed5b95870ce63be7ec7352171bc69a4cf1f157a48e3eb6b7"}, + {file = "numpy-2.3.3-cp313-cp313-macosx_14_0_arm64.whl", hash = "sha256:9dc13c6a5829610cc07422bc74d3ac083bd8323f14e2827d992f9e52e22cd6a6"}, + {file = "numpy-2.3.3-cp313-cp313-macosx_14_0_x86_64.whl", hash = "sha256:d79715d95f1894771eb4e60fb23f065663b2298f7d22945d66877aadf33d00c7"}, + {file = "numpy-2.3.3-cp313-cp313-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:952cfd0748514ea7c3afc729a0fc639e61655ce4c55ab9acfab14bda4f402b4c"}, + {file = "numpy-2.3.3-cp313-cp313-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:5b83648633d46f77039c29078751f80da65aa64d5622a3cd62aaef9d835b6c93"}, + {file = "numpy-2.3.3-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:b001bae8cea1c7dfdb2ae2b017ed0a6f2102d7a70059df1e338e307a4c78a8ae"}, + {file = "numpy-2.3.3-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:8e9aced64054739037d42fb84c54dd38b81ee238816c948c8f3ed134665dcd86"}, + {file = "numpy-2.3.3-cp313-cp313-win32.whl", hash = "sha256:9591e1221db3f37751e6442850429b3aabf7026d3b05542d102944ca7f00c8a8"}, + {file = "numpy-2.3.3-cp313-cp313-win_amd64.whl", hash = "sha256:f0dadeb302887f07431910f67a14d57209ed91130be0adea2f9793f1a4f817cf"}, + {file = "numpy-2.3.3-cp313-cp313-win_arm64.whl", hash = "sha256:3c7cf302ac6e0b76a64c4aecf1a09e51abd9b01fc7feee80f6c43e3ab1b1dbc5"}, + {file = "numpy-2.3.3-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:eda59e44957d272846bb407aad19f89dc6f58fecf3504bd144f4c5cf81a7eacc"}, + {file = "numpy-2.3.3-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:823d04112bc85ef5c4fda73ba24e6096c8f869931405a80aa8b0e604510a26bc"}, + {file = "numpy-2.3.3-cp313-cp313t-macosx_14_0_arm64.whl", hash = "sha256:40051003e03db4041aa325da2a0971ba41cf65714e65d296397cc0e32de6018b"}, + {file = "numpy-2.3.3-cp313-cp313t-macosx_14_0_x86_64.whl", hash = "sha256:6ee9086235dd6ab7ae75aba5662f582a81ced49f0f1c6de4260a78d8f2d91a19"}, + {file = "numpy-2.3.3-cp313-cp313t-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:94fcaa68757c3e2e668ddadeaa86ab05499a70725811e582b6a9858dd472fb30"}, + {file = "numpy-2.3.3-cp313-cp313t-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:da1a74b90e7483d6ce5244053399a614b1d6b7bc30a60d2f570e5071f8959d3e"}, + {file = "numpy-2.3.3-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:2990adf06d1ecee3b3dcbb4977dfab6e9f09807598d647f04d385d29e7a3c3d3"}, + {file = "numpy-2.3.3-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:ed635ff692483b8e3f0fcaa8e7eb8a75ee71aa6d975388224f70821421800cea"}, + {file = "numpy-2.3.3-cp313-cp313t-win32.whl", hash = "sha256:a333b4ed33d8dc2b373cc955ca57babc00cd6f9009991d9edc5ddbc1bac36bcd"}, + {file = "numpy-2.3.3-cp313-cp313t-win_amd64.whl", hash = "sha256:4384a169c4d8f97195980815d6fcad04933a7e1ab3b530921c3fef7a1c63426d"}, + {file = "numpy-2.3.3-cp313-cp313t-win_arm64.whl", hash = "sha256:75370986cc0bc66f4ce5110ad35aae6d182cc4ce6433c40ad151f53690130bf1"}, + {file = "numpy-2.3.3-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:cd052f1fa6a78dee696b58a914b7229ecfa41f0a6d96dc663c1220a55e137593"}, + {file = "numpy-2.3.3-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:414a97499480067d305fcac9716c29cf4d0d76db6ebf0bf3cbce666677f12652"}, + {file = "numpy-2.3.3-cp314-cp314-macosx_14_0_arm64.whl", hash = "sha256:50a5fe69f135f88a2be9b6ca0481a68a136f6febe1916e4920e12f1a34e708a7"}, + {file = "numpy-2.3.3-cp314-cp314-macosx_14_0_x86_64.whl", hash = "sha256:b912f2ed2b67a129e6a601e9d93d4fa37bef67e54cac442a2f588a54afe5c67a"}, + {file = "numpy-2.3.3-cp314-cp314-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:9e318ee0596d76d4cb3d78535dc005fa60e5ea348cd131a51e99d0bdbe0b54fe"}, + {file = "numpy-2.3.3-cp314-cp314-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:ce020080e4a52426202bdb6f7691c65bb55e49f261f31a8f506c9f6bc7450421"}, + {file = "numpy-2.3.3-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:e6687dc183aa55dae4a705b35f9c0f8cb178bcaa2f029b241ac5356221d5c021"}, + {file = "numpy-2.3.3-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:d8f3b1080782469fdc1718c4ed1d22549b5fb12af0d57d35e992158a772a37cf"}, + {file = "numpy-2.3.3-cp314-cp314-win32.whl", hash = "sha256:cb248499b0bc3be66ebd6578b83e5acacf1d6cb2a77f2248ce0e40fbec5a76d0"}, + {file = "numpy-2.3.3-cp314-cp314-win_amd64.whl", hash = "sha256:691808c2b26b0f002a032c73255d0bd89751425f379f7bcd22d140db593a96e8"}, + {file = "numpy-2.3.3-cp314-cp314-win_arm64.whl", hash = "sha256:9ad12e976ca7b10f1774b03615a2a4bab8addce37ecc77394d8e986927dc0dfe"}, + {file = "numpy-2.3.3-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:9cc48e09feb11e1db00b320e9d30a4151f7369afb96bd0e48d942d09da3a0d00"}, + {file = "numpy-2.3.3-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:901bf6123879b7f251d3631967fd574690734236075082078e0571977c6a8e6a"}, + {file = "numpy-2.3.3-cp314-cp314t-macosx_14_0_arm64.whl", hash = "sha256:7f025652034199c301049296b59fa7d52c7e625017cae4c75d8662e377bf487d"}, + {file = "numpy-2.3.3-cp314-cp314t-macosx_14_0_x86_64.whl", hash = "sha256:533ca5f6d325c80b6007d4d7fb1984c303553534191024ec6a524a4c92a5935a"}, + {file = "numpy-2.3.3-cp314-cp314t-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:0edd58682a399824633b66885d699d7de982800053acf20be1eaa46d92009c54"}, + {file = "numpy-2.3.3-cp314-cp314t-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:367ad5d8fbec5d9296d18478804a530f1191e24ab4d75ab408346ae88045d25e"}, + {file = "numpy-2.3.3-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:8f6ac61a217437946a1fa48d24c47c91a0c4f725237871117dea264982128097"}, + {file = "numpy-2.3.3-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:179a42101b845a816d464b6fe9a845dfaf308fdfc7925387195570789bb2c970"}, + {file = "numpy-2.3.3-cp314-cp314t-win32.whl", hash = "sha256:1250c5d3d2562ec4174bce2e3a1523041595f9b651065e4a4473f5f48a6bc8a5"}, + {file = "numpy-2.3.3-cp314-cp314t-win_amd64.whl", hash = "sha256:b37a0b2e5935409daebe82c1e42274d30d9dd355852529eab91dab8dcca7419f"}, + {file = "numpy-2.3.3-cp314-cp314t-win_arm64.whl", hash = "sha256:78c9f6560dc7e6b3990e32df7ea1a50bbd0e2a111e05209963f5ddcab7073b0b"}, + {file = "numpy-2.3.3-pp311-pypy311_pp73-macosx_10_15_x86_64.whl", hash = "sha256:1e02c7159791cd481e1e6d5ddd766b62a4d5acf8df4d4d1afe35ee9c5c33a41e"}, + {file = "numpy-2.3.3-pp311-pypy311_pp73-macosx_11_0_arm64.whl", hash = "sha256:dca2d0fc80b3893ae72197b39f69d55a3cd8b17ea1b50aa4c62de82419936150"}, + {file = "numpy-2.3.3-pp311-pypy311_pp73-macosx_14_0_arm64.whl", hash = "sha256:99683cbe0658f8271b333a1b1b4bb3173750ad59c0c61f5bbdc5b318918fffe3"}, + {file = "numpy-2.3.3-pp311-pypy311_pp73-macosx_14_0_x86_64.whl", hash = "sha256:d9d537a39cc9de668e5cd0e25affb17aec17b577c6b3ae8a3d866b479fbe88d0"}, + {file = "numpy-2.3.3-pp311-pypy311_pp73-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:8596ba2f8af5f93b01d97563832686d20206d303024777f6dfc2e7c7c3f1850e"}, + {file = "numpy-2.3.3-pp311-pypy311_pp73-manylinux_2_27_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:e1ec5615b05369925bd1125f27df33f3b6c8bc10d788d5999ecd8769a1fa04db"}, + {file = "numpy-2.3.3-pp311-pypy311_pp73-win_amd64.whl", hash = "sha256:2e267c7da5bf7309670523896df97f93f6e469fb931161f483cd6882b3b1a5dc"}, + {file = "numpy-2.3.3.tar.gz", hash = "sha256:ddc7c39727ba62b80dfdbedf400d1c10ddfa8eefbd7ec8dcb118be8b56d31029"}, ] [[package]] @@ -4505,14 +4855,14 @@ semsimian = ["semsimian (>=0.2.18)"] [[package]] name = "ols-client" -version = "0.1.4" +version = "0.2.1" description = "A client to the EBI Ontology Lookup Service" optional = false -python-versions = ">=3.7" +python-versions = ">=3.10" groups = ["main"] files = [ - {file = "ols_client-0.1.4-py3-none-any.whl", hash = "sha256:7bdca0590042e07cc7ee3ef3fba99c3b6862cde6c8835afb129de31284b3e010"}, - {file = "ols_client-0.1.4.tar.gz", hash = "sha256:cd2a0f39107f39eaf0f40b9098f12d442cf3d43e28228e63feb407d0aeb44470"}, + {file = "ols_client-0.2.1-py3-none-any.whl", hash = "sha256:e6d094b8d49711ed2b173b06bd3fbc62be4c8becd21def3bf4efec59096fcca8"}, + {file = "ols_client-0.2.1.tar.gz", hash = "sha256:c5078446f025e2fbe24a1a2bbb924d7372216ca05e7ff11dba87aa7721be008a"}, ] [package.dependencies] @@ -4523,8 +4873,7 @@ pystow = "*" requests = "*" [package.extras] -docs = ["sphinx", "sphinx-autodoc-typehints", "sphinx-automodapi", "sphinx-click", "sphinx-rtd-theme"] -tests = ["coverage", "pytest"] +similarity = ["numpy", "scikit-learn"] [[package]] name = "onnxruntime" @@ -4591,21 +4940,21 @@ tests = ["coverage", "pytest", "unittest-templates"] [[package]] name = "openai" -version = "1.109.1" +version = "2.3.0" description = "The official Python library for the openai API" optional = false python-versions = ">=3.8" groups = ["main"] files = [ - {file = "openai-1.109.1-py3-none-any.whl", hash = "sha256:6bcaf57086cf59159b8e27447e4e7dd019db5d29a438072fbd49c290c7e65315"}, - {file = "openai-1.109.1.tar.gz", hash = "sha256:d173ed8dbca665892a6db099b4a2dfac624f94d20a93f46eb0b56aae940ed869"}, + {file = "openai-2.3.0-py3-none-any.whl", hash = "sha256:a7aa83be6f7b0ab2e4d4d7bcaf36e3d790874c0167380c5d0afd0ed99a86bd7b"}, + {file = "openai-2.3.0.tar.gz", hash = "sha256:8d213ee5aaf91737faea2d7fc1cd608657a5367a18966372a3756ceaabfbd812"}, ] [package.dependencies] anyio = ">=3.5.0,<5" distro = ">=1.7.0,<2" httpx = ">=0.23.0,<1" -jiter = ">=0.4.0,<1" +jiter = ">=0.10.0,<1" pydantic = ">=1.9.0,<3" sniffio = "*" tqdm = ">4" @@ -4634,14 +4983,14 @@ et-xmlfile = "*" [[package]] name = "opentelemetry-api" -version = "1.35.0" +version = "1.37.0" description = "OpenTelemetry Python API" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "opentelemetry_api-1.35.0-py3-none-any.whl", hash = "sha256:c4ea7e258a244858daf18474625e9cc0149b8ee354f37843415771a40c25ee06"}, - {file = "opentelemetry_api-1.35.0.tar.gz", hash = "sha256:a111b959bcfa5b4d7dffc2fbd6a241aa72dd78dd8e79b5b1662bda896c5d2ffe"}, + {file = "opentelemetry_api-1.37.0-py3-none-any.whl", hash = "sha256:accf2024d3e89faec14302213bc39550ec0f4095d1cf5ca688e1bfb1c8612f47"}, + {file = "opentelemetry_api-1.37.0.tar.gz", hash = "sha256:540735b120355bd5112738ea53621f8d5edb35ebcd6fe21ada3ab1c61d1cd9a7"}, ] [package.dependencies] @@ -4650,68 +4999,68 @@ typing-extensions = ">=4.5.0" [[package]] name = "opentelemetry-exporter-otlp-proto-common" -version = "1.35.0" +version = "1.37.0" description = "OpenTelemetry Protobuf encoding" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "opentelemetry_exporter_otlp_proto_common-1.35.0-py3-none-any.whl", hash = "sha256:863465de697ae81279ede660f3918680b4480ef5f69dcdac04f30722ed7b74cc"}, - {file = "opentelemetry_exporter_otlp_proto_common-1.35.0.tar.gz", hash = "sha256:6f6d8c39f629b9fa5c79ce19a2829dbd93034f8ac51243cdf40ed2196f00d7eb"}, + {file = "opentelemetry_exporter_otlp_proto_common-1.37.0-py3-none-any.whl", hash = "sha256:53038428449c559b0c564b8d718df3314da387109c4d36bd1b94c9a641b0292e"}, + {file = "opentelemetry_exporter_otlp_proto_common-1.37.0.tar.gz", hash = "sha256:c87a1bdd9f41fdc408d9cc9367bb53f8d2602829659f2b90be9f9d79d0bfe62c"}, ] [package.dependencies] -opentelemetry-proto = "1.35.0" +opentelemetry-proto = "1.37.0" [[package]] name = "opentelemetry-exporter-otlp-proto-http" -version = "1.35.0" +version = "1.37.0" description = "OpenTelemetry Collector Protobuf over HTTP Exporter" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "opentelemetry_exporter_otlp_proto_http-1.35.0-py3-none-any.whl", hash = "sha256:9a001e3df3c7f160fb31056a28ed7faa2de7df68877ae909516102ae36a54e1d"}, - {file = "opentelemetry_exporter_otlp_proto_http-1.35.0.tar.gz", hash = "sha256:cf940147f91b450ef5f66e9980d40eb187582eed399fa851f4a7a45bb880de79"}, + {file = "opentelemetry_exporter_otlp_proto_http-1.37.0-py3-none-any.whl", hash = "sha256:54c42b39945a6cc9d9a2a33decb876eabb9547e0dcb49df090122773447f1aef"}, + {file = "opentelemetry_exporter_otlp_proto_http-1.37.0.tar.gz", hash = "sha256:e52e8600f1720d6de298419a802108a8f5afa63c96809ff83becb03f874e44ac"}, ] [package.dependencies] googleapis-common-protos = ">=1.52,<2.0" opentelemetry-api = ">=1.15,<2.0" -opentelemetry-exporter-otlp-proto-common = "1.35.0" -opentelemetry-proto = "1.35.0" -opentelemetry-sdk = ">=1.35.0,<1.36.0" +opentelemetry-exporter-otlp-proto-common = "1.37.0" +opentelemetry-proto = "1.37.0" +opentelemetry-sdk = ">=1.37.0,<1.38.0" requests = ">=2.7,<3.0" typing-extensions = ">=4.5.0" [[package]] name = "opentelemetry-instrumentation" -version = "0.56b0" +version = "0.58b0" description = "Instrumentation Tools & Auto Instrumentation for OpenTelemetry Python" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "opentelemetry_instrumentation-0.56b0-py3-none-any.whl", hash = "sha256:948967f7c8f5bdc6e43512ba74c9ae14acb48eb72a35b61afe8db9909f743be3"}, - {file = "opentelemetry_instrumentation-0.56b0.tar.gz", hash = "sha256:d2dbb3021188ca0ec8c5606349ee9a2919239627e8341d4d37f1d21ec3291d11"}, + {file = "opentelemetry_instrumentation-0.58b0-py3-none-any.whl", hash = "sha256:50f97ac03100676c9f7fc28197f8240c7290ca1baa12da8bfbb9a1de4f34cc45"}, + {file = "opentelemetry_instrumentation-0.58b0.tar.gz", hash = "sha256:df640f3ac715a3e05af145c18f527f4422c6ab6c467e40bd24d2ad75a00cb705"}, ] [package.dependencies] opentelemetry-api = ">=1.4,<2.0" -opentelemetry-semantic-conventions = "0.56b0" +opentelemetry-semantic-conventions = "0.58b0" packaging = ">=18.0" wrapt = ">=1.0.0,<2.0.0" [[package]] name = "opentelemetry-proto" -version = "1.35.0" +version = "1.37.0" description = "OpenTelemetry Python Proto" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "opentelemetry_proto-1.35.0-py3-none-any.whl", hash = "sha256:98fffa803164499f562718384e703be8d7dfbe680192279a0429cb150a2f8809"}, - {file = "opentelemetry_proto-1.35.0.tar.gz", hash = "sha256:532497341bd3e1c074def7c5b00172601b28bb83b48afc41a4b779f26eb4ee05"}, + {file = "opentelemetry_proto-1.37.0-py3-none-any.whl", hash = "sha256:8ed8c066ae8828bbf0c39229979bdf583a126981142378a9cbe9d6fd5701c6e2"}, + {file = "opentelemetry_proto-1.37.0.tar.gz", hash = "sha256:30f5c494faf66f77faeaefa35ed4443c5edb3b0aa46dad073ed7210e1a789538"}, ] [package.dependencies] @@ -4719,118 +5068,129 @@ protobuf = ">=5.0,<7.0" [[package]] name = "opentelemetry-sdk" -version = "1.35.0" +version = "1.37.0" description = "OpenTelemetry Python SDK" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "opentelemetry_sdk-1.35.0-py3-none-any.whl", hash = "sha256:223d9e5f5678518f4842311bb73966e0b6db5d1e0b74e35074c052cd2487f800"}, - {file = "opentelemetry_sdk-1.35.0.tar.gz", hash = "sha256:2a400b415ab68aaa6f04e8a6a9f6552908fb3090ae2ff78d6ae0c597ac581954"}, + {file = "opentelemetry_sdk-1.37.0-py3-none-any.whl", hash = "sha256:8f3c3c22063e52475c5dbced7209495c2c16723d016d39287dfc215d1771257c"}, + {file = "opentelemetry_sdk-1.37.0.tar.gz", hash = "sha256:cc8e089c10953ded765b5ab5669b198bbe0af1b3f89f1007d19acd32dc46dda5"}, ] [package.dependencies] -opentelemetry-api = "1.35.0" -opentelemetry-semantic-conventions = "0.56b0" +opentelemetry-api = "1.37.0" +opentelemetry-semantic-conventions = "0.58b0" typing-extensions = ">=4.5.0" [[package]] name = "opentelemetry-semantic-conventions" -version = "0.56b0" +version = "0.58b0" description = "OpenTelemetry Semantic Conventions" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "opentelemetry_semantic_conventions-0.56b0-py3-none-any.whl", hash = "sha256:df44492868fd6b482511cc43a942e7194be64e94945f572db24df2e279a001a2"}, - {file = "opentelemetry_semantic_conventions-0.56b0.tar.gz", hash = "sha256:c114c2eacc8ff6d3908cb328c811eaf64e6d68623840be9224dc829c4fd6c2ea"}, + {file = "opentelemetry_semantic_conventions-0.58b0-py3-none-any.whl", hash = "sha256:5564905ab1458b96684db1340232729fce3b5375a06e140e8904c78e4f815b28"}, + {file = "opentelemetry_semantic_conventions-0.58b0.tar.gz", hash = "sha256:6bd46f51264279c433755767bb44ad00f1c9e2367e1b42af563372c5a6fa0c25"}, ] [package.dependencies] -opentelemetry-api = "1.35.0" +opentelemetry-api = "1.37.0" typing-extensions = ">=4.5.0" [[package]] name = "orjson" -version = "3.11.0" +version = "3.11.3" description = "Fast, correct Python JSON library supporting dataclasses, datetimes, and numpy" optional = false python-versions = ">=3.9" groups = ["main"] markers = "extra == \"gradio\"" files = [ - {file = "orjson-3.11.0-cp310-cp310-macosx_10_15_x86_64.macosx_11_0_arm64.macosx_10_15_universal2.whl", hash = "sha256:b8913baba9751f7400f8fa4ec18a8b618ff01177490842e39e47b66c1b04bc79"}, - {file = "orjson-3.11.0-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:9d4d86910554de5c9c87bc560b3bdd315cc3988adbdc2acf5dda3797079407ed"}, - {file = "orjson-3.11.0-cp310-cp310-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:84ae3d329360cf18fb61b67c505c00dedb61b0ee23abfd50f377a58e7d7bed06"}, - {file = "orjson-3.11.0-cp310-cp310-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:47a54e660414baacd71ebf41a69bb17ea25abb3c5b69ce9e13e43be7ac20e342"}, - {file = "orjson-3.11.0-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:2560b740604751854be146169c1de7e7ee1e6120b00c1788ec3f3a012c6a243f"}, - {file = "orjson-3.11.0-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:dd7f9cd995da9e46fbac0a371f0ff6e89a21d8ecb7a8a113c0acb147b0a32f73"}, - {file = "orjson-3.11.0-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:7cf728cb3a013bdf9f4132575404bf885aa773d8bb4205656575e1890fc91990"}, - {file = "orjson-3.11.0-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:c27de273320294121200440cd5002b6aeb922d3cb9dab3357087c69f04ca6934"}, - {file = "orjson-3.11.0-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:4430ec6ff1a1f4595dd7e0fad991bdb2fed65401ed294984c490ffa025926325"}, - {file = "orjson-3.11.0-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:325be41a8d7c227d460a9795a181511ba0e731cf3fee088c63eb47e706ea7559"}, - {file = "orjson-3.11.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:d9760217b84d1aee393b4436fbe9c639e963ec7bc0f2c074581ce5fb3777e466"}, - {file = "orjson-3.11.0-cp310-cp310-win32.whl", hash = "sha256:fe36e5012f886ff91c68b87a499c227fa220e9668cea96335219874c8be5fab5"}, - {file = "orjson-3.11.0-cp310-cp310-win_amd64.whl", hash = "sha256:ebeecd5d5511b3ca9dc4e7db0ab95266afd41baf424cc2fad8c2d3a3cdae650a"}, - {file = "orjson-3.11.0-cp311-cp311-macosx_10_15_x86_64.macosx_11_0_arm64.macosx_10_15_universal2.whl", hash = "sha256:1785df7ada75c18411ff7e20ac822af904a40161ea9dfe8c55b3f6b66939add6"}, - {file = "orjson-3.11.0-cp311-cp311-macosx_15_0_arm64.whl", hash = "sha256:a57899bebbcea146616a2426d20b51b3562b4bc9f8039a3bd14fae361c23053d"}, - {file = "orjson-3.11.0-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:9b6fbc2fc825aff1456dd358c11a0ad7912a4cb4537d3db92e5334af7463a967"}, - {file = "orjson-3.11.0-cp311-cp311-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:4305a638f4cf9bed3746ca3b7c242f14e05177d5baec2527026e0f9ee6c24fb7"}, - {file = "orjson-3.11.0-cp311-cp311-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:1235fe7bbc37164f69302199d46f29cfb874018738714dccc5a5a44042c79c77"}, - {file = "orjson-3.11.0-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:a640e3954e7b4fcb160097551e54cafbde9966be3991932155b71071077881aa"}, - {file = "orjson-3.11.0-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:6d750b97d22d5566955e50b02c622f3a1d32744d7a578c878b29a873190ccb7a"}, - {file = "orjson-3.11.0-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:4bfcfe498484161e011f8190a400591c52b026de96b3b3cbd3f21e8999b9dc0e"}, - {file = "orjson-3.11.0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:feaed3ed43a1d2df75c039798eb5ec92c350c7d86be53369bafc4f3700ce7df2"}, - {file = "orjson-3.11.0-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:aa1120607ec8fc98acf8c54aac6fb0b7b003ba883401fa2d261833111e2fa071"}, - {file = "orjson-3.11.0-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:c4b48d9775b0cf1f0aca734f4c6b272cbfacfac38e6a455e6520662f9434afb7"}, - {file = "orjson-3.11.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:f018ed1986d79434ac712ff19f951cd00b4dfcb767444410fbb834ebec160abf"}, - {file = "orjson-3.11.0-cp311-cp311-win32.whl", hash = "sha256:08e191f8a55ac2c00be48e98a5d10dca004cbe8abe73392c55951bfda60fc123"}, - {file = "orjson-3.11.0-cp311-cp311-win_amd64.whl", hash = "sha256:b5a4214ea59c8a3b56f8d484b28114af74e9fba0956f9be5c3ce388ae143bf1f"}, - {file = "orjson-3.11.0-cp311-cp311-win_arm64.whl", hash = "sha256:57e8e7198a679ab21241ab3f355a7990c7447559e35940595e628c107ef23736"}, - {file = "orjson-3.11.0-cp312-cp312-macosx_10_15_x86_64.macosx_11_0_arm64.macosx_10_15_universal2.whl", hash = "sha256:b4089f940c638bb1947d54e46c1cd58f4259072fcc97bc833ea9c78903150ac9"}, - {file = "orjson-3.11.0-cp312-cp312-macosx_15_0_arm64.whl", hash = "sha256:8335a0ba1c26359fb5c82d643b4c1abbee2bc62875e0f2b5bde6c8e9e25eb68c"}, - {file = "orjson-3.11.0-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:63c1c9772dafc811d16d6a7efa3369a739da15d1720d6e58ebe7562f54d6f4a2"}, - {file = "orjson-3.11.0-cp312-cp312-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:9457ccbd8b241fb4ba516417a4c5b95ba0059df4ac801309bcb4ec3870f45ad9"}, - {file = "orjson-3.11.0-cp312-cp312-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:0846e13abe79daece94a00b92574f294acad1d362be766c04245b9b4dd0e47e1"}, - {file = "orjson-3.11.0-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:5587c85ae02f608a3f377b6af9eb04829606f518257cbffa8f5081c1aacf2e2f"}, - {file = "orjson-3.11.0-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:c7a1964a71c1567b4570c932a0084ac24ad52c8cf6253d1881400936565ed438"}, - {file = "orjson-3.11.0-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:b5a8243e73690cc6e9151c9e1dd046a8f21778d775f7d478fa1eb4daa4897c61"}, - {file = "orjson-3.11.0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:51646f6d995df37b6e1b628f092f41c0feccf1d47e3452c6e95e2474b547d842"}, - {file = "orjson-3.11.0-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:2fb8ca8f0b4e31b8aaec674c7540649b64ef02809410506a44dc68d31bd5647b"}, - {file = "orjson-3.11.0-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:64a6a3e94a44856c3f6557e6aa56a6686544fed9816ae0afa8df9077f5759791"}, - {file = "orjson-3.11.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:d69f95d484938d8fab5963e09131bcf9fbbb81fa4ec132e316eb2fb9adb8ce78"}, - {file = "orjson-3.11.0-cp312-cp312-win32.whl", hash = "sha256:8514f9f9c667ce7d7ef709ab1a73e7fcab78c297270e90b1963df7126d2b0e23"}, - {file = "orjson-3.11.0-cp312-cp312-win_amd64.whl", hash = "sha256:41b38a894520b8cb5344a35ffafdf6ae8042f56d16771b2c5eb107798cee85ee"}, - {file = "orjson-3.11.0-cp312-cp312-win_arm64.whl", hash = "sha256:5579acd235dd134467340b2f8a670c1c36023b5a69c6a3174c4792af7502bd92"}, - {file = "orjson-3.11.0-cp313-cp313-macosx_10_15_x86_64.macosx_11_0_arm64.macosx_10_15_universal2.whl", hash = "sha256:4a8ba9698655e16746fdf5266939427da0f9553305152aeb1a1cc14974a19cfb"}, - {file = "orjson-3.11.0-cp313-cp313-macosx_15_0_arm64.whl", hash = "sha256:67133847f9a35a5ef5acfa3325d4a2f7fe05c11f1505c4117bb086fc06f2a58f"}, - {file = "orjson-3.11.0-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:5f797d57814975b78f5f5423acb003db6f9be5186b72d48bd97a1000e89d331d"}, - {file = "orjson-3.11.0-cp313-cp313-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:28acd19822987c5163b9e03a6e60853a52acfee384af2b394d11cb413b889246"}, - {file = "orjson-3.11.0-cp313-cp313-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:e8d38d9e1e2cf9729658e35956cf01e13e89148beb4cb9e794c9c10c5cb252f8"}, - {file = "orjson-3.11.0-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:05f094edd2b782650b0761fd78858d9254de1c1286f5af43145b3d08cdacfd51"}, - {file = "orjson-3.11.0-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:6d09176a4a9e04a5394a4a0edd758f645d53d903b306d02f2691b97d5c736a9e"}, - {file = "orjson-3.11.0-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:2a585042104e90a61eda2564d11317b6a304eb4e71cd33e839f5af6be56c34d3"}, - {file = "orjson-3.11.0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:d2218629dbfdeeb5c9e0573d59f809d42f9d49ae6464d2f479e667aee14c3ef4"}, - {file = "orjson-3.11.0-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:613e54a2b10b51b656305c11235a9c4a5c5491ef5c283f86483d4e9e123ed5e4"}, - {file = "orjson-3.11.0-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:9dac7fbf3b8b05965986c5cfae051eb9a30fced7f15f1d13a5adc608436eb486"}, - {file = "orjson-3.11.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:93b64b254414e2be55ac5257124b5602c5f0b4d06b80bd27d1165efe8f36e836"}, - {file = "orjson-3.11.0-cp313-cp313-win32.whl", hash = "sha256:359cbe11bc940c64cb3848cf22000d2aef36aff7bfd09ca2c0b9cb309c387132"}, - {file = "orjson-3.11.0-cp313-cp313-win_amd64.whl", hash = "sha256:0759b36428067dc777b202dd286fbdd33d7f261c6455c4238ea4e8474358b1e6"}, - {file = "orjson-3.11.0-cp313-cp313-win_arm64.whl", hash = "sha256:51cdca2f36e923126d0734efaf72ddbb5d6da01dbd20eab898bdc50de80d7b5a"}, - {file = "orjson-3.11.0-cp39-cp39-macosx_10_15_x86_64.macosx_11_0_arm64.macosx_10_15_universal2.whl", hash = "sha256:d79c180cfb3ae68f13245d0ff551dca03d96258aa560830bf8a223bd68d8272c"}, - {file = "orjson-3.11.0-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:105bca887532dc71ce4b05a5de95dea447a310409d7a8cf0cb1c4a120469e9ad"}, - {file = "orjson-3.11.0-cp39-cp39-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:acf5a63ae9cdb88274126af85913ceae554d8fd71122effa24a53227abbeee16"}, - {file = "orjson-3.11.0-cp39-cp39-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:894635df36c0be32f1c8c8607e853b8865edb58e7618e57892e85d06418723eb"}, - {file = "orjson-3.11.0-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:02dd4f0a1a2be943a104ce5f3ec092631ee3e9f0b4bb9eeee3400430bd94ddef"}, - {file = "orjson-3.11.0-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:720b4bb5e1b971960a62c2fa254c2d2a14e7eb791e350d05df8583025aa59d15"}, - {file = "orjson-3.11.0-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:8bf058105a8aed144e0d1cfe7ac4174748c3fc7203f225abaeac7f4121abccb0"}, - {file = "orjson-3.11.0-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:a2788f741e5a0e885e5eaf1d91d0c9106e03cb9575b0c55ba36fd3d48b0b1e9b"}, - {file = "orjson-3.11.0-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:c60c99fe1e15894367b0340b2ff16c7c69f9c3f3a54aa3961a58c102b292ad94"}, - {file = "orjson-3.11.0-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:99d17aab984f4d029b8f3c307e6be3c63d9ee5ef55e30d761caf05e883009949"}, - {file = "orjson-3.11.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:e98f02e23611763c9e5dfcb83bd33219231091589f0d1691e721aea9c52bf329"}, - {file = "orjson-3.11.0-cp39-cp39-win32.whl", hash = "sha256:923301f33ea866b18f8836cf41d9c6d33e3b5cab8577d20fed34ec29f0e13a0d"}, - {file = "orjson-3.11.0-cp39-cp39-win_amd64.whl", hash = "sha256:475491bb78af2a0170f49e90013f1a0f1286527f3617491f8940d7e5da862da7"}, - {file = "orjson-3.11.0.tar.gz", hash = "sha256:2e4c129da624f291bcc607016a99e7f04a353f6874f3bd8d9b47b88597d5f700"}, + {file = "orjson-3.11.3-cp310-cp310-macosx_10_15_x86_64.macosx_11_0_arm64.macosx_10_15_universal2.whl", hash = "sha256:29cb1f1b008d936803e2da3d7cba726fc47232c45df531b29edf0b232dd737e7"}, + {file = "orjson-3.11.3-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:97dceed87ed9139884a55db8722428e27bd8452817fbf1869c58b49fecab1120"}, + {file = "orjson-3.11.3-cp310-cp310-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:58533f9e8266cb0ac298e259ed7b4d42ed3fa0b78ce76860626164de49e0d467"}, + {file = "orjson-3.11.3-cp310-cp310-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:0c212cfdd90512fe722fa9bd620de4d46cda691415be86b2e02243242ae81873"}, + {file = "orjson-3.11.3-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:5ff835b5d3e67d9207343effb03760c00335f8b5285bfceefd4dc967b0e48f6a"}, + {file = "orjson-3.11.3-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:f5aa4682912a450c2db89cbd92d356fef47e115dffba07992555542f344d301b"}, + {file = "orjson-3.11.3-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:d7d18dd34ea2e860553a579df02041845dee0af8985dff7f8661306f95504ddf"}, + {file = "orjson-3.11.3-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:d8b11701bc43be92ea42bd454910437b355dfb63696c06fe953ffb40b5f763b4"}, + {file = "orjson-3.11.3-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:90368277087d4af32d38bd55f9da2ff466d25325bf6167c8f382d8ee40cb2bbc"}, + {file = "orjson-3.11.3-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:fd7ff459fb393358d3a155d25b275c60b07a2c83dcd7ea962b1923f5a1134569"}, + {file = "orjson-3.11.3-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:f8d902867b699bcd09c176a280b1acdab57f924489033e53d0afe79817da37e6"}, + {file = "orjson-3.11.3-cp310-cp310-win32.whl", hash = "sha256:bb93562146120bb51e6b154962d3dadc678ed0fce96513fa6bc06599bb6f6edc"}, + {file = "orjson-3.11.3-cp310-cp310-win_amd64.whl", hash = "sha256:976c6f1975032cc327161c65d4194c549f2589d88b105a5e3499429a54479770"}, + {file = "orjson-3.11.3-cp311-cp311-macosx_10_15_x86_64.macosx_11_0_arm64.macosx_10_15_universal2.whl", hash = "sha256:9d2ae0cc6aeb669633e0124531f342a17d8e97ea999e42f12a5ad4adaa304c5f"}, + {file = "orjson-3.11.3-cp311-cp311-macosx_15_0_arm64.whl", hash = "sha256:ba21dbb2493e9c653eaffdc38819b004b7b1b246fb77bfc93dc016fe664eac91"}, + {file = "orjson-3.11.3-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:00f1a271e56d511d1569937c0447d7dce5a99a33ea0dec76673706360a051904"}, + {file = "orjson-3.11.3-cp311-cp311-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:b67e71e47caa6680d1b6f075a396d04fa6ca8ca09aafb428731da9b3ea32a5a6"}, + {file = "orjson-3.11.3-cp311-cp311-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:d7d012ebddffcce8c85734a6d9e5f08180cd3857c5f5a3ac70185b43775d043d"}, + {file = "orjson-3.11.3-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:dd759f75d6b8d1b62012b7f5ef9461d03c804f94d539a5515b454ba3a6588038"}, + {file = "orjson-3.11.3-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:6890ace0809627b0dff19cfad92d69d0fa3f089d3e359a2a532507bb6ba34efb"}, + {file = "orjson-3.11.3-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:f9d4a5e041ae435b815e568537755773d05dac031fee6a57b4ba70897a44d9d2"}, + {file = "orjson-3.11.3-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:2d68bf97a771836687107abfca089743885fb664b90138d8761cce61d5625d55"}, + {file = "orjson-3.11.3-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:bfc27516ec46f4520b18ef645864cee168d2a027dbf32c5537cb1f3e3c22dac1"}, + {file = "orjson-3.11.3-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:f66b001332a017d7945e177e282a40b6997056394e3ed7ddb41fb1813b83e824"}, + {file = "orjson-3.11.3-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:212e67806525d2561efbfe9e799633b17eb668b8964abed6b5319b2f1cfbae1f"}, + {file = "orjson-3.11.3-cp311-cp311-win32.whl", hash = "sha256:6e8e0c3b85575a32f2ffa59de455f85ce002b8bdc0662d6b9c2ed6d80ab5d204"}, + {file = "orjson-3.11.3-cp311-cp311-win_amd64.whl", hash = "sha256:6be2f1b5d3dc99a5ce5ce162fc741c22ba9f3443d3dd586e6a1211b7bc87bc7b"}, + {file = "orjson-3.11.3-cp311-cp311-win_arm64.whl", hash = "sha256:fafb1a99d740523d964b15c8db4eabbfc86ff29f84898262bf6e3e4c9e97e43e"}, + {file = "orjson-3.11.3-cp312-cp312-macosx_10_15_x86_64.macosx_11_0_arm64.macosx_10_15_universal2.whl", hash = "sha256:8c752089db84333e36d754c4baf19c0e1437012242048439c7e80eb0e6426e3b"}, + {file = "orjson-3.11.3-cp312-cp312-macosx_15_0_arm64.whl", hash = "sha256:9b8761b6cf04a856eb544acdd82fc594b978f12ac3602d6374a7edb9d86fd2c2"}, + {file = "orjson-3.11.3-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:8b13974dc8ac6ba22feaa867fc19135a3e01a134b4f7c9c28162fed4d615008a"}, + {file = "orjson-3.11.3-cp312-cp312-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:f83abab5bacb76d9c821fd5c07728ff224ed0e52d7a71b7b3de822f3df04e15c"}, + {file = "orjson-3.11.3-cp312-cp312-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:e6fbaf48a744b94091a56c62897b27c31ee2da93d826aa5b207131a1e13d4064"}, + {file = "orjson-3.11.3-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:bc779b4f4bba2847d0d2940081a7b6f7b5877e05408ffbb74fa1faf4a136c424"}, + {file = "orjson-3.11.3-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:bd4b909ce4c50faa2192da6bb684d9848d4510b736b0611b6ab4020ea6fd2d23"}, + {file = "orjson-3.11.3-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:524b765ad888dc5518bbce12c77c2e83dee1ed6b0992c1790cc5fb49bb4b6667"}, + {file = "orjson-3.11.3-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:84fd82870b97ae3cdcea9d8746e592b6d40e1e4d4527835fc520c588d2ded04f"}, + {file = "orjson-3.11.3-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:fbecb9709111be913ae6879b07bafd4b0785b44c1eb5cac8ac76da048b3885a1"}, + {file = "orjson-3.11.3-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:9dba358d55aee552bd868de348f4736ca5a4086d9a62e2bfbbeeb5629fe8b0cc"}, + {file = "orjson-3.11.3-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:eabcf2e84f1d7105f84580e03012270c7e97ecb1fb1618bda395061b2a84a049"}, + {file = "orjson-3.11.3-cp312-cp312-win32.whl", hash = "sha256:3782d2c60b8116772aea8d9b7905221437fdf53e7277282e8d8b07c220f96cca"}, + {file = "orjson-3.11.3-cp312-cp312-win_amd64.whl", hash = "sha256:79b44319268af2eaa3e315b92298de9a0067ade6e6003ddaef72f8e0bedb94f1"}, + {file = "orjson-3.11.3-cp312-cp312-win_arm64.whl", hash = "sha256:0e92a4e83341ef79d835ca21b8bd13e27c859e4e9e4d7b63defc6e58462a3710"}, + {file = "orjson-3.11.3-cp313-cp313-macosx_10_15_x86_64.macosx_11_0_arm64.macosx_10_15_universal2.whl", hash = "sha256:af40c6612fd2a4b00de648aa26d18186cd1322330bd3a3cc52f87c699e995810"}, + {file = "orjson-3.11.3-cp313-cp313-macosx_15_0_arm64.whl", hash = "sha256:9f1587f26c235894c09e8b5b7636a38091a9e6e7fe4531937534749c04face43"}, + {file = "orjson-3.11.3-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:61dcdad16da5bb486d7227a37a2e789c429397793a6955227cedbd7252eb5a27"}, + {file = "orjson-3.11.3-cp313-cp313-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:11c6d71478e2cbea0a709e8a06365fa63da81da6498a53e4c4f065881d21ae8f"}, + {file = "orjson-3.11.3-cp313-cp313-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:ff94112e0098470b665cb0ed06efb187154b63649403b8d5e9aedeb482b4548c"}, + {file = "orjson-3.11.3-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:ae8b756575aaa2a855a75192f356bbda11a89169830e1439cfb1a3e1a6dde7be"}, + {file = "orjson-3.11.3-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:c9416cc19a349c167ef76135b2fe40d03cea93680428efee8771f3e9fb66079d"}, + {file = "orjson-3.11.3-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:b822caf5b9752bc6f246eb08124c3d12bf2175b66ab74bac2ef3bbf9221ce1b2"}, + {file = "orjson-3.11.3-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:414f71e3bdd5573893bf5ecdf35c32b213ed20aa15536fe2f588f946c318824f"}, + {file = "orjson-3.11.3-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:828e3149ad8815dc14468f36ab2a4b819237c155ee1370341b91ea4c8672d2ee"}, + {file = "orjson-3.11.3-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:ac9e05f25627ffc714c21f8dfe3a579445a5c392a9c8ae7ba1d0e9fb5333f56e"}, + {file = "orjson-3.11.3-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:e44fbe4000bd321d9f3b648ae46e0196d21577cf66ae684a96ff90b1f7c93633"}, + {file = "orjson-3.11.3-cp313-cp313-win32.whl", hash = "sha256:2039b7847ba3eec1f5886e75e6763a16e18c68a63efc4b029ddf994821e2e66b"}, + {file = "orjson-3.11.3-cp313-cp313-win_amd64.whl", hash = "sha256:29be5ac4164aa8bdcba5fa0700a3c9c316b411d8ed9d39ef8a882541bd452fae"}, + {file = "orjson-3.11.3-cp313-cp313-win_arm64.whl", hash = "sha256:18bd1435cb1f2857ceb59cfb7de6f92593ef7b831ccd1b9bfb28ca530e539dce"}, + {file = "orjson-3.11.3-cp314-cp314-macosx_10_15_x86_64.macosx_11_0_arm64.macosx_10_15_universal2.whl", hash = "sha256:cf4b81227ec86935568c7edd78352a92e97af8da7bd70bdfdaa0d2e0011a1ab4"}, + {file = "orjson-3.11.3-cp314-cp314-macosx_15_0_arm64.whl", hash = "sha256:bc8bc85b81b6ac9fc4dae393a8c159b817f4c2c9dee5d12b773bddb3b95fc07e"}, + {file = "orjson-3.11.3-cp314-cp314-manylinux_2_34_aarch64.whl", hash = "sha256:88dcfc514cfd1b0de038443c7b3e6a9797ffb1b3674ef1fd14f701a13397f82d"}, + {file = "orjson-3.11.3-cp314-cp314-manylinux_2_34_x86_64.whl", hash = "sha256:d61cd543d69715d5fc0a690c7c6f8dcc307bc23abef9738957981885f5f38229"}, + {file = "orjson-3.11.3-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:2b7b153ed90ababadbef5c3eb39549f9476890d339cf47af563aea7e07db2451"}, + {file = "orjson-3.11.3-cp314-cp314-musllinux_1_2_armv7l.whl", hash = "sha256:7909ae2460f5f494fecbcd10613beafe40381fd0316e35d6acb5f3a05bfda167"}, + {file = "orjson-3.11.3-cp314-cp314-musllinux_1_2_i686.whl", hash = "sha256:2030c01cbf77bc67bee7eef1e7e31ecf28649353987775e3583062c752da0077"}, + {file = "orjson-3.11.3-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:a0169ebd1cbd94b26c7a7ad282cf5c2744fce054133f959e02eb5265deae1872"}, + {file = "orjson-3.11.3-cp314-cp314-win32.whl", hash = "sha256:0c6d7328c200c349e3a4c6d8c83e0a5ad029bdc2d417f234152bf34842d0fc8d"}, + {file = "orjson-3.11.3-cp314-cp314-win_amd64.whl", hash = "sha256:317bbe2c069bbc757b1a2e4105b64aacd3bc78279b66a6b9e51e846e4809f804"}, + {file = "orjson-3.11.3-cp314-cp314-win_arm64.whl", hash = "sha256:e8f6a7a27d7b7bec81bd5924163e9af03d49bbb63013f107b48eb5d16db711bc"}, + {file = "orjson-3.11.3-cp39-cp39-macosx_10_15_x86_64.macosx_11_0_arm64.macosx_10_15_universal2.whl", hash = "sha256:56afaf1e9b02302ba636151cfc49929c1bb66b98794291afd0e5f20fecaf757c"}, + {file = "orjson-3.11.3-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:913f629adef31d2d350d41c051ce7e33cf0fd06a5d1cb28d49b1899b23b903aa"}, + {file = "orjson-3.11.3-cp39-cp39-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:e0a23b41f8f98b4e61150a03f83e4f0d566880fe53519d445a962929a4d21045"}, + {file = "orjson-3.11.3-cp39-cp39-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:3d721fee37380a44f9d9ce6c701b3960239f4fb3d5ceea7f31cbd43882edaa2f"}, + {file = "orjson-3.11.3-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:73b92a5b69f31b1a58c0c7e31080aeaec49c6e01b9522e71ff38d08f15aa56de"}, + {file = "orjson-3.11.3-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:d2489b241c19582b3f1430cc5d732caefc1aaf378d97e7fb95b9e56bed11725f"}, + {file = "orjson-3.11.3-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:c5189a5dab8b0312eadaf9d58d3049b6a52c454256493a557405e77a3d67ab7f"}, + {file = "orjson-3.11.3-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:9d8787bdfbb65a85ea76d0e96a3b1bed7bf0fbcb16d40408dc1172ad784a49d2"}, + {file = "orjson-3.11.3-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:8e531abd745f51f8035e207e75e049553a86823d189a51809c078412cefb399a"}, + {file = "orjson-3.11.3-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:8ab962931015f170b97a3dd7bd933399c1bae8ed8ad0fb2a7151a5654b6941c7"}, + {file = "orjson-3.11.3-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:124d5ba71fee9c9902c4a7baa9425e663f7f0aecf73d31d54fe3dd357d62c1a7"}, + {file = "orjson-3.11.3-cp39-cp39-win32.whl", hash = "sha256:22724d80ee5a815a44fc76274bb7ba2e7464f5564aacb6ecddaa9970a83e3225"}, + {file = "orjson-3.11.3-cp39-cp39-win_amd64.whl", hash = "sha256:215c595c792a87d4407cb72dd5e0f6ee8e694ceeb7f9102b533c5a9bf2a916bb"}, + {file = "orjson-3.11.3.tar.gz", hash = "sha256:1c0603b1d2ffcd43a411d64797a19556ef76958aef1c182f22dc30860152a98a"}, ] [[package]] @@ -4878,54 +5238,67 @@ lint = ["black"] [[package]] name = "pandas" -version = "2.3.1" +version = "2.3.3" description = "Powerful data structures for data analysis, time series, and statistics" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "pandas-2.3.1-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:22c2e866f7209ebc3a8f08d75766566aae02bcc91d196935a1d9e59c7b990ac9"}, - {file = "pandas-2.3.1-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:3583d348546201aff730c8c47e49bc159833f971c2899d6097bce68b9112a4f1"}, - {file = "pandas-2.3.1-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:0f951fbb702dacd390561e0ea45cdd8ecfa7fb56935eb3dd78e306c19104b9b0"}, - {file = "pandas-2.3.1-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:cd05b72ec02ebfb993569b4931b2e16fbb4d6ad6ce80224a3ee838387d83a191"}, - {file = "pandas-2.3.1-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:1b916a627919a247d865aed068eb65eb91a344b13f5b57ab9f610b7716c92de1"}, - {file = "pandas-2.3.1-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:fe67dc676818c186d5a3d5425250e40f179c2a89145df477dd82945eaea89e97"}, - {file = "pandas-2.3.1-cp310-cp310-win_amd64.whl", hash = "sha256:2eb789ae0274672acbd3c575b0598d213345660120a257b47b5dafdc618aec83"}, - {file = "pandas-2.3.1-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:2b0540963d83431f5ce8870ea02a7430adca100cec8a050f0811f8e31035541b"}, - {file = "pandas-2.3.1-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:fe7317f578c6a153912bd2292f02e40c1d8f253e93c599e82620c7f69755c74f"}, - {file = "pandas-2.3.1-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:e6723a27ad7b244c0c79d8e7007092d7c8f0f11305770e2f4cd778b3ad5f9f85"}, - {file = "pandas-2.3.1-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:3462c3735fe19f2638f2c3a40bd94ec2dc5ba13abbb032dd2fa1f540a075509d"}, - {file = "pandas-2.3.1-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:98bcc8b5bf7afed22cc753a28bc4d9e26e078e777066bc53fac7904ddef9a678"}, - {file = "pandas-2.3.1-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:4d544806b485ddf29e52d75b1f559142514e60ef58a832f74fb38e48d757b299"}, - {file = "pandas-2.3.1-cp311-cp311-win_amd64.whl", hash = "sha256:b3cd4273d3cb3707b6fffd217204c52ed92859533e31dc03b7c5008aa933aaab"}, - {file = "pandas-2.3.1-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:689968e841136f9e542020698ee1c4fbe9caa2ed2213ae2388dc7b81721510d3"}, - {file = "pandas-2.3.1-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:025e92411c16cbe5bb2a4abc99732a6b132f439b8aab23a59fa593eb00704232"}, - {file = "pandas-2.3.1-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:9b7ff55f31c4fcb3e316e8f7fa194566b286d6ac430afec0d461163312c5841e"}, - {file = "pandas-2.3.1-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:7dcb79bf373a47d2a40cf7232928eb7540155abbc460925c2c96d2d30b006eb4"}, - {file = "pandas-2.3.1-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:56a342b231e8862c96bdb6ab97170e203ce511f4d0429589c8ede1ee8ece48b8"}, - {file = "pandas-2.3.1-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:ca7ed14832bce68baef331f4d7f294411bed8efd032f8109d690df45e00c4679"}, - {file = "pandas-2.3.1-cp312-cp312-win_amd64.whl", hash = "sha256:ac942bfd0aca577bef61f2bc8da8147c4ef6879965ef883d8e8d5d2dc3e744b8"}, - {file = "pandas-2.3.1-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:9026bd4a80108fac2239294a15ef9003c4ee191a0f64b90f170b40cfb7cf2d22"}, - {file = "pandas-2.3.1-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:6de8547d4fdb12421e2d047a2c446c623ff4c11f47fddb6b9169eb98ffba485a"}, - {file = "pandas-2.3.1-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:782647ddc63c83133b2506912cc6b108140a38a37292102aaa19c81c83db2928"}, - {file = "pandas-2.3.1-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:2ba6aff74075311fc88504b1db890187a3cd0f887a5b10f5525f8e2ef55bfdb9"}, - {file = "pandas-2.3.1-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:e5635178b387bd2ba4ac040f82bc2ef6e6b500483975c4ebacd34bec945fda12"}, - {file = "pandas-2.3.1-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:6f3bf5ec947526106399a9e1d26d40ee2b259c66422efdf4de63c848492d91bb"}, - {file = "pandas-2.3.1-cp313-cp313-win_amd64.whl", hash = "sha256:1c78cf43c8fde236342a1cb2c34bcff89564a7bfed7e474ed2fffa6aed03a956"}, - {file = "pandas-2.3.1-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:8dfc17328e8da77be3cf9f47509e5637ba8f137148ed0e9b5241e1baf526e20a"}, - {file = "pandas-2.3.1-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:ec6c851509364c59a5344458ab935e6451b31b818be467eb24b0fe89bd05b6b9"}, - {file = "pandas-2.3.1-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:911580460fc4884d9b05254b38a6bfadddfcc6aaef856fb5859e7ca202e45275"}, - {file = "pandas-2.3.1-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:2f4d6feeba91744872a600e6edbbd5b033005b431d5ae8379abee5bcfa479fab"}, - {file = "pandas-2.3.1-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:fe37e757f462d31a9cd7580236a82f353f5713a80e059a29753cf938c6775d96"}, - {file = "pandas-2.3.1-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:5db9637dbc24b631ff3707269ae4559bce4b7fd75c1c4d7e13f40edc42df4444"}, - {file = "pandas-2.3.1-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:4645f770f98d656f11c69e81aeb21c6fca076a44bed3dcbb9396a4311bc7f6d8"}, - {file = "pandas-2.3.1-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:342e59589cc454aaff7484d75b816a433350b3d7964d7847327edda4d532a2e3"}, - {file = "pandas-2.3.1-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:1d12f618d80379fde6af007f65f0c25bd3e40251dbd1636480dfffce2cf1e6da"}, - {file = "pandas-2.3.1-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:dd71c47a911da120d72ef173aeac0bf5241423f9bfea57320110a978457e069e"}, - {file = "pandas-2.3.1-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:09e3b1587f0f3b0913e21e8b32c3119174551deb4a4eba4a89bc7377947977e7"}, - {file = "pandas-2.3.1-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:2323294c73ed50f612f67e2bf3ae45aea04dce5690778e08a09391897f35ff88"}, - {file = "pandas-2.3.1-cp39-cp39-win_amd64.whl", hash = "sha256:b4b0de34dc8499c2db34000ef8baad684cfa4cbd836ecee05f323ebfba348c7d"}, - {file = "pandas-2.3.1.tar.gz", hash = "sha256:0a95b9ac964fe83ce317827f80304d37388ea77616b1425f0ae41c9d2d0d7bb2"}, + {file = "pandas-2.3.3-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:376c6446ae31770764215a6c937f72d917f214b43560603cd60da6408f183b6c"}, + {file = "pandas-2.3.3-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:e19d192383eab2f4ceb30b412b22ea30690c9e618f78870357ae1d682912015a"}, + {file = "pandas-2.3.3-cp310-cp310-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:5caf26f64126b6c7aec964f74266f435afef1c1b13da3b0636c7518a1fa3e2b1"}, + {file = "pandas-2.3.3-cp310-cp310-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:dd7478f1463441ae4ca7308a70e90b33470fa593429f9d4c578dd00d1fa78838"}, + {file = "pandas-2.3.3-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:4793891684806ae50d1288c9bae9330293ab4e083ccd1c5e383c34549c6e4250"}, + {file = "pandas-2.3.3-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:28083c648d9a99a5dd035ec125d42439c6c1c525098c58af0fc38dd1a7a1b3d4"}, + {file = "pandas-2.3.3-cp310-cp310-win_amd64.whl", hash = "sha256:503cf027cf9940d2ceaa1a93cfb5f8c8c7e6e90720a2850378f0b3f3b1e06826"}, + {file = "pandas-2.3.3-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:602b8615ebcc4a0c1751e71840428ddebeb142ec02c786e8ad6b1ce3c8dec523"}, + {file = "pandas-2.3.3-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:8fe25fc7b623b0ef6b5009149627e34d2a4657e880948ec3c840e9402e5c1b45"}, + {file = "pandas-2.3.3-cp311-cp311-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b468d3dad6ff947df92dcb32ede5b7bd41a9b3cceef0a30ed925f6d01fb8fa66"}, + {file = "pandas-2.3.3-cp311-cp311-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:b98560e98cb334799c0b07ca7967ac361a47326e9b4e5a7dfb5ab2b1c9d35a1b"}, + {file = "pandas-2.3.3-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:1d37b5848ba49824e5c30bedb9c830ab9b7751fd049bc7914533e01c65f79791"}, + {file = "pandas-2.3.3-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:db4301b2d1f926ae677a751eb2bd0e8c5f5319c9cb3f88b0becbbb0b07b34151"}, + {file = "pandas-2.3.3-cp311-cp311-win_amd64.whl", hash = "sha256:f086f6fe114e19d92014a1966f43a3e62285109afe874f067f5abbdcbb10e59c"}, + {file = "pandas-2.3.3-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:6d21f6d74eb1725c2efaa71a2bfc661a0689579b58e9c0ca58a739ff0b002b53"}, + {file = "pandas-2.3.3-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:3fd2f887589c7aa868e02632612ba39acb0b8948faf5cc58f0850e165bd46f35"}, + {file = "pandas-2.3.3-cp312-cp312-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:ecaf1e12bdc03c86ad4a7ea848d66c685cb6851d807a26aa245ca3d2017a1908"}, + {file = "pandas-2.3.3-cp312-cp312-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:b3d11d2fda7eb164ef27ffc14b4fcab16a80e1ce67e9f57e19ec0afaf715ba89"}, + {file = "pandas-2.3.3-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:a68e15f780eddf2b07d242e17a04aa187a7ee12b40b930bfdd78070556550e98"}, + {file = "pandas-2.3.3-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:371a4ab48e950033bcf52b6527eccb564f52dc826c02afd9a1bc0ab731bba084"}, + {file = "pandas-2.3.3-cp312-cp312-win_amd64.whl", hash = "sha256:a16dcec078a01eeef8ee61bf64074b4e524a2a3f4b3be9326420cabe59c4778b"}, + {file = "pandas-2.3.3-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:56851a737e3470de7fa88e6131f41281ed440d29a9268dcbf0002da5ac366713"}, + {file = "pandas-2.3.3-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:bdcd9d1167f4885211e401b3036c0c8d9e274eee67ea8d0758a256d60704cfe8"}, + {file = "pandas-2.3.3-cp313-cp313-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:e32e7cc9af0f1cc15548288a51a3b681cc2a219faa838e995f7dc53dbab1062d"}, + {file = "pandas-2.3.3-cp313-cp313-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:318d77e0e42a628c04dc56bcef4b40de67918f7041c2b061af1da41dcff670ac"}, + {file = "pandas-2.3.3-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:4e0a175408804d566144e170d0476b15d78458795bb18f1304fb94160cabf40c"}, + {file = "pandas-2.3.3-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:93c2d9ab0fc11822b5eece72ec9587e172f63cff87c00b062f6e37448ced4493"}, + {file = "pandas-2.3.3-cp313-cp313-win_amd64.whl", hash = "sha256:f8bfc0e12dc78f777f323f55c58649591b2cd0c43534e8355c51d3fede5f4dee"}, + {file = "pandas-2.3.3-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:75ea25f9529fdec2d2e93a42c523962261e567d250b0013b16210e1d40d7c2e5"}, + {file = "pandas-2.3.3-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:74ecdf1d301e812db96a465a525952f4dde225fdb6d8e5a521d47e1f42041e21"}, + {file = "pandas-2.3.3-cp313-cp313t-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:6435cb949cb34ec11cc9860246ccb2fdc9ecd742c12d3304989017d53f039a78"}, + {file = "pandas-2.3.3-cp313-cp313t-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:900f47d8f20860de523a1ac881c4c36d65efcb2eb850e6948140fa781736e110"}, + {file = "pandas-2.3.3-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:a45c765238e2ed7d7c608fc5bc4a6f88b642f2f01e70c0c23d2224dd21829d86"}, + {file = "pandas-2.3.3-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:c4fc4c21971a1a9f4bdb4c73978c7f7256caa3e62b323f70d6cb80db583350bc"}, + {file = "pandas-2.3.3-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:ee15f284898e7b246df8087fc82b87b01686f98ee67d85a17b7ab44143a3a9a0"}, + {file = "pandas-2.3.3-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:1611aedd912e1ff81ff41c745822980c49ce4a7907537be8692c8dbc31924593"}, + {file = "pandas-2.3.3-cp314-cp314-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:6d2cefc361461662ac48810cb14365a365ce864afe85ef1f447ff5a1e99ea81c"}, + {file = "pandas-2.3.3-cp314-cp314-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:ee67acbbf05014ea6c763beb097e03cd629961c8a632075eeb34247120abcb4b"}, + {file = "pandas-2.3.3-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:c46467899aaa4da076d5abc11084634e2d197e9460643dd455ac3db5856b24d6"}, + {file = "pandas-2.3.3-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:6253c72c6a1d990a410bc7de641d34053364ef8bcd3126f7e7450125887dffe3"}, + {file = "pandas-2.3.3-cp314-cp314-win_amd64.whl", hash = "sha256:1b07204a219b3b7350abaae088f451860223a52cfb8a6c53358e7948735158e5"}, + {file = "pandas-2.3.3-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:2462b1a365b6109d275250baaae7b760fd25c726aaca0054649286bcfbb3e8ec"}, + {file = "pandas-2.3.3-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:0242fe9a49aa8b4d78a4fa03acb397a58833ef6199e9aa40a95f027bb3a1b6e7"}, + {file = "pandas-2.3.3-cp314-cp314t-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:a21d830e78df0a515db2b3d2f5570610f5e6bd2e27749770e8bb7b524b89b450"}, + {file = "pandas-2.3.3-cp314-cp314t-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:2e3ebdb170b5ef78f19bfb71b0dc5dc58775032361fa188e814959b74d726dd5"}, + {file = "pandas-2.3.3-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:d051c0e065b94b7a3cea50eb1ec32e912cd96dba41647eb24104b6c6c14c5788"}, + {file = "pandas-2.3.3-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:3869faf4bd07b3b66a9f462417d0ca3a9df29a9f6abd5d0d0dbab15dac7abe87"}, + {file = "pandas-2.3.3-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:c503ba5216814e295f40711470446bc3fd00f0faea8a086cbc688808e26f92a2"}, + {file = "pandas-2.3.3-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:a637c5cdfa04b6d6e2ecedcb81fc52ffb0fd78ce2ebccc9ea964df9f658de8c8"}, + {file = "pandas-2.3.3-cp39-cp39-manylinux_2_24_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:854d00d556406bffe66a4c0802f334c9ad5a96b4f1f868adf036a21b11ef13ff"}, + {file = "pandas-2.3.3-cp39-cp39-manylinux_2_24_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:bf1f8a81d04ca90e32a0aceb819d34dbd378a98bf923b6398b9a3ec0bf44de29"}, + {file = "pandas-2.3.3-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:23ebd657a4d38268c7dfbdf089fbc31ea709d82e4923c5ffd4fbd5747133ce73"}, + {file = "pandas-2.3.3-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:5554c929ccc317d41a5e3d1234f3be588248e61f08a74dd17c9eabb535777dc9"}, + {file = "pandas-2.3.3-cp39-cp39-win_amd64.whl", hash = "sha256:d3e28b3e83862ccf4d85ff19cf8c20b2ae7e503881711ff2d534dc8f761131aa"}, + {file = "pandas-2.3.3.tar.gz", hash = "sha256:e05e1af93b977f7eafa636d043f9f94c7ee3ac81af99c13508215942e64c993b"}, ] [package.dependencies] @@ -4962,33 +5335,16 @@ sql-other = ["SQLAlchemy (>=2.0.0)", "adbc-driver-postgresql (>=0.8.0)", "adbc-d test = ["hypothesis (>=6.46.1)", "pytest (>=7.3.2)", "pytest-xdist (>=2.2.0)"] xml = ["lxml (>=4.9.2)"] -[[package]] -name = "pansql" -version = "0.0.1" -description = "sqldf for pandas" -optional = false -python-versions = "*" -groups = ["main"] -files = [ - {file = "pansql-0.0.1-py3-none-any.whl", hash = "sha256:0c49d8c23e418ac065af767ed350c544c0d6d96dc04e2faa1f8b37851d404988"}, - {file = "pansql-0.0.1.tar.gz", hash = "sha256:61091112442c5d663ea5c042b6327a9b6b94c6687831677dddda46f292532e29"}, -] - -[package.dependencies] -numpy = "*" -pandas = "*" -sqlalchemy = "*" - [[package]] name = "paper-qa" -version = "5.25.0" +version = "5.29.1" description = "LLM Chain for answering questions from docs" optional = false python-versions = ">=3.11" groups = ["main"] files = [ - {file = "paper_qa-5.25.0-py3-none-any.whl", hash = "sha256:f7ded3c3a0224460cee14aa2348bd0a16f453417450fee2da9a4324cabb4a911"}, - {file = "paper_qa-5.25.0.tar.gz", hash = "sha256:4f14080ab58128ca9a6116d23e3d9c9dc79e2d4310af77a9c757e60d0b113cb7"}, + {file = "paper_qa-5.29.1-py3-none-any.whl", hash = "sha256:bdd5ff496e8cfdf661f749e71b2491a112cbe8ac7f707670c7e396ee69b9c003"}, + {file = "paper_qa-5.29.1.tar.gz", hash = "sha256:c7c6b5403867d3c8b147d25053d4083cc9979152476fd8a535b7a3257e7b68fa"}, ] [package.dependencies] @@ -4999,10 +5355,10 @@ fhlmi = ">=0.25.4" html2text = "*" httpx = "*" numpy = "*" +paper-qa-pypdf = "*" pybtex = "*" pydantic = ">=2.10.1,<3.0" pydantic-settings = "*" -PyMuPDF = ">=1.24.12" rich = "*" setuptools = "*" tantivy = "*" @@ -5010,13 +5366,31 @@ tenacity = "*" tiktoken = ">=0.4.0" [package.extras] -dev = ["fhlmi (>=0.28)", "ipykernel (>=6.29)", "ipython (>=8)", "litellm (>=1.68,<1.71)", "mypy (>=1.8)", "paper-qa[ldp,local,qdrant,typing,zotero]", "pre-commit (>=3.4)", "pydantic (>=2.11,<3.0)", "pylint-pydantic", "pytest (>=8)", "pytest-asyncio", "pytest-recording", "pytest-rerunfailures", "pytest-subtests", "pytest-sugar", "pytest-timer[colorama]", "pytest-xdist", "python-dotenv", "refurb (>=2)", "typeguard", "vcrpy (>=6)"] +dev = ["fhlmi (>=0.28)", "ipykernel (>=6.29)", "ipython (>=8)", "litellm (>=1.68,<1.71)", "mypy (>=1.8)", "paper-qa[ldp,local,pymupdf,pypdf,qdrant,typing,zotero]", "pre-commit (>=3.4)", "pydantic (>=2.11,<3.0)", "pylint-pydantic", "pytest (>=8)", "pytest-asyncio", "pytest-recording", "pytest-rerunfailures", "pytest-subtests", "pytest-sugar", "pytest-timer[colorama]", "pytest-xdist", "python-dotenv", "refurb (>=2)", "typeguard", "vcrpy (>=6)"] ldp = ["ldp (>=0.25.0)"] local = ["sentence-transformers"] openreview = ["openreview-py"] +pymupdf = ["paper-qa-pymupdf"] +pypdf = ["paper-qa-pypdf"] qdrant = ["qdrant-client"] typing = ["tantivy (>=0.22.2)", "types-PyYAML", "types-setuptools"] -zotero = ["pyzotero"] +zotero = ["paper-qa-pymupdf", "pyzotero"] + +[[package]] +name = "paper-qa-pypdf" +version = "5.29.1" +description = "PaperQA readers implemented using PyPDF" +optional = false +python-versions = ">=3.11" +groups = ["main"] +files = [ + {file = "paper_qa_pypdf-5.29.1-py3-none-any.whl", hash = "sha256:5311c0ad2b2ba1ca68174259023e1776230007da7d3738ece0ff63b1b90ccd01"}, + {file = "paper_qa_pypdf-5.29.1.tar.gz", hash = "sha256:36520c7f9d96c56b584bfa345e363f6ca8dd31c81dfbbdef187a6f09b50d66b4"}, +] + +[package.dependencies] +paper-qa = "*" +PyPDF = ">=3" [[package]] name = "parse" @@ -5190,32 +5564,32 @@ xmp = ["defusedxml"] [[package]] name = "pip" -version = "25.1.1" +version = "25.2" description = "The PyPA recommended tool for installing Python packages." optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "pip-25.1.1-py3-none-any.whl", hash = "sha256:2913a38a2abf4ea6b64ab507bd9e967f3b53dc1ede74b01b0931e1ce548751af"}, - {file = "pip-25.1.1.tar.gz", hash = "sha256:3de45d411d308d5054c2168185d8da7f9a2cd753dbac8acbfa88a8909ecd9077"}, + {file = "pip-25.2-py3-none-any.whl", hash = "sha256:6d67a2b4e7f14d8b31b8b52648866fa717f45a1eb70e83002f4331d07e953717"}, + {file = "pip-25.2.tar.gz", hash = "sha256:578283f006390f85bb6282dffb876454593d637f5d1be494b5202ce4877e71f2"}, ] [[package]] name = "platformdirs" -version = "4.3.8" +version = "4.5.0" description = "A small Python package for determining appropriate platform-specific dirs, e.g. a `user data dir`." optional = false -python-versions = ">=3.9" +python-versions = ">=3.10" groups = ["main", "dev", "docs"] files = [ - {file = "platformdirs-4.3.8-py3-none-any.whl", hash = "sha256:ff7059bb7eb1179e2685604f4aaf157cfd9535242bd23742eadc3c13542139b4"}, - {file = "platformdirs-4.3.8.tar.gz", hash = "sha256:3d512d96e16bcb959a814c9f348431070822a6496326a4be0911c40b5a74c2bc"}, + {file = "platformdirs-4.5.0-py3-none-any.whl", hash = "sha256:e578a81bb873cbb89a41fcc904c7ef523cc18284b7e3b3ccf06aca1403b7ebd3"}, + {file = "platformdirs-4.5.0.tar.gz", hash = "sha256:70ddccdd7c99fc5942e9fc25636a8b34d04c24b335100223152c2803e4063312"}, ] [package.extras] -docs = ["furo (>=2024.8.6)", "proselint (>=0.14)", "sphinx (>=8.1.3)", "sphinx-autodoc-typehints (>=3)"] -test = ["appdirs (==1.4.4)", "covdefaults (>=2.3)", "pytest (>=8.3.4)", "pytest-cov (>=6)", "pytest-mock (>=3.14)"] -type = ["mypy (>=1.14.1)"] +docs = ["furo (>=2025.9.25)", "proselint (>=0.14)", "sphinx (>=8.2.3)", "sphinx-autodoc-typehints (>=3.2)"] +test = ["appdirs (==1.4.4)", "covdefaults (>=2.3)", "pytest (>=8.4.2)", "pytest-cov (>=7)", "pytest-mock (>=3.15.1)"] +type = ["mypy (>=1.18.2)"] [[package]] name = "pluggy" @@ -5322,14 +5696,14 @@ dev = ["certifi", "mypy (>=1.14.1)", "pytest (>=8.1.1)", "pytest-asyncio (>=0.25 [[package]] name = "prompt-toolkit" -version = "3.0.51" +version = "3.0.52" description = "Library for building powerful interactive command lines in Python" optional = false python-versions = ">=3.8" groups = ["main"] files = [ - {file = "prompt_toolkit-3.0.51-py3-none-any.whl", hash = "sha256:52742911fde84e2d423e2f9a4cf1de7d7ac4e51958f648d9540e0fb8db077b07"}, - {file = "prompt_toolkit-3.0.51.tar.gz", hash = "sha256:931a162e3b27fc90c86f1b48bb1fb2c528c2761475e57c9c06de13311c7b54ed"}, + {file = "prompt_toolkit-3.0.52-py3-none-any.whl", hash = "sha256:9aac639a3bbd33284347de5ad8d68ecc044b91a762dc39b7c21095fcd6a19955"}, + {file = "prompt_toolkit-3.0.52.tar.gz", hash = "sha256:28cde192929c8e7321de85de1ddbe736f1375148b02f2e17edd840042b1be855"}, ] [package.dependencies] @@ -5355,131 +5729,153 @@ python-dateutil = ">=2.8,<3.0" [[package]] name = "propcache" -version = "0.3.2" +version = "0.4.1" description = "Accelerated property cache" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "propcache-0.3.2-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:22d9962a358aedbb7a2e36187ff273adeaab9743373a272976d2e348d08c7770"}, - {file = "propcache-0.3.2-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:0d0fda578d1dc3f77b6b5a5dce3b9ad69a8250a891760a548df850a5e8da87f3"}, - {file = "propcache-0.3.2-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:3def3da3ac3ce41562d85db655d18ebac740cb3fa4367f11a52b3da9d03a5cc3"}, - {file = "propcache-0.3.2-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:9bec58347a5a6cebf239daba9bda37dffec5b8d2ce004d9fe4edef3d2815137e"}, - {file = "propcache-0.3.2-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:55ffda449a507e9fbd4aca1a7d9aa6753b07d6166140e5a18d2ac9bc49eac220"}, - {file = "propcache-0.3.2-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:64a67fb39229a8a8491dd42f864e5e263155e729c2e7ff723d6e25f596b1e8cb"}, - {file = "propcache-0.3.2-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:9da1cf97b92b51253d5b68cf5a2b9e0dafca095e36b7f2da335e27dc6172a614"}, - {file = "propcache-0.3.2-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:5f559e127134b07425134b4065be45b166183fdcb433cb6c24c8e4149056ad50"}, - {file = "propcache-0.3.2-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:aff2e4e06435d61f11a428360a932138d0ec288b0a31dd9bd78d200bd4a2b339"}, - {file = "propcache-0.3.2-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:4927842833830942a5d0a56e6f4839bc484785b8e1ce8d287359794818633ba0"}, - {file = "propcache-0.3.2-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:6107ddd08b02654a30fb8ad7a132021759d750a82578b94cd55ee2772b6ebea2"}, - {file = "propcache-0.3.2-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:70bd8b9cd6b519e12859c99f3fc9a93f375ebd22a50296c3a295028bea73b9e7"}, - {file = "propcache-0.3.2-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:2183111651d710d3097338dd1893fcf09c9f54e27ff1a8795495a16a469cc90b"}, - {file = "propcache-0.3.2-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:fb075ad271405dcad8e2a7ffc9a750a3bf70e533bd86e89f0603e607b93aa64c"}, - {file = "propcache-0.3.2-cp310-cp310-win32.whl", hash = "sha256:404d70768080d3d3bdb41d0771037da19d8340d50b08e104ca0e7f9ce55fce70"}, - {file = "propcache-0.3.2-cp310-cp310-win_amd64.whl", hash = "sha256:7435d766f978b4ede777002e6b3b6641dd229cd1da8d3d3106a45770365f9ad9"}, - {file = "propcache-0.3.2-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:0b8d2f607bd8f80ddc04088bc2a037fdd17884a6fcadc47a96e334d72f3717be"}, - {file = "propcache-0.3.2-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:06766d8f34733416e2e34f46fea488ad5d60726bb9481d3cddf89a6fa2d9603f"}, - {file = "propcache-0.3.2-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:a2dc1f4a1df4fecf4e6f68013575ff4af84ef6f478fe5344317a65d38a8e6dc9"}, - {file = "propcache-0.3.2-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:be29c4f4810c5789cf10ddf6af80b041c724e629fa51e308a7a0fb19ed1ef7bf"}, - {file = "propcache-0.3.2-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:59d61f6970ecbd8ff2e9360304d5c8876a6abd4530cb752c06586849ac8a9dc9"}, - {file = "propcache-0.3.2-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:62180e0b8dbb6b004baec00a7983e4cc52f5ada9cd11f48c3528d8cfa7b96a66"}, - {file = "propcache-0.3.2-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:c144ca294a204c470f18cf4c9d78887810d04a3e2fbb30eea903575a779159df"}, - {file = "propcache-0.3.2-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:c5c2a784234c28854878d68978265617aa6dc0780e53d44b4d67f3651a17a9a2"}, - {file = "propcache-0.3.2-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:5745bc7acdafa978ca1642891b82c19238eadc78ba2aaa293c6863b304e552d7"}, - {file = "propcache-0.3.2-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:c0075bf773d66fa8c9d41f66cc132ecc75e5bb9dd7cce3cfd14adc5ca184cb95"}, - {file = "propcache-0.3.2-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:5f57aa0847730daceff0497f417c9de353c575d8da3579162cc74ac294c5369e"}, - {file = "propcache-0.3.2-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:eef914c014bf72d18efb55619447e0aecd5fb7c2e3fa7441e2e5d6099bddff7e"}, - {file = "propcache-0.3.2-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:2a4092e8549031e82facf3decdbc0883755d5bbcc62d3aea9d9e185549936dcf"}, - {file = "propcache-0.3.2-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:85871b050f174bc0bfb437efbdb68aaf860611953ed12418e4361bc9c392749e"}, - {file = "propcache-0.3.2-cp311-cp311-win32.whl", hash = "sha256:36c8d9b673ec57900c3554264e630d45980fd302458e4ac801802a7fd2ef7897"}, - {file = "propcache-0.3.2-cp311-cp311-win_amd64.whl", hash = "sha256:e53af8cb6a781b02d2ea079b5b853ba9430fcbe18a8e3ce647d5982a3ff69f39"}, - {file = "propcache-0.3.2-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:8de106b6c84506b31c27168582cd3cb3000a6412c16df14a8628e5871ff83c10"}, - {file = "propcache-0.3.2-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:28710b0d3975117239c76600ea351934ac7b5ff56e60953474342608dbbb6154"}, - {file = "propcache-0.3.2-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:ce26862344bdf836650ed2487c3d724b00fbfec4233a1013f597b78c1cb73615"}, - {file = "propcache-0.3.2-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:bca54bd347a253af2cf4544bbec232ab982f4868de0dd684246b67a51bc6b1db"}, - {file = "propcache-0.3.2-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:55780d5e9a2ddc59711d727226bb1ba83a22dd32f64ee15594b9392b1f544eb1"}, - {file = "propcache-0.3.2-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:035e631be25d6975ed87ab23153db6a73426a48db688070d925aa27e996fe93c"}, - {file = "propcache-0.3.2-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:ee6f22b6eaa39297c751d0e80c0d3a454f112f5c6481214fcf4c092074cecd67"}, - {file = "propcache-0.3.2-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:7ca3aee1aa955438c4dba34fc20a9f390e4c79967257d830f137bd5a8a32ed3b"}, - {file = "propcache-0.3.2-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:7a4f30862869fa2b68380d677cc1c5fcf1e0f2b9ea0cf665812895c75d0ca3b8"}, - {file = "propcache-0.3.2-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:b77ec3c257d7816d9f3700013639db7491a434644c906a2578a11daf13176251"}, - {file = "propcache-0.3.2-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:cab90ac9d3f14b2d5050928483d3d3b8fb6b4018893fc75710e6aa361ecb2474"}, - {file = "propcache-0.3.2-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:0b504d29f3c47cf6b9e936c1852246c83d450e8e063d50562115a6be6d3a2535"}, - {file = "propcache-0.3.2-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:ce2ac2675a6aa41ddb2a0c9cbff53780a617ac3d43e620f8fd77ba1c84dcfc06"}, - {file = "propcache-0.3.2-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:62b4239611205294cc433845b914131b2a1f03500ff3c1ed093ed216b82621e1"}, - {file = "propcache-0.3.2-cp312-cp312-win32.whl", hash = "sha256:df4a81b9b53449ebc90cc4deefb052c1dd934ba85012aa912c7ea7b7e38b60c1"}, - {file = "propcache-0.3.2-cp312-cp312-win_amd64.whl", hash = "sha256:7046e79b989d7fe457bb755844019e10f693752d169076138abf17f31380800c"}, - {file = "propcache-0.3.2-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:ca592ed634a73ca002967458187109265e980422116c0a107cf93d81f95af945"}, - {file = "propcache-0.3.2-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:9ecb0aad4020e275652ba3975740f241bd12a61f1a784df044cf7477a02bc252"}, - {file = "propcache-0.3.2-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:7f08f1cc28bd2eade7a8a3d2954ccc673bb02062e3e7da09bc75d843386b342f"}, - {file = "propcache-0.3.2-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:d1a342c834734edb4be5ecb1e9fb48cb64b1e2320fccbd8c54bf8da8f2a84c33"}, - {file = "propcache-0.3.2-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:8a544caaae1ac73f1fecfae70ded3e93728831affebd017d53449e3ac052ac1e"}, - {file = "propcache-0.3.2-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:310d11aa44635298397db47a3ebce7db99a4cc4b9bbdfcf6c98a60c8d5261cf1"}, - {file = "propcache-0.3.2-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:4c1396592321ac83157ac03a2023aa6cc4a3cc3cfdecb71090054c09e5a7cce3"}, - {file = "propcache-0.3.2-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:8cabf5b5902272565e78197edb682017d21cf3b550ba0460ee473753f28d23c1"}, - {file = "propcache-0.3.2-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:0a2f2235ac46a7aa25bdeb03a9e7060f6ecbd213b1f9101c43b3090ffb971ef6"}, - {file = "propcache-0.3.2-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:92b69e12e34869a6970fd2f3da91669899994b47c98f5d430b781c26f1d9f387"}, - {file = "propcache-0.3.2-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:54e02207c79968ebbdffc169591009f4474dde3b4679e16634d34c9363ff56b4"}, - {file = "propcache-0.3.2-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:4adfb44cb588001f68c5466579d3f1157ca07f7504fc91ec87862e2b8e556b88"}, - {file = "propcache-0.3.2-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:fd3e6019dc1261cd0291ee8919dd91fbab7b169bb76aeef6c716833a3f65d206"}, - {file = "propcache-0.3.2-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:4c181cad81158d71c41a2bce88edce078458e2dd5ffee7eddd6b05da85079f43"}, - {file = "propcache-0.3.2-cp313-cp313-win32.whl", hash = "sha256:8a08154613f2249519e549de2330cf8e2071c2887309a7b07fb56098f5170a02"}, - {file = "propcache-0.3.2-cp313-cp313-win_amd64.whl", hash = "sha256:e41671f1594fc4ab0a6dec1351864713cb3a279910ae8b58f884a88a0a632c05"}, - {file = "propcache-0.3.2-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:9a3cf035bbaf035f109987d9d55dc90e4b0e36e04bbbb95af3055ef17194057b"}, - {file = "propcache-0.3.2-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:156c03d07dc1323d8dacaa221fbe028c5c70d16709cdd63502778e6c3ccca1b0"}, - {file = "propcache-0.3.2-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:74413c0ba02ba86f55cf60d18daab219f7e531620c15f1e23d95563f505efe7e"}, - {file = "propcache-0.3.2-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:f066b437bb3fa39c58ff97ab2ca351db465157d68ed0440abecb21715eb24b28"}, - {file = "propcache-0.3.2-cp313-cp313t-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:f1304b085c83067914721e7e9d9917d41ad87696bf70f0bc7dee450e9c71ad0a"}, - {file = "propcache-0.3.2-cp313-cp313t-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:ab50cef01b372763a13333b4e54021bdcb291fc9a8e2ccb9c2df98be51bcde6c"}, - {file = "propcache-0.3.2-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:fad3b2a085ec259ad2c2842666b2a0a49dea8463579c606426128925af1ed725"}, - {file = "propcache-0.3.2-cp313-cp313t-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:261fa020c1c14deafd54c76b014956e2f86991af198c51139faf41c4d5e83892"}, - {file = "propcache-0.3.2-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:46d7f8aa79c927e5f987ee3a80205c987717d3659f035c85cf0c3680526bdb44"}, - {file = "propcache-0.3.2-cp313-cp313t-musllinux_1_2_armv7l.whl", hash = "sha256:6d8f3f0eebf73e3c0ff0e7853f68be638b4043c65a70517bb575eff54edd8dbe"}, - {file = "propcache-0.3.2-cp313-cp313t-musllinux_1_2_i686.whl", hash = "sha256:03c89c1b14a5452cf15403e291c0ccd7751d5b9736ecb2c5bab977ad6c5bcd81"}, - {file = "propcache-0.3.2-cp313-cp313t-musllinux_1_2_ppc64le.whl", hash = "sha256:0cc17efde71e12bbaad086d679ce575268d70bc123a5a71ea7ad76f70ba30bba"}, - {file = "propcache-0.3.2-cp313-cp313t-musllinux_1_2_s390x.whl", hash = "sha256:acdf05d00696bc0447e278bb53cb04ca72354e562cf88ea6f9107df8e7fd9770"}, - {file = "propcache-0.3.2-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:4445542398bd0b5d32df908031cb1b30d43ac848e20470a878b770ec2dcc6330"}, - {file = "propcache-0.3.2-cp313-cp313t-win32.whl", hash = "sha256:f86e5d7cd03afb3a1db8e9f9f6eff15794e79e791350ac48a8c924e6f439f394"}, - {file = "propcache-0.3.2-cp313-cp313t-win_amd64.whl", hash = "sha256:9704bedf6e7cbe3c65eca4379a9b53ee6a83749f047808cbb5044d40d7d72198"}, - {file = "propcache-0.3.2-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:a7fad897f14d92086d6b03fdd2eb844777b0c4d7ec5e3bac0fbae2ab0602bbe5"}, - {file = "propcache-0.3.2-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:1f43837d4ca000243fd7fd6301947d7cb93360d03cd08369969450cc6b2ce3b4"}, - {file = "propcache-0.3.2-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:261df2e9474a5949c46e962065d88eb9b96ce0f2bd30e9d3136bcde84befd8f2"}, - {file = "propcache-0.3.2-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:e514326b79e51f0a177daab1052bc164d9d9e54133797a3a58d24c9c87a3fe6d"}, - {file = "propcache-0.3.2-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:d4a996adb6904f85894570301939afeee65f072b4fd265ed7e569e8d9058e4ec"}, - {file = "propcache-0.3.2-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:76cace5d6b2a54e55b137669b30f31aa15977eeed390c7cbfb1dafa8dfe9a701"}, - {file = "propcache-0.3.2-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:31248e44b81d59d6addbb182c4720f90b44e1efdc19f58112a3c3a1615fb47ef"}, - {file = "propcache-0.3.2-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:abb7fa19dbf88d3857363e0493b999b8011eea856b846305d8c0512dfdf8fbb1"}, - {file = "propcache-0.3.2-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:d81ac3ae39d38588ad0549e321e6f773a4e7cc68e7751524a22885d5bbadf886"}, - {file = "propcache-0.3.2-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:cc2782eb0f7a16462285b6f8394bbbd0e1ee5f928034e941ffc444012224171b"}, - {file = "propcache-0.3.2-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:db429c19a6c7e8a1c320e6a13c99799450f411b02251fb1b75e6217cf4a14fcb"}, - {file = "propcache-0.3.2-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:21d8759141a9e00a681d35a1f160892a36fb6caa715ba0b832f7747da48fb6ea"}, - {file = "propcache-0.3.2-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:2ca6d378f09adb13837614ad2754fa8afaee330254f404299611bce41a8438cb"}, - {file = "propcache-0.3.2-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:34a624af06c048946709f4278b4176470073deda88d91342665d95f7c6270fbe"}, - {file = "propcache-0.3.2-cp39-cp39-win32.whl", hash = "sha256:4ba3fef1c30f306b1c274ce0b8baaa2c3cdd91f645c48f06394068f37d3837a1"}, - {file = "propcache-0.3.2-cp39-cp39-win_amd64.whl", hash = "sha256:7a2368eed65fc69a7a7a40b27f22e85e7627b74216f0846b04ba5c116e191ec9"}, - {file = "propcache-0.3.2-py3-none-any.whl", hash = "sha256:98f1ec44fb675f5052cccc8e609c46ed23a35a1cfd18545ad4e29002d858a43f"}, - {file = "propcache-0.3.2.tar.gz", hash = "sha256:20d7d62e4e7ef05f221e0db2856b979540686342e7dd9973b815599c7057e168"}, + {file = "propcache-0.4.1-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:7c2d1fa3201efaf55d730400d945b5b3ab6e672e100ba0f9a409d950ab25d7db"}, + {file = "propcache-0.4.1-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:1eb2994229cc8ce7fe9b3db88f5465f5fd8651672840b2e426b88cdb1a30aac8"}, + {file = "propcache-0.4.1-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:66c1f011f45a3b33d7bcb22daed4b29c0c9e2224758b6be00686731e1b46f925"}, + {file = "propcache-0.4.1-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:9a52009f2adffe195d0b605c25ec929d26b36ef986ba85244891dee3b294df21"}, + {file = "propcache-0.4.1-cp310-cp310-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:5d4e2366a9c7b837555cf02fb9be2e3167d333aff716332ef1b7c3a142ec40c5"}, + {file = "propcache-0.4.1-cp310-cp310-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:9d2b6caef873b4f09e26ea7e33d65f42b944837563a47a94719cc3544319a0db"}, + {file = "propcache-0.4.1-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:2b16ec437a8c8a965ecf95739448dd938b5c7f56e67ea009f4300d8df05f32b7"}, + {file = "propcache-0.4.1-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:296f4c8ed03ca7476813fe666c9ea97869a8d7aec972618671b33a38a5182ef4"}, + {file = "propcache-0.4.1-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:1f0978529a418ebd1f49dad413a2b68af33f85d5c5ca5c6ca2a3bed375a7ac60"}, + {file = "propcache-0.4.1-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:fd138803047fb4c062b1c1dd95462f5209456bfab55c734458f15d11da288f8f"}, + {file = "propcache-0.4.1-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:8c9b3cbe4584636d72ff556d9036e0c9317fa27b3ac1f0f558e7e84d1c9c5900"}, + {file = "propcache-0.4.1-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:f93243fdc5657247533273ac4f86ae106cc6445a0efacb9a1bfe982fcfefd90c"}, + {file = "propcache-0.4.1-cp310-cp310-win32.whl", hash = "sha256:a0ee98db9c5f80785b266eb805016e36058ac72c51a064040f2bc43b61101cdb"}, + {file = "propcache-0.4.1-cp310-cp310-win_amd64.whl", hash = "sha256:1cdb7988c4e5ac7f6d175a28a9aa0c94cb6f2ebe52756a3c0cda98d2809a9e37"}, + {file = "propcache-0.4.1-cp310-cp310-win_arm64.whl", hash = "sha256:d82ad62b19645419fe79dd63b3f9253e15b30e955c0170e5cebc350c1844e581"}, + {file = "propcache-0.4.1-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:60a8fda9644b7dfd5dece8c61d8a85e271cb958075bfc4e01083c148b61a7caf"}, + {file = "propcache-0.4.1-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:c30b53e7e6bda1d547cabb47c825f3843a0a1a42b0496087bb58d8fedf9f41b5"}, + {file = "propcache-0.4.1-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:6918ecbd897443087a3b7cd978d56546a812517dcaaca51b49526720571fa93e"}, + {file = "propcache-0.4.1-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:3d902a36df4e5989763425a8ab9e98cd8ad5c52c823b34ee7ef307fd50582566"}, + {file = "propcache-0.4.1-cp311-cp311-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:a9695397f85973bb40427dedddf70d8dc4a44b22f1650dd4af9eedf443d45165"}, + {file = "propcache-0.4.1-cp311-cp311-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:2bb07ffd7eaad486576430c89f9b215f9e4be68c4866a96e97db9e97fead85dc"}, + {file = "propcache-0.4.1-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:fd6f30fdcf9ae2a70abd34da54f18da086160e4d7d9251f81f3da0ff84fc5a48"}, + {file = "propcache-0.4.1-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:fc38cba02d1acba4e2869eef1a57a43dfbd3d49a59bf90dda7444ec2be6a5570"}, + {file = "propcache-0.4.1-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:67fad6162281e80e882fb3ec355398cf72864a54069d060321f6cd0ade95fe85"}, + {file = "propcache-0.4.1-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:f10207adf04d08bec185bae14d9606a1444715bc99180f9331c9c02093e1959e"}, + {file = "propcache-0.4.1-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:e9b0d8d0845bbc4cfcdcbcdbf5086886bc8157aa963c31c777ceff7846c77757"}, + {file = "propcache-0.4.1-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:981333cb2f4c1896a12f4ab92a9cc8f09ea664e9b7dbdc4eff74627af3a11c0f"}, + {file = "propcache-0.4.1-cp311-cp311-win32.whl", hash = "sha256:f1d2f90aeec838a52f1c1a32fe9a619fefd5e411721a9117fbf82aea638fe8a1"}, + {file = "propcache-0.4.1-cp311-cp311-win_amd64.whl", hash = "sha256:364426a62660f3f699949ac8c621aad6977be7126c5807ce48c0aeb8e7333ea6"}, + {file = "propcache-0.4.1-cp311-cp311-win_arm64.whl", hash = "sha256:e53f3a38d3510c11953f3e6a33f205c6d1b001129f972805ca9b42fc308bc239"}, + {file = "propcache-0.4.1-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:e153e9cd40cc8945138822807139367f256f89c6810c2634a4f6902b52d3b4e2"}, + {file = "propcache-0.4.1-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:cd547953428f7abb73c5ad82cbb32109566204260d98e41e5dfdc682eb7f8403"}, + {file = "propcache-0.4.1-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:f048da1b4f243fc44f205dfd320933a951b8d89e0afd4c7cacc762a8b9165207"}, + {file = "propcache-0.4.1-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:ec17c65562a827bba85e3872ead335f95405ea1674860d96483a02f5c698fa72"}, + {file = "propcache-0.4.1-cp312-cp312-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:405aac25c6394ef275dee4c709be43745d36674b223ba4eb7144bf4d691b7367"}, + {file = "propcache-0.4.1-cp312-cp312-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:0013cb6f8dde4b2a2f66903b8ba740bdfe378c943c4377a200551ceb27f379e4"}, + {file = "propcache-0.4.1-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:15932ab57837c3368b024473a525e25d316d8353016e7cc0e5ba9eb343fbb1cf"}, + {file = "propcache-0.4.1-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:031dce78b9dc099f4c29785d9cf5577a3faf9ebf74ecbd3c856a7b92768c3df3"}, + {file = "propcache-0.4.1-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:ab08df6c9a035bee56e31af99be621526bd237bea9f32def431c656b29e41778"}, + {file = "propcache-0.4.1-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:4d7af63f9f93fe593afbf104c21b3b15868efb2c21d07d8732c0c4287e66b6a6"}, + {file = "propcache-0.4.1-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:cfc27c945f422e8b5071b6e93169679e4eb5bf73bbcbf1ba3ae3a83d2f78ebd9"}, + {file = "propcache-0.4.1-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:35c3277624a080cc6ec6f847cbbbb5b49affa3598c4535a0a4682a697aaa5c75"}, + {file = "propcache-0.4.1-cp312-cp312-win32.whl", hash = "sha256:671538c2262dadb5ba6395e26c1731e1d52534bfe9ae56d0b5573ce539266aa8"}, + {file = "propcache-0.4.1-cp312-cp312-win_amd64.whl", hash = "sha256:cb2d222e72399fcf5890d1d5cc1060857b9b236adff2792ff48ca2dfd46c81db"}, + {file = "propcache-0.4.1-cp312-cp312-win_arm64.whl", hash = "sha256:204483131fb222bdaaeeea9f9e6c6ed0cac32731f75dfc1d4a567fc1926477c1"}, + {file = "propcache-0.4.1-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:43eedf29202c08550aac1d14e0ee619b0430aaef78f85864c1a892294fbc28cf"}, + {file = "propcache-0.4.1-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:d62cdfcfd89ccb8de04e0eda998535c406bf5e060ffd56be6c586cbcc05b3311"}, + {file = "propcache-0.4.1-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:cae65ad55793da34db5f54e4029b89d3b9b9490d8abe1b4c7ab5d4b8ec7ebf74"}, + {file = "propcache-0.4.1-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:333ddb9031d2704a301ee3e506dc46b1fe5f294ec198ed6435ad5b6a085facfe"}, + {file = "propcache-0.4.1-cp313-cp313-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:fd0858c20f078a32cf55f7e81473d96dcf3b93fd2ccdb3d40fdf54b8573df3af"}, + {file = "propcache-0.4.1-cp313-cp313-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:678ae89ebc632c5c204c794f8dab2837c5f159aeb59e6ed0539500400577298c"}, + {file = "propcache-0.4.1-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:d472aeb4fbf9865e0c6d622d7f4d54a4e101a89715d8904282bb5f9a2f476c3f"}, + {file = "propcache-0.4.1-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:4d3df5fa7e36b3225954fba85589da77a0fe6a53e3976de39caf04a0db4c36f1"}, + {file = "propcache-0.4.1-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:ee17f18d2498f2673e432faaa71698032b0127ebf23ae5974eeaf806c279df24"}, + {file = "propcache-0.4.1-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:580e97762b950f993ae618e167e7be9256b8353c2dcd8b99ec100eb50f5286aa"}, + {file = "propcache-0.4.1-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:501d20b891688eb8e7aa903021f0b72d5a55db40ffaab27edefd1027caaafa61"}, + {file = "propcache-0.4.1-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:9a0bd56e5b100aef69bd8562b74b46254e7c8812918d3baa700c8a8009b0af66"}, + {file = "propcache-0.4.1-cp313-cp313-win32.whl", hash = "sha256:bcc9aaa5d80322bc2fb24bb7accb4a30f81e90ab8d6ba187aec0744bc302ad81"}, + {file = "propcache-0.4.1-cp313-cp313-win_amd64.whl", hash = "sha256:381914df18634f5494334d201e98245c0596067504b9372d8cf93f4bb23e025e"}, + {file = "propcache-0.4.1-cp313-cp313-win_arm64.whl", hash = "sha256:8873eb4460fd55333ea49b7d189749ecf6e55bf85080f11b1c4530ed3034cba1"}, + {file = "propcache-0.4.1-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:92d1935ee1f8d7442da9c0c4fa7ac20d07e94064184811b685f5c4fada64553b"}, + {file = "propcache-0.4.1-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:473c61b39e1460d386479b9b2f337da492042447c9b685f28be4f74d3529e566"}, + {file = "propcache-0.4.1-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:c0ef0aaafc66fbd87842a3fe3902fd889825646bc21149eafe47be6072725835"}, + {file = "propcache-0.4.1-cp313-cp313t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:f95393b4d66bfae908c3ca8d169d5f79cd65636ae15b5e7a4f6e67af675adb0e"}, + {file = "propcache-0.4.1-cp313-cp313t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:c07fda85708bc48578467e85099645167a955ba093be0a2dcba962195676e859"}, + {file = "propcache-0.4.1-cp313-cp313t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:af223b406d6d000830c6f65f1e6431783fc3f713ba3e6cc8c024d5ee96170a4b"}, + {file = "propcache-0.4.1-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:a78372c932c90ee474559c5ddfffd718238e8673c340dc21fe45c5b8b54559a0"}, + {file = "propcache-0.4.1-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:564d9f0d4d9509e1a870c920a89b2fec951b44bf5ba7d537a9e7c1ccec2c18af"}, + {file = "propcache-0.4.1-cp313-cp313t-musllinux_1_2_armv7l.whl", hash = "sha256:17612831fda0138059cc5546f4d12a2aacfb9e47068c06af35c400ba58ba7393"}, + {file = "propcache-0.4.1-cp313-cp313t-musllinux_1_2_ppc64le.whl", hash = "sha256:41a89040cb10bd345b3c1a873b2bf36413d48da1def52f268a055f7398514874"}, + {file = "propcache-0.4.1-cp313-cp313t-musllinux_1_2_s390x.whl", hash = "sha256:e35b88984e7fa64aacecea39236cee32dd9bd8c55f57ba8a75cf2399553f9bd7"}, + {file = "propcache-0.4.1-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:6f8b465489f927b0df505cbe26ffbeed4d6d8a2bbc61ce90eb074ff129ef0ab1"}, + {file = "propcache-0.4.1-cp313-cp313t-win32.whl", hash = "sha256:2ad890caa1d928c7c2965b48f3a3815c853180831d0e5503d35cf00c472f4717"}, + {file = "propcache-0.4.1-cp313-cp313t-win_amd64.whl", hash = "sha256:f7ee0e597f495cf415bcbd3da3caa3bd7e816b74d0d52b8145954c5e6fd3ff37"}, + {file = "propcache-0.4.1-cp313-cp313t-win_arm64.whl", hash = "sha256:929d7cbe1f01bb7baffb33dc14eb5691c95831450a26354cd210a8155170c93a"}, + {file = "propcache-0.4.1-cp314-cp314-macosx_10_13_universal2.whl", hash = "sha256:3f7124c9d820ba5548d431afb4632301acf965db49e666aa21c305cbe8c6de12"}, + {file = "propcache-0.4.1-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:c0d4b719b7da33599dfe3b22d3db1ef789210a0597bc650b7cee9c77c2be8c5c"}, + {file = "propcache-0.4.1-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:9f302f4783709a78240ebc311b793f123328716a60911d667e0c036bc5dcbded"}, + {file = "propcache-0.4.1-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:c80ee5802e3fb9ea37938e7eecc307fb984837091d5fd262bb37238b1ae97641"}, + {file = "propcache-0.4.1-cp314-cp314-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:ed5a841e8bb29a55fb8159ed526b26adc5bdd7e8bd7bf793ce647cb08656cdf4"}, + {file = "propcache-0.4.1-cp314-cp314-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:55c72fd6ea2da4c318e74ffdf93c4fe4e926051133657459131a95c846d16d44"}, + {file = "propcache-0.4.1-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:8326e144341460402713f91df60ade3c999d601e7eb5ff8f6f7862d54de0610d"}, + {file = "propcache-0.4.1-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:060b16ae65bc098da7f6d25bf359f1f31f688384858204fe5d652979e0015e5b"}, + {file = "propcache-0.4.1-cp314-cp314-musllinux_1_2_armv7l.whl", hash = "sha256:89eb3fa9524f7bec9de6e83cf3faed9d79bffa560672c118a96a171a6f55831e"}, + {file = "propcache-0.4.1-cp314-cp314-musllinux_1_2_ppc64le.whl", hash = "sha256:dee69d7015dc235f526fe80a9c90d65eb0039103fe565776250881731f06349f"}, + {file = "propcache-0.4.1-cp314-cp314-musllinux_1_2_s390x.whl", hash = "sha256:5558992a00dfd54ccbc64a32726a3357ec93825a418a401f5cc67df0ac5d9e49"}, + {file = "propcache-0.4.1-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:c9b822a577f560fbd9554812526831712c1436d2c046cedee4c3796d3543b144"}, + {file = "propcache-0.4.1-cp314-cp314-win32.whl", hash = "sha256:ab4c29b49d560fe48b696cdcb127dd36e0bc2472548f3bf56cc5cb3da2b2984f"}, + {file = "propcache-0.4.1-cp314-cp314-win_amd64.whl", hash = "sha256:5a103c3eb905fcea0ab98be99c3a9a5ab2de60228aa5aceedc614c0281cf6153"}, + {file = "propcache-0.4.1-cp314-cp314-win_arm64.whl", hash = "sha256:74c1fb26515153e482e00177a1ad654721bf9207da8a494a0c05e797ad27b992"}, + {file = "propcache-0.4.1-cp314-cp314t-macosx_10_13_universal2.whl", hash = "sha256:824e908bce90fb2743bd6b59db36eb4f45cd350a39637c9f73b1c1ea66f5b75f"}, + {file = "propcache-0.4.1-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:c2b5e7db5328427c57c8e8831abda175421b709672f6cfc3d630c3b7e2146393"}, + {file = "propcache-0.4.1-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:6f6ff873ed40292cd4969ef5310179afd5db59fdf055897e282485043fc80ad0"}, + {file = "propcache-0.4.1-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:49a2dc67c154db2c1463013594c458881a069fcf98940e61a0569016a583020a"}, + {file = "propcache-0.4.1-cp314-cp314t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:005f08e6a0529984491e37d8dbc3dd86f84bd78a8ceb5fa9a021f4c48d4984be"}, + {file = "propcache-0.4.1-cp314-cp314t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:5c3310452e0d31390da9035c348633b43d7e7feb2e37be252be6da45abd1abcc"}, + {file = "propcache-0.4.1-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:4c3c70630930447f9ef1caac7728c8ad1c56bc5015338b20fed0d08ea2480b3a"}, + {file = "propcache-0.4.1-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:8e57061305815dfc910a3634dcf584f08168a8836e6999983569f51a8544cd89"}, + {file = "propcache-0.4.1-cp314-cp314t-musllinux_1_2_armv7l.whl", hash = "sha256:521a463429ef54143092c11a77e04056dd00636f72e8c45b70aaa3140d639726"}, + {file = "propcache-0.4.1-cp314-cp314t-musllinux_1_2_ppc64le.whl", hash = "sha256:120c964da3fdc75e3731aa392527136d4ad35868cc556fd09bb6d09172d9a367"}, + {file = "propcache-0.4.1-cp314-cp314t-musllinux_1_2_s390x.whl", hash = "sha256:d8f353eb14ee3441ee844ade4277d560cdd68288838673273b978e3d6d2c8f36"}, + {file = "propcache-0.4.1-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:ab2943be7c652f09638800905ee1bab2c544e537edb57d527997a24c13dc1455"}, + {file = "propcache-0.4.1-cp314-cp314t-win32.whl", hash = "sha256:05674a162469f31358c30bcaa8883cb7829fa3110bf9c0991fe27d7896c42d85"}, + {file = "propcache-0.4.1-cp314-cp314t-win_amd64.whl", hash = "sha256:990f6b3e2a27d683cb7602ed6c86f15ee6b43b1194736f9baaeb93d0016633b1"}, + {file = "propcache-0.4.1-cp314-cp314t-win_arm64.whl", hash = "sha256:ecef2343af4cc68e05131e45024ba34f6095821988a9d0a02aa7c73fcc448aa9"}, + {file = "propcache-0.4.1-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:3d233076ccf9e450c8b3bc6720af226b898ef5d051a2d145f7d765e6e9f9bcff"}, + {file = "propcache-0.4.1-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:357f5bb5c377a82e105e44bd3d52ba22b616f7b9773714bff93573988ef0a5fb"}, + {file = "propcache-0.4.1-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:cbc3b6dfc728105b2a57c06791eb07a94229202ea75c59db644d7d496b698cac"}, + {file = "propcache-0.4.1-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:182b51b421f0501952d938dc0b0eb45246a5b5153c50d42b495ad5fb7517c888"}, + {file = "propcache-0.4.1-cp39-cp39-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:4b536b39c5199b96fc6245eb5fb796c497381d3942f169e44e8e392b29c9ebcc"}, + {file = "propcache-0.4.1-cp39-cp39-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:db65d2af507bbfbdcedb254a11149f894169d90488dd3e7190f7cdcb2d6cd57a"}, + {file = "propcache-0.4.1-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:fd2dbc472da1f772a4dae4fa24be938a6c544671a912e30529984dd80400cd88"}, + {file = "propcache-0.4.1-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:daede9cd44e0f8bdd9e6cc9a607fc81feb80fae7a5fc6cecaff0e0bb32e42d00"}, + {file = "propcache-0.4.1-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:71b749281b816793678ae7f3d0d84bd36e694953822eaad408d682efc5ca18e0"}, + {file = "propcache-0.4.1-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:0002004213ee1f36cfb3f9a42b5066100c44276b9b72b4e1504cddd3d692e86e"}, + {file = "propcache-0.4.1-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:fe49d0a85038f36ba9e3ffafa1103e61170b28e95b16622e11be0a0ea07c6781"}, + {file = "propcache-0.4.1-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:99d43339c83aaf4d32bda60928231848eee470c6bda8d02599cc4cebe872d183"}, + {file = "propcache-0.4.1-cp39-cp39-win32.whl", hash = "sha256:a129e76735bc792794d5177069691c3217898b9f5cee2b2661471e52ffe13f19"}, + {file = "propcache-0.4.1-cp39-cp39-win_amd64.whl", hash = "sha256:948dab269721ae9a87fd16c514a0a2c2a1bdb23a9a61b969b0f9d9ee2968546f"}, + {file = "propcache-0.4.1-cp39-cp39-win_arm64.whl", hash = "sha256:5fd37c406dd6dc85aa743e214cef35dc54bbdd1419baac4f6ae5e5b1a2976938"}, + {file = "propcache-0.4.1-py3-none-any.whl", hash = "sha256:af2a6052aeb6cf17d3e46ee169099044fd8224cbaf75c76a2ef596e8163e2237"}, + {file = "propcache-0.4.1.tar.gz", hash = "sha256:f48107a8c637e80362555f37ecf49abe20370e557cc4ab374f04ec4423c97c3d"}, ] [[package]] name = "protobuf" -version = "5.29.5" +version = "6.32.1" description = "" optional = false -python-versions = ">=3.8" +python-versions = ">=3.9" groups = ["main"] files = [ - {file = "protobuf-5.29.5-cp310-abi3-win32.whl", hash = "sha256:3f1c6468a2cfd102ff4703976138844f78ebd1fb45f49011afc5139e9e283079"}, - {file = "protobuf-5.29.5-cp310-abi3-win_amd64.whl", hash = "sha256:3f76e3a3675b4a4d867b52e4a5f5b78a2ef9565549d4037e06cf7b0942b1d3fc"}, - {file = "protobuf-5.29.5-cp38-abi3-macosx_10_9_universal2.whl", hash = "sha256:e38c5add5a311f2a6eb0340716ef9b039c1dfa428b28f25a7838ac329204a671"}, - {file = "protobuf-5.29.5-cp38-abi3-manylinux2014_aarch64.whl", hash = "sha256:fa18533a299d7ab6c55a238bf8629311439995f2e7eca5caaff08663606e9015"}, - {file = "protobuf-5.29.5-cp38-abi3-manylinux2014_x86_64.whl", hash = "sha256:63848923da3325e1bf7e9003d680ce6e14b07e55d0473253a690c3a8b8fd6e61"}, - {file = "protobuf-5.29.5-cp38-cp38-win32.whl", hash = "sha256:ef91363ad4faba7b25d844ef1ada59ff1604184c0bcd8b39b8a6bef15e1af238"}, - {file = "protobuf-5.29.5-cp38-cp38-win_amd64.whl", hash = "sha256:7318608d56b6402d2ea7704ff1e1e4597bee46d760e7e4dd42a3d45e24b87f2e"}, - {file = "protobuf-5.29.5-cp39-cp39-win32.whl", hash = "sha256:6f642dc9a61782fa72b90878af134c5afe1917c89a568cd3476d758d3c3a0736"}, - {file = "protobuf-5.29.5-cp39-cp39-win_amd64.whl", hash = "sha256:470f3af547ef17847a28e1f47200a1cbf0ba3ff57b7de50d22776607cd2ea353"}, - {file = "protobuf-5.29.5-py3-none-any.whl", hash = "sha256:6cf42630262c59b2d8de33954443d94b746c952b01434fc58a417fdbd2e84bd5"}, - {file = "protobuf-5.29.5.tar.gz", hash = "sha256:bc1463bafd4b0929216c35f437a8e28731a2b7fe3d98bb77a600efced5a15c84"}, + {file = "protobuf-6.32.1-cp310-abi3-win32.whl", hash = "sha256:a8a32a84bc9f2aad712041b8b366190f71dde248926da517bde9e832e4412085"}, + {file = "protobuf-6.32.1-cp310-abi3-win_amd64.whl", hash = "sha256:b00a7d8c25fa471f16bc8153d0e53d6c9e827f0953f3c09aaa4331c718cae5e1"}, + {file = "protobuf-6.32.1-cp39-abi3-macosx_10_9_universal2.whl", hash = "sha256:d8c7e6eb619ffdf105ee4ab76af5a68b60a9d0f66da3ea12d1640e6d8dab7281"}, + {file = "protobuf-6.32.1-cp39-abi3-manylinux2014_aarch64.whl", hash = "sha256:2f5b80a49e1eb7b86d85fcd23fe92df154b9730a725c3b38c4e43b9d77018bf4"}, + {file = "protobuf-6.32.1-cp39-abi3-manylinux2014_x86_64.whl", hash = "sha256:b1864818300c297265c83a4982fd3169f97122c299f56a56e2445c3698d34710"}, + {file = "protobuf-6.32.1-cp39-cp39-win32.whl", hash = "sha256:68ff170bac18c8178f130d1ccb94700cf72852298e016a2443bdb9502279e5f1"}, + {file = "protobuf-6.32.1-cp39-cp39-win_amd64.whl", hash = "sha256:d0975d0b2f3e6957111aa3935d08a0eb7e006b1505d825f862a1fffc8348e122"}, + {file = "protobuf-6.32.1-py3-none-any.whl", hash = "sha256:2601b779fc7d32a866c6b4404f9d42a3f67c5b9f3f15b4db3cccabe06b95c346"}, + {file = "protobuf-6.32.1.tar.gz", hash = "sha256:ee2469e4a021474ab9baafea6cd070e5bf27c7d29433504ddea1a4ee5850f68d"}, ] [[package]] @@ -5543,26 +5939,27 @@ test = ["pytest"] [[package]] name = "pycparser" -version = "2.22" +version = "2.23" description = "C parser in Python" optional = false python-versions = ">=3.8" groups = ["main"] +markers = "implementation_name != \"PyPy\"" files = [ - {file = "pycparser-2.22-py3-none-any.whl", hash = "sha256:c3702b6d3dd8c7abc1afa565d7e63d53a1d0bd86cdc24edd75470f4de499cfcc"}, - {file = "pycparser-2.22.tar.gz", hash = "sha256:491c8be9c040f5390f5bf44a5b07752bd07f56edf992381b05c701439eec10f6"}, + {file = "pycparser-2.23-py3-none-any.whl", hash = "sha256:e5c6e8d3fbad53479cab09ac03729e0a9faf2bee3db8208a550daf5af81a5934"}, + {file = "pycparser-2.23.tar.gz", hash = "sha256:78816d4f24add8f10a06d6f05b4d424ad9e96cfebf68a4ddc99c65c0720d00c2"}, ] [[package]] name = "pydantic" -version = "2.11.7" +version = "2.11.10" description = "Data validation using Python type hints" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "pydantic-2.11.7-py3-none-any.whl", hash = "sha256:dde5df002701f6de26248661f6835bbe296a47bf73990135c7d07ce741b9623b"}, - {file = "pydantic-2.11.7.tar.gz", hash = "sha256:d989c3c6cb79469287b1569f7447a17848c998458d49ebe294e975b9baf0f0db"}, + {file = "pydantic-2.11.10-py3-none-any.whl", hash = "sha256:802a655709d49bd004c31e865ef37da30b540786a46bfce02333e0e24b5fe29a"}, + {file = "pydantic-2.11.10.tar.gz", hash = "sha256:dc280f0982fbda6c38fada4e476dc0a4f3aeaf9c6ad4c28df68a666ec3c61423"}, ] [package.dependencies] @@ -5798,14 +6195,14 @@ typing-inspection = ">=0.4.0" [[package]] name = "pydantic-settings" -version = "2.10.1" +version = "2.11.0" description = "Settings management using Pydantic" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "pydantic_settings-2.10.1-py3-none-any.whl", hash = "sha256:a60952460b99cf661dc25c29c0ef171721f98bfcb52ef8d9ea4c943d7c8cc796"}, - {file = "pydantic_settings-2.10.1.tar.gz", hash = "sha256:06f0062169818d0f5524420a360d632d5857b83cffd4d42fe29597807a1614ee"}, + {file = "pydantic_settings-2.11.0-py3-none-any.whl", hash = "sha256:fe2cea3413b9530d10f3a5875adffb17ada5c1e1bab0b2885546d7310415207c"}, + {file = "pydantic_settings-2.11.0.tar.gz", hash = "sha256:d0e87a1c7d33593beb7194adb8470fc426e95ba02af83a0f23474a04c9a08180"}, ] [package.dependencies] @@ -5866,14 +6263,14 @@ jsonasobj = ">=1.2.1" [[package]] name = "pymdown-extensions" -version = "10.16" +version = "10.16.1" description = "Extension pack for Python Markdown." optional = false python-versions = ">=3.9" groups = ["docs"] files = [ - {file = "pymdown_extensions-10.16-py3-none-any.whl", hash = "sha256:f5dd064a4db588cb2d95229fc4ee63a1b16cc8b4d0e6145c0899ed8723da1df2"}, - {file = "pymdown_extensions-10.16.tar.gz", hash = "sha256:71dac4fca63fabeffd3eb9038b756161a33ec6e8d230853d3cecf562155ab3de"}, + {file = "pymdown_extensions-10.16.1-py3-none-any.whl", hash = "sha256:d6ba157a6c03146a7fb122b2b9a121300056384eafeec9c9f9e584adfdb2a32d"}, + {file = "pymdown_extensions-10.16.1.tar.gz", hash = "sha256:aace82bcccba3efc03e25d584e6a22d27a8e17caa3f4dd9f207e49b787aa9a91"}, ] [package.dependencies] @@ -5885,69 +6282,83 @@ extra = ["pygments (>=2.19.1)"] [[package]] name = "pymongo" -version = "4.13.2" +version = "4.15.3" description = "PyMongo - the Official MongoDB Python driver" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "pymongo-4.13.2-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:01065eb1838e3621a30045ab14d1a60ee62e01f65b7cf154e69c5c722ef14d2f"}, - {file = "pymongo-4.13.2-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:9ab0325d436075f5f1901cde95afae811141d162bc42d9a5befb647fda585ae6"}, - {file = "pymongo-4.13.2-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:cdd8041902963c84dc4e27034fa045ac55fabcb2a4ba5b68b880678557573e70"}, - {file = "pymongo-4.13.2-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:b00ab04630aa4af97294e9abdbe0506242396269619c26f5761fd7b2524ef501"}, - {file = "pymongo-4.13.2-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:16440d0da30ba804c6c01ea730405fdbbb476eae760588ea09e6e7d28afc06de"}, - {file = "pymongo-4.13.2-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:ad9a2d1357aed5d6750deb315f62cb6f5b3c4c03ffb650da559cb09cb29e6fe8"}, - {file = "pymongo-4.13.2-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:c793223aef21a8c415c840af1ca36c55a05d6fa3297378da35de3fb6661c0174"}, - {file = "pymongo-4.13.2-cp310-cp310-win32.whl", hash = "sha256:8ef6ae029a3390565a0510c872624514dde350007275ecd8126b09175aa02cca"}, - {file = "pymongo-4.13.2-cp310-cp310-win_amd64.whl", hash = "sha256:66f168f8c5b1e2e3d518507cf9f200f0c86ac79e2b2be9e7b6c8fd1e2f7d7824"}, - {file = "pymongo-4.13.2-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:7af8c56d0a7fcaf966d5292e951f308fb1f8bac080257349e14742725fd7990d"}, - {file = "pymongo-4.13.2-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:ad24f5864706f052b05069a6bc59ff875026e28709548131448fe1e40fc5d80f"}, - {file = "pymongo-4.13.2-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:a10069454195d1d2dda98d681b1dbac9a425f4b0fe744aed5230c734021c1cb9"}, - {file = "pymongo-4.13.2-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:3e20862b81e3863bcd72334e3577a3107604553b614a8d25ee1bb2caaea4eb90"}, - {file = "pymongo-4.13.2-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:6b4d5794ca408317c985d7acfb346a60f96f85a7c221d512ff0ecb3cce9d6110"}, - {file = "pymongo-4.13.2-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:9c8e0420fb4901006ae7893e76108c2a36a343b4f8922466d51c45e9e2ceb717"}, - {file = "pymongo-4.13.2-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:239b5f83b83008471d54095e145d4c010f534af99e87cc8877fc6827736451a0"}, - {file = "pymongo-4.13.2-cp311-cp311-win32.whl", hash = "sha256:6bceb524110c32319eb7119422e400dbcafc5b21bcc430d2049a894f69b604e5"}, - {file = "pymongo-4.13.2-cp311-cp311-win_amd64.whl", hash = "sha256:ab87484c97ae837b0a7bbdaa978fa932fbb6acada3f42c3b2bee99121a594715"}, - {file = "pymongo-4.13.2-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:ec89516622dfc8b0fdff499612c0bd235aa45eeb176c9e311bcc0af44bf952b6"}, - {file = "pymongo-4.13.2-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:f30eab4d4326df54fee54f31f93e532dc2918962f733ee8e115b33e6fe151d92"}, - {file = "pymongo-4.13.2-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:0cce9428d12ba396ea245fc4c51f20228cead01119fcc959e1c80791ea45f820"}, - {file = "pymongo-4.13.2-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:ac9241b727a69c39117c12ac1e52d817ea472260dadc66262c3fdca0bab0709b"}, - {file = "pymongo-4.13.2-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:3efc4c515b371a9fa1d198b6e03340985bfe1a55ae2d2b599a714934e7bc61ab"}, - {file = "pymongo-4.13.2-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:f57a664aa74610eb7a52fa93f2cf794a1491f4f76098343485dd7da5b3bcff06"}, - {file = "pymongo-4.13.2-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:3dcb0b8cdd499636017a53f63ef64cf9b6bd3fd9355796c5a1d228e4be4a4c94"}, - {file = "pymongo-4.13.2-cp312-cp312-win32.whl", hash = "sha256:bf43ae07804d7762b509f68e5ec73450bb8824e960b03b861143ce588b41f467"}, - {file = "pymongo-4.13.2-cp312-cp312-win_amd64.whl", hash = "sha256:812a473d584bcb02ab819d379cd5e752995026a2bb0d7713e78462b6650d3f3a"}, - {file = "pymongo-4.13.2-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:d6044ca0eb74d97f7d3415264de86a50a401b7b0b136d30705f022f9163c3124"}, - {file = "pymongo-4.13.2-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:dd326bcb92d28d28a3e7ef0121602bad78691b6d4d1f44b018a4616122f1ba8b"}, - {file = "pymongo-4.13.2-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:dfb0c21bdd58e58625c9cd8de13e859630c29c9537944ec0a14574fdf88c2ac4"}, - {file = "pymongo-4.13.2-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:c9c7d345d57f17b1361008aea78a37e8c139631a46aeb185dd2749850883c7ba"}, - {file = "pymongo-4.13.2-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:8860445a8da1b1545406fab189dc20319aff5ce28e65442b2b4a8f4228a88478"}, - {file = "pymongo-4.13.2-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:01c184b612f67d5a4c8f864ae7c40b6cc33c0e9bb05e39d08666f8831d120504"}, - {file = "pymongo-4.13.2-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:ae2ea8c62d5f3c6529407c12471385d9a05f9fb890ce68d64976340c85cd661b"}, - {file = "pymongo-4.13.2-cp313-cp313-win32.whl", hash = "sha256:d13556e91c4a8cb07393b8c8be81e66a11ebc8335a40fa4af02f4d8d3b40c8a1"}, - {file = "pymongo-4.13.2-cp313-cp313-win_amd64.whl", hash = "sha256:cfc69d7bc4d4d5872fd1e6de25e6a16e2372c7d5556b75c3b8e2204dce73e3fb"}, - {file = "pymongo-4.13.2-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:a457d2ac34c05e9e8a6bb724115b093300bf270f0655fb897df8d8604b2e3700"}, - {file = "pymongo-4.13.2-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:02f131a6e61559613b1171b53fbe21fed64e71b0cb4858c47fc9bc7c8e0e501c"}, - {file = "pymongo-4.13.2-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:8c942d1c6334e894271489080404b1a2e3b8bd5de399f2a0c14a77d966be5bc9"}, - {file = "pymongo-4.13.2-cp313-cp313t-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:850168d115680ab66a0931a6aa9dd98ed6aa5e9c3b9a6c12128049b9a5721bc5"}, - {file = "pymongo-4.13.2-cp313-cp313t-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:af7dfff90647ee77c53410f7fe8ca4fe343f8b768f40d2d0f71a5602f7b5a541"}, - {file = "pymongo-4.13.2-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:f8057f9bc9c94a8fd54ee4f5e5106e445a8f406aff2df74746f21c8791ee2403"}, - {file = "pymongo-4.13.2-cp313-cp313t-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:51040e1ba78d6671f8c65b29e2864483451e789ce93b1536de9cc4456ede87fa"}, - {file = "pymongo-4.13.2-cp313-cp313t-win32.whl", hash = "sha256:7ab86b98a18c8689514a9f8d0ec7d9ad23a949369b31c9a06ce4a45dcbffcc5e"}, - {file = "pymongo-4.13.2-cp313-cp313t-win_amd64.whl", hash = "sha256:c38168263ed94a250fc5cf9c6d33adea8ab11c9178994da1c3481c2a49d235f8"}, - {file = "pymongo-4.13.2-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:54a89739a86da31adcef41f6c3ae62b38a8bad156bba71fe5898871746c5af83"}, - {file = "pymongo-4.13.2-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:de529aebd1ddae2de778d926b3e8e2e42a9b37b5c668396aad8f28af75e606f9"}, - {file = "pymongo-4.13.2-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:34cc7d4cd7586c1c4f7af2b97447404046c2d8e7ed4c7214ed0e21dbeb17d57d"}, - {file = "pymongo-4.13.2-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:884cb88a9d4c4c9810056b9c71817bd9714bbe58c461f32b65be60c56759823b"}, - {file = "pymongo-4.13.2-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:389cb6415ec341c73f81fbf54970ccd0cd5d3fa7c238dcdb072db051d24e2cb4"}, - {file = "pymongo-4.13.2-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:49f9968ea7e6a86d4c9bd31d2095f0419efc498ea5e6067e75ade1f9e64aea3d"}, - {file = "pymongo-4.13.2-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:ae07315bb106719c678477e61077cd28505bb7d3fd0a2341e75a9510118cb785"}, - {file = "pymongo-4.13.2-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:4dc60b3f5e1448fd011c729ad5d8735f603b0a08a8773ec8e34a876ccc7de45f"}, - {file = "pymongo-4.13.2-cp39-cp39-manylinux_2_5_x86_64.manylinux1_x86_64.whl", hash = "sha256:75462d6ce34fb2dd98f8ac3732a7a1a1fbb2e293c4f6e615766731d044ad730e"}, - {file = "pymongo-4.13.2-cp39-cp39-win32.whl", hash = "sha256:b7e04c45f6a7d5a13fe064f42130d29b0730cb83dd387a623563ff3b9bd2f4d1"}, - {file = "pymongo-4.13.2-cp39-cp39-win_amd64.whl", hash = "sha256:0603145c9be5e195ae61ba7a93eb283abafdbd87f6f30e6c2dfc242940fe280c"}, - {file = "pymongo-4.13.2.tar.gz", hash = "sha256:0f64c6469c2362962e6ce97258ae1391abba1566a953a492562d2924b44815c2"}, + {file = "pymongo-4.15.3-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:482ca9b775747562ce1589df10c97a0e62a604ce5addf933e5819dd967c5e23c"}, + {file = "pymongo-4.15.3-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:c7eb497519f42ac89c30919a51f80e68a070cfc2f3b0543cac74833cd45a6b9c"}, + {file = "pymongo-4.15.3-cp310-cp310-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:4a0a054e9937ec8fdb465835509b176f6b032851c8648f6a5d1b19932d0eacd6"}, + {file = "pymongo-4.15.3-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:49fd6e158cf75771b2685a8a221a40ab96010ae34dd116abd06371dc6c38ab60"}, + {file = "pymongo-4.15.3-cp310-cp310-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:82a490f1ade4ec6a72068e3676b04c126e3043e69b38ec474a87c6444cf79098"}, + {file = "pymongo-4.15.3-cp310-cp310-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:982107c667921e896292f4be09c057e2f1a40c645c9bfc724af5dd5fb8398094"}, + {file = "pymongo-4.15.3-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:45aebbd369ca79b7c46eaea5b04d2e4afca4eda117b68965a07a9da05d774e4d"}, + {file = "pymongo-4.15.3-cp310-cp310-win32.whl", hash = "sha256:90ad56bd1d769d2f44af74f0fd0c276512361644a3c636350447994412cbc9a1"}, + {file = "pymongo-4.15.3-cp310-cp310-win_amd64.whl", hash = "sha256:8bd6dd736f5d07a825caf52c38916d5452edc0fac7aee43ec67aba6f61c2dbb7"}, + {file = "pymongo-4.15.3-cp310-cp310-win_arm64.whl", hash = "sha256:300eaf83ad053e51966be1839324341b08eaf880d3dc63ada7942d5912e09c49"}, + {file = "pymongo-4.15.3-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:39a13d8f7141294404ce46dfbabb2f2d17e9b1192456651ae831fa351f86fbeb"}, + {file = "pymongo-4.15.3-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:17d13458baf4a6a9f2e787d95adf8ec50d412accb9926a044bd1c41029c323b2"}, + {file = "pymongo-4.15.3-cp311-cp311-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:fe4bcb8acfb288e238190397d4a699aeb4adb70e8545a6f4e44f99d4e8096ab1"}, + {file = "pymongo-4.15.3-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:d09d895c7f08bcbed4d2e96a00e52e9e545ae5a37b32d2dc10099b205a21fc6d"}, + {file = "pymongo-4.15.3-cp311-cp311-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:21c0a95a4db72562fd0805e2f76496bf432ba2e27a5651f4b9c670466260c258"}, + {file = "pymongo-4.15.3-cp311-cp311-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:89e45d7fa987f4e246cdf43ff001e3f911f73eb19ba9dabc2a6d80df5c97883b"}, + {file = "pymongo-4.15.3-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:1246a82fa6dd73ac2c63aa7e463752d5d1ca91e0c7a23396b78f21273befd3a7"}, + {file = "pymongo-4.15.3-cp311-cp311-win32.whl", hash = "sha256:9483521c03f6017336f54445652ead3145154e8d3ea06418e52cea57fee43292"}, + {file = "pymongo-4.15.3-cp311-cp311-win_amd64.whl", hash = "sha256:c57dad9f289d72af1d7c47a444c4d9fa401f951cedbbcc54c7dd0c2107d6d786"}, + {file = "pymongo-4.15.3-cp311-cp311-win_arm64.whl", hash = "sha256:2fd3b99520f2bb013960ac29dece1b43f2f1b6d94351ca33ba1b1211ecf79a09"}, + {file = "pymongo-4.15.3-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:bd0497c564b0ae34fb816464ffc09986dd9ca29e2772a0f7af989e472fecc2ad"}, + {file = "pymongo-4.15.3-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:292fd5a3f045751a823a54cdea75809b2216a62cc5f74a1a96b337db613d46a8"}, + {file = "pymongo-4.15.3-cp312-cp312-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:959ef69c5e687b6b749fbf2140c7062abdb4804df013ae0507caabf30cba6875"}, + {file = "pymongo-4.15.3-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:de3bc878c3be54ae41c2cabc9e9407549ed4fec41f4e279c04e840dddd7c630c"}, + {file = "pymongo-4.15.3-cp312-cp312-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:07bcc36d11252f24fe671e7e64044d39a13d997b0502c6401161f28cc144f584"}, + {file = "pymongo-4.15.3-cp312-cp312-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:b63bac343b79bd209e830aac1f5d9d552ff415f23a924d3e51abbe3041265436"}, + {file = "pymongo-4.15.3-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:b33d59bf6fa1ca1d7d96d4fccff51e41312358194190d53ef70a84c070f5287e"}, + {file = "pymongo-4.15.3-cp312-cp312-win32.whl", hash = "sha256:b3a0ec660d61efb91c16a5962ec937011fe3572c4338216831f102e53d294e5c"}, + {file = "pymongo-4.15.3-cp312-cp312-win_amd64.whl", hash = "sha256:f6b0513e5765fdde39f36e6a29a36c67071122b5efa748940ae51075beb5e4bc"}, + {file = "pymongo-4.15.3-cp312-cp312-win_arm64.whl", hash = "sha256:c4fdd8e6eab8ff77c1c8041792b5f760d48508623cd10b50d5639e73f1eec049"}, + {file = "pymongo-4.15.3-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:a47a3218f7900f65bf0f36fcd1f2485af4945757360e7e143525db9d715d2010"}, + {file = "pymongo-4.15.3-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:09440e78dff397b2f34a624f445ac8eb44c9756a2688b85b3bf344d351d198e1"}, + {file = "pymongo-4.15.3-cp313-cp313-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:97f9babdb98c31676f97d468f7fe2dc49b8a66fb6900effddc4904c1450196c8"}, + {file = "pymongo-4.15.3-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:71413cd8f091ae25b1fec3af7c2e531cf9bdb88ce4079470e64835f6a664282a"}, + {file = "pymongo-4.15.3-cp313-cp313-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:76a8d4de8dceb69f6e06736198ff6f7e1149515ef946f192ff2594d2cc98fc53"}, + {file = "pymongo-4.15.3-cp313-cp313-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:77353978be9fc9e5fe56369682efed0aac5f92a2a1570704d62b62a3c9e1a24f"}, + {file = "pymongo-4.15.3-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:9897a837677e3814873d0572f7e5d53c23ce18e274f3b5b87f05fb6eea22615b"}, + {file = "pymongo-4.15.3-cp313-cp313-win32.whl", hash = "sha256:d66da207ccb0d68c5792eaaac984a0d9c6c8ec609c6bcfa11193a35200dc5992"}, + {file = "pymongo-4.15.3-cp313-cp313-win_amd64.whl", hash = "sha256:52f40c4b8c00bc53d4e357fe0de13d031c4cddb5d201e1a027db437e8d2887f8"}, + {file = "pymongo-4.15.3-cp313-cp313-win_arm64.whl", hash = "sha256:fb384623ece34db78d445dd578a52d28b74e8319f4d9535fbaff79d0eae82b3d"}, + {file = "pymongo-4.15.3-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:dcff15b9157c16bc796765d4d3d151df669322acfb0357e4c3ccd056153f0ff4"}, + {file = "pymongo-4.15.3-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:1f681722c9f27e86c49c2e8a838e61b6ecf2285945fd1798bd01458134257834"}, + {file = "pymongo-4.15.3-cp314-cp314-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:2c96dde79bdccd167b930a709875b0cd4321ac32641a490aebfa10bdcd0aa99b"}, + {file = "pymongo-4.15.3-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:d2d4ca446348d850ac4a5c3dc603485640ae2e7805dbb90765c3ba7d79129b37"}, + {file = "pymongo-4.15.3-cp314-cp314-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:7c0fd3de3a12ff0a8113a3f64cedb01f87397ab8eaaffa88d7f18ca66cd39385"}, + {file = "pymongo-4.15.3-cp314-cp314-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:e84dec392cf5f72d365e0aac73f627b0a3170193ebb038c3f7e7df11b7983ee7"}, + {file = "pymongo-4.15.3-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:8d4b01a48369ea6d5bc83fea535f56279f806aa3e4991189f0477696dd736289"}, + {file = "pymongo-4.15.3-cp314-cp314-win32.whl", hash = "sha256:3561fa96c3123275ec5ccf919e595547e100c412ec0894e954aa0da93ecfdb9e"}, + {file = "pymongo-4.15.3-cp314-cp314-win_amd64.whl", hash = "sha256:9df2db6bd91b07400879b6ec89827004c0c2b55fc606bb62db93cafb7677c340"}, + {file = "pymongo-4.15.3-cp314-cp314-win_arm64.whl", hash = "sha256:ff99864085d2c7f4bb672c7167680ceb7d273e9a93c1a8074c986a36dbb71cc6"}, + {file = "pymongo-4.15.3-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:ffe217d2502f3fba4e2b0dc015ce3b34f157b66dfe96835aa64432e909dd0d95"}, + {file = "pymongo-4.15.3-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:390c4954c774eda280898e73aea36482bf20cba3ecb958dbb86d6a68b9ecdd68"}, + {file = "pymongo-4.15.3-cp314-cp314t-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:7dd2a49f088890ca08930bbf96121443b48e26b02b84ba0a3e1ae2bf2c5a9b48"}, + {file = "pymongo-4.15.3-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:5f6feb678f26171f2a6b2cbb340949889154c7067972bd4cc129b62161474f08"}, + {file = "pymongo-4.15.3-cp314-cp314t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:446417a34ff6c2411ce3809e17ce9a67269c9f1cb4966b01e49e0c590cc3c6b3"}, + {file = "pymongo-4.15.3-cp314-cp314t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:cfa4a0a0f024a0336640e1201994e780a17bda5e6a7c0b4d23841eb9152e868b"}, + {file = "pymongo-4.15.3-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:9b03db2fe37c950aff94b29ded5c349b23729bccd90a0a5907bbf807d8c77298"}, + {file = "pymongo-4.15.3-cp314-cp314t-win32.whl", hash = "sha256:e7cde58ef6470c0da922b65e885fb1ffe04deef81e526bd5dea429290fa358ca"}, + {file = "pymongo-4.15.3-cp314-cp314t-win_amd64.whl", hash = "sha256:fae552767d8e5153ed498f1bca92d905d0d46311d831eefb0f06de38f7695c95"}, + {file = "pymongo-4.15.3-cp314-cp314t-win_arm64.whl", hash = "sha256:47ffb068e16ae5e43580d5c4e3b9437f05414ea80c32a1e5cac44a835859c259"}, + {file = "pymongo-4.15.3-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:58d0f4123855f05c0649f9b8ee083acc5b26e7f4afde137cd7b8dc03e9107ff3"}, + {file = "pymongo-4.15.3-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:9bc9f99e7702fdb0dcc3ff1dd490adc5d20b3941ad41e58f887d4998b9922a14"}, + {file = "pymongo-4.15.3-cp39-cp39-manylinux1_i686.manylinux_2_28_i686.manylinux_2_5_i686.whl", hash = "sha256:86b1b5b63f4355adffc329733733a9b71fdad88f37a9dc41e163aed2130f9abc"}, + {file = "pymongo-4.15.3-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:6a054d282dd922ac400b6f47ea3ef58d8b940968d76d855da831dc739b7a04de"}, + {file = "pymongo-4.15.3-cp39-cp39-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:dc583a1130e2516440b93bb2ecb55cfdac6d5373615ae472a9d1f26801f58749"}, + {file = "pymongo-4.15.3-cp39-cp39-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:5c78237e878e0296130e398151b0d4aa6c9eaf82e38fb6e0aaae2029bc7ef0ce"}, + {file = "pymongo-4.15.3-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:5c85a4c72b7965033f95c94c42dac27d886c01dbc23fe337ccb14f052a0ccc29"}, + {file = "pymongo-4.15.3-cp39-cp39-win32.whl", hash = "sha256:17fc94d1e067556b122eeb09e25c003268e8c0ea1f2f78e745b33bb59a1209c4"}, + {file = "pymongo-4.15.3-cp39-cp39-win_amd64.whl", hash = "sha256:5bf879a6ed70264574d4d8fb5a467c2a64dc76ecd72c0cb467c4464f849c8c77"}, + {file = "pymongo-4.15.3-cp39-cp39-win_arm64.whl", hash = "sha256:2f3d66f7c495efc3cfffa611b36075efe86da1860a7df75522a6fe499ee10383"}, + {file = "pymongo-4.15.3.tar.gz", hash = "sha256:7a981271347623b5319932796690c2d301668ac3a1965974ac9f5c3b8a22cea5"}, ] [package.dependencies] @@ -5955,7 +6366,7 @@ dnspython = ">=1.16.0,<3.0.0" [package.extras] aws = ["pymongo-auth-aws (>=1.1.0,<2.0.0)"] -docs = ["furo (==2024.8.6)", "readthedocs-sphinx-search (>=0.3,<1.0)", "sphinx (>=5.3,<9)", "sphinx-autobuild (>=2020.9.1)", "sphinx-rtd-theme (>=2,<4)", "sphinxcontrib-shellcheck (>=1,<2)"] +docs = ["furo (==2025.7.19)", "readthedocs-sphinx-search (>=0.3,<1.0)", "sphinx (>=5.3,<9)", "sphinx-autobuild (>=2020.9.1)", "sphinx-rtd-theme (>=2,<4)", "sphinxcontrib-shellcheck (>=1,<2)"] encryption = ["certifi ; os_name == \"nt\" or sys_platform == \"darwin\"", "pymongo-auth-aws (>=1.1.0,<2.0.0)", "pymongocrypt (>=1.13.0,<2.0.0)"] gssapi = ["pykerberos ; os_name != \"nt\"", "winkerberos (>=0.5.0) ; os_name == \"nt\""] ocsp = ["certifi ; os_name == \"nt\" or sys_platform == \"darwin\"", "cryptography (>=2.5)", "pyopenssl (>=17.2.0)", "requests (<3.0.0)", "service-identity (>=18.1.0)"] @@ -5980,37 +6391,57 @@ pywin32 = {version = ">=226", markers = "platform_system == \"Windows\""} [[package]] name = "pymupdf" -version = "1.26.3" +version = "1.26.5" description = "A high performance Python library for data extraction, analysis, conversion & manipulation of PDF (and other) documents." optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "pymupdf-1.26.3-cp39-abi3-macosx_10_9_x86_64.whl", hash = "sha256:ded891963944e5f13b03b88f6d9e982e816a4ec8689fe360876eef000c161f2b"}, - {file = "pymupdf-1.26.3-cp39-abi3-macosx_11_0_arm64.whl", hash = "sha256:436a33c738bb10eadf00395d18a6992b801ffb26521ee1f361ae786dd283327a"}, - {file = "pymupdf-1.26.3-cp39-abi3-manylinux_2_28_aarch64.whl", hash = "sha256:a2d7a3cd442f12f05103cb3bb1415111517f0a97162547a3720f3bbbc5e0b51c"}, - {file = "pymupdf-1.26.3-cp39-abi3-manylinux_2_28_x86_64.whl", hash = "sha256:454f38c8cf07eb333eb4646dca10517b6e90f57ce2daa2265a78064109d85555"}, - {file = "pymupdf-1.26.3-cp39-abi3-musllinux_1_2_x86_64.whl", hash = "sha256:759b75d2f710ff4edf8d097d2e98f60e9ecef47632cead6f949b3412facdb9f0"}, - {file = "pymupdf-1.26.3-cp39-abi3-win32.whl", hash = "sha256:a839ed44742faa1cd4956bb18068fe5aae435d67ce915e901318646c4e7bbea6"}, - {file = "pymupdf-1.26.3-cp39-abi3-win_amd64.whl", hash = "sha256:b4cd5124d05737944636cf45fc37ce5824f10e707b0342efe109c7b6bd37a9cc"}, - {file = "pymupdf-1.26.3.tar.gz", hash = "sha256:b7d2c3ffa9870e1e4416d18862f5ccd356af5fe337b4511093bbbce2ca73b7e5"}, + {file = "pymupdf-1.26.5-cp39-abi3-macosx_10_9_x86_64.whl", hash = "sha256:2bfb58f07ad631e5f71ad0bd6f1ff52700f7ba7ebb4973130e81e75b721beae1"}, + {file = "pymupdf-1.26.5-cp39-abi3-macosx_11_0_arm64.whl", hash = "sha256:d58599479bc471d3ae56c3d68d9160d0b7de8a3bd40221ddc3a4eaae2d281b86"}, + {file = "pymupdf-1.26.5-cp39-abi3-manylinux_2_28_aarch64.whl", hash = "sha256:7dfea81fdd73437a6a6ce83e1fcf556faee9327a6540571e58bf04fa362bb0cd"}, + {file = "pymupdf-1.26.5-cp39-abi3-manylinux_2_28_x86_64.whl", hash = "sha256:caad0ffeb63dcc4a29ca40f3c68d7b78d32a932e834b0056b529cc0bdbaaffc9"}, + {file = "pymupdf-1.26.5-cp39-abi3-musllinux_1_2_x86_64.whl", hash = "sha256:e24e7a7d696bd398543cc5c147869edb2026d5d5a21b7f8e35db2f20170b389e"}, + {file = "pymupdf-1.26.5-cp39-abi3-win32.whl", hash = "sha256:a2a42f5911d153a47bf5c3e162a0bfe8745eb9bec3e59fbaf87617b4003d8270"}, + {file = "pymupdf-1.26.5-cp39-abi3-win_amd64.whl", hash = "sha256:39a6fb58182b27b51ea8150a0cd2e4ee7e0cf71e9d6723978f28699b42ee61ae"}, + {file = "pymupdf-1.26.5.tar.gz", hash = "sha256:8ef335e07f648492df240f2247854d0e7c0467afb9c4dc2376ec30978ec158c3"}, ] [[package]] name = "pyparsing" -version = "3.2.3" -description = "pyparsing module - Classes and methods to define and execute parsing grammars" +version = "3.2.5" +description = "pyparsing - Classes and methods to define and execute parsing grammars" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "pyparsing-3.2.3-py3-none-any.whl", hash = "sha256:a749938e02d6fd0b59b356ca504a24982314bb090c383e3cf201c95ef7e2bfcf"}, - {file = "pyparsing-3.2.3.tar.gz", hash = "sha256:b9c13f1ab8b3b542f72e28f634bad4de758ab3ce4546e4301970ad6fa77c38be"}, + {file = "pyparsing-3.2.5-py3-none-any.whl", hash = "sha256:e38a4f02064cf41fe6593d328d0512495ad1f3d8a91c4f73fc401b3079a59a5e"}, + {file = "pyparsing-3.2.5.tar.gz", hash = "sha256:2df8d5b7b2802ef88e8d016a2eb9c7aeaa923529cd251ed0fe4608275d4105b6"}, ] [package.extras] diagrams = ["jinja2", "railroad-diagrams"] +[[package]] +name = "pypdf" +version = "6.1.1" +description = "A pure-python PDF library capable of splitting, merging, cropping, and transforming PDF files" +optional = false +python-versions = ">=3.9" +groups = ["main"] +files = [ + {file = "pypdf-6.1.1-py3-none-any.whl", hash = "sha256:7781f99493208a37a7d4275601d883e19af24e62a525c25844d22157c2e4cde7"}, + {file = "pypdf-6.1.1.tar.gz", hash = "sha256:10f44d49bf2a82e54c3c5ba3cdcbb118f2a44fc57df8ce51d6fb9b1ed9bfbe8b"}, +] + +[package.extras] +crypto = ["cryptography"] +cryptodome = ["PyCryptodome"] +dev = ["black", "flit", "pip-tools", "pre-commit", "pytest-cov", "pytest-socket", "pytest-timeout", "pytest-xdist", "wheel"] +docs = ["myst_parser", "sphinx", "sphinx_rtd_theme"] +full = ["Pillow (>=8.0.0)", "cryptography"] +image = ["Pillow (>=8.0.0)"] + [[package]] name = "pypdf2" version = "3.0.1" @@ -6032,22 +6463,22 @@ image = ["Pillow"] [[package]] name = "pyproject-api" -version = "1.9.1" +version = "1.10.0" description = "API to interact with the python pyproject.toml based projects" optional = false -python-versions = ">=3.9" +python-versions = ">=3.10" groups = ["dev"] files = [ - {file = "pyproject_api-1.9.1-py3-none-any.whl", hash = "sha256:7d6238d92f8962773dd75b5f0c4a6a27cce092a14b623b811dba656f3b628948"}, - {file = "pyproject_api-1.9.1.tar.gz", hash = "sha256:43c9918f49daab37e302038fc1aed54a8c7a91a9fa935d00b9a485f37e0f5335"}, + {file = "pyproject_api-1.10.0-py3-none-any.whl", hash = "sha256:8757c41a79c0f4ab71b99abed52b97ecf66bd20b04fa59da43b5840bac105a09"}, + {file = "pyproject_api-1.10.0.tar.gz", hash = "sha256:40c6f2d82eebdc4afee61c773ed208c04c19db4c4a60d97f8d7be3ebc0bbb330"}, ] [package.dependencies] packaging = ">=25" [package.extras] -docs = ["furo (>=2024.8.6)", "sphinx-autodoc-typehints (>=3.2)"] -testing = ["covdefaults (>=2.3)", "pytest (>=8.3.5)", "pytest-cov (>=6.1.1)", "pytest-mock (>=3.14)", "setuptools (>=80.3.1)"] +docs = ["furo (>=2025.9.25)", "sphinx-autodoc-typehints (>=3.5.1)"] +testing = ["covdefaults (>=2.3)", "pytest (>=8.4.2)", "pytest-cov (>=7)", "pytest-mock (>=3.15.1)", "setuptools (>=80.9)"] [[package]] name = "pyreadline3" @@ -6166,14 +6597,14 @@ xml = ["lxml"] [[package]] name = "pytest" -version = "8.4.1" +version = "8.4.2" description = "pytest: simple powerful testing with Python" optional = false python-versions = ">=3.9" groups = ["main", "dev"] files = [ - {file = "pytest-8.4.1-py3-none-any.whl", hash = "sha256:539c70ba6fcead8e78eebbf1115e8b589e7565830d7d006a8723f19ac8a0afb7"}, - {file = "pytest-8.4.1.tar.gz", hash = "sha256:7c67fd69174877359ed9371ec3af8a3d2b04741818c51e5e99cc1742251fa93c"}, + {file = "pytest-8.4.2-py3-none-any.whl", hash = "sha256:872f880de3fc3a5bdc88a11b39c9710c3497a547cfa9320bc3c5e62fbf272e79"}, + {file = "pytest-8.4.2.tar.gz", hash = "sha256:86c0d0b93306b961d58d62a4db4879f27fe25513d4b969df351abdddb3c30e01"}, ] [package.dependencies] @@ -6263,34 +6694,19 @@ files = [ [[package]] name = "python-ulid" -version = "3.0.0" +version = "3.1.0" description = "Universally unique lexicographically sortable identifier" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "python_ulid-3.0.0-py3-none-any.whl", hash = "sha256:e4c4942ff50dbd79167ad01ac725ec58f924b4018025ce22c858bfcff99a5e31"}, - {file = "python_ulid-3.0.0.tar.gz", hash = "sha256:e50296a47dc8209d28629a22fc81ca26c00982c78934bd7766377ba37ea49a9f"}, + {file = "python_ulid-3.1.0-py3-none-any.whl", hash = "sha256:e2cdc979c8c877029b4b7a38a6fba3bc4578e4f109a308419ff4d3ccf0a46619"}, + {file = "python_ulid-3.1.0.tar.gz", hash = "sha256:ff0410a598bc5f6b01b602851a3296ede6f91389f913a5d5f8c496003836f636"}, ] [package.extras] pydantic = ["pydantic (>=2.0)"] -[[package]] -name = "pytrie" -version = "0.4.0" -description = "A pure Python implementation of the trie data structure." -optional = false -python-versions = "*" -groups = ["main"] -files = [ - {file = "PyTrie-0.4.0-py3-none-any.whl", hash = "sha256:f687c224ee8c66cda8e8628a903011b692635ffbb08d4b39c5f92b18eb78c950"}, - {file = "PyTrie-0.4.0.tar.gz", hash = "sha256:8f4488f402d3465993fb6b6efa09866849ed8cda7903b50647b7d0342b805379"}, -] - -[package.dependencies] -sortedcontainers = "*" - [[package]] name = "pytz" version = "2025.2" @@ -6336,65 +6752,85 @@ files = [ [[package]] name = "pyyaml" -version = "6.0.2" +version = "6.0.3" description = "YAML parser and emitter for Python" optional = false python-versions = ">=3.8" groups = ["main", "dev", "docs"] files = [ - {file = "PyYAML-6.0.2-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:0a9a2848a5b7feac301353437eb7d5957887edbf81d56e903999a75a3d743086"}, - {file = "PyYAML-6.0.2-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:29717114e51c84ddfba879543fb232a6ed60086602313ca38cce623c1d62cfbf"}, - {file = "PyYAML-6.0.2-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:8824b5a04a04a047e72eea5cec3bc266db09e35de6bdfe34c9436ac5ee27d237"}, - {file = "PyYAML-6.0.2-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:7c36280e6fb8385e520936c3cb3b8042851904eba0e58d277dca80a5cfed590b"}, - {file = "PyYAML-6.0.2-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:ec031d5d2feb36d1d1a24380e4db6d43695f3748343d99434e6f5f9156aaa2ed"}, - {file = "PyYAML-6.0.2-cp310-cp310-musllinux_1_1_aarch64.whl", hash = "sha256:936d68689298c36b53b29f23c6dbb74de12b4ac12ca6cfe0e047bedceea56180"}, - {file = "PyYAML-6.0.2-cp310-cp310-musllinux_1_1_x86_64.whl", hash = "sha256:23502f431948090f597378482b4812b0caae32c22213aecf3b55325e049a6c68"}, - {file = "PyYAML-6.0.2-cp310-cp310-win32.whl", hash = "sha256:2e99c6826ffa974fe6e27cdb5ed0021786b03fc98e5ee3c5bfe1fd5015f42b99"}, - {file = "PyYAML-6.0.2-cp310-cp310-win_amd64.whl", hash = "sha256:a4d3091415f010369ae4ed1fc6b79def9416358877534caf6a0fdd2146c87a3e"}, - {file = "PyYAML-6.0.2-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:cc1c1159b3d456576af7a3e4d1ba7e6924cb39de8f67111c735f6fc832082774"}, - {file = "PyYAML-6.0.2-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:1e2120ef853f59c7419231f3bf4e7021f1b936f6ebd222406c3b60212205d2ee"}, - {file = "PyYAML-6.0.2-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:5d225db5a45f21e78dd9358e58a98702a0302f2659a3c6cd320564b75b86f47c"}, - {file = "PyYAML-6.0.2-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:5ac9328ec4831237bec75defaf839f7d4564be1e6b25ac710bd1a96321cc8317"}, - {file = "PyYAML-6.0.2-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:3ad2a3decf9aaba3d29c8f537ac4b243e36bef957511b4766cb0057d32b0be85"}, - {file = "PyYAML-6.0.2-cp311-cp311-musllinux_1_1_aarch64.whl", hash = "sha256:ff3824dc5261f50c9b0dfb3be22b4567a6f938ccce4587b38952d85fd9e9afe4"}, - {file = "PyYAML-6.0.2-cp311-cp311-musllinux_1_1_x86_64.whl", hash = "sha256:797b4f722ffa07cc8d62053e4cff1486fa6dc094105d13fea7b1de7d8bf71c9e"}, - {file = "PyYAML-6.0.2-cp311-cp311-win32.whl", hash = "sha256:11d8f3dd2b9c1207dcaf2ee0bbbfd5991f571186ec9cc78427ba5bd32afae4b5"}, - {file = "PyYAML-6.0.2-cp311-cp311-win_amd64.whl", hash = "sha256:e10ce637b18caea04431ce14fabcf5c64a1c61ec9c56b071a4b7ca131ca52d44"}, - {file = "PyYAML-6.0.2-cp312-cp312-macosx_10_9_x86_64.whl", hash = "sha256:c70c95198c015b85feafc136515252a261a84561b7b1d51e3384e0655ddf25ab"}, - {file = "PyYAML-6.0.2-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:ce826d6ef20b1bc864f0a68340c8b3287705cae2f8b4b1d932177dcc76721725"}, - {file = "PyYAML-6.0.2-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:1f71ea527786de97d1a0cc0eacd1defc0985dcf6b3f17bb77dcfc8c34bec4dc5"}, - {file = "PyYAML-6.0.2-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:9b22676e8097e9e22e36d6b7bda33190d0d400f345f23d4065d48f4ca7ae0425"}, - {file = "PyYAML-6.0.2-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:80bab7bfc629882493af4aa31a4cfa43a4c57c83813253626916b8c7ada83476"}, - {file = "PyYAML-6.0.2-cp312-cp312-musllinux_1_1_aarch64.whl", hash = "sha256:0833f8694549e586547b576dcfaba4a6b55b9e96098b36cdc7ebefe667dfed48"}, - {file = "PyYAML-6.0.2-cp312-cp312-musllinux_1_1_x86_64.whl", hash = "sha256:8b9c7197f7cb2738065c481a0461e50ad02f18c78cd75775628afb4d7137fb3b"}, - {file = "PyYAML-6.0.2-cp312-cp312-win32.whl", hash = "sha256:ef6107725bd54b262d6dedcc2af448a266975032bc85ef0172c5f059da6325b4"}, - {file = "PyYAML-6.0.2-cp312-cp312-win_amd64.whl", hash = "sha256:7e7401d0de89a9a855c839bc697c079a4af81cf878373abd7dc625847d25cbd8"}, - {file = "PyYAML-6.0.2-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:efdca5630322a10774e8e98e1af481aad470dd62c3170801852d752aa7a783ba"}, - {file = "PyYAML-6.0.2-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:50187695423ffe49e2deacb8cd10510bc361faac997de9efef88badc3bb9e2d1"}, - {file = "PyYAML-6.0.2-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:0ffe8360bab4910ef1b9e87fb812d8bc0a308b0d0eef8c8f44e0254ab3b07133"}, - {file = "PyYAML-6.0.2-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:17e311b6c678207928d649faa7cb0d7b4c26a0ba73d41e99c4fff6b6c3276484"}, - {file = "PyYAML-6.0.2-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:70b189594dbe54f75ab3a1acec5f1e3faa7e8cf2f1e08d9b561cb41b845f69d5"}, - {file = "PyYAML-6.0.2-cp313-cp313-musllinux_1_1_aarch64.whl", hash = "sha256:41e4e3953a79407c794916fa277a82531dd93aad34e29c2a514c2c0c5fe971cc"}, - {file = "PyYAML-6.0.2-cp313-cp313-musllinux_1_1_x86_64.whl", hash = "sha256:68ccc6023a3400877818152ad9a1033e3db8625d899c72eacb5a668902e4d652"}, - {file = "PyYAML-6.0.2-cp313-cp313-win32.whl", hash = "sha256:bc2fa7c6b47d6bc618dd7fb02ef6fdedb1090ec036abab80d4681424b84c1183"}, - {file = "PyYAML-6.0.2-cp313-cp313-win_amd64.whl", hash = "sha256:8388ee1976c416731879ac16da0aff3f63b286ffdd57cdeb95f3f2e085687563"}, - {file = "PyYAML-6.0.2-cp38-cp38-macosx_10_9_x86_64.whl", hash = "sha256:24471b829b3bf607e04e88d79542a9d48bb037c2267d7927a874e6c205ca7e9a"}, - {file = "PyYAML-6.0.2-cp38-cp38-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:d7fded462629cfa4b685c5416b949ebad6cec74af5e2d42905d41e257e0869f5"}, - {file = "PyYAML-6.0.2-cp38-cp38-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:d84a1718ee396f54f3a086ea0a66d8e552b2ab2017ef8b420e92edbc841c352d"}, - {file = "PyYAML-6.0.2-cp38-cp38-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:9056c1ecd25795207ad294bcf39f2db3d845767be0ea6e6a34d856f006006083"}, - {file = "PyYAML-6.0.2-cp38-cp38-musllinux_1_1_x86_64.whl", hash = "sha256:82d09873e40955485746739bcb8b4586983670466c23382c19cffecbf1fd8706"}, - {file = "PyYAML-6.0.2-cp38-cp38-win32.whl", hash = "sha256:43fa96a3ca0d6b1812e01ced1044a003533c47f6ee8aca31724f78e93ccc089a"}, - {file = "PyYAML-6.0.2-cp38-cp38-win_amd64.whl", hash = "sha256:01179a4a8559ab5de078078f37e5c1a30d76bb88519906844fd7bdea1b7729ff"}, - {file = "PyYAML-6.0.2-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:688ba32a1cffef67fd2e9398a2efebaea461578b0923624778664cc1c914db5d"}, - {file = "PyYAML-6.0.2-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:a8786accb172bd8afb8be14490a16625cbc387036876ab6ba70912730faf8e1f"}, - {file = "PyYAML-6.0.2-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:d8e03406cac8513435335dbab54c0d385e4a49e4945d2909a581c83647ca0290"}, - {file = "PyYAML-6.0.2-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:f753120cb8181e736c57ef7636e83f31b9c0d1722c516f7e86cf15b7aa57ff12"}, - {file = "PyYAML-6.0.2-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:3b1fdb9dc17f5a7677423d508ab4f243a726dea51fa5e70992e59a7411c89d19"}, - {file = "PyYAML-6.0.2-cp39-cp39-musllinux_1_1_aarch64.whl", hash = "sha256:0b69e4ce7a131fe56b7e4d770c67429700908fc0752af059838b1cfb41960e4e"}, - {file = "PyYAML-6.0.2-cp39-cp39-musllinux_1_1_x86_64.whl", hash = "sha256:a9f8c2e67970f13b16084e04f134610fd1d374bf477b17ec1599185cf611d725"}, - {file = "PyYAML-6.0.2-cp39-cp39-win32.whl", hash = "sha256:6395c297d42274772abc367baaa79683958044e5d3835486c16da75d2a694631"}, - {file = "PyYAML-6.0.2-cp39-cp39-win_amd64.whl", hash = "sha256:39693e1f8320ae4f43943590b49779ffb98acb81f788220ea932a6b6c51004d8"}, - {file = "pyyaml-6.0.2.tar.gz", hash = "sha256:d584d9ec91ad65861cc08d42e834324ef890a082e591037abe114850ff7bbc3e"}, + {file = "PyYAML-6.0.3-cp38-cp38-macosx_10_13_x86_64.whl", hash = "sha256:c2514fceb77bc5e7a2f7adfaa1feb2fb311607c9cb518dbc378688ec73d8292f"}, + {file = "PyYAML-6.0.3-cp38-cp38-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:9c57bb8c96f6d1808c030b1687b9b5fb476abaa47f0db9c0101f5e9f394e97f4"}, + {file = "PyYAML-6.0.3-cp38-cp38-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:efd7b85f94a6f21e4932043973a7ba2613b059c4a000551892ac9f1d11f5baf3"}, + {file = "PyYAML-6.0.3-cp38-cp38-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:22ba7cfcad58ef3ecddc7ed1db3409af68d023b7f940da23c6c2a1890976eda6"}, + {file = "PyYAML-6.0.3-cp38-cp38-musllinux_1_2_x86_64.whl", hash = "sha256:6344df0d5755a2c9a276d4473ae6b90647e216ab4757f8426893b5dd2ac3f369"}, + {file = "PyYAML-6.0.3-cp38-cp38-win32.whl", hash = "sha256:3ff07ec89bae51176c0549bc4c63aa6202991da2d9a6129d7aef7f1407d3f295"}, + {file = "PyYAML-6.0.3-cp38-cp38-win_amd64.whl", hash = "sha256:5cf4e27da7e3fbed4d6c3d8e797387aaad68102272f8f9752883bc32d61cb87b"}, + {file = "pyyaml-6.0.3-cp310-cp310-macosx_10_13_x86_64.whl", hash = "sha256:214ed4befebe12df36bcc8bc2b64b396ca31be9304b8f59e25c11cf94a4c033b"}, + {file = "pyyaml-6.0.3-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:02ea2dfa234451bbb8772601d7b8e426c2bfa197136796224e50e35a78777956"}, + {file = "pyyaml-6.0.3-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b30236e45cf30d2b8e7b3e85881719e98507abed1011bf463a8fa23e9c3e98a8"}, + {file = "pyyaml-6.0.3-cp310-cp310-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:66291b10affd76d76f54fad28e22e51719ef9ba22b29e1d7d03d6777a9174198"}, + {file = "pyyaml-6.0.3-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:9c7708761fccb9397fe64bbc0395abcae8c4bf7b0eac081e12b809bf47700d0b"}, + {file = "pyyaml-6.0.3-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:418cf3f2111bc80e0933b2cd8cd04f286338bb88bdc7bc8e6dd775ebde60b5e0"}, + {file = "pyyaml-6.0.3-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:5e0b74767e5f8c593e8c9b5912019159ed0533c70051e9cce3e8b6aa699fcd69"}, + {file = "pyyaml-6.0.3-cp310-cp310-win32.whl", hash = "sha256:28c8d926f98f432f88adc23edf2e6d4921ac26fb084b028c733d01868d19007e"}, + {file = "pyyaml-6.0.3-cp310-cp310-win_amd64.whl", hash = "sha256:bdb2c67c6c1390b63c6ff89f210c8fd09d9a1217a465701eac7316313c915e4c"}, + {file = "pyyaml-6.0.3-cp311-cp311-macosx_10_13_x86_64.whl", hash = "sha256:44edc647873928551a01e7a563d7452ccdebee747728c1080d881d68af7b997e"}, + {file = "pyyaml-6.0.3-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:652cb6edd41e718550aad172851962662ff2681490a8a711af6a4d288dd96824"}, + {file = "pyyaml-6.0.3-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:10892704fc220243f5305762e276552a0395f7beb4dbf9b14ec8fd43b57f126c"}, + {file = "pyyaml-6.0.3-cp311-cp311-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:850774a7879607d3a6f50d36d04f00ee69e7fc816450e5f7e58d7f17f1ae5c00"}, + {file = "pyyaml-6.0.3-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:b8bb0864c5a28024fac8a632c443c87c5aa6f215c0b126c449ae1a150412f31d"}, + {file = "pyyaml-6.0.3-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:1d37d57ad971609cf3c53ba6a7e365e40660e3be0e5175fa9f2365a379d6095a"}, + {file = "pyyaml-6.0.3-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:37503bfbfc9d2c40b344d06b2199cf0e96e97957ab1c1b546fd4f87e53e5d3e4"}, + {file = "pyyaml-6.0.3-cp311-cp311-win32.whl", hash = "sha256:8098f252adfa6c80ab48096053f512f2321f0b998f98150cea9bd23d83e1467b"}, + {file = "pyyaml-6.0.3-cp311-cp311-win_amd64.whl", hash = "sha256:9f3bfb4965eb874431221a3ff3fdcddc7e74e3b07799e0e84ca4a0f867d449bf"}, + {file = "pyyaml-6.0.3-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:7f047e29dcae44602496db43be01ad42fc6f1cc0d8cd6c83d342306c32270196"}, + {file = "pyyaml-6.0.3-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:fc09d0aa354569bc501d4e787133afc08552722d3ab34836a80547331bb5d4a0"}, + {file = "pyyaml-6.0.3-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:9149cad251584d5fb4981be1ecde53a1ca46c891a79788c0df828d2f166bda28"}, + {file = "pyyaml-6.0.3-cp312-cp312-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:5fdec68f91a0c6739b380c83b951e2c72ac0197ace422360e6d5a959d8d97b2c"}, + {file = "pyyaml-6.0.3-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:ba1cc08a7ccde2d2ec775841541641e4548226580ab850948cbfda66a1befcdc"}, + {file = "pyyaml-6.0.3-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:8dc52c23056b9ddd46818a57b78404882310fb473d63f17b07d5c40421e47f8e"}, + {file = "pyyaml-6.0.3-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:41715c910c881bc081f1e8872880d3c650acf13dfa8214bad49ed4cede7c34ea"}, + {file = "pyyaml-6.0.3-cp312-cp312-win32.whl", hash = "sha256:96b533f0e99f6579b3d4d4995707cf36df9100d67e0c8303a0c55b27b5f99bc5"}, + {file = "pyyaml-6.0.3-cp312-cp312-win_amd64.whl", hash = "sha256:5fcd34e47f6e0b794d17de1b4ff496c00986e1c83f7ab2fb8fcfe9616ff7477b"}, + {file = "pyyaml-6.0.3-cp312-cp312-win_arm64.whl", hash = "sha256:64386e5e707d03a7e172c0701abfb7e10f0fb753ee1d773128192742712a98fd"}, + {file = "pyyaml-6.0.3-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:8da9669d359f02c0b91ccc01cac4a67f16afec0dac22c2ad09f46bee0697eba8"}, + {file = "pyyaml-6.0.3-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:2283a07e2c21a2aa78d9c4442724ec1eb15f5e42a723b99cb3d822d48f5f7ad1"}, + {file = "pyyaml-6.0.3-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:ee2922902c45ae8ccada2c5b501ab86c36525b883eff4255313a253a3160861c"}, + {file = "pyyaml-6.0.3-cp313-cp313-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:a33284e20b78bd4a18c8c2282d549d10bc8408a2a7ff57653c0cf0b9be0afce5"}, + {file = "pyyaml-6.0.3-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:0f29edc409a6392443abf94b9cf89ce99889a1dd5376d94316ae5145dfedd5d6"}, + {file = "pyyaml-6.0.3-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:f7057c9a337546edc7973c0d3ba84ddcdf0daa14533c2065749c9075001090e6"}, + {file = "pyyaml-6.0.3-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:eda16858a3cab07b80edaf74336ece1f986ba330fdb8ee0d6c0d68fe82bc96be"}, + {file = "pyyaml-6.0.3-cp313-cp313-win32.whl", hash = "sha256:d0eae10f8159e8fdad514efdc92d74fd8d682c933a6dd088030f3834bc8e6b26"}, + {file = "pyyaml-6.0.3-cp313-cp313-win_amd64.whl", hash = "sha256:79005a0d97d5ddabfeeea4cf676af11e647e41d81c9a7722a193022accdb6b7c"}, + {file = "pyyaml-6.0.3-cp313-cp313-win_arm64.whl", hash = "sha256:5498cd1645aa724a7c71c8f378eb29ebe23da2fc0d7a08071d89469bf1d2defb"}, + {file = "pyyaml-6.0.3-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:8d1fab6bb153a416f9aeb4b8763bc0f22a5586065f86f7664fc23339fc1c1fac"}, + {file = "pyyaml-6.0.3-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:34d5fcd24b8445fadc33f9cf348c1047101756fd760b4dacb5c3e99755703310"}, + {file = "pyyaml-6.0.3-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:501a031947e3a9025ed4405a168e6ef5ae3126c59f90ce0cd6f2bfc477be31b7"}, + {file = "pyyaml-6.0.3-cp314-cp314-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:b3bc83488de33889877a0f2543ade9f70c67d66d9ebb4ac959502e12de895788"}, + {file = "pyyaml-6.0.3-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:c458b6d084f9b935061bc36216e8a69a7e293a2f1e68bf956dcd9e6cbcd143f5"}, + {file = "pyyaml-6.0.3-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:7c6610def4f163542a622a73fb39f534f8c101d690126992300bf3207eab9764"}, + {file = "pyyaml-6.0.3-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:5190d403f121660ce8d1d2c1bb2ef1bd05b5f68533fc5c2ea899bd15f4399b35"}, + {file = "pyyaml-6.0.3-cp314-cp314-win_amd64.whl", hash = "sha256:4a2e8cebe2ff6ab7d1050ecd59c25d4c8bd7e6f400f5f82b96557ac0abafd0ac"}, + {file = "pyyaml-6.0.3-cp314-cp314-win_arm64.whl", hash = "sha256:93dda82c9c22deb0a405ea4dc5f2d0cda384168e466364dec6255b293923b2f3"}, + {file = "pyyaml-6.0.3-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:02893d100e99e03eda1c8fd5c441d8c60103fd175728e23e431db1b589cf5ab3"}, + {file = "pyyaml-6.0.3-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:c1ff362665ae507275af2853520967820d9124984e0f7466736aea23d8611fba"}, + {file = "pyyaml-6.0.3-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:6adc77889b628398debc7b65c073bcb99c4a0237b248cacaf3fe8a557563ef6c"}, + {file = "pyyaml-6.0.3-cp314-cp314t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:a80cb027f6b349846a3bf6d73b5e95e782175e52f22108cfa17876aaeff93702"}, + {file = "pyyaml-6.0.3-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:00c4bdeba853cc34e7dd471f16b4114f4162dc03e6b7afcc2128711f0eca823c"}, + {file = "pyyaml-6.0.3-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:66e1674c3ef6f541c35191caae2d429b967b99e02040f5ba928632d9a7f0f065"}, + {file = "pyyaml-6.0.3-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:16249ee61e95f858e83976573de0f5b2893b3677ba71c9dd36b9cf8be9ac6d65"}, + {file = "pyyaml-6.0.3-cp314-cp314t-win_amd64.whl", hash = "sha256:4ad1906908f2f5ae4e5a8ddfce73c320c2a1429ec52eafd27138b7f1cbe341c9"}, + {file = "pyyaml-6.0.3-cp314-cp314t-win_arm64.whl", hash = "sha256:ebc55a14a21cb14062aa4162f906cd962b28e2e9ea38f9b4391244cd8de4ae0b"}, + {file = "pyyaml-6.0.3-cp39-cp39-macosx_10_13_x86_64.whl", hash = "sha256:b865addae83924361678b652338317d1bd7e79b1f4596f96b96c77a5a34b34da"}, + {file = "pyyaml-6.0.3-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:c3355370a2c156cffb25e876646f149d5d68f5e0a3ce86a5084dd0b64a994917"}, + {file = "pyyaml-6.0.3-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:3c5677e12444c15717b902a5798264fa7909e41153cdf9ef7ad571b704a63dd9"}, + {file = "pyyaml-6.0.3-cp39-cp39-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:5ed875a24292240029e4483f9d4a4b8a1ae08843b9c54f43fcc11e404532a8a5"}, + {file = "pyyaml-6.0.3-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:0150219816b6a1fa26fb4699fb7daa9caf09eb1999f3b70fb6e786805e80375a"}, + {file = "pyyaml-6.0.3-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:fa160448684b4e94d80416c0fa4aac48967a969efe22931448d853ada8baf926"}, + {file = "pyyaml-6.0.3-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:27c0abcb4a5dac13684a37f76e701e054692a9b2d3064b70f5e4eb54810553d7"}, + {file = "pyyaml-6.0.3-cp39-cp39-win32.whl", hash = "sha256:1ebe39cb5fc479422b83de611d14e2c0d3bb2a18bbcb01f229ab3cfbd8fee7a0"}, + {file = "pyyaml-6.0.3-cp39-cp39-win_amd64.whl", hash = "sha256:2e71d11abed7344e42a8849600193d15b6def118602c4c176f748e4583246007"}, + {file = "pyyaml-6.0.3.tar.gz", hash = "sha256:d76623373421df22fb4cf8817020cbb7ef15c725b9d5e45f17e189bfc384190f"}, ] [[package]] @@ -6425,14 +6861,14 @@ files = [ [[package]] name = "rdflib" -version = "7.1.4" +version = "7.2.1" description = "RDFLib is a Python library for working with RDF, a simple yet powerful language for representing information." optional = false -python-versions = "<4.0.0,>=3.8.1" +python-versions = ">=3.8.1" groups = ["main"] files = [ - {file = "rdflib-7.1.4-py3-none-any.whl", hash = "sha256:72f4adb1990fa5241abd22ddaf36d7cafa5d91d9ff2ba13f3086d339b213d997"}, - {file = "rdflib-7.1.4.tar.gz", hash = "sha256:fed46e24f26a788e2ab8e445f7077f00edcf95abb73bcef4b86cefa8b62dd174"}, + {file = "rdflib-7.2.1-py3-none-any.whl", hash = "sha256:1a175bc1386a167a42fbfaba003bfa05c164a2a3ca3cb9c0c97f9c9638ca6ac2"}, + {file = "rdflib-7.2.1.tar.gz", hash = "sha256:cf9b7fa25234e8925da8b1fb09700f8349b5f0f100e785fb4260e737308292ac"}, ] [package.dependencies] @@ -6478,14 +6914,14 @@ rdflib-jsonld = "0.6.1" [[package]] name = "referencing" -version = "0.36.2" +version = "0.37.0" description = "JSON Referencing + Python" optional = false -python-versions = ">=3.9" +python-versions = ">=3.10" groups = ["main"] files = [ - {file = "referencing-0.36.2-py3-none-any.whl", hash = "sha256:e8699adbbf8b5c7de96d8ffa0eb5c158b3beafce084968e2ea8bb08c6794dcd0"}, - {file = "referencing-0.36.2.tar.gz", hash = "sha256:df2e89862cd09deabbdba16944cc3f10feb6b3e6f18e902f7cc25609a34775aa"}, + {file = "referencing-0.37.0-py3-none-any.whl", hash = "sha256:381329a9f99628c9069361716891d34ad94af76e461dcb0335825aecc7692231"}, + {file = "referencing-0.37.0.tar.gz", hash = "sha256:44aefc3142c5b842538163acb373e24cce6632bd54bdb01b21ad5863489f50d8"}, ] [package.dependencies] @@ -6495,118 +6931,139 @@ typing-extensions = {version = ">=4.4.0", markers = "python_version < \"3.13\""} [[package]] name = "regex" -version = "2024.11.6" +version = "2025.9.18" description = "Alternative regular expression module, to replace re." optional = false -python-versions = ">=3.8" +python-versions = ">=3.9" groups = ["main"] files = [ - {file = "regex-2024.11.6-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:ff590880083d60acc0433f9c3f713c51f7ac6ebb9adf889c79a261ecf541aa91"}, - {file = "regex-2024.11.6-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:658f90550f38270639e83ce492f27d2c8d2cd63805c65a13a14d36ca126753f0"}, - {file = "regex-2024.11.6-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:164d8b7b3b4bcb2068b97428060b2a53be050085ef94eca7f240e7947f1b080e"}, - {file = "regex-2024.11.6-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:d3660c82f209655a06b587d55e723f0b813d3a7db2e32e5e7dc64ac2a9e86fde"}, - {file = "regex-2024.11.6-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:d22326fcdef5e08c154280b71163ced384b428343ae16a5ab2b3354aed12436e"}, - {file = "regex-2024.11.6-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:f1ac758ef6aebfc8943560194e9fd0fa18bcb34d89fd8bd2af18183afd8da3a2"}, - {file = "regex-2024.11.6-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:997d6a487ff00807ba810e0f8332c18b4eb8d29463cfb7c820dc4b6e7562d0cf"}, - {file = "regex-2024.11.6-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:02a02d2bb04fec86ad61f3ea7f49c015a0681bf76abb9857f945d26159d2968c"}, - {file = "regex-2024.11.6-cp310-cp310-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_12_x86_64.manylinux2010_x86_64.whl", hash = "sha256:f02f93b92358ee3f78660e43b4b0091229260c5d5c408d17d60bf26b6c900e86"}, - {file = "regex-2024.11.6-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:06eb1be98df10e81ebaded73fcd51989dcf534e3c753466e4b60c4697a003b67"}, - {file = "regex-2024.11.6-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:040df6fe1a5504eb0f04f048e6d09cd7c7110fef851d7c567a6b6e09942feb7d"}, - {file = "regex-2024.11.6-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:fdabbfc59f2c6edba2a6622c647b716e34e8e3867e0ab975412c5c2f79b82da2"}, - {file = "regex-2024.11.6-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:8447d2d39b5abe381419319f942de20b7ecd60ce86f16a23b0698f22e1b70008"}, - {file = "regex-2024.11.6-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:da8f5fc57d1933de22a9e23eec290a0d8a5927a5370d24bda9a6abe50683fe62"}, - {file = "regex-2024.11.6-cp310-cp310-win32.whl", hash = "sha256:b489578720afb782f6ccf2840920f3a32e31ba28a4b162e13900c3e6bd3f930e"}, - {file = "regex-2024.11.6-cp310-cp310-win_amd64.whl", hash = "sha256:5071b2093e793357c9d8b2929dfc13ac5f0a6c650559503bb81189d0a3814519"}, - {file = "regex-2024.11.6-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:5478c6962ad548b54a591778e93cd7c456a7a29f8eca9c49e4f9a806dcc5d638"}, - {file = "regex-2024.11.6-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:2c89a8cc122b25ce6945f0423dc1352cb9593c68abd19223eebbd4e56612c5b7"}, - {file = "regex-2024.11.6-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:94d87b689cdd831934fa3ce16cc15cd65748e6d689f5d2b8f4f4df2065c9fa20"}, - {file = "regex-2024.11.6-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:1062b39a0a2b75a9c694f7a08e7183a80c63c0d62b301418ffd9c35f55aaa114"}, - {file = "regex-2024.11.6-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:167ed4852351d8a750da48712c3930b031f6efdaa0f22fa1933716bfcd6bf4a3"}, - {file = "regex-2024.11.6-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:2d548dafee61f06ebdb584080621f3e0c23fff312f0de1afc776e2a2ba99a74f"}, - {file = "regex-2024.11.6-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:f2a19f302cd1ce5dd01a9099aaa19cae6173306d1302a43b627f62e21cf18ac0"}, - {file = "regex-2024.11.6-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:bec9931dfb61ddd8ef2ebc05646293812cb6b16b60cf7c9511a832b6f1854b55"}, - {file = "regex-2024.11.6-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:9714398225f299aa85267fd222f7142fcb5c769e73d7733344efc46f2ef5cf89"}, - {file = "regex-2024.11.6-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:202eb32e89f60fc147a41e55cb086db2a3f8cb82f9a9a88440dcfc5d37faae8d"}, - {file = "regex-2024.11.6-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:4181b814e56078e9b00427ca358ec44333765f5ca1b45597ec7446d3a1ef6e34"}, - {file = "regex-2024.11.6-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:068376da5a7e4da51968ce4c122a7cd31afaaec4fccc7856c92f63876e57b51d"}, - {file = "regex-2024.11.6-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:ac10f2c4184420d881a3475fb2c6f4d95d53a8d50209a2500723d831036f7c45"}, - {file = "regex-2024.11.6-cp311-cp311-win32.whl", hash = "sha256:c36f9b6f5f8649bb251a5f3f66564438977b7ef8386a52460ae77e6070d309d9"}, - {file = "regex-2024.11.6-cp311-cp311-win_amd64.whl", hash = "sha256:02e28184be537f0e75c1f9b2f8847dc51e08e6e171c6bde130b2687e0c33cf60"}, - {file = "regex-2024.11.6-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:52fb28f528778f184f870b7cf8f225f5eef0a8f6e3778529bdd40c7b3920796a"}, - {file = "regex-2024.11.6-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:fdd6028445d2460f33136c55eeb1f601ab06d74cb3347132e1c24250187500d9"}, - {file = "regex-2024.11.6-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:805e6b60c54bf766b251e94526ebad60b7de0c70f70a4e6210ee2891acb70bf2"}, - {file = "regex-2024.11.6-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:b85c2530be953a890eaffde05485238f07029600e8f098cdf1848d414a8b45e4"}, - {file = "regex-2024.11.6-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:bb26437975da7dc36b7efad18aa9dd4ea569d2357ae6b783bf1118dabd9ea577"}, - {file = "regex-2024.11.6-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:abfa5080c374a76a251ba60683242bc17eeb2c9818d0d30117b4486be10c59d3"}, - {file = "regex-2024.11.6-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:70b7fa6606c2881c1db9479b0eaa11ed5dfa11c8d60a474ff0e095099f39d98e"}, - {file = "regex-2024.11.6-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:0c32f75920cf99fe6b6c539c399a4a128452eaf1af27f39bce8909c9a3fd8cbe"}, - {file = "regex-2024.11.6-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:982e6d21414e78e1f51cf595d7f321dcd14de1f2881c5dc6a6e23bbbbd68435e"}, - {file = "regex-2024.11.6-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:a7c2155f790e2fb448faed6dd241386719802296ec588a8b9051c1f5c481bc29"}, - {file = "regex-2024.11.6-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:149f5008d286636e48cd0b1dd65018548944e495b0265b45e1bffecce1ef7f39"}, - {file = "regex-2024.11.6-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:e5364a4502efca094731680e80009632ad6624084aff9a23ce8c8c6820de3e51"}, - {file = "regex-2024.11.6-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:0a86e7eeca091c09e021db8eb72d54751e527fa47b8d5787caf96d9831bd02ad"}, - {file = "regex-2024.11.6-cp312-cp312-win32.whl", hash = "sha256:32f9a4c643baad4efa81d549c2aadefaeba12249b2adc5af541759237eee1c54"}, - {file = "regex-2024.11.6-cp312-cp312-win_amd64.whl", hash = "sha256:a93c194e2df18f7d264092dc8539b8ffb86b45b899ab976aa15d48214138e81b"}, - {file = "regex-2024.11.6-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:a6ba92c0bcdf96cbf43a12c717eae4bc98325ca3730f6b130ffa2e3c3c723d84"}, - {file = "regex-2024.11.6-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:525eab0b789891ac3be914d36893bdf972d483fe66551f79d3e27146191a37d4"}, - {file = "regex-2024.11.6-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:086a27a0b4ca227941700e0b31425e7a28ef1ae8e5e05a33826e17e47fbfdba0"}, - {file = "regex-2024.11.6-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:bde01f35767c4a7899b7eb6e823b125a64de314a8ee9791367c9a34d56af18d0"}, - {file = "regex-2024.11.6-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:b583904576650166b3d920d2bcce13971f6f9e9a396c673187f49811b2769dc7"}, - {file = "regex-2024.11.6-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:1c4de13f06a0d54fa0d5ab1b7138bfa0d883220965a29616e3ea61b35d5f5fc7"}, - {file = "regex-2024.11.6-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:3cde6e9f2580eb1665965ce9bf17ff4952f34f5b126beb509fee8f4e994f143c"}, - {file = "regex-2024.11.6-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:0d7f453dca13f40a02b79636a339c5b62b670141e63efd511d3f8f73fba162b3"}, - {file = "regex-2024.11.6-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:59dfe1ed21aea057a65c6b586afd2a945de04fc7db3de0a6e3ed5397ad491b07"}, - {file = "regex-2024.11.6-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:b97c1e0bd37c5cd7902e65f410779d39eeda155800b65fc4d04cc432efa9bc6e"}, - {file = "regex-2024.11.6-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:f9d1e379028e0fc2ae3654bac3cbbef81bf3fd571272a42d56c24007979bafb6"}, - {file = "regex-2024.11.6-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:13291b39131e2d002a7940fb176e120bec5145f3aeb7621be6534e46251912c4"}, - {file = "regex-2024.11.6-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:4f51f88c126370dcec4908576c5a627220da6c09d0bff31cfa89f2523843316d"}, - {file = "regex-2024.11.6-cp313-cp313-win32.whl", hash = "sha256:63b13cfd72e9601125027202cad74995ab26921d8cd935c25f09c630436348ff"}, - {file = "regex-2024.11.6-cp313-cp313-win_amd64.whl", hash = "sha256:2b3361af3198667e99927da8b84c1b010752fa4b1115ee30beaa332cabc3ef1a"}, - {file = "regex-2024.11.6-cp38-cp38-macosx_10_9_universal2.whl", hash = "sha256:3a51ccc315653ba012774efca4f23d1d2a8a8f278a6072e29c7147eee7da446b"}, - {file = "regex-2024.11.6-cp38-cp38-macosx_10_9_x86_64.whl", hash = "sha256:ad182d02e40de7459b73155deb8996bbd8e96852267879396fb274e8700190e3"}, - {file = "regex-2024.11.6-cp38-cp38-macosx_11_0_arm64.whl", hash = "sha256:ba9b72e5643641b7d41fa1f6d5abda2c9a263ae835b917348fc3c928182ad467"}, - {file = "regex-2024.11.6-cp38-cp38-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:40291b1b89ca6ad8d3f2b82782cc33807f1406cf68c8d440861da6304d8ffbbd"}, - {file = "regex-2024.11.6-cp38-cp38-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:cdf58d0e516ee426a48f7b2c03a332a4114420716d55769ff7108c37a09951bf"}, - {file = "regex-2024.11.6-cp38-cp38-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:a36fdf2af13c2b14738f6e973aba563623cb77d753bbbd8d414d18bfaa3105dd"}, - {file = "regex-2024.11.6-cp38-cp38-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:d1cee317bfc014c2419a76bcc87f071405e3966da434e03e13beb45f8aced1a6"}, - {file = "regex-2024.11.6-cp38-cp38-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:50153825ee016b91549962f970d6a4442fa106832e14c918acd1c8e479916c4f"}, - {file = "regex-2024.11.6-cp38-cp38-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_12_x86_64.manylinux2010_x86_64.whl", hash = "sha256:ea1bfda2f7162605f6e8178223576856b3d791109f15ea99a9f95c16a7636fb5"}, - {file = "regex-2024.11.6-cp38-cp38-musllinux_1_2_aarch64.whl", hash = "sha256:df951c5f4a1b1910f1a99ff42c473ff60f8225baa1cdd3539fe2819d9543e9df"}, - {file = "regex-2024.11.6-cp38-cp38-musllinux_1_2_i686.whl", hash = "sha256:072623554418a9911446278f16ecb398fb3b540147a7828c06e2011fa531e773"}, - {file = "regex-2024.11.6-cp38-cp38-musllinux_1_2_ppc64le.whl", hash = "sha256:f654882311409afb1d780b940234208a252322c24a93b442ca714d119e68086c"}, - {file = "regex-2024.11.6-cp38-cp38-musllinux_1_2_s390x.whl", hash = "sha256:89d75e7293d2b3e674db7d4d9b1bee7f8f3d1609428e293771d1a962617150cc"}, - {file = "regex-2024.11.6-cp38-cp38-musllinux_1_2_x86_64.whl", hash = "sha256:f65557897fc977a44ab205ea871b690adaef6b9da6afda4790a2484b04293a5f"}, - {file = "regex-2024.11.6-cp38-cp38-win32.whl", hash = "sha256:6f44ec28b1f858c98d3036ad5d7d0bfc568bdd7a74f9c24e25f41ef1ebfd81a4"}, - {file = "regex-2024.11.6-cp38-cp38-win_amd64.whl", hash = "sha256:bb8f74f2f10dbf13a0be8de623ba4f9491faf58c24064f32b65679b021ed0001"}, - {file = "regex-2024.11.6-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:5704e174f8ccab2026bd2f1ab6c510345ae8eac818b613d7d73e785f1310f839"}, - {file = "regex-2024.11.6-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:220902c3c5cc6af55d4fe19ead504de80eb91f786dc102fbd74894b1551f095e"}, - {file = "regex-2024.11.6-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:5e7e351589da0850c125f1600a4c4ba3c722efefe16b297de54300f08d734fbf"}, - {file = "regex-2024.11.6-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:5056b185ca113c88e18223183aa1a50e66507769c9640a6ff75859619d73957b"}, - {file = "regex-2024.11.6-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:2e34b51b650b23ed3354b5a07aab37034d9f923db2a40519139af34f485f77d0"}, - {file = "regex-2024.11.6-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:5670bce7b200273eee1840ef307bfa07cda90b38ae56e9a6ebcc9f50da9c469b"}, - {file = "regex-2024.11.6-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:08986dce1339bc932923e7d1232ce9881499a0e02925f7402fb7c982515419ef"}, - {file = "regex-2024.11.6-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:93c0b12d3d3bc25af4ebbf38f9ee780a487e8bf6954c115b9f015822d3bb8e48"}, - {file = "regex-2024.11.6-cp39-cp39-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_12_x86_64.manylinux2010_x86_64.whl", hash = "sha256:764e71f22ab3b305e7f4c21f1a97e1526a25ebdd22513e251cf376760213da13"}, - {file = "regex-2024.11.6-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:f056bf21105c2515c32372bbc057f43eb02aae2fda61052e2f7622c801f0b4e2"}, - {file = "regex-2024.11.6-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:69ab78f848845569401469da20df3e081e6b5a11cb086de3eed1d48f5ed57c95"}, - {file = "regex-2024.11.6-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:86fddba590aad9208e2fa8b43b4c098bb0ec74f15718bb6a704e3c63e2cef3e9"}, - {file = "regex-2024.11.6-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:684d7a212682996d21ca12ef3c17353c021fe9de6049e19ac8481ec35574a70f"}, - {file = "regex-2024.11.6-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:a03e02f48cd1abbd9f3b7e3586d97c8f7a9721c436f51a5245b3b9483044480b"}, - {file = "regex-2024.11.6-cp39-cp39-win32.whl", hash = "sha256:41758407fc32d5c3c5de163888068cfee69cb4c2be844e7ac517a52770f9af57"}, - {file = "regex-2024.11.6-cp39-cp39-win_amd64.whl", hash = "sha256:b2837718570f95dd41675328e111345f9b7095d821bac435aac173ac80b19983"}, - {file = "regex-2024.11.6.tar.gz", hash = "sha256:7ab159b063c52a0333c884e4679f8d7a85112ee3078fe3d9004b2dd875585519"}, + {file = "regex-2025.9.18-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:12296202480c201c98a84aecc4d210592b2f55e200a1d193235c4db92b9f6788"}, + {file = "regex-2025.9.18-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:220381f1464a581f2ea988f2220cf2a67927adcef107d47d6897ba5a2f6d51a4"}, + {file = "regex-2025.9.18-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:87f681bfca84ebd265278b5daa1dcb57f4db315da3b5d044add7c30c10442e61"}, + {file = "regex-2025.9.18-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:34d674cbba70c9398074c8a1fcc1a79739d65d1105de2a3c695e2b05ea728251"}, + {file = "regex-2025.9.18-cp310-cp310-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:385c9b769655cb65ea40b6eea6ff763cbb6d69b3ffef0b0db8208e1833d4e746"}, + {file = "regex-2025.9.18-cp310-cp310-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:8900b3208e022570ae34328712bef6696de0804c122933414014bae791437ab2"}, + {file = "regex-2025.9.18-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:c204e93bf32cd7a77151d44b05eb36f469d0898e3fba141c026a26b79d9914a0"}, + {file = "regex-2025.9.18-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:3acc471d1dd7e5ff82e6cacb3b286750decd949ecd4ae258696d04f019817ef8"}, + {file = "regex-2025.9.18-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:6479d5555122433728760e5f29edb4c2b79655a8deb681a141beb5c8a025baea"}, + {file = "regex-2025.9.18-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:431bd2a8726b000eb6f12429c9b438a24062a535d06783a93d2bcbad3698f8a8"}, + {file = "regex-2025.9.18-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:0cc3521060162d02bd36927e20690129200e5ac9d2c6d32b70368870b122db25"}, + {file = "regex-2025.9.18-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:a021217b01be2d51632ce056d7a837d3fa37c543ede36e39d14063176a26ae29"}, + {file = "regex-2025.9.18-cp310-cp310-win32.whl", hash = "sha256:4a12a06c268a629cb67cc1d009b7bb0be43e289d00d5111f86a2efd3b1949444"}, + {file = "regex-2025.9.18-cp310-cp310-win_amd64.whl", hash = "sha256:47acd811589301298c49db2c56bde4f9308d6396da92daf99cba781fa74aa450"}, + {file = "regex-2025.9.18-cp310-cp310-win_arm64.whl", hash = "sha256:16bd2944e77522275e5ee36f867e19995bcaa533dcb516753a26726ac7285442"}, + {file = "regex-2025.9.18-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:51076980cd08cd13c88eb7365427ae27f0d94e7cebe9ceb2bb9ffdae8fc4d82a"}, + {file = "regex-2025.9.18-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:828446870bd7dee4e0cbeed767f07961aa07f0ea3129f38b3ccecebc9742e0b8"}, + {file = "regex-2025.9.18-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:c28821d5637866479ec4cc23b8c990f5bc6dd24e5e4384ba4a11d38a526e1414"}, + {file = "regex-2025.9.18-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:726177ade8e481db669e76bf99de0b278783be8acd11cef71165327abd1f170a"}, + {file = "regex-2025.9.18-cp311-cp311-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:f5cca697da89b9f8ea44115ce3130f6c54c22f541943ac8e9900461edc2b8bd4"}, + {file = "regex-2025.9.18-cp311-cp311-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:dfbde38f38004703c35666a1e1c088b778e35d55348da2b7b278914491698d6a"}, + {file = "regex-2025.9.18-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:f2f422214a03fab16bfa495cfec72bee4aaa5731843b771860a471282f1bf74f"}, + {file = "regex-2025.9.18-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:a295916890f4df0902e4286bc7223ee7f9e925daa6dcdec4192364255b70561a"}, + {file = "regex-2025.9.18-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:5db95ff632dbabc8c38c4e82bf545ab78d902e81160e6e455598014f0abe66b9"}, + {file = "regex-2025.9.18-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:fb967eb441b0f15ae610b7069bdb760b929f267efbf522e814bbbfffdf125ce2"}, + {file = "regex-2025.9.18-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:f04d2f20da4053d96c08f7fde6e1419b7ec9dbcee89c96e3d731fca77f411b95"}, + {file = "regex-2025.9.18-cp311-cp311-win32.whl", hash = "sha256:895197241fccf18c0cea7550c80e75f185b8bd55b6924fcae269a1a92c614a07"}, + {file = "regex-2025.9.18-cp311-cp311-win_amd64.whl", hash = "sha256:7e2b414deae99166e22c005e154a5513ac31493db178d8aec92b3269c9cce8c9"}, + {file = "regex-2025.9.18-cp311-cp311-win_arm64.whl", hash = "sha256:fb137ec7c5c54f34a25ff9b31f6b7b0c2757be80176435bf367111e3f71d72df"}, + {file = "regex-2025.9.18-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:436e1b31d7efd4dcd52091d076482031c611dde58bf9c46ca6d0a26e33053a7e"}, + {file = "regex-2025.9.18-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:c190af81e5576b9c5fdc708f781a52ff20f8b96386c6e2e0557a78402b029f4a"}, + {file = "regex-2025.9.18-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:e4121f1ce2b2b5eec4b397cc1b277686e577e658d8f5870b7eb2d726bd2300ab"}, + {file = "regex-2025.9.18-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:300e25dbbf8299d87205e821a201057f2ef9aa3deb29caa01cd2cac669e508d5"}, + {file = "regex-2025.9.18-cp312-cp312-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:7b47fcf9f5316c0bdaf449e879407e1b9937a23c3b369135ca94ebc8d74b1742"}, + {file = "regex-2025.9.18-cp312-cp312-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:57a161bd3acaa4b513220b49949b07e252165e6b6dc910ee7617a37ff4f5b425"}, + {file = "regex-2025.9.18-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:4f130c3a7845ba42de42f380fff3c8aebe89a810747d91bcf56d40a069f15352"}, + {file = "regex-2025.9.18-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:5f96fa342b6f54dcba928dd452e8d8cb9f0d63e711d1721cd765bb9f73bb048d"}, + {file = "regex-2025.9.18-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:0f0d676522d68c207828dcd01fb6f214f63f238c283d9f01d85fc664c7c85b56"}, + {file = "regex-2025.9.18-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:40532bff8a1a0621e7903ae57fce88feb2e8a9a9116d341701302c9302aef06e"}, + {file = "regex-2025.9.18-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:039f11b618ce8d71a1c364fdee37da1012f5a3e79b1b2819a9f389cd82fd6282"}, + {file = "regex-2025.9.18-cp312-cp312-win32.whl", hash = "sha256:e1dd06f981eb226edf87c55d523131ade7285137fbde837c34dc9d1bf309f459"}, + {file = "regex-2025.9.18-cp312-cp312-win_amd64.whl", hash = "sha256:3d86b5247bf25fa3715e385aa9ff272c307e0636ce0c9595f64568b41f0a9c77"}, + {file = "regex-2025.9.18-cp312-cp312-win_arm64.whl", hash = "sha256:032720248cbeeae6444c269b78cb15664458b7bb9ed02401d3da59fe4d68c3a5"}, + {file = "regex-2025.9.18-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:2a40f929cd907c7e8ac7566ac76225a77701a6221bca937bdb70d56cb61f57b2"}, + {file = "regex-2025.9.18-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:c90471671c2cdf914e58b6af62420ea9ecd06d1554d7474d50133ff26ae88feb"}, + {file = "regex-2025.9.18-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:1a351aff9e07a2dabb5022ead6380cff17a4f10e4feb15f9100ee56c4d6d06af"}, + {file = "regex-2025.9.18-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:bc4b8e9d16e20ddfe16430c23468a8707ccad3365b06d4536142e71823f3ca29"}, + {file = "regex-2025.9.18-cp313-cp313-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:4b8cdbddf2db1c5e80338ba2daa3cfa3dec73a46fff2a7dda087c8efbf12d62f"}, + {file = "regex-2025.9.18-cp313-cp313-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:a276937d9d75085b2c91fb48244349c6954f05ee97bba0963ce24a9d915b8b68"}, + {file = "regex-2025.9.18-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:92a8e375ccdc1256401c90e9dc02b8642894443d549ff5e25e36d7cf8a80c783"}, + {file = "regex-2025.9.18-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:0dc6893b1f502d73037cf807a321cdc9be29ef3d6219f7970f842475873712ac"}, + {file = "regex-2025.9.18-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:a61e85bfc63d232ac14b015af1261f826260c8deb19401c0597dbb87a864361e"}, + {file = "regex-2025.9.18-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:1ef86a9ebc53f379d921fb9a7e42b92059ad3ee800fcd9e0fe6181090e9f6c23"}, + {file = "regex-2025.9.18-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:d3bc882119764ba3a119fbf2bd4f1b47bc56c1da5d42df4ed54ae1e8e66fdf8f"}, + {file = "regex-2025.9.18-cp313-cp313-win32.whl", hash = "sha256:3810a65675845c3bdfa58c3c7d88624356dd6ee2fc186628295e0969005f928d"}, + {file = "regex-2025.9.18-cp313-cp313-win_amd64.whl", hash = "sha256:16eaf74b3c4180ede88f620f299e474913ab6924d5c4b89b3833bc2345d83b3d"}, + {file = "regex-2025.9.18-cp313-cp313-win_arm64.whl", hash = "sha256:4dc98ba7dd66bd1261927a9f49bd5ee2bcb3660f7962f1ec02617280fc00f5eb"}, + {file = "regex-2025.9.18-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:fe5d50572bc885a0a799410a717c42b1a6b50e2f45872e2b40f4f288f9bce8a2"}, + {file = "regex-2025.9.18-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:1b9d9a2d6cda6621551ca8cf7a06f103adf72831153f3c0d982386110870c4d3"}, + {file = "regex-2025.9.18-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:13202e4c4ac0ef9a317fff817674b293c8f7e8c68d3190377d8d8b749f566e12"}, + {file = "regex-2025.9.18-cp313-cp313t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:874ff523b0fecffb090f80ae53dc93538f8db954c8bb5505f05b7787ab3402a0"}, + {file = "regex-2025.9.18-cp313-cp313t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:d13ab0490128f2bb45d596f754148cd750411afc97e813e4b3a61cf278a23bb6"}, + {file = "regex-2025.9.18-cp313-cp313t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:05440bc172bc4b4b37fb9667e796597419404dbba62e171e1f826d7d2a9ebcef"}, + {file = "regex-2025.9.18-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:5514b8e4031fdfaa3d27e92c75719cbe7f379e28cacd939807289bce76d0e35a"}, + {file = "regex-2025.9.18-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:65d3c38c39efce73e0d9dc019697b39903ba25b1ad45ebbd730d2cf32741f40d"}, + {file = "regex-2025.9.18-cp313-cp313t-musllinux_1_2_ppc64le.whl", hash = "sha256:ae77e447ebc144d5a26d50055c6ddba1d6ad4a865a560ec7200b8b06bc529368"}, + {file = "regex-2025.9.18-cp313-cp313t-musllinux_1_2_s390x.whl", hash = "sha256:e3ef8cf53dc8df49d7e28a356cf824e3623764e9833348b655cfed4524ab8a90"}, + {file = "regex-2025.9.18-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:9feb29817df349c976da9a0debf775c5c33fc1c8ad7b9f025825da99374770b7"}, + {file = "regex-2025.9.18-cp313-cp313t-win32.whl", hash = "sha256:168be0d2f9b9d13076940b1ed774f98595b4e3c7fc54584bba81b3cc4181742e"}, + {file = "regex-2025.9.18-cp313-cp313t-win_amd64.whl", hash = "sha256:d59ecf3bb549e491c8104fea7313f3563c7b048e01287db0a90485734a70a730"}, + {file = "regex-2025.9.18-cp313-cp313t-win_arm64.whl", hash = "sha256:dbef80defe9fb21310948a2595420b36c6d641d9bea4c991175829b2cc4bc06a"}, + {file = "regex-2025.9.18-cp314-cp314-macosx_10_13_universal2.whl", hash = "sha256:c6db75b51acf277997f3adcd0ad89045d856190d13359f15ab5dda21581d9129"}, + {file = "regex-2025.9.18-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:8f9698b6f6895d6db810e0bda5364f9ceb9e5b11328700a90cae573574f61eea"}, + {file = "regex-2025.9.18-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:29cd86aa7cb13a37d0f0d7c21d8d949fe402ffa0ea697e635afedd97ab4b69f1"}, + {file = "regex-2025.9.18-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:7c9f285a071ee55cd9583ba24dde006e53e17780bb309baa8e4289cd472bcc47"}, + {file = "regex-2025.9.18-cp314-cp314-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:5adf266f730431e3be9021d3e5b8d5ee65e563fec2883ea8093944d21863b379"}, + {file = "regex-2025.9.18-cp314-cp314-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:1137cabc0f38807de79e28d3f6e3e3f2cc8cfb26bead754d02e6d1de5f679203"}, + {file = "regex-2025.9.18-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:7cc9e5525cada99699ca9223cce2d52e88c52a3d2a0e842bd53de5497c604164"}, + {file = "regex-2025.9.18-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:bbb9246568f72dce29bcd433517c2be22c7791784b223a810225af3b50d1aafb"}, + {file = "regex-2025.9.18-cp314-cp314-musllinux_1_2_ppc64le.whl", hash = "sha256:6a52219a93dd3d92c675383efff6ae18c982e2d7651c792b1e6d121055808743"}, + {file = "regex-2025.9.18-cp314-cp314-musllinux_1_2_s390x.whl", hash = "sha256:ae9b3840c5bd456780e3ddf2f737ab55a79b790f6409182012718a35c6d43282"}, + {file = "regex-2025.9.18-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:d488c236ac497c46a5ac2005a952c1a0e22a07be9f10c3e735bc7d1209a34773"}, + {file = "regex-2025.9.18-cp314-cp314-win32.whl", hash = "sha256:0c3506682ea19beefe627a38872d8da65cc01ffa25ed3f2e422dffa1474f0788"}, + {file = "regex-2025.9.18-cp314-cp314-win_amd64.whl", hash = "sha256:57929d0f92bebb2d1a83af372cd0ffba2263f13f376e19b1e4fa32aec4efddc3"}, + {file = "regex-2025.9.18-cp314-cp314-win_arm64.whl", hash = "sha256:6a4b44df31d34fa51aa5c995d3aa3c999cec4d69b9bd414a8be51984d859f06d"}, + {file = "regex-2025.9.18-cp314-cp314t-macosx_10_13_universal2.whl", hash = "sha256:b176326bcd544b5e9b17d6943f807697c0cb7351f6cfb45bf5637c95ff7e6306"}, + {file = "regex-2025.9.18-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:0ffd9e230b826b15b369391bec167baed57c7ce39efc35835448618860995946"}, + {file = "regex-2025.9.18-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:ec46332c41add73f2b57e2f5b642f991f6b15e50e9f86285e08ffe3a512ac39f"}, + {file = "regex-2025.9.18-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b80fa342ed1ea095168a3f116637bd1030d39c9ff38dc04e54ef7c521e01fc95"}, + {file = "regex-2025.9.18-cp314-cp314t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:f4d97071c0ba40f0cf2a93ed76e660654c399a0a04ab7d85472239460f3da84b"}, + {file = "regex-2025.9.18-cp314-cp314t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:0ac936537ad87cef9e0e66c5144484206c1354224ee811ab1519a32373e411f3"}, + {file = "regex-2025.9.18-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:dec57f96d4def58c422d212d414efe28218d58537b5445cf0c33afb1b4768571"}, + {file = "regex-2025.9.18-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:48317233294648bf7cd068857f248e3a57222259a5304d32c7552e2284a1b2ad"}, + {file = "regex-2025.9.18-cp314-cp314t-musllinux_1_2_ppc64le.whl", hash = "sha256:274687e62ea3cf54846a9b25fc48a04459de50af30a7bd0b61a9e38015983494"}, + {file = "regex-2025.9.18-cp314-cp314t-musllinux_1_2_s390x.whl", hash = "sha256:a78722c86a3e7e6aadf9579e3b0ad78d955f2d1f1a8ca4f67d7ca258e8719d4b"}, + {file = "regex-2025.9.18-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:06104cd203cdef3ade989a1c45b6215bf42f8b9dd705ecc220c173233f7cba41"}, + {file = "regex-2025.9.18-cp314-cp314t-win32.whl", hash = "sha256:2e1eddc06eeaffd249c0adb6fafc19e2118e6308c60df9db27919e96b5656096"}, + {file = "regex-2025.9.18-cp314-cp314t-win_amd64.whl", hash = "sha256:8620d247fb8c0683ade51217b459cb4a1081c0405a3072235ba43a40d355c09a"}, + {file = "regex-2025.9.18-cp314-cp314t-win_arm64.whl", hash = "sha256:b7531a8ef61de2c647cdf68b3229b071e46ec326b3138b2180acb4275f470b01"}, + {file = "regex-2025.9.18-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:3dbcfcaa18e9480669030d07371713c10b4f1a41f791ffa5cb1a99f24e777f40"}, + {file = "regex-2025.9.18-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:1e85f73ef7095f0380208269055ae20524bfde3f27c5384126ddccf20382a638"}, + {file = "regex-2025.9.18-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:9098e29b3ea4ffffeade423f6779665e2a4f8db64e699c0ed737ef0db6ba7b12"}, + {file = "regex-2025.9.18-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:90b6b7a2d0f45b7ecaaee1aec6b362184d6596ba2092dd583ffba1b78dd0231c"}, + {file = "regex-2025.9.18-cp39-cp39-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:c81b892af4a38286101502eae7aec69f7cd749a893d9987a92776954f3943408"}, + {file = "regex-2025.9.18-cp39-cp39-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:3b524d010973f2e1929aeb635418d468d869a5f77b52084d9f74c272189c251d"}, + {file = "regex-2025.9.18-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:6b498437c026a3d5d0be0020023ff76d70ae4d77118e92f6f26c9d0423452446"}, + {file = "regex-2025.9.18-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:0716e4d6e58853d83f6563f3cf25c281ff46cf7107e5f11879e32cb0b59797d9"}, + {file = "regex-2025.9.18-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:065b6956749379d41db2625f880b637d4acc14c0a4de0d25d609a62850e96d36"}, + {file = "regex-2025.9.18-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:d4a691494439287c08ddb9b5793da605ee80299dd31e95fa3f323fac3c33d9d4"}, + {file = "regex-2025.9.18-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:ef8d10cc0989565bcbe45fb4439f044594d5c2b8919d3d229ea2c4238f1d55b0"}, + {file = "regex-2025.9.18-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:4baeb1b16735ac969a7eeecc216f1f8b7caf60431f38a2671ae601f716a32d25"}, + {file = "regex-2025.9.18-cp39-cp39-win32.whl", hash = "sha256:8e5f41ad24a1e0b5dfcf4c4e5d9f5bd54c895feb5708dd0c1d0d35693b24d478"}, + {file = "regex-2025.9.18-cp39-cp39-win_amd64.whl", hash = "sha256:50e8290707f2fb8e314ab3831e594da71e062f1d623b05266f8cfe4db4949afd"}, + {file = "regex-2025.9.18-cp39-cp39-win_arm64.whl", hash = "sha256:039a9d7195fd88c943d7c777d4941e8ef736731947becce773c31a1009cb3c35"}, + {file = "regex-2025.9.18.tar.gz", hash = "sha256:c5ba23274c61c6fef447ba6a39333297d0c247f53059dba0bca415cac511edc4"}, ] [[package]] name = "requests" -version = "2.32.4" +version = "2.32.5" description = "Python HTTP for Humans." optional = false -python-versions = ">=3.8" +python-versions = ">=3.9" groups = ["main", "docs"] files = [ - {file = "requests-2.32.4-py3-none-any.whl", hash = "sha256:27babd3cda2a6d50b30443204ee89830707d396671944c998b5975b031ac2b2c"}, - {file = "requests-2.32.4.tar.gz", hash = "sha256:27d0316682c8a29834d3264820024b62a36942083d52caf2f14c0591336d3422"}, + {file = "requests-2.32.5-py3-none-any.whl", hash = "sha256:2462f94637a34fd532264295e186976db0f5d453d1cdd31473c85a6a161affb6"}, + {file = "requests-2.32.5.tar.gz", hash = "sha256:dbba0bac56e100853db0ea71b82b4dfd5fe2bf6d3754a8893c3af500cec7d7cf"}, ] [package.dependencies] @@ -6694,14 +7151,14 @@ files = [ [[package]] name = "rich" -version = "14.0.0" +version = "14.2.0" description = "Render rich text, tables, progress bars, syntax highlighting, markdown and more to the terminal" optional = false python-versions = ">=3.8.0" groups = ["main"] files = [ - {file = "rich-14.0.0-py3-none-any.whl", hash = "sha256:1c9491e1951aac09caffd42f448ee3d04e58923ffe14993f6e83068dc395d7e0"}, - {file = "rich-14.0.0.tar.gz", hash = "sha256:82f1bc23a6a21ebca4ae0c45af9bdbc492ed20231dcb63f297d6d1021a9d5725"}, + {file = "rich-14.2.0-py3-none-any.whl", hash = "sha256:76bc51fe2e57d2b1be1f96c524b890b816e334ab4c1e45888799bfaab0021edd"}, + {file = "rich-14.2.0.tar.gz", hash = "sha256:73ff50c7c0c1c77c8243079283f4edb376f0f6442433aecb8ce7e6d0b92d1fe4"}, ] [package.dependencies] @@ -6729,156 +7186,167 @@ test = ["pytest (>=8)"] [[package]] name = "rpds-py" -version = "0.26.0" +version = "0.27.1" description = "Python bindings to Rust's persistent data structures (rpds)" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "rpds_py-0.26.0-cp310-cp310-macosx_10_12_x86_64.whl", hash = "sha256:4c70c70f9169692b36307a95f3d8c0a9fcd79f7b4a383aad5eaa0e9718b79b37"}, - {file = "rpds_py-0.26.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:777c62479d12395bfb932944e61e915741e364c843afc3196b694db3d669fcd0"}, - {file = "rpds_py-0.26.0-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:ec671691e72dff75817386aa02d81e708b5a7ec0dec6669ec05213ff6b77e1bd"}, - {file = "rpds_py-0.26.0-cp310-cp310-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:6a1cb5d6ce81379401bbb7f6dbe3d56de537fb8235979843f0d53bc2e9815a79"}, - {file = "rpds_py-0.26.0-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:4f789e32fa1fb6a7bf890e0124e7b42d1e60d28ebff57fe806719abb75f0e9a3"}, - {file = "rpds_py-0.26.0-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:9c55b0a669976cf258afd718de3d9ad1b7d1fe0a91cd1ab36f38b03d4d4aeaaf"}, - {file = "rpds_py-0.26.0-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:c70d9ec912802ecfd6cd390dadb34a9578b04f9bcb8e863d0a7598ba5e9e7ccc"}, - {file = "rpds_py-0.26.0-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:3021933c2cb7def39d927b9862292e0f4c75a13d7de70eb0ab06efed4c508c19"}, - {file = "rpds_py-0.26.0-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:8a7898b6ca3b7d6659e55cdac825a2e58c638cbf335cde41f4619e290dd0ad11"}, - {file = "rpds_py-0.26.0-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:12bff2ad9447188377f1b2794772f91fe68bb4bbfa5a39d7941fbebdbf8c500f"}, - {file = "rpds_py-0.26.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:191aa858f7d4902e975d4cf2f2d9243816c91e9605070aeb09c0a800d187e323"}, - {file = "rpds_py-0.26.0-cp310-cp310-win32.whl", hash = "sha256:b37a04d9f52cb76b6b78f35109b513f6519efb481d8ca4c321f6a3b9580b3f45"}, - {file = "rpds_py-0.26.0-cp310-cp310-win_amd64.whl", hash = "sha256:38721d4c9edd3eb6670437d8d5e2070063f305bfa2d5aa4278c51cedcd508a84"}, - {file = "rpds_py-0.26.0-cp311-cp311-macosx_10_12_x86_64.whl", hash = "sha256:9e8cb77286025bdb21be2941d64ac6ca016130bfdcd228739e8ab137eb4406ed"}, - {file = "rpds_py-0.26.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:5e09330b21d98adc8ccb2dbb9fc6cb434e8908d4c119aeaa772cb1caab5440a0"}, - {file = "rpds_py-0.26.0-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:2c9c1b92b774b2e68d11193dc39620d62fd8ab33f0a3c77ecdabe19c179cdbc1"}, - {file = "rpds_py-0.26.0-cp311-cp311-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:824e6d3503ab990d7090768e4dfd9e840837bae057f212ff9f4f05ec6d1975e7"}, - {file = "rpds_py-0.26.0-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:8ad7fd2258228bf288f2331f0a6148ad0186b2e3643055ed0db30990e59817a6"}, - {file = "rpds_py-0.26.0-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:0dc23bbb3e06ec1ea72d515fb572c1fea59695aefbffb106501138762e1e915e"}, - {file = "rpds_py-0.26.0-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:d80bf832ac7b1920ee29a426cdca335f96a2b5caa839811803e999b41ba9030d"}, - {file = "rpds_py-0.26.0-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:0919f38f5542c0a87e7b4afcafab6fd2c15386632d249e9a087498571250abe3"}, - {file = "rpds_py-0.26.0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:d422b945683e409000c888e384546dbab9009bb92f7c0b456e217988cf316107"}, - {file = "rpds_py-0.26.0-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:77a7711fa562ba2da1aa757e11024ad6d93bad6ad7ede5afb9af144623e5f76a"}, - {file = "rpds_py-0.26.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:238e8c8610cb7c29460e37184f6799547f7e09e6a9bdbdab4e8edb90986a2318"}, - {file = "rpds_py-0.26.0-cp311-cp311-win32.whl", hash = "sha256:893b022bfbdf26d7bedb083efeea624e8550ca6eb98bf7fea30211ce95b9201a"}, - {file = "rpds_py-0.26.0-cp311-cp311-win_amd64.whl", hash = "sha256:87a5531de9f71aceb8af041d72fc4cab4943648d91875ed56d2e629bef6d4c03"}, - {file = "rpds_py-0.26.0-cp311-cp311-win_arm64.whl", hash = "sha256:de2713f48c1ad57f89ac25b3cb7daed2156d8e822cf0eca9b96a6f990718cc41"}, - {file = "rpds_py-0.26.0-cp312-cp312-macosx_10_12_x86_64.whl", hash = "sha256:894514d47e012e794f1350f076c427d2347ebf82f9b958d554d12819849a369d"}, - {file = "rpds_py-0.26.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:fc921b96fa95a097add244da36a1d9e4f3039160d1d30f1b35837bf108c21136"}, - {file = "rpds_py-0.26.0-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:3e1157659470aa42a75448b6e943c895be8c70531c43cb78b9ba990778955582"}, - {file = "rpds_py-0.26.0-cp312-cp312-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:521ccf56f45bb3a791182dc6b88ae5f8fa079dd705ee42138c76deb1238e554e"}, - {file = "rpds_py-0.26.0-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:9def736773fd56b305c0eef698be5192c77bfa30d55a0e5885f80126c4831a15"}, - {file = "rpds_py-0.26.0-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:cdad4ea3b4513b475e027be79e5a0ceac8ee1c113a1a11e5edc3c30c29f964d8"}, - {file = "rpds_py-0.26.0-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:82b165b07f416bdccf5c84546a484cc8f15137ca38325403864bfdf2b5b72f6a"}, - {file = "rpds_py-0.26.0-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:d04cab0a54b9dba4d278fe955a1390da3cf71f57feb78ddc7cb67cbe0bd30323"}, - {file = "rpds_py-0.26.0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:79061ba1a11b6a12743a2b0f72a46aa2758613d454aa6ba4f5a265cc48850158"}, - {file = "rpds_py-0.26.0-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:f405c93675d8d4c5ac87364bb38d06c988e11028a64b52a47158a355079661f3"}, - {file = "rpds_py-0.26.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:dafd4c44b74aa4bed4b250f1aed165b8ef5de743bcca3b88fc9619b6087093d2"}, - {file = "rpds_py-0.26.0-cp312-cp312-win32.whl", hash = "sha256:3da5852aad63fa0c6f836f3359647870e21ea96cf433eb393ffa45263a170d44"}, - {file = "rpds_py-0.26.0-cp312-cp312-win_amd64.whl", hash = "sha256:cf47cfdabc2194a669dcf7a8dbba62e37a04c5041d2125fae0233b720da6f05c"}, - {file = "rpds_py-0.26.0-cp312-cp312-win_arm64.whl", hash = "sha256:20ab1ae4fa534f73647aad289003f1104092890849e0266271351922ed5574f8"}, - {file = "rpds_py-0.26.0-cp313-cp313-macosx_10_12_x86_64.whl", hash = "sha256:696764a5be111b036256c0b18cd29783fab22154690fc698062fc1b0084b511d"}, - {file = "rpds_py-0.26.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:1e6c15d2080a63aaed876e228efe4f814bc7889c63b1e112ad46fdc8b368b9e1"}, - {file = "rpds_py-0.26.0-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:390e3170babf42462739a93321e657444f0862c6d722a291accc46f9d21ed04e"}, - {file = "rpds_py-0.26.0-cp313-cp313-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:7da84c2c74c0f5bc97d853d9e17bb83e2dcafcff0dc48286916001cc114379a1"}, - {file = "rpds_py-0.26.0-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:4c5fe114a6dd480a510b6d3661d09d67d1622c4bf20660a474507aaee7eeeee9"}, - {file = "rpds_py-0.26.0-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:3100b3090269f3a7ea727b06a6080d4eb7439dca4c0e91a07c5d133bb1727ea7"}, - {file = "rpds_py-0.26.0-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:2c03c9b0c64afd0320ae57de4c982801271c0c211aa2d37f3003ff5feb75bb04"}, - {file = "rpds_py-0.26.0-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:5963b72ccd199ade6ee493723d18a3f21ba7d5b957017607f815788cef50eaf1"}, - {file = "rpds_py-0.26.0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:9da4e873860ad5bab3291438525cae80169daecbfafe5657f7f5fb4d6b3f96b9"}, - {file = "rpds_py-0.26.0-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:5afaddaa8e8c7f1f7b4c5c725c0070b6eed0228f705b90a1732a48e84350f4e9"}, - {file = "rpds_py-0.26.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:4916dc96489616a6f9667e7526af8fa693c0fdb4f3acb0e5d9f4400eb06a47ba"}, - {file = "rpds_py-0.26.0-cp313-cp313-win32.whl", hash = "sha256:2a343f91b17097c546b93f7999976fd6c9d5900617aa848c81d794e062ab302b"}, - {file = "rpds_py-0.26.0-cp313-cp313-win_amd64.whl", hash = "sha256:0a0b60701f2300c81b2ac88a5fb893ccfa408e1c4a555a77f908a2596eb875a5"}, - {file = "rpds_py-0.26.0-cp313-cp313-win_arm64.whl", hash = "sha256:257d011919f133a4746958257f2c75238e3ff54255acd5e3e11f3ff41fd14256"}, - {file = "rpds_py-0.26.0-cp313-cp313t-macosx_10_12_x86_64.whl", hash = "sha256:529c8156d7506fba5740e05da8795688f87119cce330c244519cf706a4a3d618"}, - {file = "rpds_py-0.26.0-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:f53ec51f9d24e9638a40cabb95078ade8c99251945dad8d57bf4aabe86ecee35"}, - {file = "rpds_py-0.26.0-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:7ab504c4d654e4a29558eaa5bb8cea5fdc1703ea60a8099ffd9c758472cf913f"}, - {file = "rpds_py-0.26.0-cp313-cp313t-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:fd0641abca296bc1a00183fe44f7fced8807ed49d501f188faa642d0e4975b83"}, - {file = "rpds_py-0.26.0-cp313-cp313t-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:69b312fecc1d017b5327afa81d4da1480f51c68810963a7336d92203dbb3d4f1"}, - {file = "rpds_py-0.26.0-cp313-cp313t-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:c741107203954f6fc34d3066d213d0a0c40f7bb5aafd698fb39888af277c70d8"}, - {file = "rpds_py-0.26.0-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:fc3e55a7db08dc9a6ed5fb7103019d2c1a38a349ac41901f9f66d7f95750942f"}, - {file = "rpds_py-0.26.0-cp313-cp313t-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:9e851920caab2dbcae311fd28f4313c6953993893eb5c1bb367ec69d9a39e7ed"}, - {file = "rpds_py-0.26.0-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:dfbf280da5f876d0b00c81f26bedce274e72a678c28845453885a9b3c22ae632"}, - {file = "rpds_py-0.26.0-cp313-cp313t-musllinux_1_2_i686.whl", hash = "sha256:1cc81d14ddfa53d7f3906694d35d54d9d3f850ef8e4e99ee68bc0d1e5fed9a9c"}, - {file = "rpds_py-0.26.0-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:dca83c498b4650a91efcf7b88d669b170256bf8017a5db6f3e06c2bf031f57e0"}, - {file = "rpds_py-0.26.0-cp313-cp313t-win32.whl", hash = "sha256:4d11382bcaf12f80b51d790dee295c56a159633a8e81e6323b16e55d81ae37e9"}, - {file = "rpds_py-0.26.0-cp313-cp313t-win_amd64.whl", hash = "sha256:ff110acded3c22c033e637dd8896e411c7d3a11289b2edf041f86663dbc791e9"}, - {file = "rpds_py-0.26.0-cp314-cp314-macosx_10_12_x86_64.whl", hash = "sha256:da619979df60a940cd434084355c514c25cf8eb4cf9a508510682f6c851a4f7a"}, - {file = "rpds_py-0.26.0-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:ea89a2458a1a75f87caabefe789c87539ea4e43b40f18cff526052e35bbb4fdf"}, - {file = "rpds_py-0.26.0-cp314-cp314-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:feac1045b3327a45944e7dcbeb57530339f6b17baff154df51ef8b0da34c8c12"}, - {file = "rpds_py-0.26.0-cp314-cp314-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:b818a592bd69bfe437ee8368603d4a2d928c34cffcdf77c2e761a759ffd17d20"}, - {file = "rpds_py-0.26.0-cp314-cp314-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:1a8b0dd8648709b62d9372fc00a57466f5fdeefed666afe3fea5a6c9539a0331"}, - {file = "rpds_py-0.26.0-cp314-cp314-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:6d3498ad0df07d81112aa6ec6c95a7e7b1ae00929fb73e7ebee0f3faaeabad2f"}, - {file = "rpds_py-0.26.0-cp314-cp314-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:24a4146ccb15be237fdef10f331c568e1b0e505f8c8c9ed5d67759dac58ac246"}, - {file = "rpds_py-0.26.0-cp314-cp314-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:a9a63785467b2d73635957d32a4f6e73d5e4df497a16a6392fa066b753e87387"}, - {file = "rpds_py-0.26.0-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:de4ed93a8c91debfd5a047be327b7cc8b0cc6afe32a716bbbc4aedca9e2a83af"}, - {file = "rpds_py-0.26.0-cp314-cp314-musllinux_1_2_i686.whl", hash = "sha256:caf51943715b12af827696ec395bfa68f090a4c1a1d2509eb4e2cb69abbbdb33"}, - {file = "rpds_py-0.26.0-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:4a59e5bc386de021f56337f757301b337d7ab58baa40174fb150accd480bc953"}, - {file = "rpds_py-0.26.0-cp314-cp314-win32.whl", hash = "sha256:92c8db839367ef16a662478f0a2fe13e15f2227da3c1430a782ad0f6ee009ec9"}, - {file = "rpds_py-0.26.0-cp314-cp314-win_amd64.whl", hash = "sha256:b0afb8cdd034150d4d9f53926226ed27ad15b7f465e93d7468caaf5eafae0d37"}, - {file = "rpds_py-0.26.0-cp314-cp314-win_arm64.whl", hash = "sha256:ca3f059f4ba485d90c8dc75cb5ca897e15325e4e609812ce57f896607c1c0867"}, - {file = "rpds_py-0.26.0-cp314-cp314t-macosx_10_12_x86_64.whl", hash = "sha256:5afea17ab3a126006dc2f293b14ffc7ef3c85336cf451564a0515ed7648033da"}, - {file = "rpds_py-0.26.0-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:69f0c0a3df7fd3a7eec50a00396104bb9a843ea6d45fcc31c2d5243446ffd7a7"}, - {file = "rpds_py-0.26.0-cp314-cp314t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:801a71f70f9813e82d2513c9a96532551fce1e278ec0c64610992c49c04c2dad"}, - {file = "rpds_py-0.26.0-cp314-cp314t-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:df52098cde6d5e02fa75c1f6244f07971773adb4a26625edd5c18fee906fa84d"}, - {file = "rpds_py-0.26.0-cp314-cp314t-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:9bc596b30f86dc6f0929499c9e574601679d0341a0108c25b9b358a042f51bca"}, - {file = "rpds_py-0.26.0-cp314-cp314t-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:9dfbe56b299cf5875b68eb6f0ebaadc9cac520a1989cac0db0765abfb3709c19"}, - {file = "rpds_py-0.26.0-cp314-cp314t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:ac64f4b2bdb4ea622175c9ab7cf09444e412e22c0e02e906978b3b488af5fde8"}, - {file = "rpds_py-0.26.0-cp314-cp314t-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:181ef9b6bbf9845a264f9aa45c31836e9f3c1f13be565d0d010e964c661d1e2b"}, - {file = "rpds_py-0.26.0-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:49028aa684c144ea502a8e847d23aed5e4c2ef7cadfa7d5eaafcb40864844b7a"}, - {file = "rpds_py-0.26.0-cp314-cp314t-musllinux_1_2_i686.whl", hash = "sha256:e5d524d68a474a9688336045bbf76cb0def88549c1b2ad9dbfec1fb7cfbe9170"}, - {file = "rpds_py-0.26.0-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:c1851f429b822831bd2edcbe0cfd12ee9ea77868f8d3daf267b189371671c80e"}, - {file = "rpds_py-0.26.0-cp314-cp314t-win32.whl", hash = "sha256:7bdb17009696214c3b66bb3590c6d62e14ac5935e53e929bcdbc5a495987a84f"}, - {file = "rpds_py-0.26.0-cp314-cp314t-win_amd64.whl", hash = "sha256:f14440b9573a6f76b4ee4770c13f0b5921f71dde3b6fcb8dabbefd13b7fe05d7"}, - {file = "rpds_py-0.26.0-cp39-cp39-macosx_10_12_x86_64.whl", hash = "sha256:7a48af25d9b3c15684059d0d1fc0bc30e8eee5ca521030e2bffddcab5be40226"}, - {file = "rpds_py-0.26.0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:0c71c2f6bf36e61ee5c47b2b9b5d47e4d1baad6426bfed9eea3e858fc6ee8806"}, - {file = "rpds_py-0.26.0-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:1d815d48b1804ed7867b539236b6dd62997850ca1c91cad187f2ddb1b7bbef19"}, - {file = "rpds_py-0.26.0-cp39-cp39-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:84cfbd4d4d2cdeb2be61a057a258d26b22877266dd905809e94172dff01a42ae"}, - {file = "rpds_py-0.26.0-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:fbaa70553ca116c77717f513e08815aec458e6b69a028d4028d403b3bc84ff37"}, - {file = "rpds_py-0.26.0-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:39bfea47c375f379d8e87ab4bb9eb2c836e4f2069f0f65731d85e55d74666387"}, - {file = "rpds_py-0.26.0-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:1533b7eb683fb5f38c1d68a3c78f5fdd8f1412fa6b9bf03b40f450785a0ab915"}, - {file = "rpds_py-0.26.0-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:c5ab0ee51f560d179b057555b4f601b7df909ed31312d301b99f8b9fc6028284"}, - {file = "rpds_py-0.26.0-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:e5162afc9e0d1f9cae3b577d9c29ddbab3505ab39012cb794d94a005825bde21"}, - {file = "rpds_py-0.26.0-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:43f10b007033f359bc3fa9cd5e6c1e76723f056ffa9a6b5c117cc35720a80292"}, - {file = "rpds_py-0.26.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:e3730a48e5622e598293eee0762b09cff34dd3f271530f47b0894891281f051d"}, - {file = "rpds_py-0.26.0-cp39-cp39-win32.whl", hash = "sha256:4b1f66eb81eab2e0ff5775a3a312e5e2e16bf758f7b06be82fb0d04078c7ac51"}, - {file = "rpds_py-0.26.0-cp39-cp39-win_amd64.whl", hash = "sha256:519067e29f67b5c90e64fb1a6b6e9d2ec0ba28705c51956637bac23a2f4ddae1"}, - {file = "rpds_py-0.26.0-pp310-pypy310_pp73-macosx_10_12_x86_64.whl", hash = "sha256:3c0909c5234543ada2515c05dc08595b08d621ba919629e94427e8e03539c958"}, - {file = "rpds_py-0.26.0-pp310-pypy310_pp73-macosx_11_0_arm64.whl", hash = "sha256:c1fb0cda2abcc0ac62f64e2ea4b4e64c57dfd6b885e693095460c61bde7bb18e"}, - {file = "rpds_py-0.26.0-pp310-pypy310_pp73-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:84d142d2d6cf9b31c12aa4878d82ed3b2324226270b89b676ac62ccd7df52d08"}, - {file = "rpds_py-0.26.0-pp310-pypy310_pp73-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:a547e21c5610b7e9093d870be50682a6a6cf180d6da0f42c47c306073bfdbbf6"}, - {file = "rpds_py-0.26.0-pp310-pypy310_pp73-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:35e9a70a0f335371275cdcd08bc5b8051ac494dd58bff3bbfb421038220dc871"}, - {file = "rpds_py-0.26.0-pp310-pypy310_pp73-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:0dfa6115c6def37905344d56fb54c03afc49104e2ca473d5dedec0f6606913b4"}, - {file = "rpds_py-0.26.0-pp310-pypy310_pp73-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:313cfcd6af1a55a286a3c9a25f64af6d0e46cf60bc5798f1db152d97a216ff6f"}, - {file = "rpds_py-0.26.0-pp310-pypy310_pp73-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:f7bf2496fa563c046d05e4d232d7b7fd61346e2402052064b773e5c378bf6f73"}, - {file = "rpds_py-0.26.0-pp310-pypy310_pp73-musllinux_1_2_aarch64.whl", hash = "sha256:aa81873e2c8c5aa616ab8e017a481a96742fdf9313c40f14338ca7dbf50cb55f"}, - {file = "rpds_py-0.26.0-pp310-pypy310_pp73-musllinux_1_2_i686.whl", hash = "sha256:68ffcf982715f5b5b7686bdd349ff75d422e8f22551000c24b30eaa1b7f7ae84"}, - {file = "rpds_py-0.26.0-pp310-pypy310_pp73-musllinux_1_2_x86_64.whl", hash = "sha256:6188de70e190847bb6db3dc3981cbadff87d27d6fe9b4f0e18726d55795cee9b"}, - {file = "rpds_py-0.26.0-pp310-pypy310_pp73-win_amd64.whl", hash = "sha256:1c962145c7473723df9722ba4c058de12eb5ebedcb4e27e7d902920aa3831ee8"}, - {file = "rpds_py-0.26.0-pp311-pypy311_pp73-macosx_10_12_x86_64.whl", hash = "sha256:f61a9326f80ca59214d1cceb0a09bb2ece5b2563d4e0cd37bfd5515c28510674"}, - {file = "rpds_py-0.26.0-pp311-pypy311_pp73-macosx_11_0_arm64.whl", hash = "sha256:183f857a53bcf4b1b42ef0f57ca553ab56bdd170e49d8091e96c51c3d69ca696"}, - {file = "rpds_py-0.26.0-pp311-pypy311_pp73-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:941c1cfdf4799d623cf3aa1d326a6b4fdb7a5799ee2687f3516738216d2262fb"}, - {file = "rpds_py-0.26.0-pp311-pypy311_pp73-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:72a8d9564a717ee291f554eeb4bfeafe2309d5ec0aa6c475170bdab0f9ee8e88"}, - {file = "rpds_py-0.26.0-pp311-pypy311_pp73-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:511d15193cbe013619dd05414c35a7dedf2088fcee93c6bbb7c77859765bd4e8"}, - {file = "rpds_py-0.26.0-pp311-pypy311_pp73-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:aea1f9741b603a8d8fedb0ed5502c2bc0accbc51f43e2ad1337fe7259c2b77a5"}, - {file = "rpds_py-0.26.0-pp311-pypy311_pp73-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:4019a9d473c708cf2f16415688ef0b4639e07abaa569d72f74745bbeffafa2c7"}, - {file = "rpds_py-0.26.0-pp311-pypy311_pp73-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:093d63b4b0f52d98ebae33b8c50900d3d67e0666094b1be7a12fffd7f65de74b"}, - {file = "rpds_py-0.26.0-pp311-pypy311_pp73-musllinux_1_2_aarch64.whl", hash = "sha256:2abe21d8ba64cded53a2a677e149ceb76dcf44284202d737178afe7ba540c1eb"}, - {file = "rpds_py-0.26.0-pp311-pypy311_pp73-musllinux_1_2_i686.whl", hash = "sha256:4feb7511c29f8442cbbc28149a92093d32e815a28aa2c50d333826ad2a20fdf0"}, - {file = "rpds_py-0.26.0-pp311-pypy311_pp73-musllinux_1_2_x86_64.whl", hash = "sha256:e99685fc95d386da368013e7fb4269dd39c30d99f812a8372d62f244f662709c"}, - {file = "rpds_py-0.26.0-pp39-pypy39_pp73-macosx_10_12_x86_64.whl", hash = "sha256:a90a13408a7a856b87be8a9f008fff53c5080eea4e4180f6c2e546e4a972fb5d"}, - {file = "rpds_py-0.26.0-pp39-pypy39_pp73-macosx_11_0_arm64.whl", hash = "sha256:3ac51b65e8dc76cf4949419c54c5528adb24fc721df722fd452e5fbc236f5c40"}, - {file = "rpds_py-0.26.0-pp39-pypy39_pp73-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:59b2093224a18c6508d95cfdeba8db9cbfd6f3494e94793b58972933fcee4c6d"}, - {file = "rpds_py-0.26.0-pp39-pypy39_pp73-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:4f01a5d6444a3258b00dc07b6ea4733e26f8072b788bef750baa37b370266137"}, - {file = "rpds_py-0.26.0-pp39-pypy39_pp73-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:b6e2c12160c72aeda9d1283e612f68804621f448145a210f1bf1d79151c47090"}, - {file = "rpds_py-0.26.0-pp39-pypy39_pp73-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:cb28c1f569f8d33b2b5dcd05d0e6ef7005d8639c54c2f0be824f05aedf715255"}, - {file = "rpds_py-0.26.0-pp39-pypy39_pp73-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:1766b5724c3f779317d5321664a343c07773c8c5fd1532e4039e6cc7d1a815be"}, - {file = "rpds_py-0.26.0-pp39-pypy39_pp73-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:b6d9e5a2ed9c4988c8f9b28b3bc0e3e5b1aaa10c28d210a594ff3a8c02742daf"}, - {file = "rpds_py-0.26.0-pp39-pypy39_pp73-musllinux_1_2_aarch64.whl", hash = "sha256:b5f7a446ddaf6ca0fad9a5535b56fbfc29998bf0e0b450d174bbec0d600e1d72"}, - {file = "rpds_py-0.26.0-pp39-pypy39_pp73-musllinux_1_2_i686.whl", hash = "sha256:eed5ac260dd545fbc20da5f4f15e7efe36a55e0e7cf706e4ec005b491a9546a0"}, - {file = "rpds_py-0.26.0-pp39-pypy39_pp73-musllinux_1_2_x86_64.whl", hash = "sha256:582462833ba7cee52e968b0341b85e392ae53d44c0f9af6a5927c80e539a8b67"}, - {file = "rpds_py-0.26.0-pp39-pypy39_pp73-win_amd64.whl", hash = "sha256:69a607203441e07e9a8a529cff1d5b73f6a160f22db1097211e6212a68567d11"}, - {file = "rpds_py-0.26.0.tar.gz", hash = "sha256:20dae58a859b0906f0685642e591056f1e787f3a8b39c8e8749a45dc7d26bdb0"}, + {file = "rpds_py-0.27.1-cp310-cp310-macosx_10_12_x86_64.whl", hash = "sha256:68afeec26d42ab3b47e541b272166a0b4400313946871cba3ed3a4fc0cab1cef"}, + {file = "rpds_py-0.27.1-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:74e5b2f7bb6fa38b1b10546d27acbacf2a022a8b5543efb06cfebc72a59c85be"}, + {file = "rpds_py-0.27.1-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:9024de74731df54546fab0bfbcdb49fae19159ecaecfc8f37c18d2c7e2c0bd61"}, + {file = "rpds_py-0.27.1-cp310-cp310-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:31d3ebadefcd73b73928ed0b2fd696f7fefda8629229f81929ac9c1854d0cffb"}, + {file = "rpds_py-0.27.1-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:b2e7f8f169d775dd9092a1743768d771f1d1300453ddfe6325ae3ab5332b4657"}, + {file = "rpds_py-0.27.1-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:3d905d16f77eb6ab2e324e09bfa277b4c8e5e6b8a78a3e7ff8f3cdf773b4c013"}, + {file = "rpds_py-0.27.1-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:50c946f048209e6362e22576baea09193809f87687a95a8db24e5fbdb307b93a"}, + {file = "rpds_py-0.27.1-cp310-cp310-manylinux_2_31_riscv64.whl", hash = "sha256:3deab27804d65cd8289eb814c2c0e807c4b9d9916c9225e363cb0cf875eb67c1"}, + {file = "rpds_py-0.27.1-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:8b61097f7488de4be8244c89915da8ed212832ccf1e7c7753a25a394bf9b1f10"}, + {file = "rpds_py-0.27.1-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:8a3f29aba6e2d7d90528d3c792555a93497fe6538aa65eb675b44505be747808"}, + {file = "rpds_py-0.27.1-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:dd6cd0485b7d347304067153a6dc1d73f7d4fd995a396ef32a24d24b8ac63ac8"}, + {file = "rpds_py-0.27.1-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:6f4461bf931108c9fa226ffb0e257c1b18dc2d44cd72b125bec50ee0ab1248a9"}, + {file = "rpds_py-0.27.1-cp310-cp310-win32.whl", hash = "sha256:ee5422d7fb21f6a00c1901bf6559c49fee13a5159d0288320737bbf6585bd3e4"}, + {file = "rpds_py-0.27.1-cp310-cp310-win_amd64.whl", hash = "sha256:3e039aabf6d5f83c745d5f9a0a381d031e9ed871967c0a5c38d201aca41f3ba1"}, + {file = "rpds_py-0.27.1-cp311-cp311-macosx_10_12_x86_64.whl", hash = "sha256:be898f271f851f68b318872ce6ebebbc62f303b654e43bf72683dbdc25b7c881"}, + {file = "rpds_py-0.27.1-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:62ac3d4e3e07b58ee0ddecd71d6ce3b1637de2d373501412df395a0ec5f9beb5"}, + {file = "rpds_py-0.27.1-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:4708c5c0ceb2d034f9991623631d3d23cb16e65c83736ea020cdbe28d57c0a0e"}, + {file = "rpds_py-0.27.1-cp311-cp311-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:abfa1171a9952d2e0002aba2ad3780820b00cc3d9c98c6630f2e93271501f66c"}, + {file = "rpds_py-0.27.1-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:4b507d19f817ebaca79574b16eb2ae412e5c0835542c93fe9983f1e432aca195"}, + {file = "rpds_py-0.27.1-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:168b025f8fd8d8d10957405f3fdcef3dc20f5982d398f90851f4abc58c566c52"}, + {file = "rpds_py-0.27.1-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:cb56c6210ef77caa58e16e8c17d35c63fe3f5b60fd9ba9d424470c3400bcf9ed"}, + {file = "rpds_py-0.27.1-cp311-cp311-manylinux_2_31_riscv64.whl", hash = "sha256:d252f2d8ca0195faa707f8eb9368955760880b2b42a8ee16d382bf5dd807f89a"}, + {file = "rpds_py-0.27.1-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:6e5e54da1e74b91dbc7996b56640f79b195d5925c2b78efaa8c5d53e1d88edde"}, + {file = "rpds_py-0.27.1-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:ffce0481cc6e95e5b3f0a47ee17ffbd234399e6d532f394c8dce320c3b089c21"}, + {file = "rpds_py-0.27.1-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:a205fdfe55c90c2cd8e540ca9ceba65cbe6629b443bc05db1f590a3db8189ff9"}, + {file = "rpds_py-0.27.1-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:689fb5200a749db0415b092972e8eba85847c23885c8543a8b0f5c009b1a5948"}, + {file = "rpds_py-0.27.1-cp311-cp311-win32.whl", hash = "sha256:3182af66048c00a075010bc7f4860f33913528a4b6fc09094a6e7598e462fe39"}, + {file = "rpds_py-0.27.1-cp311-cp311-win_amd64.whl", hash = "sha256:b4938466c6b257b2f5c4ff98acd8128ec36b5059e5c8f8372d79316b1c36bb15"}, + {file = "rpds_py-0.27.1-cp311-cp311-win_arm64.whl", hash = "sha256:2f57af9b4d0793e53266ee4325535a31ba48e2f875da81a9177c9926dfa60746"}, + {file = "rpds_py-0.27.1-cp312-cp312-macosx_10_12_x86_64.whl", hash = "sha256:ae2775c1973e3c30316892737b91f9283f9908e3cc7625b9331271eaaed7dc90"}, + {file = "rpds_py-0.27.1-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:2643400120f55c8a96f7c9d858f7be0c88d383cd4653ae2cf0d0c88f668073e5"}, + {file = "rpds_py-0.27.1-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:16323f674c089b0360674a4abd28d5042947d54ba620f72514d69be4ff64845e"}, + {file = "rpds_py-0.27.1-cp312-cp312-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:9a1f4814b65eacac94a00fc9a526e3fdafd78e439469644032032d0d63de4881"}, + {file = "rpds_py-0.27.1-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:7ba32c16b064267b22f1850a34051121d423b6f7338a12b9459550eb2096e7ec"}, + {file = "rpds_py-0.27.1-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:e5c20f33fd10485b80f65e800bbe5f6785af510b9f4056c5a3c612ebc83ba6cb"}, + {file = "rpds_py-0.27.1-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:466bfe65bd932da36ff279ddd92de56b042f2266d752719beb97b08526268ec5"}, + {file = "rpds_py-0.27.1-cp312-cp312-manylinux_2_31_riscv64.whl", hash = "sha256:41e532bbdcb57c92ba3be62c42e9f096431b4cf478da9bc3bc6ce5c38ab7ba7a"}, + {file = "rpds_py-0.27.1-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:f149826d742b406579466283769a8ea448eed82a789af0ed17b0cd5770433444"}, + {file = "rpds_py-0.27.1-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:80c60cfb5310677bd67cb1e85a1e8eb52e12529545441b43e6f14d90b878775a"}, + {file = "rpds_py-0.27.1-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:7ee6521b9baf06085f62ba9c7a3e5becffbc32480d2f1b351559c001c38ce4c1"}, + {file = "rpds_py-0.27.1-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:a512c8263249a9d68cac08b05dd59d2b3f2061d99b322813cbcc14c3c7421998"}, + {file = "rpds_py-0.27.1-cp312-cp312-win32.whl", hash = "sha256:819064fa048ba01b6dadc5116f3ac48610435ac9a0058bbde98e569f9e785c39"}, + {file = "rpds_py-0.27.1-cp312-cp312-win_amd64.whl", hash = "sha256:d9199717881f13c32c4046a15f024971a3b78ad4ea029e8da6b86e5aa9cf4594"}, + {file = "rpds_py-0.27.1-cp312-cp312-win_arm64.whl", hash = "sha256:33aa65b97826a0e885ef6e278fbd934e98cdcfed80b63946025f01e2f5b29502"}, + {file = "rpds_py-0.27.1-cp313-cp313-macosx_10_12_x86_64.whl", hash = "sha256:e4b9fcfbc021633863a37e92571d6f91851fa656f0180246e84cbd8b3f6b329b"}, + {file = "rpds_py-0.27.1-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:1441811a96eadca93c517d08df75de45e5ffe68aa3089924f963c782c4b898cf"}, + {file = "rpds_py-0.27.1-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:55266dafa22e672f5a4f65019015f90336ed31c6383bd53f5e7826d21a0e0b83"}, + {file = "rpds_py-0.27.1-cp313-cp313-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:d78827d7ac08627ea2c8e02c9e5b41180ea5ea1f747e9db0915e3adf36b62dcf"}, + {file = "rpds_py-0.27.1-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:ae92443798a40a92dc5f0b01d8a7c93adde0c4dc965310a29ae7c64d72b9fad2"}, + {file = "rpds_py-0.27.1-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:c46c9dd2403b66a2a3b9720ec4b74d4ab49d4fabf9f03dfdce2d42af913fe8d0"}, + {file = "rpds_py-0.27.1-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:2efe4eb1d01b7f5f1939f4ef30ecea6c6b3521eec451fb93191bf84b2a522418"}, + {file = "rpds_py-0.27.1-cp313-cp313-manylinux_2_31_riscv64.whl", hash = "sha256:15d3b4d83582d10c601f481eca29c3f138d44c92187d197aff663a269197c02d"}, + {file = "rpds_py-0.27.1-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:4ed2e16abbc982a169d30d1a420274a709949e2cbdef119fe2ec9d870b42f274"}, + {file = "rpds_py-0.27.1-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:a75f305c9b013289121ec0f1181931975df78738cdf650093e6b86d74aa7d8dd"}, + {file = "rpds_py-0.27.1-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:67ce7620704745881a3d4b0ada80ab4d99df390838839921f99e63c474f82cf2"}, + {file = "rpds_py-0.27.1-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:9d992ac10eb86d9b6f369647b6a3f412fc0075cfd5d799530e84d335e440a002"}, + {file = "rpds_py-0.27.1-cp313-cp313-win32.whl", hash = "sha256:4f75e4bd8ab8db624e02c8e2fc4063021b58becdbe6df793a8111d9343aec1e3"}, + {file = "rpds_py-0.27.1-cp313-cp313-win_amd64.whl", hash = "sha256:f9025faafc62ed0b75a53e541895ca272815bec18abe2249ff6501c8f2e12b83"}, + {file = "rpds_py-0.27.1-cp313-cp313-win_arm64.whl", hash = "sha256:ed10dc32829e7d222b7d3b93136d25a406ba9788f6a7ebf6809092da1f4d279d"}, + {file = "rpds_py-0.27.1-cp313-cp313t-macosx_10_12_x86_64.whl", hash = "sha256:92022bbbad0d4426e616815b16bc4127f83c9a74940e1ccf3cfe0b387aba0228"}, + {file = "rpds_py-0.27.1-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:47162fdab9407ec3f160805ac3e154df042e577dd53341745fc7fb3f625e6d92"}, + {file = "rpds_py-0.27.1-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:fb89bec23fddc489e5d78b550a7b773557c9ab58b7946154a10a6f7a214a48b2"}, + {file = "rpds_py-0.27.1-cp313-cp313t-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:e48af21883ded2b3e9eb48cb7880ad8598b31ab752ff3be6457001d78f416723"}, + {file = "rpds_py-0.27.1-cp313-cp313t-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:6f5b7bd8e219ed50299e58551a410b64daafb5017d54bbe822e003856f06a802"}, + {file = "rpds_py-0.27.1-cp313-cp313t-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:08f1e20bccf73b08d12d804d6e1c22ca5530e71659e6673bce31a6bb71c1e73f"}, + {file = "rpds_py-0.27.1-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:0dc5dceeaefcc96dc192e3a80bbe1d6c410c469e97bdd47494a7d930987f18b2"}, + {file = "rpds_py-0.27.1-cp313-cp313t-manylinux_2_31_riscv64.whl", hash = "sha256:d76f9cc8665acdc0c9177043746775aa7babbf479b5520b78ae4002d889f5c21"}, + {file = "rpds_py-0.27.1-cp313-cp313t-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:134fae0e36022edad8290a6661edf40c023562964efea0cc0ec7f5d392d2aaef"}, + {file = "rpds_py-0.27.1-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:eb11a4f1b2b63337cfd3b4d110af778a59aae51c81d195768e353d8b52f88081"}, + {file = "rpds_py-0.27.1-cp313-cp313t-musllinux_1_2_i686.whl", hash = "sha256:13e608ac9f50a0ed4faec0e90ece76ae33b34c0e8656e3dceb9a7db994c692cd"}, + {file = "rpds_py-0.27.1-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:dd2135527aa40f061350c3f8f89da2644de26cd73e4de458e79606384f4f68e7"}, + {file = "rpds_py-0.27.1-cp313-cp313t-win32.whl", hash = "sha256:3020724ade63fe320a972e2ffd93b5623227e684315adce194941167fee02688"}, + {file = "rpds_py-0.27.1-cp313-cp313t-win_amd64.whl", hash = "sha256:8ee50c3e41739886606388ba3ab3ee2aae9f35fb23f833091833255a31740797"}, + {file = "rpds_py-0.27.1-cp314-cp314-macosx_10_12_x86_64.whl", hash = "sha256:acb9aafccaae278f449d9c713b64a9e68662e7799dbd5859e2c6b3c67b56d334"}, + {file = "rpds_py-0.27.1-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:b7fb801aa7f845ddf601c49630deeeccde7ce10065561d92729bfe81bd21fb33"}, + {file = "rpds_py-0.27.1-cp314-cp314-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:fe0dd05afb46597b9a2e11c351e5e4283c741237e7f617ffb3252780cca9336a"}, + {file = "rpds_py-0.27.1-cp314-cp314-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:b6dfb0e058adb12d8b1d1b25f686e94ffa65d9995a5157afe99743bf7369d62b"}, + {file = "rpds_py-0.27.1-cp314-cp314-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:ed090ccd235f6fa8bb5861684567f0a83e04f52dfc2e5c05f2e4b1309fcf85e7"}, + {file = "rpds_py-0.27.1-cp314-cp314-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:bf876e79763eecf3e7356f157540d6a093cef395b65514f17a356f62af6cc136"}, + {file = "rpds_py-0.27.1-cp314-cp314-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:12ed005216a51b1d6e2b02a7bd31885fe317e45897de81d86dcce7d74618ffff"}, + {file = "rpds_py-0.27.1-cp314-cp314-manylinux_2_31_riscv64.whl", hash = "sha256:ee4308f409a40e50593c7e3bb8cbe0b4d4c66d1674a316324f0c2f5383b486f9"}, + {file = "rpds_py-0.27.1-cp314-cp314-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:0b08d152555acf1f455154d498ca855618c1378ec810646fcd7c76416ac6dc60"}, + {file = "rpds_py-0.27.1-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:dce51c828941973a5684d458214d3a36fcd28da3e1875d659388f4f9f12cc33e"}, + {file = "rpds_py-0.27.1-cp314-cp314-musllinux_1_2_i686.whl", hash = "sha256:c1476d6f29eb81aa4151c9a31219b03f1f798dc43d8af1250a870735516a1212"}, + {file = "rpds_py-0.27.1-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:3ce0cac322b0d69b63c9cdb895ee1b65805ec9ffad37639f291dd79467bee675"}, + {file = "rpds_py-0.27.1-cp314-cp314-win32.whl", hash = "sha256:dfbfac137d2a3d0725758cd141f878bf4329ba25e34979797c89474a89a8a3a3"}, + {file = "rpds_py-0.27.1-cp314-cp314-win_amd64.whl", hash = "sha256:a6e57b0abfe7cc513450fcf529eb486b6e4d3f8aee83e92eb5f1ef848218d456"}, + {file = "rpds_py-0.27.1-cp314-cp314-win_arm64.whl", hash = "sha256:faf8d146f3d476abfee026c4ae3bdd9ca14236ae4e4c310cbd1cf75ba33d24a3"}, + {file = "rpds_py-0.27.1-cp314-cp314t-macosx_10_12_x86_64.whl", hash = "sha256:ba81d2b56b6d4911ce735aad0a1d4495e808b8ee4dc58715998741a26874e7c2"}, + {file = "rpds_py-0.27.1-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:84f7d509870098de0e864cad0102711c1e24e9b1a50ee713b65928adb22269e4"}, + {file = "rpds_py-0.27.1-cp314-cp314t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:a9e960fc78fecd1100539f14132425e1d5fe44ecb9239f8f27f079962021523e"}, + {file = "rpds_py-0.27.1-cp314-cp314t-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:62f85b665cedab1a503747617393573995dac4600ff51869d69ad2f39eb5e817"}, + {file = "rpds_py-0.27.1-cp314-cp314t-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:fed467af29776f6556250c9ed85ea5a4dd121ab56a5f8b206e3e7a4c551e48ec"}, + {file = "rpds_py-0.27.1-cp314-cp314t-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:f2729615f9d430af0ae6b36cf042cb55c0936408d543fb691e1a9e36648fd35a"}, + {file = "rpds_py-0.27.1-cp314-cp314t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:1b207d881a9aef7ba753d69c123a35d96ca7cb808056998f6b9e8747321f03b8"}, + {file = "rpds_py-0.27.1-cp314-cp314t-manylinux_2_31_riscv64.whl", hash = "sha256:639fd5efec029f99b79ae47e5d7e00ad8a773da899b6309f6786ecaf22948c48"}, + {file = "rpds_py-0.27.1-cp314-cp314t-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:fecc80cb2a90e28af8a9b366edacf33d7a91cbfe4c2c4544ea1246e949cfebeb"}, + {file = "rpds_py-0.27.1-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:42a89282d711711d0a62d6f57d81aa43a1368686c45bc1c46b7f079d55692734"}, + {file = "rpds_py-0.27.1-cp314-cp314t-musllinux_1_2_i686.whl", hash = "sha256:cf9931f14223de59551ab9d38ed18d92f14f055a5f78c1d8ad6493f735021bbb"}, + {file = "rpds_py-0.27.1-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:f39f58a27cc6e59f432b568ed8429c7e1641324fbe38131de852cd77b2d534b0"}, + {file = "rpds_py-0.27.1-cp314-cp314t-win32.whl", hash = "sha256:d5fa0ee122dc09e23607a28e6d7b150da16c662e66409bbe85230e4c85bb528a"}, + {file = "rpds_py-0.27.1-cp314-cp314t-win_amd64.whl", hash = "sha256:6567d2bb951e21232c2f660c24cf3470bb96de56cdcb3f071a83feeaff8a2772"}, + {file = "rpds_py-0.27.1-cp39-cp39-macosx_10_12_x86_64.whl", hash = "sha256:c918c65ec2e42c2a78d19f18c553d77319119bf43aa9e2edf7fb78d624355527"}, + {file = "rpds_py-0.27.1-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:1fea2b1a922c47c51fd07d656324531adc787e415c8b116530a1d29c0516c62d"}, + {file = "rpds_py-0.27.1-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:bbf94c58e8e0cd6b6f38d8de67acae41b3a515c26169366ab58bdca4a6883bb8"}, + {file = "rpds_py-0.27.1-cp39-cp39-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:c2a8fed130ce946d5c585eddc7c8eeef0051f58ac80a8ee43bd17835c144c2cc"}, + {file = "rpds_py-0.27.1-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:037a2361db72ee98d829bc2c5b7cc55598ae0a5e0ec1823a56ea99374cfd73c1"}, + {file = "rpds_py-0.27.1-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:5281ed1cc1d49882f9997981c88df1a22e140ab41df19071222f7e5fc4e72125"}, + {file = "rpds_py-0.27.1-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:2fd50659a069c15eef8aa3d64bbef0d69fd27bb4a50c9ab4f17f83a16cbf8905"}, + {file = "rpds_py-0.27.1-cp39-cp39-manylinux_2_31_riscv64.whl", hash = "sha256:c4b676c4ae3921649a15d28ed10025548e9b561ded473aa413af749503c6737e"}, + {file = "rpds_py-0.27.1-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:079bc583a26db831a985c5257797b2b5d3affb0386e7ff886256762f82113b5e"}, + {file = "rpds_py-0.27.1-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:4e44099bd522cba71a2c6b97f68e19f40e7d85399de899d66cdb67b32d7cb786"}, + {file = "rpds_py-0.27.1-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:e202e6d4188e53c6661af813b46c37ca2c45e497fc558bacc1a7630ec2695aec"}, + {file = "rpds_py-0.27.1-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:f41f814b8eaa48768d1bb551591f6ba45f87ac76899453e8ccd41dba1289b04b"}, + {file = "rpds_py-0.27.1-cp39-cp39-win32.whl", hash = "sha256:9e71f5a087ead99563c11fdaceee83ee982fd39cf67601f4fd66cb386336ee52"}, + {file = "rpds_py-0.27.1-cp39-cp39-win_amd64.whl", hash = "sha256:71108900c9c3c8590697244b9519017a400d9ba26a36c48381b3f64743a44aab"}, + {file = "rpds_py-0.27.1-pp310-pypy310_pp73-macosx_10_12_x86_64.whl", hash = "sha256:7ba22cb9693df986033b91ae1d7a979bc399237d45fccf875b76f62bb9e52ddf"}, + {file = "rpds_py-0.27.1-pp310-pypy310_pp73-macosx_11_0_arm64.whl", hash = "sha256:5b640501be9288c77738b5492b3fd3abc4ba95c50c2e41273c8a1459f08298d3"}, + {file = "rpds_py-0.27.1-pp310-pypy310_pp73-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:fb08b65b93e0c6dd70aac7f7890a9c0938d5ec71d5cb32d45cf844fb8ae47636"}, + {file = "rpds_py-0.27.1-pp310-pypy310_pp73-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:d7ff07d696a7a38152ebdb8212ca9e5baab56656749f3d6004b34ab726b550b8"}, + {file = "rpds_py-0.27.1-pp310-pypy310_pp73-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:fb7c72262deae25366e3b6c0c0ba46007967aea15d1eea746e44ddba8ec58dcc"}, + {file = "rpds_py-0.27.1-pp310-pypy310_pp73-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:7b002cab05d6339716b03a4a3a2ce26737f6231d7b523f339fa061d53368c9d8"}, + {file = "rpds_py-0.27.1-pp310-pypy310_pp73-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:23f6b69d1c26c4704fec01311963a41d7de3ee0570a84ebde4d544e5a1859ffc"}, + {file = "rpds_py-0.27.1-pp310-pypy310_pp73-manylinux_2_31_riscv64.whl", hash = "sha256:530064db9146b247351f2a0250b8f00b289accea4596a033e94be2389977de71"}, + {file = "rpds_py-0.27.1-pp310-pypy310_pp73-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:7b90b0496570bd6b0321724a330d8b545827c4df2034b6ddfc5f5275f55da2ad"}, + {file = "rpds_py-0.27.1-pp310-pypy310_pp73-musllinux_1_2_aarch64.whl", hash = "sha256:879b0e14a2da6a1102a3fc8af580fc1ead37e6d6692a781bd8c83da37429b5ab"}, + {file = "rpds_py-0.27.1-pp310-pypy310_pp73-musllinux_1_2_i686.whl", hash = "sha256:0d807710df3b5faa66c731afa162ea29717ab3be17bdc15f90f2d9f183da4059"}, + {file = "rpds_py-0.27.1-pp310-pypy310_pp73-musllinux_1_2_x86_64.whl", hash = "sha256:3adc388fc3afb6540aec081fa59e6e0d3908722771aa1e37ffe22b220a436f0b"}, + {file = "rpds_py-0.27.1-pp310-pypy310_pp73-win_amd64.whl", hash = "sha256:c796c0c1cc68cb08b0284db4229f5af76168172670c74908fdbd4b7d7f515819"}, + {file = "rpds_py-0.27.1-pp311-pypy311_pp73-macosx_10_12_x86_64.whl", hash = "sha256:cdfe4bb2f9fe7458b7453ad3c33e726d6d1c7c0a72960bcc23800d77384e42df"}, + {file = "rpds_py-0.27.1-pp311-pypy311_pp73-macosx_11_0_arm64.whl", hash = "sha256:8fabb8fd848a5f75a2324e4a84501ee3a5e3c78d8603f83475441866e60b94a3"}, + {file = "rpds_py-0.27.1-pp311-pypy311_pp73-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:eda8719d598f2f7f3e0f885cba8646644b55a187762bec091fa14a2b819746a9"}, + {file = "rpds_py-0.27.1-pp311-pypy311_pp73-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:3c64d07e95606ec402a0a1c511fe003873fa6af630bda59bac77fac8b4318ebc"}, + {file = "rpds_py-0.27.1-pp311-pypy311_pp73-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:93a2ed40de81bcff59aabebb626562d48332f3d028ca2036f1d23cbb52750be4"}, + {file = "rpds_py-0.27.1-pp311-pypy311_pp73-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:387ce8c44ae94e0ec50532d9cb0edce17311024c9794eb196b90e1058aadeb66"}, + {file = "rpds_py-0.27.1-pp311-pypy311_pp73-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:aaf94f812c95b5e60ebaf8bfb1898a7d7cb9c1af5744d4a67fa47796e0465d4e"}, + {file = "rpds_py-0.27.1-pp311-pypy311_pp73-manylinux_2_31_riscv64.whl", hash = "sha256:4848ca84d6ded9b58e474dfdbad4b8bfb450344c0551ddc8d958bf4b36aa837c"}, + {file = "rpds_py-0.27.1-pp311-pypy311_pp73-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:2bde09cbcf2248b73c7c323be49b280180ff39fadcfe04e7b6f54a678d02a7cf"}, + {file = "rpds_py-0.27.1-pp311-pypy311_pp73-musllinux_1_2_aarch64.whl", hash = "sha256:94c44ee01fd21c9058f124d2d4f0c9dc7634bec93cd4b38eefc385dabe71acbf"}, + {file = "rpds_py-0.27.1-pp311-pypy311_pp73-musllinux_1_2_i686.whl", hash = "sha256:df8b74962e35c9249425d90144e721eed198e6555a0e22a563d29fe4486b51f6"}, + {file = "rpds_py-0.27.1-pp311-pypy311_pp73-musllinux_1_2_x86_64.whl", hash = "sha256:dc23e6820e3b40847e2f4a7726462ba0cf53089512abe9ee16318c366494c17a"}, + {file = "rpds_py-0.27.1-pp39-pypy39_pp73-macosx_10_12_x86_64.whl", hash = "sha256:aa8933159edc50be265ed22b401125c9eebff3171f570258854dbce3ecd55475"}, + {file = "rpds_py-0.27.1-pp39-pypy39_pp73-macosx_11_0_arm64.whl", hash = "sha256:a50431bf02583e21bf273c71b89d710e7a710ad5e39c725b14e685610555926f"}, + {file = "rpds_py-0.27.1-pp39-pypy39_pp73-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:78af06ddc7fe5cc0e967085a9115accee665fb912c22a3f54bad70cc65b05fe6"}, + {file = "rpds_py-0.27.1-pp39-pypy39_pp73-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:70d0738ef8fee13c003b100c2fbd667ec4f133468109b3472d249231108283a3"}, + {file = "rpds_py-0.27.1-pp39-pypy39_pp73-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:e2f6fd8a1cea5bbe599b6e78a6e5ee08db434fc8ffea51ff201c8765679698b3"}, + {file = "rpds_py-0.27.1-pp39-pypy39_pp73-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:8177002868d1426305bb5de1e138161c2ec9eb2d939be38291d7c431c4712df8"}, + {file = "rpds_py-0.27.1-pp39-pypy39_pp73-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:008b839781d6c9bf3b6a8984d1d8e56f0ec46dc56df61fd669c49b58ae800400"}, + {file = "rpds_py-0.27.1-pp39-pypy39_pp73-manylinux_2_31_riscv64.whl", hash = "sha256:a55b9132bb1ade6c734ddd2759c8dc132aa63687d259e725221f106b83a0e485"}, + {file = "rpds_py-0.27.1-pp39-pypy39_pp73-manylinux_2_5_i686.manylinux1_i686.whl", hash = "sha256:a46fdec0083a26415f11d5f236b79fa1291c32aaa4a17684d82f7017a1f818b1"}, + {file = "rpds_py-0.27.1-pp39-pypy39_pp73-musllinux_1_2_aarch64.whl", hash = "sha256:8a63b640a7845f2bdd232eb0d0a4a2dd939bcdd6c57e6bb134526487f3160ec5"}, + {file = "rpds_py-0.27.1-pp39-pypy39_pp73-musllinux_1_2_i686.whl", hash = "sha256:7e32721e5d4922deaaf963469d795d5bde6093207c52fec719bd22e5d1bedbc4"}, + {file = "rpds_py-0.27.1-pp39-pypy39_pp73-musllinux_1_2_x86_64.whl", hash = "sha256:2c426b99a068601b5f4623573df7a7c3d72e87533a2dd2253353a03e7502566c"}, + {file = "rpds_py-0.27.1-pp39-pypy39_pp73-win_amd64.whl", hash = "sha256:4fc9b7fe29478824361ead6e14e4f5aed570d477e06088826537e202d25fe859"}, + {file = "rpds_py-0.27.1.tar.gz", hash = "sha256:26a1c73171d10b7acccbded82bf6a586ab8203601e565badc74bbbf8bc5a10f8"}, ] [[package]] @@ -6898,43 +7366,44 @@ pyasn1 = ">=0.1.3" [[package]] name = "ruff" -version = "0.12.4" +version = "0.14.0" description = "An extremely fast Python linter and code formatter, written in Rust." optional = false python-versions = ">=3.7" groups = ["main"] -markers = "extra == \"gradio\" and sys_platform != \"emscripten\"" -files = [ - {file = "ruff-0.12.4-py3-none-linux_armv6l.whl", hash = "sha256:cb0d261dac457ab939aeb247e804125a5d521b21adf27e721895b0d3f83a0d0a"}, - {file = "ruff-0.12.4-py3-none-macosx_10_12_x86_64.whl", hash = "sha256:55c0f4ca9769408d9b9bac530c30d3e66490bd2beb2d3dae3e4128a1f05c7442"}, - {file = "ruff-0.12.4-py3-none-macosx_11_0_arm64.whl", hash = "sha256:a8224cc3722c9ad9044da7f89c4c1ec452aef2cfe3904365025dd2f51daeae0e"}, - {file = "ruff-0.12.4-py3-none-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:e9949d01d64fa3672449a51ddb5d7548b33e130240ad418884ee6efa7a229586"}, - {file = "ruff-0.12.4-py3-none-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:be0593c69df9ad1465e8a2d10e3defd111fdb62dcd5be23ae2c06da77e8fcffb"}, - {file = "ruff-0.12.4-py3-none-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:a7dea966bcb55d4ecc4cc3270bccb6f87a337326c9dcd3c07d5b97000dbff41c"}, - {file = "ruff-0.12.4-py3-none-manylinux_2_17_ppc64.manylinux2014_ppc64.whl", hash = "sha256:afcfa3ab5ab5dd0e1c39bf286d829e042a15e966b3726eea79528e2e24d8371a"}, - {file = "ruff-0.12.4-py3-none-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:c057ce464b1413c926cdb203a0f858cd52f3e73dcb3270a3318d1630f6395bb3"}, - {file = "ruff-0.12.4-py3-none-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:e64b90d1122dc2713330350626b10d60818930819623abbb56535c6466cce045"}, - {file = "ruff-0.12.4-py3-none-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:2abc48f3d9667fdc74022380b5c745873499ff827393a636f7a59da1515e7c57"}, - {file = "ruff-0.12.4-py3-none-musllinux_1_2_aarch64.whl", hash = "sha256:2b2449dc0c138d877d629bea151bee8c0ae3b8e9c43f5fcaafcd0c0d0726b184"}, - {file = "ruff-0.12.4-py3-none-musllinux_1_2_armv7l.whl", hash = "sha256:56e45bb11f625db55f9b70477062e6a1a04d53628eda7784dce6e0f55fd549eb"}, - {file = "ruff-0.12.4-py3-none-musllinux_1_2_i686.whl", hash = "sha256:478fccdb82ca148a98a9ff43658944f7ab5ec41c3c49d77cd99d44da019371a1"}, - {file = "ruff-0.12.4-py3-none-musllinux_1_2_x86_64.whl", hash = "sha256:0fc426bec2e4e5f4c4f182b9d2ce6a75c85ba9bcdbe5c6f2a74fcb8df437df4b"}, - {file = "ruff-0.12.4-py3-none-win32.whl", hash = "sha256:4de27977827893cdfb1211d42d84bc180fceb7b72471104671c59be37041cf93"}, - {file = "ruff-0.12.4-py3-none-win_amd64.whl", hash = "sha256:fe0b9e9eb23736b453143d72d2ceca5db323963330d5b7859d60d101147d461a"}, - {file = "ruff-0.12.4-py3-none-win_arm64.whl", hash = "sha256:0618ec4442a83ab545e5b71202a5c0ed7791e8471435b94e655b570a5031a98e"}, - {file = "ruff-0.12.4.tar.gz", hash = "sha256:13efa16df6c6eeb7d0f091abae50f58e9522f3843edb40d56ad52a5a4a4b6873"}, +markers = "extra == \"gradio\"" +files = [ + {file = "ruff-0.14.0-py3-none-linux_armv6l.whl", hash = "sha256:58e15bffa7054299becf4bab8a1187062c6f8cafbe9f6e39e0d5aface455d6b3"}, + {file = "ruff-0.14.0-py3-none-macosx_10_12_x86_64.whl", hash = "sha256:838d1b065f4df676b7c9957992f2304e41ead7a50a568185efd404297d5701e8"}, + {file = "ruff-0.14.0-py3-none-macosx_11_0_arm64.whl", hash = "sha256:703799d059ba50f745605b04638fa7e9682cc3da084b2092feee63500ff3d9b8"}, + {file = "ruff-0.14.0-py3-none-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:3ba9a8925e90f861502f7d974cc60e18ca29c72bb0ee8bfeabb6ade35a3abde7"}, + {file = "ruff-0.14.0-py3-none-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:e41f785498bd200ffc276eb9e1570c019c1d907b07cfb081092c8ad51975bbe7"}, + {file = "ruff-0.14.0-py3-none-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:30a58c087aef4584c193aebf2700f0fbcfc1e77b89c7385e3139956fa90434e2"}, + {file = "ruff-0.14.0-py3-none-manylinux_2_17_ppc64.manylinux2014_ppc64.whl", hash = "sha256:f8d07350bc7af0a5ce8812b7d5c1a7293cf02476752f23fdfc500d24b79b783c"}, + {file = "ruff-0.14.0-py3-none-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:eec3bbbf3a7d5482b5c1f42d5fc972774d71d107d447919fca620b0be3e3b75e"}, + {file = "ruff-0.14.0-py3-none-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:16b68e183a0e28e5c176d51004aaa40559e8f90065a10a559176713fcf435206"}, + {file = "ruff-0.14.0-py3-none-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:eb732d17db2e945cfcbbc52af0143eda1da36ca8ae25083dd4f66f1542fdf82e"}, + {file = "ruff-0.14.0-py3-none-manylinux_2_31_riscv64.whl", hash = "sha256:c958f66ab884b7873e72df38dcabee03d556a8f2ee1b8538ee1c2bbd619883dd"}, + {file = "ruff-0.14.0-py3-none-musllinux_1_2_aarch64.whl", hash = "sha256:7eb0499a2e01f6e0c285afc5bac43ab380cbfc17cd43a2e1dd10ec97d6f2c42d"}, + {file = "ruff-0.14.0-py3-none-musllinux_1_2_armv7l.whl", hash = "sha256:4c63b2d99fafa05efca0ab198fd48fa6030d57e4423df3f18e03aa62518c565f"}, + {file = "ruff-0.14.0-py3-none-musllinux_1_2_i686.whl", hash = "sha256:668fce701b7a222f3f5327f86909db2bbe99c30877c8001ff934c5413812ac02"}, + {file = "ruff-0.14.0-py3-none-musllinux_1_2_x86_64.whl", hash = "sha256:a86bf575e05cb68dcb34e4c7dfe1064d44d3f0c04bbc0491949092192b515296"}, + {file = "ruff-0.14.0-py3-none-win32.whl", hash = "sha256:7450a243d7125d1c032cb4b93d9625dea46c8c42b4f06c6b709baac168e10543"}, + {file = "ruff-0.14.0-py3-none-win_amd64.whl", hash = "sha256:ea95da28cd874c4d9c922b39381cbd69cb7e7b49c21b8152b014bd4f52acddc2"}, + {file = "ruff-0.14.0-py3-none-win_arm64.whl", hash = "sha256:f42c9495f5c13ff841b1da4cb3c2a42075409592825dada7c5885c2c844ac730"}, + {file = "ruff-0.14.0.tar.gz", hash = "sha256:62ec8969b7510f77945df916de15da55311fade8d6050995ff7f680afe582c57"}, ] [[package]] name = "s3transfer" -version = "0.13.1" +version = "0.14.0" description = "An Amazon S3 Transfer Manager" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "s3transfer-0.13.1-py3-none-any.whl", hash = "sha256:a981aa7429be23fe6dfc13e80e4020057cbab622b08c0315288758d67cabc724"}, - {file = "s3transfer-0.13.1.tar.gz", hash = "sha256:c3fdba22ba1bd367922f27ec8032d6a1cf5f10c934fb5d68cf60fd5a23d936cf"}, + {file = "s3transfer-0.14.0-py3-none-any.whl", hash = "sha256:ea3b790c7077558ed1f02a3072fb3cb992bbbd253392f4b6e9e8976941c7d456"}, + {file = "s3transfer-0.14.0.tar.gz", hash = "sha256:eff12264e7c8b4985074ccce27a3b38a485bb7f7422cc8046fee9be4983e4125"}, ] [package.dependencies] @@ -6964,38 +7433,43 @@ dev = ["pytest"] [[package]] name = "scikit-learn" -version = "1.7.1" +version = "1.7.2" description = "A set of python modules for machine learning and data mining" optional = false python-versions = ">=3.10" groups = ["main"] files = [ - {file = "scikit_learn-1.7.1-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:406204dd4004f0517f0b23cf4b28c6245cbd51ab1b6b78153bc784def214946d"}, - {file = "scikit_learn-1.7.1-cp310-cp310-macosx_12_0_arm64.whl", hash = "sha256:16af2e44164f05d04337fd1fc3ae7c4ea61fd9b0d527e22665346336920fe0e1"}, - {file = "scikit_learn-1.7.1-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:2f2e78e56a40c7587dea9a28dc4a49500fa2ead366869418c66f0fd75b80885c"}, - {file = "scikit_learn-1.7.1-cp310-cp310-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b62b76ad408a821475b43b7bb90a9b1c9a4d8d125d505c2df0539f06d6e631b1"}, - {file = "scikit_learn-1.7.1-cp310-cp310-win_amd64.whl", hash = "sha256:9963b065677a4ce295e8ccdee80a1dd62b37249e667095039adcd5bce6e90deb"}, - {file = "scikit_learn-1.7.1-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:90c8494ea23e24c0fb371afc474618c1019dc152ce4a10e4607e62196113851b"}, - {file = "scikit_learn-1.7.1-cp311-cp311-macosx_12_0_arm64.whl", hash = "sha256:bb870c0daf3bf3be145ec51df8ac84720d9972170786601039f024bf6d61a518"}, - {file = "scikit_learn-1.7.1-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:40daccd1b5623f39e8943ab39735cadf0bdce80e67cdca2adcb5426e987320a8"}, - {file = "scikit_learn-1.7.1-cp311-cp311-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:30d1f413cfc0aa5a99132a554f1d80517563c34a9d3e7c118fde2d273c6fe0f7"}, - {file = "scikit_learn-1.7.1-cp311-cp311-win_amd64.whl", hash = "sha256:c711d652829a1805a95d7fe96654604a8f16eab5a9e9ad87b3e60173415cb650"}, - {file = "scikit_learn-1.7.1-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:3cee419b49b5bbae8796ecd690f97aa412ef1674410c23fc3257c6b8b85b8087"}, - {file = "scikit_learn-1.7.1-cp312-cp312-macosx_12_0_arm64.whl", hash = "sha256:2fd8b8d35817b0d9ebf0b576f7d5ffbbabdb55536b0655a8aaae629d7ffd2e1f"}, - {file = "scikit_learn-1.7.1-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:588410fa19a96a69763202f1d6b7b91d5d7a5d73be36e189bc6396bfb355bd87"}, - {file = "scikit_learn-1.7.1-cp312-cp312-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:e3142f0abe1ad1d1c31a2ae987621e41f6b578144a911ff4ac94781a583adad7"}, - {file = "scikit_learn-1.7.1-cp312-cp312-win_amd64.whl", hash = "sha256:3ddd9092c1bd469acab337d87930067c87eac6bd544f8d5027430983f1e1ae88"}, - {file = "scikit_learn-1.7.1-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:b7839687fa46d02e01035ad775982f2470be2668e13ddd151f0f55a5bf123bae"}, - {file = "scikit_learn-1.7.1-cp313-cp313-macosx_12_0_arm64.whl", hash = "sha256:a10f276639195a96c86aa572ee0698ad64ee939a7b042060b98bd1930c261d10"}, - {file = "scikit_learn-1.7.1-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:13679981fdaebc10cc4c13c43344416a86fcbc61449cb3e6517e1df9d12c8309"}, - {file = "scikit_learn-1.7.1-cp313-cp313-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:4f1262883c6a63f067a980a8cdd2d2e7f2513dddcef6a9eaada6416a7a7cbe43"}, - {file = "scikit_learn-1.7.1-cp313-cp313-win_amd64.whl", hash = "sha256:ca6d31fb10e04d50bfd2b50d66744729dbb512d4efd0223b864e2fdbfc4cee11"}, - {file = "scikit_learn-1.7.1-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:781674d096303cfe3d351ae6963ff7c958db61cde3421cd490e3a5a58f2a94ae"}, - {file = "scikit_learn-1.7.1-cp313-cp313t-macosx_12_0_arm64.whl", hash = "sha256:10679f7f125fe7ecd5fad37dd1aa2daae7e3ad8df7f3eefa08901b8254b3e12c"}, - {file = "scikit_learn-1.7.1-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:1f812729e38c8cb37f760dce71a9b83ccfb04f59b3dca7c6079dcdc60544fa9e"}, - {file = "scikit_learn-1.7.1-cp313-cp313t-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:88e1a20131cf741b84b89567e1717f27a2ced228e0f29103426102bc2e3b8ef7"}, - {file = "scikit_learn-1.7.1-cp313-cp313t-win_amd64.whl", hash = "sha256:b1bd1d919210b6a10b7554b717c9000b5485aa95a1d0f177ae0d7ee8ec750da5"}, - {file = "scikit_learn-1.7.1.tar.gz", hash = "sha256:24b3f1e976a4665aa74ee0fcaac2b8fccc6ae77c8e07ab25da3ba6d3292b9802"}, + {file = "scikit_learn-1.7.2-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:6b33579c10a3081d076ab403df4a4190da4f4432d443521674637677dc91e61f"}, + {file = "scikit_learn-1.7.2-cp310-cp310-macosx_12_0_arm64.whl", hash = "sha256:36749fb62b3d961b1ce4fedf08fa57a1986cd409eff2d783bca5d4b9b5fce51c"}, + {file = "scikit_learn-1.7.2-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:7a58814265dfc52b3295b1900cfb5701589d30a8bb026c7540f1e9d3499d5ec8"}, + {file = "scikit_learn-1.7.2-cp310-cp310-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:4a847fea807e278f821a0406ca01e387f97653e284ecbd9750e3ee7c90347f18"}, + {file = "scikit_learn-1.7.2-cp310-cp310-win_amd64.whl", hash = "sha256:ca250e6836d10e6f402436d6463d6c0e4d8e0234cfb6a9a47835bd392b852ce5"}, + {file = "scikit_learn-1.7.2-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:c7509693451651cd7361d30ce4e86a1347493554f172b1c72a39300fa2aea79e"}, + {file = "scikit_learn-1.7.2-cp311-cp311-macosx_12_0_arm64.whl", hash = "sha256:0486c8f827c2e7b64837c731c8feff72c0bd2b998067a8a9cbc10643c31f0fe1"}, + {file = "scikit_learn-1.7.2-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:89877e19a80c7b11a2891a27c21c4894fb18e2c2e077815bcade10d34287b20d"}, + {file = "scikit_learn-1.7.2-cp311-cp311-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:8da8bf89d4d79aaec192d2bda62f9b56ae4e5b4ef93b6a56b5de4977e375c1f1"}, + {file = "scikit_learn-1.7.2-cp311-cp311-win_amd64.whl", hash = "sha256:9b7ed8d58725030568523e937c43e56bc01cadb478fc43c042a9aca1dacb3ba1"}, + {file = "scikit_learn-1.7.2-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:8d91a97fa2b706943822398ab943cde71858a50245e31bc71dba62aab1d60a96"}, + {file = "scikit_learn-1.7.2-cp312-cp312-macosx_12_0_arm64.whl", hash = "sha256:acbc0f5fd2edd3432a22c69bed78e837c70cf896cd7993d71d51ba6708507476"}, + {file = "scikit_learn-1.7.2-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:e5bf3d930aee75a65478df91ac1225ff89cd28e9ac7bd1196853a9229b6adb0b"}, + {file = "scikit_learn-1.7.2-cp312-cp312-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b4d6e9deed1a47aca9fe2f267ab8e8fe82ee20b4526b2c0cd9e135cea10feb44"}, + {file = "scikit_learn-1.7.2-cp312-cp312-win_amd64.whl", hash = "sha256:6088aa475f0785e01bcf8529f55280a3d7d298679f50c0bb70a2364a82d0b290"}, + {file = "scikit_learn-1.7.2-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:0b7dacaa05e5d76759fb071558a8b5130f4845166d88654a0f9bdf3eb57851b7"}, + {file = "scikit_learn-1.7.2-cp313-cp313-macosx_12_0_arm64.whl", hash = "sha256:abebbd61ad9e1deed54cca45caea8ad5f79e1b93173dece40bb8e0c658dbe6fe"}, + {file = "scikit_learn-1.7.2-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:502c18e39849c0ea1a5d681af1dbcf15f6cce601aebb657aabbfe84133c1907f"}, + {file = "scikit_learn-1.7.2-cp313-cp313-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:7a4c328a71785382fe3fe676a9ecf2c86189249beff90bf85e22bdb7efaf9ae0"}, + {file = "scikit_learn-1.7.2-cp313-cp313-win_amd64.whl", hash = "sha256:63a9afd6f7b229aad94618c01c252ce9e6fa97918c5ca19c9a17a087d819440c"}, + {file = "scikit_learn-1.7.2-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:9acb6c5e867447b4e1390930e3944a005e2cb115922e693c08a323421a6966e8"}, + {file = "scikit_learn-1.7.2-cp313-cp313t-macosx_12_0_arm64.whl", hash = "sha256:2a41e2a0ef45063e654152ec9d8bcfc39f7afce35b08902bfe290c2498a67a6a"}, + {file = "scikit_learn-1.7.2-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:98335fb98509b73385b3ab2bd0639b1f610541d3988ee675c670371d6a87aa7c"}, + {file = "scikit_learn-1.7.2-cp313-cp313t-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:191e5550980d45449126e23ed1d5e9e24b2c68329ee1f691a3987476e115e09c"}, + {file = "scikit_learn-1.7.2-cp313-cp313t-win_amd64.whl", hash = "sha256:57dc4deb1d3762c75d685507fbd0bc17160144b2f2ba4ccea5dc285ab0d0e973"}, + {file = "scikit_learn-1.7.2-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:fa8f63940e29c82d1e67a45d5297bdebbcb585f5a5a50c4914cc2e852ab77f33"}, + {file = "scikit_learn-1.7.2-cp314-cp314-macosx_12_0_arm64.whl", hash = "sha256:f95dc55b7902b91331fa4e5845dd5bde0580c9cd9612b1b2791b7e80c3d32615"}, + {file = "scikit_learn-1.7.2-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:9656e4a53e54578ad10a434dc1f993330568cfee176dff07112b8785fb413106"}, + {file = "scikit_learn-1.7.2-cp314-cp314-manylinux_2_27_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:96dc05a854add0e50d3f47a1ef21a10a595016da5b007c7d9cd9d0bffd1fcc61"}, + {file = "scikit_learn-1.7.2-cp314-cp314-win_amd64.whl", hash = "sha256:bb24510ed3f9f61476181e4db51ce801e2ba37541def12dc9333b946fc7a9cf8"}, + {file = "scikit_learn-1.7.2.tar.gz", hash = "sha256:20e9e49ecd130598f1ca38a1d85090e1a600147b9c02fa6f15d69cb53d968fda"}, ] [package.dependencies] @@ -7015,49 +7489,73 @@ tests = ["matplotlib (>=3.5.0)", "mypy (>=1.15)", "numpydoc (>=1.2.0)", "pandas [[package]] name = "scipy" -version = "1.16.0" +version = "1.16.2" description = "Fundamental algorithms for scientific computing in Python" optional = false python-versions = ">=3.11" groups = ["main"] files = [ - {file = "scipy-1.16.0-cp311-cp311-macosx_10_14_x86_64.whl", hash = "sha256:deec06d831b8f6b5fb0b652433be6a09db29e996368ce5911faf673e78d20085"}, - {file = "scipy-1.16.0-cp311-cp311-macosx_12_0_arm64.whl", hash = "sha256:d30c0fe579bb901c61ab4bb7f3eeb7281f0d4c4a7b52dbf563c89da4fd2949be"}, - {file = "scipy-1.16.0-cp311-cp311-macosx_14_0_arm64.whl", hash = "sha256:b2243561b45257f7391d0f49972fca90d46b79b8dbcb9b2cb0f9df928d370ad4"}, - {file = "scipy-1.16.0-cp311-cp311-macosx_14_0_x86_64.whl", hash = "sha256:e6d7dfc148135e9712d87c5f7e4f2ddc1304d1582cb3a7d698bbadedb61c7afd"}, - {file = "scipy-1.16.0-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:90452f6a9f3fe5a2cf3748e7be14f9cc7d9b124dce19667b54f5b429d680d539"}, - {file = "scipy-1.16.0-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:a2f0bf2f58031c8701a8b601df41701d2a7be17c7ffac0a4816aeba89c4cdac8"}, - {file = "scipy-1.16.0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:6c4abb4c11fc0b857474241b812ce69ffa6464b4bd8f4ecb786cf240367a36a7"}, - {file = "scipy-1.16.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:b370f8f6ac6ef99815b0d5c9f02e7ade77b33007d74802efc8316c8db98fd11e"}, - {file = "scipy-1.16.0-cp311-cp311-win_amd64.whl", hash = "sha256:a16ba90847249bedce8aa404a83fb8334b825ec4a8e742ce6012a7a5e639f95c"}, - {file = "scipy-1.16.0-cp312-cp312-macosx_10_14_x86_64.whl", hash = "sha256:7eb6bd33cef4afb9fa5f1fb25df8feeb1e52d94f21a44f1d17805b41b1da3180"}, - {file = "scipy-1.16.0-cp312-cp312-macosx_12_0_arm64.whl", hash = "sha256:1dbc8fdba23e4d80394ddfab7a56808e3e6489176d559c6c71935b11a2d59db1"}, - {file = "scipy-1.16.0-cp312-cp312-macosx_14_0_arm64.whl", hash = "sha256:7dcf42c380e1e3737b343dec21095c9a9ad3f9cbe06f9c05830b44b1786c9e90"}, - {file = "scipy-1.16.0-cp312-cp312-macosx_14_0_x86_64.whl", hash = "sha256:26ec28675f4a9d41587266084c626b02899db373717d9312fa96ab17ca1ae94d"}, - {file = "scipy-1.16.0-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:952358b7e58bd3197cfbd2f2f2ba829f258404bdf5db59514b515a8fe7a36c52"}, - {file = "scipy-1.16.0-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:03931b4e870c6fef5b5c0970d52c9f6ddd8c8d3e934a98f09308377eba6f3824"}, - {file = "scipy-1.16.0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:512c4f4f85912767c351a0306824ccca6fd91307a9f4318efe8fdbd9d30562ef"}, - {file = "scipy-1.16.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:e69f798847e9add03d512eaf5081a9a5c9a98757d12e52e6186ed9681247a1ac"}, - {file = "scipy-1.16.0-cp312-cp312-win_amd64.whl", hash = "sha256:adf9b1999323ba335adc5d1dc7add4781cb5a4b0ef1e98b79768c05c796c4e49"}, - {file = "scipy-1.16.0-cp313-cp313-macosx_10_14_x86_64.whl", hash = "sha256:e9f414cbe9ca289a73e0cc92e33a6a791469b6619c240aa32ee18abdce8ab451"}, - {file = "scipy-1.16.0-cp313-cp313-macosx_12_0_arm64.whl", hash = "sha256:bbba55fb97ba3cdef9b1ee973f06b09d518c0c7c66a009c729c7d1592be1935e"}, - {file = "scipy-1.16.0-cp313-cp313-macosx_14_0_arm64.whl", hash = "sha256:58e0d4354eacb6004e7aa1cd350e5514bd0270acaa8d5b36c0627bb3bb486974"}, - {file = "scipy-1.16.0-cp313-cp313-macosx_14_0_x86_64.whl", hash = "sha256:75b2094ec975c80efc273567436e16bb794660509c12c6a31eb5c195cbf4b6dc"}, - {file = "scipy-1.16.0-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:6b65d232157a380fdd11a560e7e21cde34fdb69d65c09cb87f6cc024ee376351"}, - {file = "scipy-1.16.0-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:1d8747f7736accd39289943f7fe53a8333be7f15a82eea08e4afe47d79568c32"}, - {file = "scipy-1.16.0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:eb9f147a1b8529bb7fec2a85cf4cf42bdfadf9e83535c309a11fdae598c88e8b"}, - {file = "scipy-1.16.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:d2b83c37edbfa837a8923d19c749c1935ad3d41cf196006a24ed44dba2ec4358"}, - {file = "scipy-1.16.0-cp313-cp313-win_amd64.whl", hash = "sha256:79a3c13d43c95aa80b87328a46031cf52508cf5f4df2767602c984ed1d3c6bbe"}, - {file = "scipy-1.16.0-cp313-cp313t-macosx_10_14_x86_64.whl", hash = "sha256:f91b87e1689f0370690e8470916fe1b2308e5b2061317ff76977c8f836452a47"}, - {file = "scipy-1.16.0-cp313-cp313t-macosx_12_0_arm64.whl", hash = "sha256:88a6ca658fb94640079e7a50b2ad3b67e33ef0f40e70bdb7dc22017dae73ac08"}, - {file = "scipy-1.16.0-cp313-cp313t-macosx_14_0_arm64.whl", hash = "sha256:ae902626972f1bd7e4e86f58fd72322d7f4ec7b0cfc17b15d4b7006efc385176"}, - {file = "scipy-1.16.0-cp313-cp313t-macosx_14_0_x86_64.whl", hash = "sha256:8cb824c1fc75ef29893bc32b3ddd7b11cf9ab13c1127fe26413a05953b8c32ed"}, - {file = "scipy-1.16.0-cp313-cp313t-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:de2db7250ff6514366a9709c2cba35cb6d08498e961cba20d7cff98a7ee88938"}, - {file = "scipy-1.16.0-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:e85800274edf4db8dd2e4e93034f92d1b05c9421220e7ded9988b16976f849c1"}, - {file = "scipy-1.16.0-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:4f720300a3024c237ace1cb11f9a84c38beb19616ba7c4cdcd771047a10a1706"}, - {file = "scipy-1.16.0-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:aad603e9339ddb676409b104c48a027e9916ce0d2838830691f39552b38a352e"}, - {file = "scipy-1.16.0-cp313-cp313t-win_amd64.whl", hash = "sha256:f56296fefca67ba605fd74d12f7bd23636267731a72cb3947963e76b8c0a25db"}, - {file = "scipy-1.16.0.tar.gz", hash = "sha256:b5ef54021e832869c8cfb03bc3bf20366cbcd426e02a58e8a58d7584dfbb8f62"}, + {file = "scipy-1.16.2-cp311-cp311-macosx_10_14_x86_64.whl", hash = "sha256:6ab88ea43a57da1af33292ebd04b417e8e2eaf9d5aa05700be8d6e1b6501cd92"}, + {file = "scipy-1.16.2-cp311-cp311-macosx_12_0_arm64.whl", hash = "sha256:c95e96c7305c96ede73a7389f46ccd6c659c4da5ef1b2789466baeaed3622b6e"}, + {file = "scipy-1.16.2-cp311-cp311-macosx_14_0_arm64.whl", hash = "sha256:87eb178db04ece7c698220d523c170125dbffebb7af0345e66c3554f6f60c173"}, + {file = "scipy-1.16.2-cp311-cp311-macosx_14_0_x86_64.whl", hash = "sha256:4e409eac067dcee96a57fbcf424c13f428037827ec7ee3cb671ff525ca4fc34d"}, + {file = "scipy-1.16.2-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:e574be127bb760f0dad24ff6e217c80213d153058372362ccb9555a10fc5e8d2"}, + {file = "scipy-1.16.2-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:f5db5ba6188d698ba7abab982ad6973265b74bb40a1efe1821b58c87f73892b9"}, + {file = "scipy-1.16.2-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:ec6e74c4e884104ae006d34110677bfe0098203a3fec2f3faf349f4cb05165e3"}, + {file = "scipy-1.16.2-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:912f46667d2d3834bc3d57361f854226475f695eb08c08a904aadb1c936b6a88"}, + {file = "scipy-1.16.2-cp311-cp311-win_amd64.whl", hash = "sha256:91e9e8a37befa5a69e9cacbe0bcb79ae5afb4a0b130fd6db6ee6cc0d491695fa"}, + {file = "scipy-1.16.2-cp311-cp311-win_arm64.whl", hash = "sha256:f3bf75a6dcecab62afde4d1f973f1692be013110cad5338007927db8da73249c"}, + {file = "scipy-1.16.2-cp312-cp312-macosx_10_14_x86_64.whl", hash = "sha256:89d6c100fa5c48472047632e06f0876b3c4931aac1f4291afc81a3644316bb0d"}, + {file = "scipy-1.16.2-cp312-cp312-macosx_12_0_arm64.whl", hash = "sha256:ca748936cd579d3f01928b30a17dc474550b01272d8046e3e1ee593f23620371"}, + {file = "scipy-1.16.2-cp312-cp312-macosx_14_0_arm64.whl", hash = "sha256:fac4f8ce2ddb40e2e3d0f7ec36d2a1e7f92559a2471e59aec37bd8d9de01fec0"}, + {file = "scipy-1.16.2-cp312-cp312-macosx_14_0_x86_64.whl", hash = "sha256:033570f1dcefd79547a88e18bccacff025c8c647a330381064f561d43b821232"}, + {file = "scipy-1.16.2-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:ea3421209bf00c8a5ef2227de496601087d8f638a2363ee09af059bd70976dc1"}, + {file = "scipy-1.16.2-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:f66bd07ba6f84cd4a380b41d1bf3c59ea488b590a2ff96744845163309ee8e2f"}, + {file = "scipy-1.16.2-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:5e9feab931bd2aea4a23388c962df6468af3d808ddf2d40f94a81c5dc38f32ef"}, + {file = "scipy-1.16.2-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:03dfc75e52f72cf23ec2ced468645321407faad8f0fe7b1f5b49264adbc29cb1"}, + {file = "scipy-1.16.2-cp312-cp312-win_amd64.whl", hash = "sha256:0ce54e07bbb394b417457409a64fd015be623f36e330ac49306433ffe04bc97e"}, + {file = "scipy-1.16.2-cp312-cp312-win_arm64.whl", hash = "sha256:2a8ffaa4ac0df81a0b94577b18ee079f13fecdb924df3328fc44a7dc5ac46851"}, + {file = "scipy-1.16.2-cp313-cp313-macosx_10_14_x86_64.whl", hash = "sha256:84f7bf944b43e20b8a894f5fe593976926744f6c185bacfcbdfbb62736b5cc70"}, + {file = "scipy-1.16.2-cp313-cp313-macosx_12_0_arm64.whl", hash = "sha256:5c39026d12edc826a1ef2ad35ad1e6d7f087f934bb868fc43fa3049c8b8508f9"}, + {file = "scipy-1.16.2-cp313-cp313-macosx_14_0_arm64.whl", hash = "sha256:e52729ffd45b68777c5319560014d6fd251294200625d9d70fd8626516fc49f5"}, + {file = "scipy-1.16.2-cp313-cp313-macosx_14_0_x86_64.whl", hash = "sha256:024dd4a118cccec09ca3209b7e8e614931a6ffb804b2a601839499cb88bdf925"}, + {file = "scipy-1.16.2-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:7a5dc7ee9c33019973a470556081b0fd3c9f4c44019191039f9769183141a4d9"}, + {file = "scipy-1.16.2-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:c2275ff105e508942f99d4e3bc56b6ef5e4b3c0af970386ca56b777608ce95b7"}, + {file = "scipy-1.16.2-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:af80196eaa84f033e48444d2e0786ec47d328ba00c71e4299b602235ffef9acb"}, + {file = "scipy-1.16.2-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:9fb1eb735fe3d6ed1f89918224e3385fbf6f9e23757cacc35f9c78d3b712dd6e"}, + {file = "scipy-1.16.2-cp313-cp313-win_amd64.whl", hash = "sha256:fda714cf45ba43c9d3bae8f2585c777f64e3f89a2e073b668b32ede412d8f52c"}, + {file = "scipy-1.16.2-cp313-cp313-win_arm64.whl", hash = "sha256:2f5350da923ccfd0b00e07c3e5cfb316c1c0d6c1d864c07a72d092e9f20db104"}, + {file = "scipy-1.16.2-cp313-cp313t-macosx_10_14_x86_64.whl", hash = "sha256:53d8d2ee29b925344c13bda64ab51785f016b1b9617849dac10897f0701b20c1"}, + {file = "scipy-1.16.2-cp313-cp313t-macosx_12_0_arm64.whl", hash = "sha256:9e05e33657efb4c6a9d23bd8300101536abd99c85cca82da0bffff8d8764d08a"}, + {file = "scipy-1.16.2-cp313-cp313t-macosx_14_0_arm64.whl", hash = "sha256:7fe65b36036357003b3ef9d37547abeefaa353b237e989c21027b8ed62b12d4f"}, + {file = "scipy-1.16.2-cp313-cp313t-macosx_14_0_x86_64.whl", hash = "sha256:6406d2ac6d40b861cccf57f49592f9779071655e9f75cd4f977fa0bdd09cb2e4"}, + {file = "scipy-1.16.2-cp313-cp313t-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:ff4dc42bd321991fbf611c23fc35912d690f731c9914bf3af8f417e64aca0f21"}, + {file = "scipy-1.16.2-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:654324826654d4d9133e10675325708fb954bc84dae6e9ad0a52e75c6b1a01d7"}, + {file = "scipy-1.16.2-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:63870a84cd15c44e65220eaed2dac0e8f8b26bbb991456a033c1d9abfe8a94f8"}, + {file = "scipy-1.16.2-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:fa01f0f6a3050fa6a9771a95d5faccc8e2f5a92b4a2e5440a0fa7264a2398472"}, + {file = "scipy-1.16.2-cp313-cp313t-win_amd64.whl", hash = "sha256:116296e89fba96f76353a8579820c2512f6e55835d3fad7780fece04367de351"}, + {file = "scipy-1.16.2-cp313-cp313t-win_arm64.whl", hash = "sha256:98e22834650be81d42982360382b43b17f7ba95e0e6993e2a4f5b9ad9283a94d"}, + {file = "scipy-1.16.2-cp314-cp314-macosx_10_14_x86_64.whl", hash = "sha256:567e77755019bb7461513c87f02bb73fb65b11f049aaaa8ca17cfaa5a5c45d77"}, + {file = "scipy-1.16.2-cp314-cp314-macosx_12_0_arm64.whl", hash = "sha256:17d9bb346194e8967296621208fcdfd39b55498ef7d2f376884d5ac47cec1a70"}, + {file = "scipy-1.16.2-cp314-cp314-macosx_14_0_arm64.whl", hash = "sha256:0a17541827a9b78b777d33b623a6dcfe2ef4a25806204d08ead0768f4e529a88"}, + {file = "scipy-1.16.2-cp314-cp314-macosx_14_0_x86_64.whl", hash = "sha256:d7d4c6ba016ffc0f9568d012f5f1eb77ddd99412aea121e6fa8b4c3b7cbad91f"}, + {file = "scipy-1.16.2-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:9702c4c023227785c779cba2e1d6f7635dbb5b2e0936cdd3a4ecb98d78fd41eb"}, + {file = "scipy-1.16.2-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:d1cdf0ac28948d225decdefcc45ad7dd91716c29ab56ef32f8e0d50657dffcc7"}, + {file = "scipy-1.16.2-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:70327d6aa572a17c2941cdfb20673f82e536e91850a2e4cb0c5b858b690e1548"}, + {file = "scipy-1.16.2-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:5221c0b2a4b58aa7c4ed0387d360fd90ee9086d383bb34d9f2789fafddc8a936"}, + {file = "scipy-1.16.2-cp314-cp314-win_amd64.whl", hash = "sha256:f5a85d7b2b708025af08f060a496dd261055b617d776fc05a1a1cc69e09fe9ff"}, + {file = "scipy-1.16.2-cp314-cp314-win_arm64.whl", hash = "sha256:2cc73a33305b4b24556957d5857d6253ce1e2dcd67fa0ff46d87d1670b3e1e1d"}, + {file = "scipy-1.16.2-cp314-cp314t-macosx_10_14_x86_64.whl", hash = "sha256:9ea2a3fed83065d77367775d689401a703d0f697420719ee10c0780bcab594d8"}, + {file = "scipy-1.16.2-cp314-cp314t-macosx_12_0_arm64.whl", hash = "sha256:7280d926f11ca945c3ef92ba960fa924e1465f8d07ce3a9923080363390624c4"}, + {file = "scipy-1.16.2-cp314-cp314t-macosx_14_0_arm64.whl", hash = "sha256:8afae1756f6a1fe04636407ef7dbece33d826a5d462b74f3d0eb82deabefd831"}, + {file = "scipy-1.16.2-cp314-cp314t-macosx_14_0_x86_64.whl", hash = "sha256:5c66511f29aa8d233388e7416a3f20d5cae7a2744d5cee2ecd38c081f4e861b3"}, + {file = "scipy-1.16.2-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.whl", hash = "sha256:efe6305aeaa0e96b0ccca5ff647a43737d9a092064a3894e46c414db84bc54ac"}, + {file = "scipy-1.16.2-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.whl", hash = "sha256:7f3a337d9ae06a1e8d655ee9d8ecb835ea5ddcdcbd8d23012afa055ab014f374"}, + {file = "scipy-1.16.2-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:bab3605795d269067d8ce78a910220262711b753de8913d3deeaedb5dded3bb6"}, + {file = "scipy-1.16.2-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:b0348d8ddb55be2a844c518cd8cc8deeeb8aeba707cf834db5758fc89b476a2c"}, + {file = "scipy-1.16.2-cp314-cp314t-win_amd64.whl", hash = "sha256:26284797e38b8a75e14ea6631d29bda11e76ceaa6ddb6fdebbfe4c4d90faf2f9"}, + {file = "scipy-1.16.2-cp314-cp314t-win_arm64.whl", hash = "sha256:d2a4472c231328d4de38d5f1f68fdd6d28a615138f842580a8a321b5845cf779"}, + {file = "scipy-1.16.2.tar.gz", hash = "sha256:af029b153d243a80afb6eabe40b0a07f8e35c9adc269c019f364ad747f826a6b"}, ] [package.dependencies] @@ -7066,27 +7564,27 @@ numpy = ">=1.25.2,<2.6" [package.extras] dev = ["cython-lint (>=0.12.2)", "doit (>=0.36.0)", "mypy (==1.10.0)", "pycodestyle", "pydevtool", "rich-click", "ruff (>=0.0.292)", "types-psutil", "typing_extensions"] doc = ["intersphinx_registry", "jupyterlite-pyodide-kernel", "jupyterlite-sphinx (>=0.19.1)", "jupytext", "linkify-it-py", "matplotlib (>=3.5)", "myst-nb (>=1.2.0)", "numpydoc", "pooch", "pydata-sphinx-theme (>=0.15.2)", "sphinx (>=5.0.0,<8.2.0)", "sphinx-copybutton", "sphinx-design (>=0.4.0)"] -test = ["Cython", "array-api-strict (>=2.3.1)", "asv", "gmpy2", "hypothesis (>=6.30)", "meson", "mpmath", "ninja ; sys_platform != \"emscripten\"", "pooch", "pytest", "pytest-cov", "pytest-timeout", "pytest-xdist", "scikit-umfpack", "threadpoolctl"] +test = ["Cython", "array-api-strict (>=2.3.1)", "asv", "gmpy2", "hypothesis (>=6.30)", "meson", "mpmath", "ninja ; sys_platform != \"emscripten\"", "pooch", "pytest (>=8.0.0)", "pytest-cov", "pytest-timeout", "pytest-xdist", "scikit-umfpack", "threadpoolctl"] [[package]] name = "selenium" -version = "4.34.2" +version = "4.36.0" description = "Official Python bindings for Selenium WebDriver" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "selenium-4.34.2-py3-none-any.whl", hash = "sha256:ea208f7db9e3b26e58c4a817ea9dd29454576d6ea55937d754df079ad588e1ad"}, - {file = "selenium-4.34.2.tar.gz", hash = "sha256:0f6d147595f08c6d4bad87b34c39dcacb4650aedc78e3956c8eac1bb752a3854"}, + {file = "selenium-4.36.0-py3-none-any.whl", hash = "sha256:525fdfe96b99c27d9a2c773c75aa7413f4c24bdb7b9749c1950aa3b5f79ed915"}, + {file = "selenium-4.36.0.tar.gz", hash = "sha256:0eced83038736c3a013b824116df0b6dbb83e93721545f51b680451013416723"}, ] [package.dependencies] certifi = ">=2025.6.15" -trio = ">=0.30.0,<0.31.0" -trio-websocket = ">=0.12.2,<0.13.0" -typing_extensions = ">=4.14.0,<4.15.0" -urllib3 = {version = ">=2.5.0,<2.6.0", extras = ["socks"]} -websocket-client = ">=1.8.0,<1.9.0" +trio = ">=0.30.0,<1.0" +trio-websocket = ">=0.12.2,<1.0" +typing_extensions = ">=4.14.0,<5.0" +urllib3 = {version = ">=2.5.0,<3.0", extras = ["socks"]} +websocket-client = ">=1.8.0,<2.0" [[package]] name = "semantic-version" @@ -7220,14 +7718,14 @@ files = [ [[package]] name = "soupsieve" -version = "2.7" +version = "2.8" description = "A modern CSS selector implementation for Beautiful Soup." optional = false -python-versions = ">=3.8" +python-versions = ">=3.9" groups = ["main"] files = [ - {file = "soupsieve-2.7-py3-none-any.whl", hash = "sha256:6e60cc5c1ffaf1cebcc12e8188320b72071e922c2e897f737cadce79ad5d30c4"}, - {file = "soupsieve-2.7.tar.gz", hash = "sha256:ad282f9b6926286d2ead4750552c8a6142bc4c783fd66b0293547c8fe6ae126a"}, + {file = "soupsieve-2.8-py3-none-any.whl", hash = "sha256:0cc76456a30e20f5d7f2e14a98a4ae2ee4e5abdc7c5ea0aafe795f344bc7984c"}, + {file = "soupsieve-2.8.tar.gz", hash = "sha256:e2dd4a40a628cb5f28f6d4b0db8800b8f581b65bb380b97de22ba5ca8d72572f"}, ] [[package]] @@ -7306,14 +7804,14 @@ test = ["cython (>=3.0)", "defusedxml (>=0.7.1)", "pytest (>=8.0)", "pytest-xdis [[package]] name = "sphinx-click" -version = "6.0.0" +version = "6.1.0" description = "Sphinx extension that automatically documents click applications" optional = false -python-versions = ">=3.8" +python-versions = ">=3.10" groups = ["main"] files = [ - {file = "sphinx_click-6.0.0-py3-none-any.whl", hash = "sha256:1e0a3c83bcb7c55497751b19d07ebe56b5d7b85eb76dd399cf9061b497adc317"}, - {file = "sphinx_click-6.0.0.tar.gz", hash = "sha256:f5d664321dc0c6622ff019f1e1c84e58ce0cecfddeb510e004cf60c2a3ab465b"}, + {file = "sphinx_click-6.1.0-py3-none-any.whl", hash = "sha256:7dbed856c3d0be75a394da444850d5fc7ecc5694534400aa5ed4f4849a8643f9"}, + {file = "sphinx_click-6.1.0.tar.gz", hash = "sha256:c702e0751c1a0b6ad649e4f7faebd0dc09a3cc7ca3b50f959698383772f50eef"}, ] [package.dependencies] @@ -7321,6 +7819,10 @@ click = ">=8.0" docutils = "*" sphinx = ">=4.0" +[package.extras] +docs = ["reno"] +test = ["pytest", "pytest-cov"] + [[package]] name = "sphinxcontrib-applehelp" version = "2.0.0" @@ -7423,73 +7925,73 @@ test = ["pytest"] [[package]] name = "sqlalchemy" -version = "2.0.41" +version = "2.0.44" description = "Database Abstraction Library" optional = false python-versions = ">=3.7" groups = ["main"] files = [ - {file = "SQLAlchemy-2.0.41-cp37-cp37m-macosx_10_9_x86_64.whl", hash = "sha256:6854175807af57bdb6425e47adbce7d20a4d79bbfd6f6d6519cd10bb7109a7f8"}, - {file = "SQLAlchemy-2.0.41-cp37-cp37m-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:05132c906066142103b83d9c250b60508af556982a385d96c4eaa9fb9720ac2b"}, - {file = "SQLAlchemy-2.0.41-cp37-cp37m-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:8b4af17bda11e907c51d10686eda89049f9ce5669b08fbe71a29747f1e876036"}, - {file = "SQLAlchemy-2.0.41-cp37-cp37m-musllinux_1_2_aarch64.whl", hash = "sha256:c0b0e5e1b5d9f3586601048dd68f392dc0cc99a59bb5faf18aab057ce00d00b2"}, - {file = "SQLAlchemy-2.0.41-cp37-cp37m-musllinux_1_2_x86_64.whl", hash = "sha256:0b3dbf1e7e9bc95f4bac5e2fb6d3fb2f083254c3fdd20a1789af965caf2d2348"}, - {file = "SQLAlchemy-2.0.41-cp37-cp37m-win32.whl", hash = "sha256:1e3f196a0c59b0cae9a0cd332eb1a4bda4696e863f4f1cf84ab0347992c548c2"}, - {file = "SQLAlchemy-2.0.41-cp37-cp37m-win_amd64.whl", hash = "sha256:6ab60a5089a8f02009f127806f777fca82581c49e127f08413a66056bd9166dd"}, - {file = "sqlalchemy-2.0.41-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:b1f09b6821406ea1f94053f346f28f8215e293344209129a9c0fcc3578598d7b"}, - {file = "sqlalchemy-2.0.41-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:1936af879e3db023601196a1684d28e12f19ccf93af01bf3280a3262c4b6b4e5"}, - {file = "sqlalchemy-2.0.41-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:b2ac41acfc8d965fb0c464eb8f44995770239668956dc4cdf502d1b1ffe0d747"}, - {file = "sqlalchemy-2.0.41-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:81c24e0c0fde47a9723c81d5806569cddef103aebbf79dbc9fcbb617153dea30"}, - {file = "sqlalchemy-2.0.41-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:23a8825495d8b195c4aa9ff1c430c28f2c821e8c5e2d98089228af887e5d7e29"}, - {file = "sqlalchemy-2.0.41-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:60c578c45c949f909a4026b7807044e7e564adf793537fc762b2489d522f3d11"}, - {file = "sqlalchemy-2.0.41-cp310-cp310-win32.whl", hash = "sha256:118c16cd3f1b00c76d69343e38602006c9cfb9998fa4f798606d28d63f23beda"}, - {file = "sqlalchemy-2.0.41-cp310-cp310-win_amd64.whl", hash = "sha256:7492967c3386df69f80cf67efd665c0f667cee67032090fe01d7d74b0e19bb08"}, - {file = "sqlalchemy-2.0.41-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:6375cd674fe82d7aa9816d1cb96ec592bac1726c11e0cafbf40eeee9a4516b5f"}, - {file = "sqlalchemy-2.0.41-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:9f8c9fdd15a55d9465e590a402f42082705d66b05afc3ffd2d2eb3c6ba919560"}, - {file = "sqlalchemy-2.0.41-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:32f9dc8c44acdee06c8fc6440db9eae8b4af8b01e4b1aee7bdd7241c22edff4f"}, - {file = "sqlalchemy-2.0.41-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:90c11ceb9a1f482c752a71f203a81858625d8df5746d787a4786bca4ffdf71c6"}, - {file = "sqlalchemy-2.0.41-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:911cc493ebd60de5f285bcae0491a60b4f2a9f0f5c270edd1c4dbaef7a38fc04"}, - {file = "sqlalchemy-2.0.41-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:03968a349db483936c249f4d9cd14ff2c296adfa1290b660ba6516f973139582"}, - {file = "sqlalchemy-2.0.41-cp311-cp311-win32.whl", hash = "sha256:293cd444d82b18da48c9f71cd7005844dbbd06ca19be1ccf6779154439eec0b8"}, - {file = "sqlalchemy-2.0.41-cp311-cp311-win_amd64.whl", hash = "sha256:3d3549fc3e40667ec7199033a4e40a2f669898a00a7b18a931d3efb4c7900504"}, - {file = "sqlalchemy-2.0.41-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:81f413674d85cfd0dfcd6512e10e0f33c19c21860342a4890c3a2b59479929f9"}, - {file = "sqlalchemy-2.0.41-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:598d9ebc1e796431bbd068e41e4de4dc34312b7aa3292571bb3674a0cb415dd1"}, - {file = "sqlalchemy-2.0.41-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:a104c5694dfd2d864a6f91b0956eb5d5883234119cb40010115fd45a16da5e70"}, - {file = "sqlalchemy-2.0.41-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:6145afea51ff0af7f2564a05fa95eb46f542919e6523729663a5d285ecb3cf5e"}, - {file = "sqlalchemy-2.0.41-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:b46fa6eae1cd1c20e6e6f44e19984d438b6b2d8616d21d783d150df714f44078"}, - {file = "sqlalchemy-2.0.41-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:41836fe661cc98abfae476e14ba1906220f92c4e528771a8a3ae6a151242d2ae"}, - {file = "sqlalchemy-2.0.41-cp312-cp312-win32.whl", hash = "sha256:a8808d5cf866c781150d36a3c8eb3adccfa41a8105d031bf27e92c251e3969d6"}, - {file = "sqlalchemy-2.0.41-cp312-cp312-win_amd64.whl", hash = "sha256:5b14e97886199c1f52c14629c11d90c11fbb09e9334fa7bb5f6d068d9ced0ce0"}, - {file = "sqlalchemy-2.0.41-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:4eeb195cdedaf17aab6b247894ff2734dcead6c08f748e617bfe05bd5a218443"}, - {file = "sqlalchemy-2.0.41-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:d4ae769b9c1c7757e4ccce94b0641bc203bbdf43ba7a2413ab2523d8d047d8dc"}, - {file = "sqlalchemy-2.0.41-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:a62448526dd9ed3e3beedc93df9bb6b55a436ed1474db31a2af13b313a70a7e1"}, - {file = "sqlalchemy-2.0.41-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:dc56c9788617b8964ad02e8fcfeed4001c1f8ba91a9e1f31483c0dffb207002a"}, - {file = "sqlalchemy-2.0.41-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:c153265408d18de4cc5ded1941dcd8315894572cddd3c58df5d5b5705b3fa28d"}, - {file = "sqlalchemy-2.0.41-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:4f67766965996e63bb46cfbf2ce5355fc32d9dd3b8ad7e536a920ff9ee422e23"}, - {file = "sqlalchemy-2.0.41-cp313-cp313-win32.whl", hash = "sha256:bfc9064f6658a3d1cadeaa0ba07570b83ce6801a1314985bf98ec9b95d74e15f"}, - {file = "sqlalchemy-2.0.41-cp313-cp313-win_amd64.whl", hash = "sha256:82ca366a844eb551daff9d2e6e7a9e5e76d2612c8564f58db6c19a726869c1df"}, - {file = "sqlalchemy-2.0.41-cp38-cp38-macosx_10_9_x86_64.whl", hash = "sha256:90144d3b0c8b139408da50196c5cad2a6909b51b23df1f0538411cd23ffa45d3"}, - {file = "sqlalchemy-2.0.41-cp38-cp38-macosx_11_0_arm64.whl", hash = "sha256:023b3ee6169969beea3bb72312e44d8b7c27c75b347942d943cf49397b7edeb5"}, - {file = "sqlalchemy-2.0.41-cp38-cp38-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:725875a63abf7c399d4548e686debb65cdc2549e1825437096a0af1f7e374814"}, - {file = "sqlalchemy-2.0.41-cp38-cp38-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:81965cc20848ab06583506ef54e37cf15c83c7e619df2ad16807c03100745dea"}, - {file = "sqlalchemy-2.0.41-cp38-cp38-musllinux_1_2_aarch64.whl", hash = "sha256:dd5ec3aa6ae6e4d5b5de9357d2133c07be1aff6405b136dad753a16afb6717dd"}, - {file = "sqlalchemy-2.0.41-cp38-cp38-musllinux_1_2_x86_64.whl", hash = "sha256:ff8e80c4c4932c10493ff97028decfdb622de69cae87e0f127a7ebe32b4069c6"}, - {file = "sqlalchemy-2.0.41-cp38-cp38-win32.whl", hash = "sha256:4d44522480e0bf34c3d63167b8cfa7289c1c54264c2950cc5fc26e7850967e45"}, - {file = "sqlalchemy-2.0.41-cp38-cp38-win_amd64.whl", hash = "sha256:81eedafa609917040d39aa9332e25881a8e7a0862495fcdf2023a9667209deda"}, - {file = "sqlalchemy-2.0.41-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:9a420a91913092d1e20c86a2f5f1fc85c1a8924dbcaf5e0586df8aceb09c9cc2"}, - {file = "sqlalchemy-2.0.41-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:906e6b0d7d452e9a98e5ab8507c0da791856b2380fdee61b765632bb8698026f"}, - {file = "sqlalchemy-2.0.41-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:a373a400f3e9bac95ba2a06372c4fd1412a7cee53c37fc6c05f829bf672b8769"}, - {file = "sqlalchemy-2.0.41-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:087b6b52de812741c27231b5a3586384d60c353fbd0e2f81405a814b5591dc8b"}, - {file = "sqlalchemy-2.0.41-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:34ea30ab3ec98355235972dadc497bb659cc75f8292b760394824fab9cf39826"}, - {file = "sqlalchemy-2.0.41-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:8280856dd7c6a68ab3a164b4a4b1c51f7691f6d04af4d4ca23d6ecf2261b7923"}, - {file = "sqlalchemy-2.0.41-cp39-cp39-win32.whl", hash = "sha256:b50eab9994d64f4a823ff99a0ed28a6903224ddbe7fef56a6dd865eec9243440"}, - {file = "sqlalchemy-2.0.41-cp39-cp39-win_amd64.whl", hash = "sha256:5e22575d169529ac3e0a120cf050ec9daa94b6a9597993d1702884f6954a7d71"}, - {file = "sqlalchemy-2.0.41-py3-none-any.whl", hash = "sha256:57df5dc6fdb5ed1a88a1ed2195fd31927e705cad62dedd86b46972752a80f576"}, - {file = "sqlalchemy-2.0.41.tar.gz", hash = "sha256:edba70118c4be3c2b1f90754d308d0b79c6fe2c0fdc52d8ddf603916f83f4db9"}, -] - -[package.dependencies] -greenlet = {version = ">=1", markers = "python_version < \"3.14\" and (platform_machine == \"aarch64\" or platform_machine == \"ppc64le\" or platform_machine == \"x86_64\" or platform_machine == \"amd64\" or platform_machine == \"AMD64\" or platform_machine == \"win32\" or platform_machine == \"WIN32\")"} + {file = "SQLAlchemy-2.0.44-cp37-cp37m-macosx_10_9_x86_64.whl", hash = "sha256:471733aabb2e4848d609141a9e9d56a427c0a038f4abf65dd19d7a21fd563632"}, + {file = "SQLAlchemy-2.0.44-cp37-cp37m-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:48bf7d383a35e668b984c805470518b635d48b95a3c57cb03f37eaa3551b5f9f"}, + {file = "SQLAlchemy-2.0.44-cp37-cp37m-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:2bf4bb6b3d6228fcf3a71b50231199fb94d2dd2611b66d33be0578ea3e6c2726"}, + {file = "SQLAlchemy-2.0.44-cp37-cp37m-musllinux_1_2_aarch64.whl", hash = "sha256:e998cf7c29473bd077704cea3577d23123094311f59bdc4af551923b168332b1"}, + {file = "SQLAlchemy-2.0.44-cp37-cp37m-musllinux_1_2_x86_64.whl", hash = "sha256:ebac3f0b5732014a126b43c2b7567f2f0e0afea7d9119a3378bde46d3dcad88e"}, + {file = "SQLAlchemy-2.0.44-cp37-cp37m-win32.whl", hash = "sha256:3255d821ee91bdf824795e936642bbf43a4c7cedf5d1aed8d24524e66843aa74"}, + {file = "SQLAlchemy-2.0.44-cp37-cp37m-win_amd64.whl", hash = "sha256:78e6c137ba35476adb5432103ae1534f2f5295605201d946a4198a0dea4b38e7"}, + {file = "sqlalchemy-2.0.44-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:7c77f3080674fc529b1bd99489378c7f63fcb4ba7f8322b79732e0258f0ea3ce"}, + {file = "sqlalchemy-2.0.44-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:4c26ef74ba842d61635b0152763d057c8d48215d5be9bb8b7604116a059e9985"}, + {file = "sqlalchemy-2.0.44-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:f4a172b31785e2f00780eccab00bc240ccdbfdb8345f1e6063175b3ff12ad1b0"}, + {file = "sqlalchemy-2.0.44-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:f9480c0740aabd8cb29c329b422fb65358049840b34aba0adf63162371d2a96e"}, + {file = "sqlalchemy-2.0.44-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:17835885016b9e4d0135720160db3095dc78c583e7b902b6be799fb21035e749"}, + {file = "sqlalchemy-2.0.44-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:cbe4f85f50c656d753890f39468fcd8190c5f08282caf19219f684225bfd5fd2"}, + {file = "sqlalchemy-2.0.44-cp310-cp310-win32.whl", hash = "sha256:2fcc4901a86ed81dc76703f3b93ff881e08761c63263c46991081fd7f034b165"}, + {file = "sqlalchemy-2.0.44-cp310-cp310-win_amd64.whl", hash = "sha256:9919e77403a483ab81e3423151e8ffc9dd992c20d2603bf17e4a8161111e55f5"}, + {file = "sqlalchemy-2.0.44-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:0fe3917059c7ab2ee3f35e77757062b1bea10a0b6ca633c58391e3f3c6c488dd"}, + {file = "sqlalchemy-2.0.44-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:de4387a354ff230bc979b46b2207af841dc8bf29847b6c7dbe60af186d97aefa"}, + {file = "sqlalchemy-2.0.44-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:c3678a0fb72c8a6a29422b2732fe423db3ce119c34421b5f9955873eb9b62c1e"}, + {file = "sqlalchemy-2.0.44-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:3cf6872a23601672d61a68f390e44703442639a12ee9dd5a88bbce52a695e46e"}, + {file = "sqlalchemy-2.0.44-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:329aa42d1be9929603f406186630135be1e7a42569540577ba2c69952b7cf399"}, + {file = "sqlalchemy-2.0.44-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:70e03833faca7166e6a9927fbee7c27e6ecde436774cd0b24bbcc96353bce06b"}, + {file = "sqlalchemy-2.0.44-cp311-cp311-win32.whl", hash = "sha256:253e2f29843fb303eca6b2fc645aca91fa7aa0aa70b38b6950da92d44ff267f3"}, + {file = "sqlalchemy-2.0.44-cp311-cp311-win_amd64.whl", hash = "sha256:7a8694107eb4308a13b425ca8c0e67112f8134c846b6e1f722698708741215d5"}, + {file = "sqlalchemy-2.0.44-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:72fea91746b5890f9e5e0997f16cbf3d53550580d76355ba2d998311b17b2250"}, + {file = "sqlalchemy-2.0.44-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:585c0c852a891450edbb1eaca8648408a3cc125f18cf433941fa6babcc359e29"}, + {file = "sqlalchemy-2.0.44-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:9b94843a102efa9ac68a7a30cd46df3ff1ed9c658100d30a725d10d9c60a2f44"}, + {file = "sqlalchemy-2.0.44-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:119dc41e7a7defcefc57189cfa0e61b1bf9c228211aba432b53fb71ef367fda1"}, + {file = "sqlalchemy-2.0.44-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:0765e318ee9179b3718c4fd7ba35c434f4dd20332fbc6857a5e8df17719c24d7"}, + {file = "sqlalchemy-2.0.44-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:2e7b5b079055e02d06a4308d0481658e4f06bc7ef211567edc8f7d5dce52018d"}, + {file = "sqlalchemy-2.0.44-cp312-cp312-win32.whl", hash = "sha256:846541e58b9a81cce7dee8329f352c318de25aa2f2bbe1e31587eb1f057448b4"}, + {file = "sqlalchemy-2.0.44-cp312-cp312-win_amd64.whl", hash = "sha256:7cbcb47fd66ab294703e1644f78971f6f2f1126424d2b300678f419aa73c7b6e"}, + {file = "sqlalchemy-2.0.44-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:ff486e183d151e51b1d694c7aa1695747599bb00b9f5f604092b54b74c64a8e1"}, + {file = "sqlalchemy-2.0.44-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:0b1af8392eb27b372ddb783b317dea0f650241cea5bd29199b22235299ca2e45"}, + {file = "sqlalchemy-2.0.44-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:2b61188657e3a2b9ac4e8f04d6cf8e51046e28175f79464c67f2fd35bceb0976"}, + {file = "sqlalchemy-2.0.44-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:b87e7b91a5d5973dda5f00cd61ef72ad75a1db73a386b62877d4875a8840959c"}, + {file = "sqlalchemy-2.0.44-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:15f3326f7f0b2bfe406ee562e17f43f36e16167af99c4c0df61db668de20002d"}, + {file = "sqlalchemy-2.0.44-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:1e77faf6ff919aa8cd63f1c4e561cac1d9a454a191bb864d5dd5e545935e5a40"}, + {file = "sqlalchemy-2.0.44-cp313-cp313-win32.whl", hash = "sha256:ee51625c2d51f8baadf2829fae817ad0b66b140573939dd69284d2ba3553ae73"}, + {file = "sqlalchemy-2.0.44-cp313-cp313-win_amd64.whl", hash = "sha256:c1c80faaee1a6c3428cecf40d16a2365bcf56c424c92c2b6f0f9ad204b899e9e"}, + {file = "sqlalchemy-2.0.44-cp38-cp38-macosx_10_9_x86_64.whl", hash = "sha256:2fc44e5965ea46909a416fff0af48a219faefd5773ab79e5f8a5fcd5d62b2667"}, + {file = "sqlalchemy-2.0.44-cp38-cp38-macosx_11_0_arm64.whl", hash = "sha256:dc8b3850d2a601ca2320d081874033684e246d28e1c5e89db0864077cfc8f5a9"}, + {file = "sqlalchemy-2.0.44-cp38-cp38-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:d733dec0614bb8f4bcb7c8af88172b974f685a31dc3a65cca0527e3120de5606"}, + {file = "sqlalchemy-2.0.44-cp38-cp38-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:22be14009339b8bc16d6b9dc8780bacaba3402aa7581658e246114abbd2236e3"}, + {file = "sqlalchemy-2.0.44-cp38-cp38-musllinux_1_2_aarch64.whl", hash = "sha256:357bade0e46064f88f2c3a99808233e67b0051cdddf82992379559322dfeb183"}, + {file = "sqlalchemy-2.0.44-cp38-cp38-musllinux_1_2_x86_64.whl", hash = "sha256:4848395d932e93c1595e59a8672aa7400e8922c39bb9b0668ed99ac6fa867822"}, + {file = "sqlalchemy-2.0.44-cp38-cp38-win32.whl", hash = "sha256:2f19644f27c76f07e10603580a47278abb2a70311136a7f8fd27dc2e096b9013"}, + {file = "sqlalchemy-2.0.44-cp38-cp38-win_amd64.whl", hash = "sha256:1df4763760d1de0dfc8192cc96d8aa293eb1a44f8f7a5fbe74caf1b551905c5e"}, + {file = "sqlalchemy-2.0.44-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:f7027414f2b88992877573ab780c19ecb54d3a536bef3397933573d6b5068be4"}, + {file = "sqlalchemy-2.0.44-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:3fe166c7d00912e8c10d3a9a0ce105569a31a3d0db1a6e82c4e0f4bf16d5eca9"}, + {file = "sqlalchemy-2.0.44-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:3caef1ff89b1caefc28f0368b3bde21a7e3e630c2eddac16abd9e47bd27cc36a"}, + {file = "sqlalchemy-2.0.44-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:cc2856d24afa44295735e72f3c75d6ee7fdd4336d8d3a8f3d44de7aa6b766df2"}, + {file = "sqlalchemy-2.0.44-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:11bac86b0deada30b6b5f93382712ff0e911fe8d31cb9bf46e6b149ae175eff0"}, + {file = "sqlalchemy-2.0.44-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:4d18cd0e9a0f37c9f4088e50e3839fcb69a380a0ec957408e0b57cff08ee0a26"}, + {file = "sqlalchemy-2.0.44-cp39-cp39-win32.whl", hash = "sha256:9e9018544ab07614d591a26c1bd4293ddf40752cc435caf69196740516af7100"}, + {file = "sqlalchemy-2.0.44-cp39-cp39-win_amd64.whl", hash = "sha256:8e0e4e66fd80f277a8c3de016a81a554e76ccf6b8d881ee0b53200305a8433f6"}, + {file = "sqlalchemy-2.0.44-py3-none-any.whl", hash = "sha256:19de7ca1246fbef9f9d1bff8f1ab25641569df226364a0e40457dc5457c54b05"}, + {file = "sqlalchemy-2.0.44.tar.gz", hash = "sha256:0ae7454e1ab1d780aee69fd2aae7d6b8670a581d8847f2d1e0f7ddfbf47e5a22"}, +] + +[package.dependencies] +greenlet = {version = ">=1", markers = "platform_machine == \"aarch64\" or platform_machine == \"ppc64le\" or platform_machine == \"x86_64\" or platform_machine == \"amd64\" or platform_machine == \"AMD64\" or platform_machine == \"win32\" or platform_machine == \"WIN32\""} typing-extensions = ">=4.6.0" [package.extras] @@ -7608,14 +8110,14 @@ tui = ["trogon"] [[package]] name = "sse-starlette" -version = "2.4.1" +version = "3.0.2" description = "SSE plugin for Starlette" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "sse_starlette-2.4.1-py3-none-any.whl", hash = "sha256:08b77ea898ab1a13a428b2b6f73cfe6d0e607a7b4e15b9bb23e4a37b087fd39a"}, - {file = "sse_starlette-2.4.1.tar.gz", hash = "sha256:7c8a800a1ca343e9165fc06bbda45c78e4c6166320707ae30b416c42da070926"}, + {file = "sse_starlette-3.0.2-py3-none-any.whl", hash = "sha256:16b7cbfddbcd4eaca11f7b586f3b8a080f1afe952c15813455b162edea619e5a"}, + {file = "sse_starlette-3.0.2.tar.gz", hash = "sha256:ccd60b5765ebb3584d0de2d7a6e4f745672581de4f5005ab31c3a25d10b52b3a"}, ] [package.dependencies] @@ -7623,39 +8125,42 @@ anyio = ">=4.7.0" [package.extras] daphne = ["daphne (>=4.2.0)"] -examples = ["aiosqlite (>=0.21.0)", "fastapi (>=0.115.12)", "sqlalchemy[asyncio,examples] (>=2.0.41)", "starlette (>=0.41.3)", "uvicorn (>=0.34.0)"] +examples = ["aiosqlite (>=0.21.0)", "fastapi (>=0.115.12)", "sqlalchemy[asyncio] (>=2.0.41)", "starlette (>=0.41.3)", "uvicorn (>=0.34.0)"] granian = ["granian (>=2.3.1)"] uvicorn = ["uvicorn (>=0.34.0)"] [[package]] name = "sssom" -version = "0.4.16" +version = "0.4.17" description = "Operations on SSSOM mapping tables" optional = false -python-versions = "<4.0.0,>=3.9" +python-versions = "<4.0.0,>=3.10" groups = ["main"] files = [ - {file = "sssom-0.4.16-py3-none-any.whl", hash = "sha256:02db2a20ae5a700d827715d517ce796022df403f4961ec852a4d4d0525ae33e5"}, - {file = "sssom-0.4.16.tar.gz", hash = "sha256:d0d925ae19525d986136ee993dc8f43ecef12115f5296cec5c75d5bc1696370c"}, + {file = "sssom-0.4.17-py3-none-any.whl", hash = "sha256:a7db403d568e826e73ea384ac2039ff32b61322be98fc4fafb22f0ac0cbd8620"}, + {file = "sssom-0.4.17.tar.gz", hash = "sha256:b8312997425d778af1c9225bba6dcbddd00951a5f3178b8e3bc7001be5f8f924"}, ] [package.dependencies] click = ">=8.1.6" curies = ">=0.10.18" -deprecation = ">=2.1.0,<3.0.0" -importlib-resources = ">=6.1.1,<7.0.0" +deprecation = ">=2.1.0" linkml = ">1.7.10" -linkml-runtime = ">=1.7.5,<2.0.0" -networkx = {version = ">=3.1", extras = ["networkx"]} +linkml-runtime = ">=1.7.5" pandas = ">1.0.3" -pansql = {version = ">=0.0.1", extras = ["pansql"]} -pyyaml = ">=6.0.1,<7.0.0" +pyyaml = ">=6.0.1" rdflib = ">=6.0.0" -scipy = {version = "*", extras = ["scipy"]} sparqlwrapper = ">=2.0.0" -sssom-schema = ">=1.0.0,<2.0.0" +sssom-schema = "1.0.0" validators = ">=0.20.0" +[package.extras] +docs = ["myst-parser (>=0.18.1)", "sphinx (>=6.1.3)", "sphinx-autodoc-typehints (>=1.2.0)", "sphinx-click (>=4.3.0)", "sphinx-rtd-theme (>=1.0.0)"] +networkx = ["networkx (>=3.1)"] +pansql = ["pansql (>=0.0.1)"] +rdflib-endpoint = ["fastapi", "httpx", "rdflib-endpoint", "uvicorn"] +scipy = ["scipy"] + [[package]] name = "sssom-schema" version = "1.0.0" @@ -7673,14 +8178,14 @@ linkml-runtime = "*" [[package]] name = "starlette" -version = "0.47.2" +version = "0.48.0" description = "The little ASGI library that shines." optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "starlette-0.47.2-py3-none-any.whl", hash = "sha256:c5847e96134e5c5371ee9fac6fdf1a67336d5815e09eb2a01fdb57a351ef915b"}, - {file = "starlette-0.47.2.tar.gz", hash = "sha256:6ae9aa5db235e4846decc1e7b79c4f346adf41e9777aebeb49dfd09bbd7023d8"}, + {file = "starlette-0.48.0-py3-none-any.whl", hash = "sha256:0764ca97b097582558ecb498132ed0c7d942f233f365b86ba37770e026510659"}, + {file = "starlette-0.48.0.tar.gz", hash = "sha256:7e8cee469a8ab2352911528110ce9088fdc6a37d9876926e73da7ce4aa4c7a46"}, ] [package.dependencies] @@ -7725,38 +8230,38 @@ widechars = ["wcwidth"] [[package]] name = "tantivy" -version = "0.24.0" +version = "0.25.0" description = "Official Python bindings for the Tantivy search engine" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "tantivy-0.24.0-cp310-cp310-macosx_10_12_x86_64.macosx_11_0_arm64.macosx_10_12_universal2.whl", hash = "sha256:1ebb01b1d54b9034d86b9ba73f395e99a4395df0ac375a3bc4c894895755e803"}, - {file = "tantivy-0.24.0-cp310-cp310-macosx_10_12_x86_64.whl", hash = "sha256:d272d5a44104f7c2c0e0fde9c92abab5dff5a7c35576fbc6072be48ce7d18fe0"}, - {file = "tantivy-0.24.0-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:3df864d2b50b57c528ea0ea6b708b405eb9545d8a77d465ceae364f0bff5c938"}, - {file = "tantivy-0.24.0-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:29e32e23fa2988ff82c0904b83239466d17bf0027a0f76982c3b58fd715c731d"}, - {file = "tantivy-0.24.0-cp310-none-win_amd64.whl", hash = "sha256:71d7590b36c2cd5dca08983b4af87cae80c402892d720f4101fc8a4e144f322b"}, - {file = "tantivy-0.24.0-cp311-cp311-macosx_10_12_x86_64.macosx_11_0_arm64.macosx_10_12_universal2.whl", hash = "sha256:0af621585a65016a7104adc5b4ab93be7510ee1e5e26a7034557c7efbae1a519"}, - {file = "tantivy-0.24.0-cp311-cp311-macosx_10_12_x86_64.whl", hash = "sha256:41105b984310363a57e6ee0dcb5385cc4ad484fb0f5c57fde2ce8ca0fcdb6c31"}, - {file = "tantivy-0.24.0-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:b1958accf29e18c400e3c9e8bec4d5a093b1478243a4dc9a097213c7b0883b3c"}, - {file = "tantivy-0.24.0-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:ec5ad8578cd190d1a09839bb8add732edb4414e04e1b3a3f13dcfa9af5ceb347"}, - {file = "tantivy-0.24.0-cp311-none-win_amd64.whl", hash = "sha256:0bc9dd935793cee66e18634a4c36756bf793637974ec16d6d9a72b789cae4d74"}, - {file = "tantivy-0.24.0-cp312-cp312-macosx_10_12_x86_64.macosx_11_0_arm64.macosx_10_12_universal2.whl", hash = "sha256:1db056810986a7ca99cee25ae8121716febacc7a2002202cc96e1a32fe0ff132"}, - {file = "tantivy-0.24.0-cp312-cp312-macosx_10_12_x86_64.whl", hash = "sha256:b723e1d52c2cffeb20a9c3661ae8e5a71bc527f97e01bb072cac8a93e7ba546d"}, - {file = "tantivy-0.24.0-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:0ffdff6962043b9bb637d93dcdd3572e52f1a5f9a8edcfe75881d7fd2ea90b69"}, - {file = "tantivy-0.24.0-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:d349edd90f463bf51f8e0a6441e7129ec178e6d7df78a42b9bd9d68e4793c5cc"}, - {file = "tantivy-0.24.0-cp312-none-win_amd64.whl", hash = "sha256:eab1db72776b0c42f675cf4a7dd64b41de89290afcc4932e90f7b104fdaa2a58"}, - {file = "tantivy-0.24.0-cp313-cp313-macosx_10_12_x86_64.macosx_11_0_arm64.macosx_10_12_universal2.whl", hash = "sha256:476752ba60b48f95c5182cdfd115491671b188d672f7af480189e27249a208ff"}, - {file = "tantivy-0.24.0-cp313-cp313-macosx_10_12_x86_64.whl", hash = "sha256:3f474b8a18ababaddb930548e816ac9ed78fa1f24ab103b7befebd004c5124b1"}, - {file = "tantivy-0.24.0-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:b18cc68b0cf8eb5c45935e225f2114252551ee9993799d5745f84dbd3adf8856"}, - {file = "tantivy-0.24.0-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:05ba05214eb1e935a3bff8dfd10af39c77fa4f1390ddb768b377b660e7eacdae"}, - {file = "tantivy-0.24.0-cp313-none-win_amd64.whl", hash = "sha256:9191e256b466f45ab2db6001853a6194407a66ffd575751632ab2d9ed8558a65"}, - {file = "tantivy-0.24.0-cp39-cp39-macosx_10_12_x86_64.macosx_11_0_arm64.macosx_10_12_universal2.whl", hash = "sha256:4212d03eac1949f212381ec87ce50091b6b9d0657fc75ac129f15b5c5bc1c0cf"}, - {file = "tantivy-0.24.0-cp39-cp39-macosx_10_12_x86_64.whl", hash = "sha256:e62735615944bd407306021c5caadfec5801a2eef9c101ddc0e51d16b46b60ba"}, - {file = "tantivy-0.24.0-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:57e4be77441fbfb065112ad979abf4781965896585613ffc7d7fbfa660a8c039"}, - {file = "tantivy-0.24.0-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:06732b06bd53d448908250956ee463a51a999d3300e09754315d658621ae74aa"}, - {file = "tantivy-0.24.0-cp39-none-win_amd64.whl", hash = "sha256:7c8fa4567b64372feef26a794050b2f7e9a10fdc752cddd7e400091c73c34066"}, - {file = "tantivy-0.24.0.tar.gz", hash = "sha256:70085830512501dc8104f4d7ae68c7b8f7a2c1d489fbfc6fe411184d5803710a"}, + {file = "tantivy-0.25.0-cp310-cp310-macosx_10_12_x86_64.macosx_11_0_arm64.macosx_10_12_universal2.whl", hash = "sha256:3783c1374713f759c77c86d3644ed98c9515e6c724ccfa899c6bb928eb79e541"}, + {file = "tantivy-0.25.0-cp310-cp310-macosx_10_12_x86_64.whl", hash = "sha256:c561f634bfc77dea96503def9a054d6c5b68a7fbf4d390387239169de2887b45"}, + {file = "tantivy-0.25.0-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:b84582cd91aa9995d329adce556e41704d473ca3894b8e559ac632bc837f3292"}, + {file = "tantivy-0.25.0-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:842c4ce3c4fb259aa791e538bc1992cf66f7f241a8e25cc661ee0c89437e8d99"}, + {file = "tantivy-0.25.0-cp310-none-win_amd64.whl", hash = "sha256:00ca3589f03ec832d72e5ff716968c2f125230cfb225a82dabebe79f8ac40d9c"}, + {file = "tantivy-0.25.0-cp311-cp311-macosx_10_12_x86_64.macosx_11_0_arm64.macosx_10_12_universal2.whl", hash = "sha256:918b167251d13d1ae1bac699a3a5400f0b0146507f19c44abda55e14d2a6f323"}, + {file = "tantivy-0.25.0-cp311-cp311-macosx_10_12_x86_64.whl", hash = "sha256:74213b84a8236233bc6d580d952614441e5525d96bdf3953715b8edec130dbce"}, + {file = "tantivy-0.25.0-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:66724d92abd414313c5c659dd950de07368263ae0d098c8693bace7667689ad0"}, + {file = "tantivy-0.25.0-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:c01fa1e090bd2ddb2c4a23722da7fd65e00f0576e4bf7769d8d033ba681a374d"}, + {file = "tantivy-0.25.0-cp311-none-win_amd64.whl", hash = "sha256:36dc1ec1ed52e6fd72f5614ebf65ec57d306a1d99a6941722cb22661187e349a"}, + {file = "tantivy-0.25.0-cp312-cp312-macosx_10_12_x86_64.macosx_11_0_arm64.macosx_10_12_universal2.whl", hash = "sha256:41c4ee2a3f3a095a933acf5222f922283db229fd15cb7c98d37e3a44596e4434"}, + {file = "tantivy-0.25.0-cp312-cp312-macosx_10_12_x86_64.whl", hash = "sha256:f5e6f893bf16308d121ad9afdeb703ed332ed05b0daa7268d5a7897b60d8d458"}, + {file = "tantivy-0.25.0-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:5e2c40e9aa6ebaca4e7d83b2bdf0af4b28cd2e4c1aa323b1aa71da1bdca24e09"}, + {file = "tantivy-0.25.0-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:6b0afc3e00982be99ce782f6e50ad6dd5696ebb24f7b46cbf6f4680df4a2cb34"}, + {file = "tantivy-0.25.0-cp312-none-win_amd64.whl", hash = "sha256:a976c5b77d7f561ae0a7877e516aae072604750994ad9934862b5c6e87d14f5a"}, + {file = "tantivy-0.25.0-cp313-cp313-macosx_10_12_x86_64.macosx_11_0_arm64.macosx_10_12_universal2.whl", hash = "sha256:af3b59b82ca3b9a5c67628b240557962a14dc9001fa5ef2825135cf9bb2562e0"}, + {file = "tantivy-0.25.0-cp313-cp313-macosx_10_12_x86_64.whl", hash = "sha256:4fe7abb005225a9ad18e925db471f34241c84feb88de43e8f8980b0b067b0444"}, + {file = "tantivy-0.25.0-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:7f73e4433599fdbf7e9524d81d520717505762a7688077ccb79402caf50a0a84"}, + {file = "tantivy-0.25.0-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:3815dcf503df089f2bc31d26f8e9e0aed8e7fa04b0079f977e53b227c1e297dc"}, + {file = "tantivy-0.25.0-cp313-none-win_amd64.whl", hash = "sha256:0e78872dd3aa357ce02a63feff1bfe9809092f7131bf3fe758c8fc74dce6f727"}, + {file = "tantivy-0.25.0-cp39-cp39-macosx_10_12_x86_64.macosx_11_0_arm64.macosx_10_12_universal2.whl", hash = "sha256:1a66682537907b824eb1ff6c685e198ed147a6025bc99f6d2bafe31bb26bb06b"}, + {file = "tantivy-0.25.0-cp39-cp39-macosx_10_12_x86_64.whl", hash = "sha256:c5f6b7b525336d9f712e2bf6b128164d464eb6beabb8f627d6ef3eabe3ecc473"}, + {file = "tantivy-0.25.0-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:4f196e7e08878157d5f315418ccaffd274137c106e9eb7b54c7e8d31ddbe8de5"}, + {file = "tantivy-0.25.0-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:9b690c17c0a3401f9f1e670732a407978312965f45d795a4aac91e032a8f40f6"}, + {file = "tantivy-0.25.0-cp39-none-win_amd64.whl", hash = "sha256:900fbb99cbc93f32aadb2b981397c84d6207a2e2af178a222b3ad01fb74ecf34"}, + {file = "tantivy-0.25.0.tar.gz", hash = "sha256:587acbaa08a6287eaa7591c21bc5af5a577c8a3c347b1121032241a5912f17b6"}, ] [package.extras] @@ -7764,14 +8269,14 @@ dev = ["nox"] [[package]] name = "tenacity" -version = "8.5.0" +version = "9.1.2" description = "Retry code until it succeeds" optional = false -python-versions = ">=3.8" +python-versions = ">=3.9" groups = ["main"] files = [ - {file = "tenacity-8.5.0-py3-none-any.whl", hash = "sha256:b594c2a5945830c267ce6b79a166228323ed52718f30302c1359836112346687"}, - {file = "tenacity-8.5.0.tar.gz", hash = "sha256:8bc6c0c8a09b31e6cad13c47afbed1a567518250a9a171418582ed8d9c20ca78"}, + {file = "tenacity-9.1.2-py3-none-any.whl", hash = "sha256:f77bf36710d8b73a50b2dd155c97b870017ad21afe6ab300326b0371b3b05138"}, + {file = "tenacity-9.1.2.tar.gz", hash = "sha256:1169d376c297e7de388d18b4481760d478b0e99a777cad3a9c86e556f4b697cb"}, ] [package.extras] @@ -7792,43 +8297,69 @@ files = [ [[package]] name = "tiktoken" -version = "0.9.0" +version = "0.12.0" description = "tiktoken is a fast BPE tokeniser for use with OpenAI's models" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "tiktoken-0.9.0-cp310-cp310-macosx_10_12_x86_64.whl", hash = "sha256:586c16358138b96ea804c034b8acf3f5d3f0258bd2bc3b0227af4af5d622e382"}, - {file = "tiktoken-0.9.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:d9c59ccc528c6c5dd51820b3474402f69d9a9e1d656226848ad68a8d5b2e5108"}, - {file = "tiktoken-0.9.0-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:f0968d5beeafbca2a72c595e8385a1a1f8af58feaebb02b227229b69ca5357fd"}, - {file = "tiktoken-0.9.0-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:92a5fb085a6a3b7350b8fc838baf493317ca0e17bd95e8642f95fc69ecfed1de"}, - {file = "tiktoken-0.9.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:15a2752dea63d93b0332fb0ddb05dd909371ededa145fe6a3242f46724fa7990"}, - {file = "tiktoken-0.9.0-cp310-cp310-win_amd64.whl", hash = "sha256:26113fec3bd7a352e4b33dbaf1bd8948de2507e30bd95a44e2b1156647bc01b4"}, - {file = "tiktoken-0.9.0-cp311-cp311-macosx_10_12_x86_64.whl", hash = "sha256:f32cc56168eac4851109e9b5d327637f15fd662aa30dd79f964b7c39fbadd26e"}, - {file = "tiktoken-0.9.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:45556bc41241e5294063508caf901bf92ba52d8ef9222023f83d2483a3055348"}, - {file = "tiktoken-0.9.0-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:03935988a91d6d3216e2ec7c645afbb3d870b37bcb67ada1943ec48678e7ee33"}, - {file = "tiktoken-0.9.0-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:8b3d80aad8d2c6b9238fc1a5524542087c52b860b10cbf952429ffb714bc1136"}, - {file = "tiktoken-0.9.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:b2a21133be05dc116b1d0372af051cd2c6aa1d2188250c9b553f9fa49301b336"}, - {file = "tiktoken-0.9.0-cp311-cp311-win_amd64.whl", hash = "sha256:11a20e67fdf58b0e2dea7b8654a288e481bb4fc0289d3ad21291f8d0849915fb"}, - {file = "tiktoken-0.9.0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:e88f121c1c22b726649ce67c089b90ddda8b9662545a8aeb03cfef15967ddd03"}, - {file = "tiktoken-0.9.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:a6600660f2f72369acb13a57fb3e212434ed38b045fd8cc6cdd74947b4b5d210"}, - {file = "tiktoken-0.9.0-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:95e811743b5dfa74f4b227927ed86cbc57cad4df859cb3b643be797914e41794"}, - {file = "tiktoken-0.9.0-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:99376e1370d59bcf6935c933cb9ba64adc29033b7e73f5f7569f3aad86552b22"}, - {file = "tiktoken-0.9.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:badb947c32739fb6ddde173e14885fb3de4d32ab9d8c591cbd013c22b4c31dd2"}, - {file = "tiktoken-0.9.0-cp312-cp312-win_amd64.whl", hash = "sha256:5a62d7a25225bafed786a524c1b9f0910a1128f4232615bf3f8257a73aaa3b16"}, - {file = "tiktoken-0.9.0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:2b0e8e05a26eda1249e824156d537015480af7ae222ccb798e5234ae0285dbdb"}, - {file = "tiktoken-0.9.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:27d457f096f87685195eea0165a1807fae87b97b2161fe8c9b1df5bd74ca6f63"}, - {file = "tiktoken-0.9.0-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:2cf8ded49cddf825390e36dd1ad35cd49589e8161fdcb52aa25f0583e90a3e01"}, - {file = "tiktoken-0.9.0-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:cc156cb314119a8bb9748257a2eaebd5cc0753b6cb491d26694ed42fc7cb3139"}, - {file = "tiktoken-0.9.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:cd69372e8c9dd761f0ab873112aba55a0e3e506332dd9f7522ca466e817b1b7a"}, - {file = "tiktoken-0.9.0-cp313-cp313-win_amd64.whl", hash = "sha256:5ea0edb6f83dc56d794723286215918c1cde03712cbbafa0348b33448faf5b95"}, - {file = "tiktoken-0.9.0-cp39-cp39-macosx_10_12_x86_64.whl", hash = "sha256:c6386ca815e7d96ef5b4ac61e0048cd32ca5a92d5781255e13b31381d28667dc"}, - {file = "tiktoken-0.9.0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:75f6d5db5bc2c6274b674ceab1615c1778e6416b14705827d19b40e6355f03e0"}, - {file = "tiktoken-0.9.0-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:e15b16f61e6f4625a57a36496d28dd182a8a60ec20a534c5343ba3cafa156ac7"}, - {file = "tiktoken-0.9.0-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:3ebcec91babf21297022882344c3f7d9eed855931466c3311b1ad6b64befb3df"}, - {file = "tiktoken-0.9.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:e5fd49e7799579240f03913447c0cdfa1129625ebd5ac440787afc4345990427"}, - {file = "tiktoken-0.9.0-cp39-cp39-win_amd64.whl", hash = "sha256:26242ca9dc8b58e875ff4ca078b9a94d2f0813e6a535dcd2205df5d49d927cc7"}, - {file = "tiktoken-0.9.0.tar.gz", hash = "sha256:d02a5ca6a938e0490e1ff957bc48c8b078c88cb83977be1625b1fd8aac792c5d"}, + {file = "tiktoken-0.12.0-cp310-cp310-macosx_10_12_x86_64.whl", hash = "sha256:3de02f5a491cfd179aec916eddb70331814bd6bf764075d39e21d5862e533970"}, + {file = "tiktoken-0.12.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:b6cfb6d9b7b54d20af21a912bfe63a2727d9cfa8fbda642fd8322c70340aad16"}, + {file = "tiktoken-0.12.0-cp310-cp310-manylinux_2_28_aarch64.whl", hash = "sha256:cde24cdb1b8a08368f709124f15b36ab5524aac5fa830cc3fdce9c03d4fb8030"}, + {file = "tiktoken-0.12.0-cp310-cp310-manylinux_2_28_x86_64.whl", hash = "sha256:6de0da39f605992649b9cfa6f84071e3f9ef2cec458d08c5feb1b6f0ff62e134"}, + {file = "tiktoken-0.12.0-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:6faa0534e0eefbcafaccb75927a4a380463a2eaa7e26000f0173b920e98b720a"}, + {file = "tiktoken-0.12.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:82991e04fc860afb933efb63957affc7ad54f83e2216fe7d319007dab1ba5892"}, + {file = "tiktoken-0.12.0-cp310-cp310-win_amd64.whl", hash = "sha256:6fb2995b487c2e31acf0a9e17647e3b242235a20832642bb7a9d1a181c0c1bb1"}, + {file = "tiktoken-0.12.0-cp311-cp311-macosx_10_12_x86_64.whl", hash = "sha256:6e227c7f96925003487c33b1b32265fad2fbcec2b7cf4817afb76d416f40f6bb"}, + {file = "tiktoken-0.12.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:c06cf0fcc24c2cb2adb5e185c7082a82cba29c17575e828518c2f11a01f445aa"}, + {file = "tiktoken-0.12.0-cp311-cp311-manylinux_2_28_aarch64.whl", hash = "sha256:f18f249b041851954217e9fd8e5c00b024ab2315ffda5ed77665a05fa91f42dc"}, + {file = "tiktoken-0.12.0-cp311-cp311-manylinux_2_28_x86_64.whl", hash = "sha256:47a5bc270b8c3db00bb46ece01ef34ad050e364b51d406b6f9730b64ac28eded"}, + {file = "tiktoken-0.12.0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:508fa71810c0efdcd1b898fda574889ee62852989f7c1667414736bcb2b9a4bd"}, + {file = "tiktoken-0.12.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:a1af81a6c44f008cba48494089dd98cccb8b313f55e961a52f5b222d1e507967"}, + {file = "tiktoken-0.12.0-cp311-cp311-win_amd64.whl", hash = "sha256:3e68e3e593637b53e56f7237be560f7a394451cb8c11079755e80ae64b9e6def"}, + {file = "tiktoken-0.12.0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:b97f74aca0d78a1ff21b8cd9e9925714c15a9236d6ceacf5c7327c117e6e21e8"}, + {file = "tiktoken-0.12.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:2b90f5ad190a4bb7c3eb30c5fa32e1e182ca1ca79f05e49b448438c3e225a49b"}, + {file = "tiktoken-0.12.0-cp312-cp312-manylinux_2_28_aarch64.whl", hash = "sha256:65b26c7a780e2139e73acc193e5c63ac754021f160df919add909c1492c0fb37"}, + {file = "tiktoken-0.12.0-cp312-cp312-manylinux_2_28_x86_64.whl", hash = "sha256:edde1ec917dfd21c1f2f8046b86348b0f54a2c0547f68149d8600859598769ad"}, + {file = "tiktoken-0.12.0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:35a2f8ddd3824608b3d650a000c1ef71f730d0c56486845705a8248da00f9fe5"}, + {file = "tiktoken-0.12.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:83d16643edb7fa2c99eff2ab7733508aae1eebb03d5dfc46f5565862810f24e3"}, + {file = "tiktoken-0.12.0-cp312-cp312-win_amd64.whl", hash = "sha256:ffc5288f34a8bc02e1ea7047b8d041104791d2ddbf42d1e5fa07822cbffe16bd"}, + {file = "tiktoken-0.12.0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:775c2c55de2310cc1bc9a3ad8826761cbdc87770e586fd7b6da7d4589e13dab3"}, + {file = "tiktoken-0.12.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:a01b12f69052fbe4b080a2cfb867c4de12c704b56178edf1d1d7b273561db160"}, + {file = "tiktoken-0.12.0-cp313-cp313-manylinux_2_28_aarch64.whl", hash = "sha256:01d99484dc93b129cd0964f9d34eee953f2737301f18b3c7257bf368d7615baa"}, + {file = "tiktoken-0.12.0-cp313-cp313-manylinux_2_28_x86_64.whl", hash = "sha256:4a1a4fcd021f022bfc81904a911d3df0f6543b9e7627b51411da75ff2fe7a1be"}, + {file = "tiktoken-0.12.0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:981a81e39812d57031efdc9ec59fa32b2a5a5524d20d4776574c4b4bd2e9014a"}, + {file = "tiktoken-0.12.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:9baf52f84a3f42eef3ff4e754a0db79a13a27921b457ca9832cf944c6be4f8f3"}, + {file = "tiktoken-0.12.0-cp313-cp313-win_amd64.whl", hash = "sha256:b8a0cd0c789a61f31bf44851defbd609e8dd1e2c8589c614cc1060940ef1f697"}, + {file = "tiktoken-0.12.0-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:d5f89ea5680066b68bcb797ae85219c72916c922ef0fcdd3480c7d2315ffff16"}, + {file = "tiktoken-0.12.0-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:b4e7ed1c6a7a8a60a3230965bdedba8cc58f68926b835e519341413370e0399a"}, + {file = "tiktoken-0.12.0-cp313-cp313t-manylinux_2_28_aarch64.whl", hash = "sha256:fc530a28591a2d74bce821d10b418b26a094bf33839e69042a6e86ddb7a7fb27"}, + {file = "tiktoken-0.12.0-cp313-cp313t-manylinux_2_28_x86_64.whl", hash = "sha256:06a9f4f49884139013b138920a4c393aa6556b2f8f536345f11819389c703ebb"}, + {file = "tiktoken-0.12.0-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:04f0e6a985d95913cabc96a741c5ffec525a2c72e9df086ff17ebe35985c800e"}, + {file = "tiktoken-0.12.0-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:0ee8f9ae00c41770b5f9b0bb1235474768884ae157de3beb5439ca0fd70f3e25"}, + {file = "tiktoken-0.12.0-cp313-cp313t-win_amd64.whl", hash = "sha256:dc2dd125a62cb2b3d858484d6c614d136b5b848976794edfb63688d539b8b93f"}, + {file = "tiktoken-0.12.0-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:a90388128df3b3abeb2bfd1895b0681412a8d7dc644142519e6f0a97c2111646"}, + {file = "tiktoken-0.12.0-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:da900aa0ad52247d8794e307d6446bd3cdea8e192769b56276695d34d2c9aa88"}, + {file = "tiktoken-0.12.0-cp314-cp314-manylinux_2_28_aarch64.whl", hash = "sha256:285ba9d73ea0d6171e7f9407039a290ca77efcdb026be7769dccc01d2c8d7fff"}, + {file = "tiktoken-0.12.0-cp314-cp314-manylinux_2_28_x86_64.whl", hash = "sha256:d186a5c60c6a0213f04a7a802264083dea1bbde92a2d4c7069e1a56630aef830"}, + {file = "tiktoken-0.12.0-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:604831189bd05480f2b885ecd2d1986dc7686f609de48208ebbbddeea071fc0b"}, + {file = "tiktoken-0.12.0-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:8f317e8530bb3a222547b85a58583238c8f74fd7a7408305f9f63246d1a0958b"}, + {file = "tiktoken-0.12.0-cp314-cp314-win_amd64.whl", hash = "sha256:399c3dd672a6406719d84442299a490420b458c44d3ae65516302a99675888f3"}, + {file = "tiktoken-0.12.0-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:c2c714c72bc00a38ca969dae79e8266ddec999c7ceccd603cc4f0d04ccd76365"}, + {file = "tiktoken-0.12.0-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:cbb9a3ba275165a2cb0f9a83f5d7025afe6b9d0ab01a22b50f0e74fee2ad253e"}, + {file = "tiktoken-0.12.0-cp314-cp314t-manylinux_2_28_aarch64.whl", hash = "sha256:dfdfaa5ffff8993a3af94d1125870b1d27aed7cb97aa7eb8c1cefdbc87dbee63"}, + {file = "tiktoken-0.12.0-cp314-cp314t-manylinux_2_28_x86_64.whl", hash = "sha256:584c3ad3d0c74f5269906eb8a659c8bfc6144a52895d9261cdaf90a0ae5f4de0"}, + {file = "tiktoken-0.12.0-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:54c891b416a0e36b8e2045b12b33dd66fb34a4fe7965565f1b482da50da3e86a"}, + {file = "tiktoken-0.12.0-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:5edb8743b88d5be814b1a8a8854494719080c28faaa1ccbef02e87354fe71ef0"}, + {file = "tiktoken-0.12.0-cp314-cp314t-win_amd64.whl", hash = "sha256:f61c0aea5565ac82e2ec50a05e02a6c44734e91b51c10510b084ea1b8e633a71"}, + {file = "tiktoken-0.12.0-cp39-cp39-macosx_10_12_x86_64.whl", hash = "sha256:d51d75a5bffbf26f86554d28e78bfb921eae998edc2675650fd04c7e1f0cdc1e"}, + {file = "tiktoken-0.12.0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:09eb4eae62ae7e4c62364d9ec3a57c62eea707ac9a2b2c5d6bd05de6724ea179"}, + {file = "tiktoken-0.12.0-cp39-cp39-manylinux_2_28_aarch64.whl", hash = "sha256:df37684ace87d10895acb44b7f447d4700349b12197a526da0d4a4149fde074c"}, + {file = "tiktoken-0.12.0-cp39-cp39-manylinux_2_28_x86_64.whl", hash = "sha256:4c9614597ac94bb294544345ad8cf30dac2129c05e2db8dc53e082f355857af7"}, + {file = "tiktoken-0.12.0-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:20cf97135c9a50de0b157879c3c4accbb29116bcf001283d26e073ff3b345946"}, + {file = "tiktoken-0.12.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:15d875454bbaa3728be39880ddd11a5a2a9e548c29418b41e8fd8a767172b5ec"}, + {file = "tiktoken-0.12.0-cp39-cp39-win_amd64.whl", hash = "sha256:2cff3688ba3c639ebe816f8d58ffbbb0aa7433e23e08ab1cade5d175fc973fb3"}, + {file = "tiktoken-0.12.0.tar.gz", hash = "sha256:b18ba7ee2b093863978fcb14f74b3707cdc8d4d4d3836853ce7ec60772139931"}, ] [package.dependencies] @@ -7859,36 +8390,36 @@ test = ["pytest", "ruff"] [[package]] name = "tokenizers" -version = "0.21.2" +version = "0.22.1" description = "" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "tokenizers-0.21.2-cp39-abi3-macosx_10_12_x86_64.whl", hash = "sha256:342b5dfb75009f2255ab8dec0041287260fed5ce00c323eb6bab639066fef8ec"}, - {file = "tokenizers-0.21.2-cp39-abi3-macosx_11_0_arm64.whl", hash = "sha256:126df3205d6f3a93fea80c7a8a266a78c1bd8dd2fe043386bafdd7736a23e45f"}, - {file = "tokenizers-0.21.2-cp39-abi3-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:4a32cd81be21168bd0d6a0f0962d60177c447a1aa1b1e48fa6ec9fc728ee0b12"}, - {file = "tokenizers-0.21.2-cp39-abi3-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:8bd8999538c405133c2ab999b83b17c08b7fc1b48c1ada2469964605a709ef91"}, - {file = "tokenizers-0.21.2-cp39-abi3-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:5e9944e61239b083a41cf8fc42802f855e1dca0f499196df37a8ce219abac6eb"}, - {file = "tokenizers-0.21.2-cp39-abi3-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:514cd43045c5d546f01142ff9c79a96ea69e4b5cda09e3027708cb2e6d5762ab"}, - {file = "tokenizers-0.21.2-cp39-abi3-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:b1b9405822527ec1e0f7d8d2fdb287a5730c3a6518189c968254a8441b21faae"}, - {file = "tokenizers-0.21.2-cp39-abi3-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:fed9a4d51c395103ad24f8e7eb976811c57fbec2af9f133df471afcd922e5020"}, - {file = "tokenizers-0.21.2-cp39-abi3-musllinux_1_2_aarch64.whl", hash = "sha256:2c41862df3d873665ec78b6be36fcc30a26e3d4902e9dd8608ed61d49a48bc19"}, - {file = "tokenizers-0.21.2-cp39-abi3-musllinux_1_2_armv7l.whl", hash = "sha256:ed21dc7e624e4220e21758b2e62893be7101453525e3d23264081c9ef9a6d00d"}, - {file = "tokenizers-0.21.2-cp39-abi3-musllinux_1_2_i686.whl", hash = "sha256:0e73770507e65a0e0e2a1affd6b03c36e3bc4377bd10c9ccf51a82c77c0fe365"}, - {file = "tokenizers-0.21.2-cp39-abi3-musllinux_1_2_x86_64.whl", hash = "sha256:106746e8aa9014a12109e58d540ad5465b4c183768ea96c03cbc24c44d329958"}, - {file = "tokenizers-0.21.2-cp39-abi3-win32.whl", hash = "sha256:cabda5a6d15d620b6dfe711e1af52205266d05b379ea85a8a301b3593c60e962"}, - {file = "tokenizers-0.21.2-cp39-abi3-win_amd64.whl", hash = "sha256:58747bb898acdb1007f37a7bbe614346e98dc28708ffb66a3fd50ce169ac6c98"}, - {file = "tokenizers-0.21.2.tar.gz", hash = "sha256:fdc7cffde3e2113ba0e6cc7318c40e3438a4d74bbc62bf04bcc63bdfb082ac77"}, + {file = "tokenizers-0.22.1-cp39-abi3-macosx_10_12_x86_64.whl", hash = "sha256:59fdb013df17455e5f950b4b834a7b3ee2e0271e6378ccb33aa74d178b513c73"}, + {file = "tokenizers-0.22.1-cp39-abi3-macosx_11_0_arm64.whl", hash = "sha256:8d4e484f7b0827021ac5f9f71d4794aaef62b979ab7608593da22b1d2e3c4edc"}, + {file = "tokenizers-0.22.1-cp39-abi3-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:19d2962dd28bc67c1f205ab180578a78eef89ac60ca7ef7cbe9635a46a56422a"}, + {file = "tokenizers-0.22.1-cp39-abi3-manylinux_2_17_armv7l.manylinux2014_armv7l.whl", hash = "sha256:38201f15cdb1f8a6843e6563e6e79f4abd053394992b9bbdf5213ea3469b4ae7"}, + {file = "tokenizers-0.22.1-cp39-abi3-manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:d1cbe5454c9a15df1b3443c726063d930c16f047a3cc724b9e6e1a91140e5a21"}, + {file = "tokenizers-0.22.1-cp39-abi3-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:e7d094ae6312d69cc2a872b54b91b309f4f6fbce871ef28eb27b52a98e4d0214"}, + {file = "tokenizers-0.22.1-cp39-abi3-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:afd7594a56656ace95cdd6df4cca2e4059d294c5cfb1679c57824b605556cb2f"}, + {file = "tokenizers-0.22.1-cp39-abi3-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:e2ef6063d7a84994129732b47e7915e8710f27f99f3a3260b8a38fc7ccd083f4"}, + {file = "tokenizers-0.22.1-cp39-abi3-musllinux_1_2_aarch64.whl", hash = "sha256:ba0a64f450b9ef412c98f6bcd2a50c6df6e2443b560024a09fa6a03189726879"}, + {file = "tokenizers-0.22.1-cp39-abi3-musllinux_1_2_armv7l.whl", hash = "sha256:331d6d149fa9c7d632cde4490fb8bbb12337fa3a0232e77892be656464f4b446"}, + {file = "tokenizers-0.22.1-cp39-abi3-musllinux_1_2_i686.whl", hash = "sha256:607989f2ea68a46cb1dfbaf3e3aabdf3f21d8748312dbeb6263d1b3b66c5010a"}, + {file = "tokenizers-0.22.1-cp39-abi3-musllinux_1_2_x86_64.whl", hash = "sha256:a0f307d490295717726598ef6fa4f24af9d484809223bbc253b201c740a06390"}, + {file = "tokenizers-0.22.1-cp39-abi3-win32.whl", hash = "sha256:b5120eed1442765cd90b903bb6cfef781fd8fe64e34ccaecbae4c619b7b12a82"}, + {file = "tokenizers-0.22.1-cp39-abi3-win_amd64.whl", hash = "sha256:65fd6e3fb11ca1e78a6a93602490f134d1fdeb13bcef99389d5102ea318ed138"}, + {file = "tokenizers-0.22.1.tar.gz", hash = "sha256:61de6522785310a309b3407bac22d99c4db5dba349935e99e4d15ea2226af2d9"}, ] [package.dependencies] -huggingface-hub = ">=0.16.4,<1.0" +huggingface-hub = ">=0.16.4,<2.0" [package.extras] dev = ["tokenizers[testing]"] docs = ["setuptools-rust", "sphinx", "sphinx-rtd-theme"] -testing = ["black (==22.3)", "datasets", "numpy", "pytest", "requests", "ruff"] +testing = ["black (==22.3)", "datasets", "numpy", "pytest", "pytest-asyncio", "requests", "ruff"] [[package]] name = "tomlkit" @@ -7905,29 +8436,26 @@ files = [ [[package]] name = "tox" -version = "4.27.0" +version = "4.31.0" description = "tox is a generic virtualenv management and test command line tool" optional = false -python-versions = ">=3.9" +python-versions = ">=3.10" groups = ["dev"] files = [ - {file = "tox-4.27.0-py3-none-any.whl", hash = "sha256:2b8a7fb986b82aa2c830c0615082a490d134e0626dbc9189986da46a313c4f20"}, - {file = "tox-4.27.0.tar.gz", hash = "sha256:b97d5ecc0c0d5755bcc5348387fef793e1bfa68eb33746412f4c60881d7f5f57"}, + {file = "tox-4.31.0-py3-none-any.whl", hash = "sha256:328f392e6567e46cb0f9b625679456744dde940287dd1b39117627dc4b21d5da"}, + {file = "tox-4.31.0.tar.gz", hash = "sha256:266381ffef35615ec0d40ae4969a9e43b506017597c0413d6545a603cc8c7561"}, ] [package.dependencies] -cachetools = ">=5.5.1" +cachetools = ">=6.2" chardet = ">=5.2" colorama = ">=0.4.6" -filelock = ">=3.16.1" -packaging = ">=24.2" -platformdirs = ">=4.3.6" -pluggy = ">=1.5" -pyproject-api = ">=1.8" -virtualenv = ">=20.31" - -[package.extras] -test = ["devpi-process (>=1.0.2)", "pytest (>=8.3.4)", "pytest-mock (>=3.14)"] +filelock = ">=3.20" +packaging = ">=25" +platformdirs = ">=4.5" +pluggy = ">=1.6" +pyproject-api = ">=1.9.1" +virtualenv = ">=20.34" [[package]] name = "tqdm" @@ -7953,14 +8481,14 @@ telegram = ["requests"] [[package]] name = "trio" -version = "0.30.0" +version = "0.31.0" description = "A friendly Python library for async concurrency and I/O" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "trio-0.30.0-py3-none-any.whl", hash = "sha256:3bf4f06b8decf8d3cf00af85f40a89824669e2d033bb32469d34840edcfc22a5"}, - {file = "trio-0.30.0.tar.gz", hash = "sha256:0781c857c0c81f8f51e0089929a26b5bb63d57f927728a5586f7e36171f064df"}, + {file = "trio-0.31.0-py3-none-any.whl", hash = "sha256:b5d14cd6293d79298b49c3485ffd9c07e3ce03a6da8c7dfbe0cb3dd7dc9a4774"}, + {file = "trio-0.31.0.tar.gz", hash = "sha256:f71d551ccaa79d0cb73017a33ef3264fde8335728eb4c6391451fe5d253a9d5b"}, ] [package.dependencies] @@ -7990,14 +8518,14 @@ wsproto = ">=0.14" [[package]] name = "typer" -version = "0.16.0" +version = "0.19.2" description = "Typer, build great CLIs. Easy to code. Based on Python type hints." optional = false -python-versions = ">=3.7" +python-versions = ">=3.8" groups = ["main"] files = [ - {file = "typer-0.16.0-py3-none-any.whl", hash = "sha256:1f79bed11d4d02d4310e3c1b7ba594183bcedb0ac73b27a9e5f28f6fb5b98855"}, - {file = "typer-0.16.0.tar.gz", hash = "sha256:af377ffaee1dbe37ae9440cb4e8f11686ea5ce4e9bae01b84ae7c63b87f1dd3b"}, + {file = "typer-0.19.2-py3-none-any.whl", hash = "sha256:755e7e19670ffad8283db353267cb81ef252f595aa6834a0d1ca9312d9326cb9"}, + {file = "typer-0.19.2.tar.gz", hash = "sha256:9ad824308ded0ad06cc716434705f691d4ee0bfd0fb081839d2e426860e7fdca"}, ] [package.dependencies] @@ -8008,27 +8536,27 @@ typing-extensions = ">=3.7.4.3" [[package]] name = "types-python-dateutil" -version = "2.9.0.20250708" +version = "2.9.0.20251008" description = "Typing stubs for python-dateutil" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "types_python_dateutil-2.9.0.20250708-py3-none-any.whl", hash = "sha256:4d6d0cc1cc4d24a2dc3816024e502564094497b713f7befda4d5bc7a8e3fd21f"}, - {file = "types_python_dateutil-2.9.0.20250708.tar.gz", hash = "sha256:ccdbd75dab2d6c9696c350579f34cffe2c281e4c5f27a585b2a2438dd1d5c8ab"}, + {file = "types_python_dateutil-2.9.0.20251008-py3-none-any.whl", hash = "sha256:b9a5232c8921cf7661b29c163ccc56055c418ab2c6eabe8f917cbcc73a4c4157"}, + {file = "types_python_dateutil-2.9.0.20251008.tar.gz", hash = "sha256:c3826289c170c93ebd8360c3485311187df740166dbab9dd3b792e69f2bc1f9c"}, ] [[package]] name = "types-requests" -version = "2.32.4.20250611" +version = "2.32.4.20250913" description = "Typing stubs for requests" optional = false python-versions = ">=3.9" groups = ["main"] markers = "platform_system != \"Emscripten\"" files = [ - {file = "types_requests-2.32.4.20250611-py3-none-any.whl", hash = "sha256:ad2fe5d3b0cb3c2c902c8815a70e7fb2302c4b8c1f77bdcd738192cdb3878072"}, - {file = "types_requests-2.32.4.20250611.tar.gz", hash = "sha256:741c8777ed6425830bf51e54d6abe245f79b4dcb9019f1622b773463946bf826"}, + {file = "types_requests-2.32.4.20250913-py3-none-any.whl", hash = "sha256:78c9c1fffebbe0fa487a418e0fa5252017e9c60d1a2da394077f1780f655d7e1"}, + {file = "types_requests-2.32.4.20250913.tar.gz", hash = "sha256:abd6d4f9ce3a9383f269775a9835a4c24e5cd6b9f647d64f88aa4613c33def5d"}, ] [package.dependencies] @@ -8036,26 +8564,26 @@ urllib3 = ">=2" [[package]] name = "typing-extensions" -version = "4.14.1" +version = "4.15.0" description = "Backported and Experimental Type Hints for Python 3.9+" optional = false python-versions = ">=3.9" groups = ["main", "dev"] files = [ - {file = "typing_extensions-4.14.1-py3-none-any.whl", hash = "sha256:d1e1e3b58374dc93031d6eda2420a48ea44a36c2b4766a4fdeb3710755731d76"}, - {file = "typing_extensions-4.14.1.tar.gz", hash = "sha256:38b39f4aeeab64884ce9f74c94263ef78f3c22467c8724005483154c26648d36"}, + {file = "typing_extensions-4.15.0-py3-none-any.whl", hash = "sha256:f0fa19c6845758ab08074a0cfa8b7aecb71c999ca73d62883bc25cc018c4e548"}, + {file = "typing_extensions-4.15.0.tar.gz", hash = "sha256:0cea48d173cc12fa28ecabc3b837ea3cf6f38c6d1136f85cbaaf598984861466"}, ] [[package]] name = "typing-inspection" -version = "0.4.1" +version = "0.4.2" description = "Runtime typing introspection tools" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "typing_inspection-0.4.1-py3-none-any.whl", hash = "sha256:389055682238f53b04f7badcb49b989835495a96700ced5dab2d8feae4b26f51"}, - {file = "typing_inspection-0.4.1.tar.gz", hash = "sha256:6ae134cc0203c33377d43188d4064e9b357dba58cff3185f22924610e70a9d28"}, + {file = "typing_inspection-0.4.2-py3-none-any.whl", hash = "sha256:4ed1cacbdc298c220f1bd249ed5287caa16f34d44ef4e9c3d0cbad5b521545e7"}, + {file = "typing_inspection-0.4.2.tar.gz", hash = "sha256:ba561c48a67c5958007083d386c3295464928b01faa735ab8547c5692e87f464"}, ] [package.dependencies] @@ -8145,15 +8673,15 @@ zstd = ["zstandard (>=0.18.0)"] [[package]] name = "uvicorn" -version = "0.35.0" +version = "0.37.0" description = "The lightning-fast ASGI server." optional = false python-versions = ">=3.9" groups = ["main"] -markers = "sys_platform != \"emscripten\"" +markers = "sys_platform != \"emscripten\" or extra == \"gradio\"" files = [ - {file = "uvicorn-0.35.0-py3-none-any.whl", hash = "sha256:197535216b25ff9b785e29a0b79199f55222193d47f820816e7da751e9bc8d4a"}, - {file = "uvicorn-0.35.0.tar.gz", hash = "sha256:bc662f087f7cf2ce11a1d7fd70b90c9f98ef2e2831556dd078d131b96cc94a01"}, + {file = "uvicorn-0.37.0-py3-none-any.whl", hash = "sha256:913b2b88672343739927ce381ff9e2ad62541f9f8289664fa1d1d3803fa2ce6c"}, + {file = "uvicorn-0.37.0.tar.gz", hash = "sha256:4115c8add6d3fd536c8ee77f0e14a7fd2ebba939fed9b02583a97f80648f9e13"}, ] [package.dependencies] @@ -8180,14 +8708,14 @@ crypto-eth-addresses = ["eth-hash[pycryptodome] (>=0.7.0)"] [[package]] name = "virtualenv" -version = "20.32.0" +version = "20.35.3" description = "Virtual Python Environment builder" optional = false python-versions = ">=3.8" groups = ["dev"] files = [ - {file = "virtualenv-20.32.0-py3-none-any.whl", hash = "sha256:2c310aecb62e5aa1b06103ed7c2977b81e042695de2697d01017ff0f1034af56"}, - {file = "virtualenv-20.32.0.tar.gz", hash = "sha256:886bf75cadfdc964674e6e33eb74d787dff31ca314ceace03ca5810620f4ecf0"}, + {file = "virtualenv-20.35.3-py3-none-any.whl", hash = "sha256:63d106565078d8c8d0b206d48080f938a8b25361e19432d2c9db40d2899c810a"}, + {file = "virtualenv-20.35.3.tar.gz", hash = "sha256:4f1a845d131133bdff10590489610c98c168ff99dc75d6c96853801f7f67af44"}, ] [package.dependencies] @@ -8244,14 +8772,14 @@ watchmedo = ["PyYAML (>=3.10)"] [[package]] name = "wcwidth" -version = "0.2.13" +version = "0.2.14" description = "Measures the displayed width of unicode strings in a terminal" optional = false -python-versions = "*" +python-versions = ">=3.6" groups = ["main"] files = [ - {file = "wcwidth-0.2.13-py2.py3-none-any.whl", hash = "sha256:3da69048e4540d84af32131829ff948f1e022c1c6bdb8d6102117aac784f6859"}, - {file = "wcwidth-0.2.13.tar.gz", hash = "sha256:72ea0c06399eb286d978fdedb6923a9eb47e1c486ce63e9b4e64fc18303972b5"}, + {file = "wcwidth-0.2.14-py2.py3-none-any.whl", hash = "sha256:a7bb560c8aee30f9957e5f9895805edd20602f2d7f720186dfd906e82b4982e1"}, + {file = "wcwidth-0.2.14.tar.gz", hash = "sha256:4d478375d31bc5395a3c55c40ccdf3354688364cd61c4f6adacaa9215d0b3605"}, ] [[package]] @@ -8280,20 +8808,20 @@ files = [ [[package]] name = "websocket-client" -version = "1.8.0" +version = "1.9.0" description = "WebSocket client for Python with low level API options" optional = false -python-versions = ">=3.8" +python-versions = ">=3.9" groups = ["main"] files = [ - {file = "websocket_client-1.8.0-py3-none-any.whl", hash = "sha256:17b44cc997f5c498e809b22cdf2d9c7a9e71c02c8cc2b6c56e7c2d1239bfa526"}, - {file = "websocket_client-1.8.0.tar.gz", hash = "sha256:3239df9f44da632f96012472805d40a23281a991027ce11d2f45a6f24ac4c3da"}, + {file = "websocket_client-1.9.0-py3-none-any.whl", hash = "sha256:af248a825037ef591efbf6ed20cc5faa03d3b47b9e5a2230a529eeee1c1fc3ef"}, + {file = "websocket_client-1.9.0.tar.gz", hash = "sha256:9e813624b6eb619999a97dc7958469217c3176312b3a16a4bd1bc7e08a46ec98"}, ] [package.extras] -docs = ["Sphinx (>=6.0)", "myst-parser (>=2.0.0)", "sphinx-rtd-theme (>=1.1.0)"] +docs = ["Sphinx (>=6.0)", "myst-parser (>=2.0.0)", "sphinx_rtd_theme (>=1.1.0)"] optional = ["python-socks", "wsaccel"] -test = ["websockets"] +test = ["pytest", "websockets"] [[package]] name = "websockets" @@ -8391,91 +8919,93 @@ requests = ">=2.0.0,<3.0.0" [[package]] name = "wrapt" -version = "1.17.2" +version = "1.17.3" description = "Module for decorators, wrappers and monkey patching." optional = false python-versions = ">=3.8" groups = ["main"] files = [ - {file = "wrapt-1.17.2-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:3d57c572081fed831ad2d26fd430d565b76aa277ed1d30ff4d40670b1c0dd984"}, - {file = "wrapt-1.17.2-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:b5e251054542ae57ac7f3fba5d10bfff615b6c2fb09abeb37d2f1463f841ae22"}, - {file = "wrapt-1.17.2-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:80dd7db6a7cb57ffbc279c4394246414ec99537ae81ffd702443335a61dbf3a7"}, - {file = "wrapt-1.17.2-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:0a6e821770cf99cc586d33833b2ff32faebdbe886bd6322395606cf55153246c"}, - {file = "wrapt-1.17.2-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:b60fb58b90c6d63779cb0c0c54eeb38941bae3ecf7a73c764c52c88c2dcb9d72"}, - {file = "wrapt-1.17.2-cp310-cp310-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:b870b5df5b71d8c3359d21be8f0d6c485fa0ebdb6477dda51a1ea54a9b558061"}, - {file = "wrapt-1.17.2-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:4011d137b9955791f9084749cba9a367c68d50ab8d11d64c50ba1688c9b457f2"}, - {file = "wrapt-1.17.2-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:1473400e5b2733e58b396a04eb7f35f541e1fb976d0c0724d0223dd607e0f74c"}, - {file = "wrapt-1.17.2-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:3cedbfa9c940fdad3e6e941db7138e26ce8aad38ab5fe9dcfadfed9db7a54e62"}, - {file = "wrapt-1.17.2-cp310-cp310-win32.whl", hash = "sha256:582530701bff1dec6779efa00c516496968edd851fba224fbd86e46cc6b73563"}, - {file = "wrapt-1.17.2-cp310-cp310-win_amd64.whl", hash = "sha256:58705da316756681ad3c9c73fd15499aa4d8c69f9fd38dc8a35e06c12468582f"}, - {file = "wrapt-1.17.2-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:ff04ef6eec3eee8a5efef2401495967a916feaa353643defcc03fc74fe213b58"}, - {file = "wrapt-1.17.2-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:4db983e7bca53819efdbd64590ee96c9213894272c776966ca6306b73e4affda"}, - {file = "wrapt-1.17.2-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:9abc77a4ce4c6f2a3168ff34b1da9b0f311a8f1cfd694ec96b0603dff1c79438"}, - {file = "wrapt-1.17.2-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:0b929ac182f5ace000d459c59c2c9c33047e20e935f8e39371fa6e3b85d56f4a"}, - {file = "wrapt-1.17.2-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:f09b286faeff3c750a879d336fb6d8713206fc97af3adc14def0cdd349df6000"}, - {file = "wrapt-1.17.2-cp311-cp311-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:1a7ed2d9d039bd41e889f6fb9364554052ca21ce823580f6a07c4ec245c1f5d6"}, - {file = "wrapt-1.17.2-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:129a150f5c445165ff941fc02ee27df65940fcb8a22a61828b1853c98763a64b"}, - {file = "wrapt-1.17.2-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:1fb5699e4464afe5c7e65fa51d4f99e0b2eadcc176e4aa33600a3df7801d6662"}, - {file = "wrapt-1.17.2-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:9a2bce789a5ea90e51a02dfcc39e31b7f1e662bc3317979aa7e5538e3a034f72"}, - {file = "wrapt-1.17.2-cp311-cp311-win32.whl", hash = "sha256:4afd5814270fdf6380616b321fd31435a462019d834f83c8611a0ce7484c7317"}, - {file = "wrapt-1.17.2-cp311-cp311-win_amd64.whl", hash = "sha256:acc130bc0375999da18e3d19e5a86403667ac0c4042a094fefb7eec8ebac7cf3"}, - {file = "wrapt-1.17.2-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:d5e2439eecc762cd85e7bd37161d4714aa03a33c5ba884e26c81559817ca0925"}, - {file = "wrapt-1.17.2-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:3fc7cb4c1c744f8c05cd5f9438a3caa6ab94ce8344e952d7c45a8ed59dd88392"}, - {file = "wrapt-1.17.2-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:8fdbdb757d5390f7c675e558fd3186d590973244fab0c5fe63d373ade3e99d40"}, - {file = "wrapt-1.17.2-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:5bb1d0dbf99411f3d871deb6faa9aabb9d4e744d67dcaaa05399af89d847a91d"}, - {file = "wrapt-1.17.2-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:d18a4865f46b8579d44e4fe1e2bcbc6472ad83d98e22a26c963d46e4c125ef0b"}, - {file = "wrapt-1.17.2-cp312-cp312-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:bc570b5f14a79734437cb7b0500376b6b791153314986074486e0b0fa8d71d98"}, - {file = "wrapt-1.17.2-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:6d9187b01bebc3875bac9b087948a2bccefe464a7d8f627cf6e48b1bbae30f82"}, - {file = "wrapt-1.17.2-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:9e8659775f1adf02eb1e6f109751268e493c73716ca5761f8acb695e52a756ae"}, - {file = "wrapt-1.17.2-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:e8b2816ebef96d83657b56306152a93909a83f23994f4b30ad4573b00bd11bb9"}, - {file = "wrapt-1.17.2-cp312-cp312-win32.whl", hash = "sha256:468090021f391fe0056ad3e807e3d9034e0fd01adcd3bdfba977b6fdf4213ea9"}, - {file = "wrapt-1.17.2-cp312-cp312-win_amd64.whl", hash = "sha256:ec89ed91f2fa8e3f52ae53cd3cf640d6feff92ba90d62236a81e4e563ac0e991"}, - {file = "wrapt-1.17.2-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:6ed6ffac43aecfe6d86ec5b74b06a5be33d5bb9243d055141e8cabb12aa08125"}, - {file = "wrapt-1.17.2-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:35621ae4c00e056adb0009f8e86e28eb4a41a4bfa8f9bfa9fca7d343fe94f998"}, - {file = "wrapt-1.17.2-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:a604bf7a053f8362d27eb9fefd2097f82600b856d5abe996d623babd067b1ab5"}, - {file = "wrapt-1.17.2-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:5cbabee4f083b6b4cd282f5b817a867cf0b1028c54d445b7ec7cfe6505057cf8"}, - {file = "wrapt-1.17.2-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:49703ce2ddc220df165bd2962f8e03b84c89fee2d65e1c24a7defff6f988f4d6"}, - {file = "wrapt-1.17.2-cp313-cp313-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:8112e52c5822fc4253f3901b676c55ddf288614dc7011634e2719718eaa187dc"}, - {file = "wrapt-1.17.2-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:9fee687dce376205d9a494e9c121e27183b2a3df18037f89d69bd7b35bcf59e2"}, - {file = "wrapt-1.17.2-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:18983c537e04d11cf027fbb60a1e8dfd5190e2b60cc27bc0808e653e7b218d1b"}, - {file = "wrapt-1.17.2-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:703919b1633412ab54bcf920ab388735832fdcb9f9a00ae49387f0fe67dad504"}, - {file = "wrapt-1.17.2-cp313-cp313-win32.whl", hash = "sha256:abbb9e76177c35d4e8568e58650aa6926040d6a9f6f03435b7a522bf1c487f9a"}, - {file = "wrapt-1.17.2-cp313-cp313-win_amd64.whl", hash = "sha256:69606d7bb691b50a4240ce6b22ebb319c1cfb164e5f6569835058196e0f3a845"}, - {file = "wrapt-1.17.2-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:4a721d3c943dae44f8e243b380cb645a709ba5bd35d3ad27bc2ed947e9c68192"}, - {file = "wrapt-1.17.2-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:766d8bbefcb9e00c3ac3b000d9acc51f1b399513f44d77dfe0eb026ad7c9a19b"}, - {file = "wrapt-1.17.2-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:e496a8ce2c256da1eb98bd15803a79bee00fc351f5dfb9ea82594a3f058309e0"}, - {file = "wrapt-1.17.2-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:40d615e4fe22f4ad3528448c193b218e077656ca9ccb22ce2cb20db730f8d306"}, - {file = "wrapt-1.17.2-cp313-cp313t-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:a5aaeff38654462bc4b09023918b7f21790efb807f54c000a39d41d69cf552cb"}, - {file = "wrapt-1.17.2-cp313-cp313t-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:9a7d15bbd2bc99e92e39f49a04653062ee6085c0e18b3b7512a4f2fe91f2d681"}, - {file = "wrapt-1.17.2-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:e3890b508a23299083e065f435a492b5435eba6e304a7114d2f919d400888cc6"}, - {file = "wrapt-1.17.2-cp313-cp313t-musllinux_1_2_i686.whl", hash = "sha256:8c8b293cd65ad716d13d8dd3624e42e5a19cc2a2f1acc74b30c2c13f15cb61a6"}, - {file = "wrapt-1.17.2-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:4c82b8785d98cdd9fed4cac84d765d234ed3251bd6afe34cb7ac523cb93e8b4f"}, - {file = "wrapt-1.17.2-cp313-cp313t-win32.whl", hash = "sha256:13e6afb7fe71fe7485a4550a8844cc9ffbe263c0f1a1eea569bc7091d4898555"}, - {file = "wrapt-1.17.2-cp313-cp313t-win_amd64.whl", hash = "sha256:eaf675418ed6b3b31c7a989fd007fa7c3be66ce14e5c3b27336383604c9da85c"}, - {file = "wrapt-1.17.2-cp38-cp38-macosx_10_9_universal2.whl", hash = "sha256:5c803c401ea1c1c18de70a06a6f79fcc9c5acfc79133e9869e730ad7f8ad8ef9"}, - {file = "wrapt-1.17.2-cp38-cp38-macosx_10_9_x86_64.whl", hash = "sha256:f917c1180fdb8623c2b75a99192f4025e412597c50b2ac870f156de8fb101119"}, - {file = "wrapt-1.17.2-cp38-cp38-macosx_11_0_arm64.whl", hash = "sha256:ecc840861360ba9d176d413a5489b9a0aff6d6303d7e733e2c4623cfa26904a6"}, - {file = "wrapt-1.17.2-cp38-cp38-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:bb87745b2e6dc56361bfde481d5a378dc314b252a98d7dd19a651a3fa58f24a9"}, - {file = "wrapt-1.17.2-cp38-cp38-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:58455b79ec2661c3600e65c0a716955adc2410f7383755d537584b0de41b1d8a"}, - {file = "wrapt-1.17.2-cp38-cp38-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:b4e42a40a5e164cbfdb7b386c966a588b1047558a990981ace551ed7e12ca9c2"}, - {file = "wrapt-1.17.2-cp38-cp38-musllinux_1_2_aarch64.whl", hash = "sha256:91bd7d1773e64019f9288b7a5101f3ae50d3d8e6b1de7edee9c2ccc1d32f0c0a"}, - {file = "wrapt-1.17.2-cp38-cp38-musllinux_1_2_i686.whl", hash = "sha256:bb90fb8bda722a1b9d48ac1e6c38f923ea757b3baf8ebd0c82e09c5c1a0e7a04"}, - {file = "wrapt-1.17.2-cp38-cp38-musllinux_1_2_x86_64.whl", hash = "sha256:08e7ce672e35efa54c5024936e559469436f8b8096253404faeb54d2a878416f"}, - {file = "wrapt-1.17.2-cp38-cp38-win32.whl", hash = "sha256:410a92fefd2e0e10d26210e1dfb4a876ddaf8439ef60d6434f21ef8d87efc5b7"}, - {file = "wrapt-1.17.2-cp38-cp38-win_amd64.whl", hash = "sha256:95c658736ec15602da0ed73f312d410117723914a5c91a14ee4cdd72f1d790b3"}, - {file = "wrapt-1.17.2-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:99039fa9e6306880572915728d7f6c24a86ec57b0a83f6b2491e1d8ab0235b9a"}, - {file = "wrapt-1.17.2-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:2696993ee1eebd20b8e4ee4356483c4cb696066ddc24bd70bcbb80fa56ff9061"}, - {file = "wrapt-1.17.2-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:612dff5db80beef9e649c6d803a8d50c409082f1fedc9dbcdfde2983b2025b82"}, - {file = "wrapt-1.17.2-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:62c2caa1585c82b3f7a7ab56afef7b3602021d6da34fbc1cf234ff139fed3cd9"}, - {file = "wrapt-1.17.2-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:c958bcfd59bacc2d0249dcfe575e71da54f9dcf4a8bdf89c4cb9a68a1170d73f"}, - {file = "wrapt-1.17.2-cp39-cp39-manylinux_2_5_x86_64.manylinux1_x86_64.manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:fc78a84e2dfbc27afe4b2bd7c80c8db9bca75cc5b85df52bfe634596a1da846b"}, - {file = "wrapt-1.17.2-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:ba0f0eb61ef00ea10e00eb53a9129501f52385c44853dbd6c4ad3f403603083f"}, - {file = "wrapt-1.17.2-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:1e1fe0e6ab7775fd842bc39e86f6dcfc4507ab0ffe206093e76d61cde37225c8"}, - {file = "wrapt-1.17.2-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:c86563182421896d73858e08e1db93afdd2b947a70064b813d515d66549e15f9"}, - {file = "wrapt-1.17.2-cp39-cp39-win32.whl", hash = "sha256:f393cda562f79828f38a819f4788641ac7c4085f30f1ce1a68672baa686482bb"}, - {file = "wrapt-1.17.2-cp39-cp39-win_amd64.whl", hash = "sha256:36ccae62f64235cf8ddb682073a60519426fdd4725524ae38874adf72b5f2aeb"}, - {file = "wrapt-1.17.2-py3-none-any.whl", hash = "sha256:b18f2d1533a71f069c7f82d524a52599053d4c7166e9dd374ae2136b7f40f7c8"}, - {file = "wrapt-1.17.2.tar.gz", hash = "sha256:41388e9d4d1522446fe79d3213196bd9e3b301a336965b9e27ca2788ebd122f3"}, + {file = "wrapt-1.17.3-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:88bbae4d40d5a46142e70d58bf664a89b6b4befaea7b2ecc14e03cedb8e06c04"}, + {file = "wrapt-1.17.3-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:e6b13af258d6a9ad602d57d889f83b9d5543acd471eee12eb51f5b01f8eb1bc2"}, + {file = "wrapt-1.17.3-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:fd341868a4b6714a5962c1af0bd44f7c404ef78720c7de4892901e540417111c"}, + {file = "wrapt-1.17.3-cp310-cp310-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:f9b2601381be482f70e5d1051a5965c25fb3625455a2bf520b5a077b22afb775"}, + {file = "wrapt-1.17.3-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:343e44b2a8e60e06a7e0d29c1671a0d9951f59174f3709962b5143f60a2a98bd"}, + {file = "wrapt-1.17.3-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:33486899acd2d7d3066156b03465b949da3fd41a5da6e394ec49d271baefcf05"}, + {file = "wrapt-1.17.3-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:e6f40a8aa5a92f150bdb3e1c44b7e98fb7113955b2e5394122fa5532fec4b418"}, + {file = "wrapt-1.17.3-cp310-cp310-win32.whl", hash = "sha256:a36692b8491d30a8c75f1dfee65bef119d6f39ea84ee04d9f9311f83c5ad9390"}, + {file = "wrapt-1.17.3-cp310-cp310-win_amd64.whl", hash = "sha256:afd964fd43b10c12213574db492cb8f73b2f0826c8df07a68288f8f19af2ebe6"}, + {file = "wrapt-1.17.3-cp310-cp310-win_arm64.whl", hash = "sha256:af338aa93554be859173c39c85243970dc6a289fa907402289eeae7543e1ae18"}, + {file = "wrapt-1.17.3-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:273a736c4645e63ac582c60a56b0acb529ef07f78e08dc6bfadf6a46b19c0da7"}, + {file = "wrapt-1.17.3-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:5531d911795e3f935a9c23eb1c8c03c211661a5060aab167065896bbf62a5f85"}, + {file = "wrapt-1.17.3-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:0610b46293c59a3adbae3dee552b648b984176f8562ee0dba099a56cfbe4df1f"}, + {file = "wrapt-1.17.3-cp311-cp311-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:b32888aad8b6e68f83a8fdccbf3165f5469702a7544472bdf41f582970ed3311"}, + {file = "wrapt-1.17.3-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:8cccf4f81371f257440c88faed6b74f1053eef90807b77e31ca057b2db74edb1"}, + {file = "wrapt-1.17.3-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:d8a210b158a34164de8bb68b0e7780041a903d7b00c87e906fb69928bf7890d5"}, + {file = "wrapt-1.17.3-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:79573c24a46ce11aab457b472efd8d125e5a51da2d1d24387666cd85f54c05b2"}, + {file = "wrapt-1.17.3-cp311-cp311-win32.whl", hash = "sha256:c31eebe420a9a5d2887b13000b043ff6ca27c452a9a22fa71f35f118e8d4bf89"}, + {file = "wrapt-1.17.3-cp311-cp311-win_amd64.whl", hash = "sha256:0b1831115c97f0663cb77aa27d381237e73ad4f721391a9bfb2fe8bc25fa6e77"}, + {file = "wrapt-1.17.3-cp311-cp311-win_arm64.whl", hash = "sha256:5a7b3c1ee8265eb4c8f1b7d29943f195c00673f5ab60c192eba2d4a7eae5f46a"}, + {file = "wrapt-1.17.3-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:ab232e7fdb44cdfbf55fc3afa31bcdb0d8980b9b95c38b6405df2acb672af0e0"}, + {file = "wrapt-1.17.3-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:9baa544e6acc91130e926e8c802a17f3b16fbea0fd441b5a60f5cf2cc5c3deba"}, + {file = "wrapt-1.17.3-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:6b538e31eca1a7ea4605e44f81a48aa24c4632a277431a6ed3f328835901f4fd"}, + {file = "wrapt-1.17.3-cp312-cp312-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:042ec3bb8f319c147b1301f2393bc19dba6e176b7da446853406d041c36c7828"}, + {file = "wrapt-1.17.3-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:3af60380ba0b7b5aeb329bc4e402acd25bd877e98b3727b0135cb5c2efdaefe9"}, + {file = "wrapt-1.17.3-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:0b02e424deef65c9f7326d8c19220a2c9040c51dc165cddb732f16198c168396"}, + {file = "wrapt-1.17.3-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:74afa28374a3c3a11b3b5e5fca0ae03bef8450d6aa3ab3a1e2c30e3a75d023dc"}, + {file = "wrapt-1.17.3-cp312-cp312-win32.whl", hash = "sha256:4da9f45279fff3543c371d5ababc57a0384f70be244de7759c85a7f989cb4ebe"}, + {file = "wrapt-1.17.3-cp312-cp312-win_amd64.whl", hash = "sha256:e71d5c6ebac14875668a1e90baf2ea0ef5b7ac7918355850c0908ae82bcb297c"}, + {file = "wrapt-1.17.3-cp312-cp312-win_arm64.whl", hash = "sha256:604d076c55e2fdd4c1c03d06dc1a31b95130010517b5019db15365ec4a405fc6"}, + {file = "wrapt-1.17.3-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:a47681378a0439215912ef542c45a783484d4dd82bac412b71e59cf9c0e1cea0"}, + {file = "wrapt-1.17.3-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:54a30837587c6ee3cd1a4d1c2ec5d24e77984d44e2f34547e2323ddb4e22eb77"}, + {file = "wrapt-1.17.3-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:16ecf15d6af39246fe33e507105d67e4b81d8f8d2c6598ff7e3ca1b8a37213f7"}, + {file = "wrapt-1.17.3-cp313-cp313-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:6fd1ad24dc235e4ab88cda009e19bf347aabb975e44fd5c2fb22a3f6e4141277"}, + {file = "wrapt-1.17.3-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:0ed61b7c2d49cee3c027372df5809a59d60cf1b6c2f81ee980a091f3afed6a2d"}, + {file = "wrapt-1.17.3-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:423ed5420ad5f5529db9ce89eac09c8a2f97da18eb1c870237e84c5a5c2d60aa"}, + {file = "wrapt-1.17.3-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:e01375f275f010fcbf7f643b4279896d04e571889b8a5b3f848423d91bf07050"}, + {file = "wrapt-1.17.3-cp313-cp313-win32.whl", hash = "sha256:53e5e39ff71b3fc484df8a522c933ea2b7cdd0d5d15ae82e5b23fde87d44cbd8"}, + {file = "wrapt-1.17.3-cp313-cp313-win_amd64.whl", hash = "sha256:1f0b2f40cf341ee8cc1a97d51ff50dddb9fcc73241b9143ec74b30fc4f44f6cb"}, + {file = "wrapt-1.17.3-cp313-cp313-win_arm64.whl", hash = "sha256:7425ac3c54430f5fc5e7b6f41d41e704db073309acfc09305816bc6a0b26bb16"}, + {file = "wrapt-1.17.3-cp314-cp314-macosx_10_13_universal2.whl", hash = "sha256:cf30f6e3c077c8e6a9a7809c94551203c8843e74ba0c960f4a98cd80d4665d39"}, + {file = "wrapt-1.17.3-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:e228514a06843cae89621384cfe3a80418f3c04aadf8a3b14e46a7be704e4235"}, + {file = "wrapt-1.17.3-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:5ea5eb3c0c071862997d6f3e02af1d055f381b1d25b286b9d6644b79db77657c"}, + {file = "wrapt-1.17.3-cp314-cp314-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:281262213373b6d5e4bb4353bc36d1ba4084e6d6b5d242863721ef2bf2c2930b"}, + {file = "wrapt-1.17.3-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:dc4a8d2b25efb6681ecacad42fca8859f88092d8732b170de6a5dddd80a1c8fa"}, + {file = "wrapt-1.17.3-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:373342dd05b1d07d752cecbec0c41817231f29f3a89aa8b8843f7b95992ed0c7"}, + {file = "wrapt-1.17.3-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:d40770d7c0fd5cbed9d84b2c3f2e156431a12c9a37dc6284060fb4bec0b7ffd4"}, + {file = "wrapt-1.17.3-cp314-cp314-win32.whl", hash = "sha256:fbd3c8319de8e1dc79d346929cd71d523622da527cca14e0c1d257e31c2b8b10"}, + {file = "wrapt-1.17.3-cp314-cp314-win_amd64.whl", hash = "sha256:e1a4120ae5705f673727d3253de3ed0e016f7cd78dc463db1b31e2463e1f3cf6"}, + {file = "wrapt-1.17.3-cp314-cp314-win_arm64.whl", hash = "sha256:507553480670cab08a800b9463bdb881b2edeed77dc677b0a5915e6106e91a58"}, + {file = "wrapt-1.17.3-cp314-cp314t-macosx_10_13_universal2.whl", hash = "sha256:ed7c635ae45cfbc1a7371f708727bf74690daedc49b4dba310590ca0bd28aa8a"}, + {file = "wrapt-1.17.3-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:249f88ed15503f6492a71f01442abddd73856a0032ae860de6d75ca62eed8067"}, + {file = "wrapt-1.17.3-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:5a03a38adec8066d5a37bea22f2ba6bbf39fcdefbe2d91419ab864c3fb515454"}, + {file = "wrapt-1.17.3-cp314-cp314t-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:5d4478d72eb61c36e5b446e375bbc49ed002430d17cdec3cecb36993398e1a9e"}, + {file = "wrapt-1.17.3-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:223db574bb38637e8230eb14b185565023ab624474df94d2af18f1cdb625216f"}, + {file = "wrapt-1.17.3-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:e405adefb53a435f01efa7ccdec012c016b5a1d3f35459990afc39b6be4d5056"}, + {file = "wrapt-1.17.3-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:88547535b787a6c9ce4086917b6e1d291aa8ed914fdd3a838b3539dc95c12804"}, + {file = "wrapt-1.17.3-cp314-cp314t-win32.whl", hash = "sha256:41b1d2bc74c2cac6f9074df52b2efbef2b30bdfe5f40cb78f8ca22963bc62977"}, + {file = "wrapt-1.17.3-cp314-cp314t-win_amd64.whl", hash = "sha256:73d496de46cd2cdbdbcce4ae4bcdb4afb6a11234a1df9c085249d55166b95116"}, + {file = "wrapt-1.17.3-cp314-cp314t-win_arm64.whl", hash = "sha256:f38e60678850c42461d4202739f9bf1e3a737c7ad283638251e79cc49effb6b6"}, + {file = "wrapt-1.17.3-cp38-cp38-macosx_10_9_universal2.whl", hash = "sha256:70d86fa5197b8947a2fa70260b48e400bf2ccacdcab97bb7de47e3d1e6312225"}, + {file = "wrapt-1.17.3-cp38-cp38-macosx_10_9_x86_64.whl", hash = "sha256:df7d30371a2accfe4013e90445f6388c570f103d61019b6b7c57e0265250072a"}, + {file = "wrapt-1.17.3-cp38-cp38-macosx_11_0_arm64.whl", hash = "sha256:caea3e9c79d5f0d2c6d9ab96111601797ea5da8e6d0723f77eabb0d4068d2b2f"}, + {file = "wrapt-1.17.3-cp38-cp38-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:758895b01d546812d1f42204bd443b8c433c44d090248bf22689df673ccafe00"}, + {file = "wrapt-1.17.3-cp38-cp38-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:02b551d101f31694fc785e58e0720ef7d9a10c4e62c1c9358ce6f63f23e30a56"}, + {file = "wrapt-1.17.3-cp38-cp38-musllinux_1_2_aarch64.whl", hash = "sha256:656873859b3b50eeebe6db8b1455e99d90c26ab058db8e427046dbc35c3140a5"}, + {file = "wrapt-1.17.3-cp38-cp38-musllinux_1_2_x86_64.whl", hash = "sha256:a9a2203361a6e6404f80b99234fe7fb37d1fc73487b5a78dc1aa5b97201e0f22"}, + {file = "wrapt-1.17.3-cp38-cp38-win32.whl", hash = "sha256:55cbbc356c2842f39bcc553cf695932e8b30e30e797f961860afb308e6b1bb7c"}, + {file = "wrapt-1.17.3-cp38-cp38-win_amd64.whl", hash = "sha256:ad85e269fe54d506b240d2d7b9f5f2057c2aa9a2ea5b32c66f8902f768117ed2"}, + {file = "wrapt-1.17.3-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:30ce38e66630599e1193798285706903110d4f057aab3168a34b7fdc85569afc"}, + {file = "wrapt-1.17.3-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:65d1d00fbfb3ea5f20add88bbc0f815150dbbde3b026e6c24759466c8b5a9ef9"}, + {file = "wrapt-1.17.3-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:a7c06742645f914f26c7f1fa47b8bc4c91d222f76ee20116c43d5ef0912bba2d"}, + {file = "wrapt-1.17.3-cp39-cp39-manylinux1_x86_64.manylinux_2_28_x86_64.manylinux_2_5_x86_64.whl", hash = "sha256:7e18f01b0c3e4a07fe6dfdb00e29049ba17eadbc5e7609a2a3a4af83ab7d710a"}, + {file = "wrapt-1.17.3-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:0f5f51a6466667a5a356e6381d362d259125b57f059103dd9fdc8c0cf1d14139"}, + {file = "wrapt-1.17.3-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:59923aa12d0157f6b82d686c3fd8e1166fa8cdfb3e17b42ce3b6147ff81528df"}, + {file = "wrapt-1.17.3-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:46acc57b331e0b3bcb3e1ca3b421d65637915cfcd65eb783cb2f78a511193f9b"}, + {file = "wrapt-1.17.3-cp39-cp39-win32.whl", hash = "sha256:3e62d15d3cfa26e3d0788094de7b64efa75f3a53875cdbccdf78547aed547a81"}, + {file = "wrapt-1.17.3-cp39-cp39-win_amd64.whl", hash = "sha256:1f23fa283f51c890eda8e34e4937079114c74b4c81d2b2f1f1d94948f5cc3d7f"}, + {file = "wrapt-1.17.3-cp39-cp39-win_arm64.whl", hash = "sha256:24c2ed34dc222ed754247a2702b1e1e89fdbaa4016f324b4b8f1a802d4ffe87f"}, + {file = "wrapt-1.17.3-py3-none-any.whl", hash = "sha256:7171ae35d2c33d326ac19dd8facb1e82e5fd04ef8c6c0e394d7af55a55051c22"}, + {file = "wrapt-1.17.3.tar.gz", hash = "sha256:f66eb08feaa410fe4eebd17f2a2c8e2e46d3476e9f8c783daa8e09e0faa666d0"}, ] [[package]] @@ -8495,128 +9025,157 @@ h11 = ">=0.9.0,<1" [[package]] name = "xmltodict" -version = "0.14.2" +version = "1.0.2" description = "Makes working with XML feel like you are working with JSON" optional = false -python-versions = ">=3.6" +python-versions = ">=3.9" groups = ["main"] files = [ - {file = "xmltodict-0.14.2-py2.py3-none-any.whl", hash = "sha256:20cc7d723ed729276e808f26fb6b3599f786cbc37e06c65e192ba77c40f20aac"}, - {file = "xmltodict-0.14.2.tar.gz", hash = "sha256:201e7c28bb210e374999d1dde6382923ab0ed1a8a5faeece48ab525b7810a553"}, + {file = "xmltodict-1.0.2-py3-none-any.whl", hash = "sha256:62d0fddb0dcbc9f642745d8bbf4d81fd17d6dfaec5a15b5c1876300aad92af0d"}, + {file = "xmltodict-1.0.2.tar.gz", hash = "sha256:54306780b7c2175a3967cad1db92f218207e5bc1aba697d887807c0fb68b7649"}, ] +[package.extras] +test = ["pytest", "pytest-cov"] + [[package]] name = "yarl" -version = "1.20.1" +version = "1.22.0" description = "Yet another URL library" optional = false python-versions = ">=3.9" groups = ["main"] files = [ - {file = "yarl-1.20.1-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:6032e6da6abd41e4acda34d75a816012717000fa6839f37124a47fcefc49bec4"}, - {file = "yarl-1.20.1-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:2c7b34d804b8cf9b214f05015c4fee2ebe7ed05cf581e7192c06555c71f4446a"}, - {file = "yarl-1.20.1-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:0c869f2651cc77465f6cd01d938d91a11d9ea5d798738c1dc077f3de0b5e5fed"}, - {file = "yarl-1.20.1-cp310-cp310-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:62915e6688eb4d180d93840cda4110995ad50c459bf931b8b3775b37c264af1e"}, - {file = "yarl-1.20.1-cp310-cp310-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:41ebd28167bc6af8abb97fec1a399f412eec5fd61a3ccbe2305a18b84fb4ca73"}, - {file = "yarl-1.20.1-cp310-cp310-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:21242b4288a6d56f04ea193adde174b7e347ac46ce6bc84989ff7c1b1ecea84e"}, - {file = "yarl-1.20.1-cp310-cp310-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:bea21cdae6c7eb02ba02a475f37463abfe0a01f5d7200121b03e605d6a0439f8"}, - {file = "yarl-1.20.1-cp310-cp310-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:1f8a891e4a22a89f5dde7862994485e19db246b70bb288d3ce73a34422e55b23"}, - {file = "yarl-1.20.1-cp310-cp310-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:dd803820d44c8853a109a34e3660e5a61beae12970da479cf44aa2954019bf70"}, - {file = "yarl-1.20.1-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:b982fa7f74c80d5c0c7b5b38f908971e513380a10fecea528091405f519b9ebb"}, - {file = "yarl-1.20.1-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:33f29ecfe0330c570d997bcf1afd304377f2e48f61447f37e846a6058a4d33b2"}, - {file = "yarl-1.20.1-cp310-cp310-musllinux_1_2_i686.whl", hash = "sha256:835ab2cfc74d5eb4a6a528c57f05688099da41cf4957cf08cad38647e4a83b30"}, - {file = "yarl-1.20.1-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:46b5e0ccf1943a9a6e766b2c2b8c732c55b34e28be57d8daa2b3c1d1d4009309"}, - {file = "yarl-1.20.1-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:df47c55f7d74127d1b11251fe6397d84afdde0d53b90bedb46a23c0e534f9d24"}, - {file = "yarl-1.20.1-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:76d12524d05841276b0e22573f28d5fbcb67589836772ae9244d90dd7d66aa13"}, - {file = "yarl-1.20.1-cp310-cp310-win32.whl", hash = "sha256:6c4fbf6b02d70e512d7ade4b1f998f237137f1417ab07ec06358ea04f69134f8"}, - {file = "yarl-1.20.1-cp310-cp310-win_amd64.whl", hash = "sha256:aef6c4d69554d44b7f9d923245f8ad9a707d971e6209d51279196d8e8fe1ae16"}, - {file = "yarl-1.20.1-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:47ee6188fea634bdfaeb2cc420f5b3b17332e6225ce88149a17c413c77ff269e"}, - {file = "yarl-1.20.1-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:d0f6500f69e8402d513e5eedb77a4e1818691e8f45e6b687147963514d84b44b"}, - {file = "yarl-1.20.1-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:7a8900a42fcdaad568de58887c7b2f602962356908eedb7628eaf6021a6e435b"}, - {file = "yarl-1.20.1-cp311-cp311-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:bad6d131fda8ef508b36be3ece16d0902e80b88ea7200f030a0f6c11d9e508d4"}, - {file = "yarl-1.20.1-cp311-cp311-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:df018d92fe22aaebb679a7f89fe0c0f368ec497e3dda6cb81a567610f04501f1"}, - {file = "yarl-1.20.1-cp311-cp311-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:8f969afbb0a9b63c18d0feecf0db09d164b7a44a053e78a7d05f5df163e43833"}, - {file = "yarl-1.20.1-cp311-cp311-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:812303eb4aa98e302886ccda58d6b099e3576b1b9276161469c25803a8db277d"}, - {file = "yarl-1.20.1-cp311-cp311-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:98c4a7d166635147924aa0bf9bfe8d8abad6fffa6102de9c99ea04a1376f91e8"}, - {file = "yarl-1.20.1-cp311-cp311-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:12e768f966538e81e6e7550f9086a6236b16e26cd964cf4df35349970f3551cf"}, - {file = "yarl-1.20.1-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:fe41919b9d899661c5c28a8b4b0acf704510b88f27f0934ac7a7bebdd8938d5e"}, - {file = "yarl-1.20.1-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:8601bc010d1d7780592f3fc1bdc6c72e2b6466ea34569778422943e1a1f3c389"}, - {file = "yarl-1.20.1-cp311-cp311-musllinux_1_2_i686.whl", hash = "sha256:daadbdc1f2a9033a2399c42646fbd46da7992e868a5fe9513860122d7fe7a73f"}, - {file = "yarl-1.20.1-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:03aa1e041727cb438ca762628109ef1333498b122e4c76dd858d186a37cec845"}, - {file = "yarl-1.20.1-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:642980ef5e0fa1de5fa96d905c7e00cb2c47cb468bfcac5a18c58e27dbf8d8d1"}, - {file = "yarl-1.20.1-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:86971e2795584fe8c002356d3b97ef6c61862720eeff03db2a7c86b678d85b3e"}, - {file = "yarl-1.20.1-cp311-cp311-win32.whl", hash = "sha256:597f40615b8d25812f14562699e287f0dcc035d25eb74da72cae043bb884d773"}, - {file = "yarl-1.20.1-cp311-cp311-win_amd64.whl", hash = "sha256:26ef53a9e726e61e9cd1cda6b478f17e350fb5800b4bd1cd9fe81c4d91cfeb2e"}, - {file = "yarl-1.20.1-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:bdcc4cd244e58593a4379fe60fdee5ac0331f8eb70320a24d591a3be197b94a9"}, - {file = "yarl-1.20.1-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:b29a2c385a5f5b9c7d9347e5812b6f7ab267193c62d282a540b4fc528c8a9d2a"}, - {file = "yarl-1.20.1-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:1112ae8154186dfe2de4732197f59c05a83dc814849a5ced892b708033f40dc2"}, - {file = "yarl-1.20.1-cp312-cp312-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:90bbd29c4fe234233f7fa2b9b121fb63c321830e5d05b45153a2ca68f7d310ee"}, - {file = "yarl-1.20.1-cp312-cp312-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:680e19c7ce3710ac4cd964e90dad99bf9b5029372ba0c7cbfcd55e54d90ea819"}, - {file = "yarl-1.20.1-cp312-cp312-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:4a979218c1fdb4246a05efc2cc23859d47c89af463a90b99b7c56094daf25a16"}, - {file = "yarl-1.20.1-cp312-cp312-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:255b468adf57b4a7b65d8aad5b5138dce6a0752c139965711bdcb81bc370e1b6"}, - {file = "yarl-1.20.1-cp312-cp312-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:a97d67108e79cfe22e2b430d80d7571ae57d19f17cda8bb967057ca8a7bf5bfd"}, - {file = "yarl-1.20.1-cp312-cp312-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:8570d998db4ddbfb9a590b185a0a33dbf8aafb831d07a5257b4ec9948df9cb0a"}, - {file = "yarl-1.20.1-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:97c75596019baae7c71ccf1d8cc4738bc08134060d0adfcbe5642f778d1dca38"}, - {file = "yarl-1.20.1-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:1c48912653e63aef91ff988c5432832692ac5a1d8f0fb8a33091520b5bbe19ef"}, - {file = "yarl-1.20.1-cp312-cp312-musllinux_1_2_i686.whl", hash = "sha256:4c3ae28f3ae1563c50f3d37f064ddb1511ecc1d5584e88c6b7c63cf7702a6d5f"}, - {file = "yarl-1.20.1-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:c5e9642f27036283550f5f57dc6156c51084b458570b9d0d96100c8bebb186a8"}, - {file = "yarl-1.20.1-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:2c26b0c49220d5799f7b22c6838409ee9bc58ee5c95361a4d7831f03cc225b5a"}, - {file = "yarl-1.20.1-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:564ab3d517e3d01c408c67f2e5247aad4019dcf1969982aba3974b4093279004"}, - {file = "yarl-1.20.1-cp312-cp312-win32.whl", hash = "sha256:daea0d313868da1cf2fac6b2d3a25c6e3a9e879483244be38c8e6a41f1d876a5"}, - {file = "yarl-1.20.1-cp312-cp312-win_amd64.whl", hash = "sha256:48ea7d7f9be0487339828a4de0360d7ce0efc06524a48e1810f945c45b813698"}, - {file = "yarl-1.20.1-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:0b5ff0fbb7c9f1b1b5ab53330acbfc5247893069e7716840c8e7d5bb7355038a"}, - {file = "yarl-1.20.1-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:14f326acd845c2b2e2eb38fb1346c94f7f3b01a4f5c788f8144f9b630bfff9a3"}, - {file = "yarl-1.20.1-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:f60e4ad5db23f0b96e49c018596707c3ae89f5d0bd97f0ad3684bcbad899f1e7"}, - {file = "yarl-1.20.1-cp313-cp313-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:49bdd1b8e00ce57e68ba51916e4bb04461746e794e7c4d4bbc42ba2f18297691"}, - {file = "yarl-1.20.1-cp313-cp313-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:66252d780b45189975abfed839616e8fd2dbacbdc262105ad7742c6ae58f3e31"}, - {file = "yarl-1.20.1-cp313-cp313-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:59174e7332f5d153d8f7452a102b103e2e74035ad085f404df2e40e663a22b28"}, - {file = "yarl-1.20.1-cp313-cp313-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:e3968ec7d92a0c0f9ac34d5ecfd03869ec0cab0697c91a45db3fbbd95fe1b653"}, - {file = "yarl-1.20.1-cp313-cp313-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:d1a4fbb50e14396ba3d375f68bfe02215d8e7bc3ec49da8341fe3157f59d2ff5"}, - {file = "yarl-1.20.1-cp313-cp313-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:11a62c839c3a8eac2410e951301309426f368388ff2f33799052787035793b02"}, - {file = "yarl-1.20.1-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:041eaa14f73ff5a8986b4388ac6bb43a77f2ea09bf1913df7a35d4646db69e53"}, - {file = "yarl-1.20.1-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:377fae2fef158e8fd9d60b4c8751387b8d1fb121d3d0b8e9b0be07d1b41e83dc"}, - {file = "yarl-1.20.1-cp313-cp313-musllinux_1_2_i686.whl", hash = "sha256:1c92f4390e407513f619d49319023664643d3339bd5e5a56a3bebe01bc67ec04"}, - {file = "yarl-1.20.1-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:d25ddcf954df1754ab0f86bb696af765c5bfaba39b74095f27eececa049ef9a4"}, - {file = "yarl-1.20.1-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:909313577e9619dcff8c31a0ea2aa0a2a828341d92673015456b3ae492e7317b"}, - {file = "yarl-1.20.1-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:793fd0580cb9664548c6b83c63b43c477212c0260891ddf86809e1c06c8b08f1"}, - {file = "yarl-1.20.1-cp313-cp313-win32.whl", hash = "sha256:468f6e40285de5a5b3c44981ca3a319a4b208ccc07d526b20b12aeedcfa654b7"}, - {file = "yarl-1.20.1-cp313-cp313-win_amd64.whl", hash = "sha256:495b4ef2fea40596bfc0affe3837411d6aa3371abcf31aac0ccc4bdd64d4ef5c"}, - {file = "yarl-1.20.1-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:f60233b98423aab21d249a30eb27c389c14929f47be8430efa7dbd91493a729d"}, - {file = "yarl-1.20.1-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:6f3eff4cc3f03d650d8755c6eefc844edde99d641d0dcf4da3ab27141a5f8ddf"}, - {file = "yarl-1.20.1-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:69ff8439d8ba832d6bed88af2c2b3445977eba9a4588b787b32945871c2444e3"}, - {file = "yarl-1.20.1-cp313-cp313t-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:3cf34efa60eb81dd2645a2e13e00bb98b76c35ab5061a3989c7a70f78c85006d"}, - {file = "yarl-1.20.1-cp313-cp313t-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:8e0fe9364ad0fddab2688ce72cb7a8e61ea42eff3c7caeeb83874a5d479c896c"}, - {file = "yarl-1.20.1-cp313-cp313t-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:8f64fbf81878ba914562c672024089e3401974a39767747691c65080a67b18c1"}, - {file = "yarl-1.20.1-cp313-cp313t-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:f6342d643bf9a1de97e512e45e4b9560a043347e779a173250824f8b254bd5ce"}, - {file = "yarl-1.20.1-cp313-cp313t-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:56dac5f452ed25eef0f6e3c6a066c6ab68971d96a9fb441791cad0efba6140d3"}, - {file = "yarl-1.20.1-cp313-cp313t-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:c7d7f497126d65e2cad8dc5f97d34c27b19199b6414a40cb36b52f41b79014be"}, - {file = "yarl-1.20.1-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:67e708dfb8e78d8a19169818eeb5c7a80717562de9051bf2413aca8e3696bf16"}, - {file = "yarl-1.20.1-cp313-cp313t-musllinux_1_2_armv7l.whl", hash = "sha256:595c07bc79af2494365cc96ddeb772f76272364ef7c80fb892ef9d0649586513"}, - {file = "yarl-1.20.1-cp313-cp313t-musllinux_1_2_i686.whl", hash = "sha256:7bdd2f80f4a7df852ab9ab49484a4dee8030023aa536df41f2d922fd57bf023f"}, - {file = "yarl-1.20.1-cp313-cp313t-musllinux_1_2_ppc64le.whl", hash = "sha256:c03bfebc4ae8d862f853a9757199677ab74ec25424d0ebd68a0027e9c639a390"}, - {file = "yarl-1.20.1-cp313-cp313t-musllinux_1_2_s390x.whl", hash = "sha256:344d1103e9c1523f32a5ed704d576172d2cabed3122ea90b1d4e11fe17c66458"}, - {file = "yarl-1.20.1-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:88cab98aa4e13e1ade8c141daeedd300a4603b7132819c484841bb7af3edce9e"}, - {file = "yarl-1.20.1-cp313-cp313t-win32.whl", hash = "sha256:b121ff6a7cbd4abc28985b6028235491941b9fe8fe226e6fdc539c977ea1739d"}, - {file = "yarl-1.20.1-cp313-cp313t-win_amd64.whl", hash = "sha256:541d050a355bbbc27e55d906bc91cb6fe42f96c01413dd0f4ed5a5240513874f"}, - {file = "yarl-1.20.1-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:e42ba79e2efb6845ebab49c7bf20306c4edf74a0b20fc6b2ccdd1a219d12fad3"}, - {file = "yarl-1.20.1-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:41493b9b7c312ac448b7f0a42a089dffe1d6e6e981a2d76205801a023ed26a2b"}, - {file = "yarl-1.20.1-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:f5a5928ff5eb13408c62a968ac90d43f8322fd56d87008b8f9dabf3c0f6ee983"}, - {file = "yarl-1.20.1-cp39-cp39-manylinux_2_17_aarch64.manylinux2014_aarch64.whl", hash = "sha256:30c41ad5d717b3961b2dd785593b67d386b73feca30522048d37298fee981805"}, - {file = "yarl-1.20.1-cp39-cp39-manylinux_2_17_armv7l.manylinux2014_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:59febc3969b0781682b469d4aca1a5cab7505a4f7b85acf6db01fa500fa3f6ba"}, - {file = "yarl-1.20.1-cp39-cp39-manylinux_2_17_ppc64le.manylinux2014_ppc64le.whl", hash = "sha256:d2b6fb3622b7e5bf7a6e5b679a69326b4279e805ed1699d749739a61d242449e"}, - {file = "yarl-1.20.1-cp39-cp39-manylinux_2_17_s390x.manylinux2014_s390x.whl", hash = "sha256:749d73611db8d26a6281086f859ea7ec08f9c4c56cec864e52028c8b328db723"}, - {file = "yarl-1.20.1-cp39-cp39-manylinux_2_17_x86_64.manylinux2014_x86_64.whl", hash = "sha256:9427925776096e664c39e131447aa20ec738bdd77c049c48ea5200db2237e000"}, - {file = "yarl-1.20.1-cp39-cp39-manylinux_2_5_i686.manylinux1_i686.manylinux_2_17_i686.manylinux2014_i686.whl", hash = "sha256:ff70f32aa316393eaf8222d518ce9118148eddb8a53073c2403863b41033eed5"}, - {file = "yarl-1.20.1-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:c7ddf7a09f38667aea38801da8b8d6bfe81df767d9dfc8c88eb45827b195cd1c"}, - {file = "yarl-1.20.1-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:57edc88517d7fc62b174fcfb2e939fbc486a68315d648d7e74d07fac42cec240"}, - {file = "yarl-1.20.1-cp39-cp39-musllinux_1_2_i686.whl", hash = "sha256:dab096ce479d5894d62c26ff4f699ec9072269d514b4edd630a393223f45a0ee"}, - {file = "yarl-1.20.1-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:14a85f3bd2d7bb255be7183e5d7d6e70add151a98edf56a770d6140f5d5f4010"}, - {file = "yarl-1.20.1-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:2c89b5c792685dd9cd3fa9761c1b9f46fc240c2a3265483acc1565769996a3f8"}, - {file = "yarl-1.20.1-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:69e9b141de5511021942a6866990aea6d111c9042235de90e08f94cf972ca03d"}, - {file = "yarl-1.20.1-cp39-cp39-win32.whl", hash = "sha256:b5f307337819cdfdbb40193cad84978a029f847b0a357fbe49f712063cfc4f06"}, - {file = "yarl-1.20.1-cp39-cp39-win_amd64.whl", hash = "sha256:eae7bfe2069f9c1c5b05fc7fe5d612e5bbc089a39309904ee8b829e322dcad00"}, - {file = "yarl-1.20.1-py3-none-any.whl", hash = "sha256:83b8eb083fe4683c6115795d9fc1cfaf2cbbefb19b3a1cb68f6527460f483a77"}, - {file = "yarl-1.20.1.tar.gz", hash = "sha256:d017a4997ee50c91fd5466cef416231bb82177b93b029906cefc542ce14c35ac"}, + {file = "yarl-1.22.0-cp310-cp310-macosx_10_9_universal2.whl", hash = "sha256:c7bd6683587567e5a49ee6e336e0612bec8329be1b7d4c8af5687dcdeb67ee1e"}, + {file = "yarl-1.22.0-cp310-cp310-macosx_10_9_x86_64.whl", hash = "sha256:5cdac20da754f3a723cceea5b3448e1a2074866406adeb4ef35b469d089adb8f"}, + {file = "yarl-1.22.0-cp310-cp310-macosx_11_0_arm64.whl", hash = "sha256:07a524d84df0c10f41e3ee918846e1974aba4ec017f990dc735aad487a0bdfdf"}, + {file = "yarl-1.22.0-cp310-cp310-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:e1b329cb8146d7b736677a2440e422eadd775d1806a81db2d4cded80a48efc1a"}, + {file = "yarl-1.22.0-cp310-cp310-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:75976c6945d85dbb9ee6308cd7ff7b1fb9409380c82d6119bd778d8fcfe2931c"}, + {file = "yarl-1.22.0-cp310-cp310-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:80ddf7a5f8c86cb3eb4bc9028b07bbbf1f08a96c5c0bc1244be5e8fefcb94147"}, + {file = "yarl-1.22.0-cp310-cp310-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:d332fc2e3c94dad927f2112395772a4e4fedbcf8f80efc21ed7cdfae4d574fdb"}, + {file = "yarl-1.22.0-cp310-cp310-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:0cf71bf877efeac18b38d3930594c0948c82b64547c1cf420ba48722fe5509f6"}, + {file = "yarl-1.22.0-cp310-cp310-musllinux_1_2_aarch64.whl", hash = "sha256:663e1cadaddae26be034a6ab6072449a8426ddb03d500f43daf952b74553bba0"}, + {file = "yarl-1.22.0-cp310-cp310-musllinux_1_2_armv7l.whl", hash = "sha256:6dcbb0829c671f305be48a7227918cfcd11276c2d637a8033a99a02b67bf9eda"}, + {file = "yarl-1.22.0-cp310-cp310-musllinux_1_2_ppc64le.whl", hash = "sha256:f0d97c18dfd9a9af4490631905a3f131a8e4c9e80a39353919e2cfed8f00aedc"}, + {file = "yarl-1.22.0-cp310-cp310-musllinux_1_2_s390x.whl", hash = "sha256:437840083abe022c978470b942ff832c3940b2ad3734d424b7eaffcd07f76737"}, + {file = "yarl-1.22.0-cp310-cp310-musllinux_1_2_x86_64.whl", hash = "sha256:a899cbd98dce6f5d8de1aad31cb712ec0a530abc0a86bd6edaa47c1090138467"}, + {file = "yarl-1.22.0-cp310-cp310-win32.whl", hash = "sha256:595697f68bd1f0c1c159fcb97b661fc9c3f5db46498043555d04805430e79bea"}, + {file = "yarl-1.22.0-cp310-cp310-win_amd64.whl", hash = "sha256:cb95a9b1adaa48e41815a55ae740cfda005758104049a640a398120bf02515ca"}, + {file = "yarl-1.22.0-cp310-cp310-win_arm64.whl", hash = "sha256:b85b982afde6df99ecc996990d4ad7ccbdbb70e2a4ba4de0aecde5922ba98a0b"}, + {file = "yarl-1.22.0-cp311-cp311-macosx_10_9_universal2.whl", hash = "sha256:1ab72135b1f2db3fed3997d7e7dc1b80573c67138023852b6efb336a5eae6511"}, + {file = "yarl-1.22.0-cp311-cp311-macosx_10_9_x86_64.whl", hash = "sha256:669930400e375570189492dc8d8341301578e8493aec04aebc20d4717f899dd6"}, + {file = "yarl-1.22.0-cp311-cp311-macosx_11_0_arm64.whl", hash = "sha256:792a2af6d58177ef7c19cbf0097aba92ca1b9cb3ffdd9c7470e156c8f9b5e028"}, + {file = "yarl-1.22.0-cp311-cp311-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:3ea66b1c11c9150f1372f69afb6b8116f2dd7286f38e14ea71a44eee9ec51b9d"}, + {file = "yarl-1.22.0-cp311-cp311-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:3e2daa88dc91870215961e96a039ec73e4937da13cf77ce17f9cad0c18df3503"}, + {file = "yarl-1.22.0-cp311-cp311-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:ba440ae430c00eee41509353628600212112cd5018d5def7e9b05ea7ac34eb65"}, + {file = "yarl-1.22.0-cp311-cp311-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:e6438cc8f23a9c1478633d216b16104a586b9761db62bfacb6425bac0a36679e"}, + {file = "yarl-1.22.0-cp311-cp311-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:4c52a6e78aef5cf47a98ef8e934755abf53953379b7d53e68b15ff4420e6683d"}, + {file = "yarl-1.22.0-cp311-cp311-musllinux_1_2_aarch64.whl", hash = "sha256:3b06bcadaac49c70f4c88af4ffcfbe3dc155aab3163e75777818092478bcbbe7"}, + {file = "yarl-1.22.0-cp311-cp311-musllinux_1_2_armv7l.whl", hash = "sha256:6944b2dc72c4d7f7052683487e3677456050ff77fcf5e6204e98caf785ad1967"}, + {file = "yarl-1.22.0-cp311-cp311-musllinux_1_2_ppc64le.whl", hash = "sha256:d5372ca1df0f91a86b047d1277c2aaf1edb32d78bbcefffc81b40ffd18f027ed"}, + {file = "yarl-1.22.0-cp311-cp311-musllinux_1_2_s390x.whl", hash = "sha256:51af598701f5299012b8416486b40fceef8c26fc87dc6d7d1f6fc30609ea0aa6"}, + {file = "yarl-1.22.0-cp311-cp311-musllinux_1_2_x86_64.whl", hash = "sha256:b266bd01fedeffeeac01a79ae181719ff848a5a13ce10075adbefc8f1daee70e"}, + {file = "yarl-1.22.0-cp311-cp311-win32.whl", hash = "sha256:a9b1ba5610a4e20f655258d5a1fdc7ebe3d837bb0e45b581398b99eb98b1f5ca"}, + {file = "yarl-1.22.0-cp311-cp311-win_amd64.whl", hash = "sha256:078278b9b0b11568937d9509b589ee83ef98ed6d561dfe2020e24a9fd08eaa2b"}, + {file = "yarl-1.22.0-cp311-cp311-win_arm64.whl", hash = "sha256:b6a6f620cfe13ccec221fa312139135166e47ae169f8253f72a0abc0dae94376"}, + {file = "yarl-1.22.0-cp312-cp312-macosx_10_13_universal2.whl", hash = "sha256:e340382d1afa5d32b892b3ff062436d592ec3d692aeea3bef3a5cfe11bbf8c6f"}, + {file = "yarl-1.22.0-cp312-cp312-macosx_10_13_x86_64.whl", hash = "sha256:f1e09112a2c31ffe8d80be1b0988fa6a18c5d5cad92a9ffbb1c04c91bfe52ad2"}, + {file = "yarl-1.22.0-cp312-cp312-macosx_11_0_arm64.whl", hash = "sha256:939fe60db294c786f6b7c2d2e121576628468f65453d86b0fe36cb52f987bd74"}, + {file = "yarl-1.22.0-cp312-cp312-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:e1651bf8e0398574646744c1885a41198eba53dc8a9312b954073f845c90a8df"}, + {file = "yarl-1.22.0-cp312-cp312-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:b8a0588521a26bf92a57a1705b77b8b59044cdceccac7151bd8d229e66b8dedb"}, + {file = "yarl-1.22.0-cp312-cp312-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:42188e6a615c1a75bcaa6e150c3fe8f3e8680471a6b10150c5f7e83f47cc34d2"}, + {file = "yarl-1.22.0-cp312-cp312-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:f6d2cb59377d99718913ad9a151030d6f83ef420a2b8f521d94609ecc106ee82"}, + {file = "yarl-1.22.0-cp312-cp312-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:50678a3b71c751d58d7908edc96d332af328839eea883bb554a43f539101277a"}, + {file = "yarl-1.22.0-cp312-cp312-musllinux_1_2_aarch64.whl", hash = "sha256:1e8fbaa7cec507aa24ea27a01456e8dd4b6fab829059b69844bd348f2d467124"}, + {file = "yarl-1.22.0-cp312-cp312-musllinux_1_2_armv7l.whl", hash = "sha256:433885ab5431bc3d3d4f2f9bd15bfa1614c522b0f1405d62c4f926ccd69d04fa"}, + {file = "yarl-1.22.0-cp312-cp312-musllinux_1_2_ppc64le.whl", hash = "sha256:b790b39c7e9a4192dc2e201a282109ed2985a1ddbd5ac08dc56d0e121400a8f7"}, + {file = "yarl-1.22.0-cp312-cp312-musllinux_1_2_s390x.whl", hash = "sha256:31f0b53913220599446872d757257be5898019c85e7971599065bc55065dc99d"}, + {file = "yarl-1.22.0-cp312-cp312-musllinux_1_2_x86_64.whl", hash = "sha256:a49370e8f711daec68d09b821a34e1167792ee2d24d405cbc2387be4f158b520"}, + {file = "yarl-1.22.0-cp312-cp312-win32.whl", hash = "sha256:70dfd4f241c04bd9239d53b17f11e6ab672b9f1420364af63e8531198e3f5fe8"}, + {file = "yarl-1.22.0-cp312-cp312-win_amd64.whl", hash = "sha256:8884d8b332a5e9b88e23f60bb166890009429391864c685e17bd73a9eda9105c"}, + {file = "yarl-1.22.0-cp312-cp312-win_arm64.whl", hash = "sha256:ea70f61a47f3cc93bdf8b2f368ed359ef02a01ca6393916bc8ff877427181e74"}, + {file = "yarl-1.22.0-cp313-cp313-macosx_10_13_universal2.whl", hash = "sha256:8dee9c25c74997f6a750cd317b8ca63545169c098faee42c84aa5e506c819b53"}, + {file = "yarl-1.22.0-cp313-cp313-macosx_10_13_x86_64.whl", hash = "sha256:01e73b85a5434f89fc4fe27dcda2aff08ddf35e4d47bbbea3bdcd25321af538a"}, + {file = "yarl-1.22.0-cp313-cp313-macosx_11_0_arm64.whl", hash = "sha256:22965c2af250d20c873cdbee8ff958fb809940aeb2e74ba5f20aaf6b7ac8c70c"}, + {file = "yarl-1.22.0-cp313-cp313-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b4f15793aa49793ec8d1c708ab7f9eded1aa72edc5174cae703651555ed1b601"}, + {file = "yarl-1.22.0-cp313-cp313-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:e5542339dcf2747135c5c85f68680353d5cb9ffd741c0f2e8d832d054d41f35a"}, + {file = "yarl-1.22.0-cp313-cp313-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:5c401e05ad47a75869c3ab3e35137f8468b846770587e70d71e11de797d113df"}, + {file = "yarl-1.22.0-cp313-cp313-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:243dda95d901c733f5b59214d28b0120893d91777cb8aa043e6ef059d3cddfe2"}, + {file = "yarl-1.22.0-cp313-cp313-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:bec03d0d388060058f5d291a813f21c011041938a441c593374da6077fe21b1b"}, + {file = "yarl-1.22.0-cp313-cp313-musllinux_1_2_aarch64.whl", hash = "sha256:b0748275abb8c1e1e09301ee3cf90c8a99678a4e92e4373705f2a2570d581273"}, + {file = "yarl-1.22.0-cp313-cp313-musllinux_1_2_armv7l.whl", hash = "sha256:47fdb18187e2a4e18fda2c25c05d8251a9e4a521edaed757fef033e7d8498d9a"}, + {file = "yarl-1.22.0-cp313-cp313-musllinux_1_2_ppc64le.whl", hash = "sha256:c7044802eec4524fde550afc28edda0dd5784c4c45f0be151a2d3ba017daca7d"}, + {file = "yarl-1.22.0-cp313-cp313-musllinux_1_2_s390x.whl", hash = "sha256:139718f35149ff544caba20fce6e8a2f71f1e39b92c700d8438a0b1d2a631a02"}, + {file = "yarl-1.22.0-cp313-cp313-musllinux_1_2_x86_64.whl", hash = "sha256:e1b51bebd221006d3d2f95fbe124b22b247136647ae5dcc8c7acafba66e5ee67"}, + {file = "yarl-1.22.0-cp313-cp313-win32.whl", hash = "sha256:d3e32536234a95f513bd374e93d717cf6b2231a791758de6c509e3653f234c95"}, + {file = "yarl-1.22.0-cp313-cp313-win_amd64.whl", hash = "sha256:47743b82b76d89a1d20b83e60d5c20314cbd5ba2befc9cda8f28300c4a08ed4d"}, + {file = "yarl-1.22.0-cp313-cp313-win_arm64.whl", hash = "sha256:5d0fcda9608875f7d052eff120c7a5da474a6796fe4d83e152e0e4d42f6d1a9b"}, + {file = "yarl-1.22.0-cp313-cp313t-macosx_10_13_universal2.whl", hash = "sha256:719ae08b6972befcba4310e49edb1161a88cdd331e3a694b84466bd938a6ab10"}, + {file = "yarl-1.22.0-cp313-cp313t-macosx_10_13_x86_64.whl", hash = "sha256:47d8a5c446df1c4db9d21b49619ffdba90e77c89ec6e283f453856c74b50b9e3"}, + {file = "yarl-1.22.0-cp313-cp313t-macosx_11_0_arm64.whl", hash = "sha256:cfebc0ac8333520d2d0423cbbe43ae43c8838862ddb898f5ca68565e395516e9"}, + {file = "yarl-1.22.0-cp313-cp313t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:4398557cbf484207df000309235979c79c4356518fd5c99158c7d38203c4da4f"}, + {file = "yarl-1.22.0-cp313-cp313t-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:2ca6fd72a8cd803be290d42f2dec5cdcd5299eeb93c2d929bf060ad9efaf5de0"}, + {file = "yarl-1.22.0-cp313-cp313t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:ca1f59c4e1ab6e72f0a23c13fca5430f889634166be85dbf1013683e49e3278e"}, + {file = "yarl-1.22.0-cp313-cp313t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:6c5010a52015e7c70f86eb967db0f37f3c8bd503a695a49f8d45700144667708"}, + {file = "yarl-1.22.0-cp313-cp313t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:9d7672ecf7557476642c88497c2f8d8542f8e36596e928e9bcba0e42e1e7d71f"}, + {file = "yarl-1.22.0-cp313-cp313t-musllinux_1_2_aarch64.whl", hash = "sha256:3b7c88eeef021579d600e50363e0b6ee4f7f6f728cd3486b9d0f3ee7b946398d"}, + {file = "yarl-1.22.0-cp313-cp313t-musllinux_1_2_armv7l.whl", hash = "sha256:f4afb5c34f2c6fecdcc182dfcfc6af6cccf1aa923eed4d6a12e9d96904e1a0d8"}, + {file = "yarl-1.22.0-cp313-cp313t-musllinux_1_2_ppc64le.whl", hash = "sha256:59c189e3e99a59cf8d83cbb31d4db02d66cda5a1a4374e8a012b51255341abf5"}, + {file = "yarl-1.22.0-cp313-cp313t-musllinux_1_2_s390x.whl", hash = "sha256:5a3bf7f62a289fa90f1990422dc8dff5a458469ea71d1624585ec3a4c8d6960f"}, + {file = "yarl-1.22.0-cp313-cp313t-musllinux_1_2_x86_64.whl", hash = "sha256:de6b9a04c606978fdfe72666fa216ffcf2d1a9f6a381058d4378f8d7b1e5de62"}, + {file = "yarl-1.22.0-cp313-cp313t-win32.whl", hash = "sha256:1834bb90991cc2999f10f97f5f01317f99b143284766d197e43cd5b45eb18d03"}, + {file = "yarl-1.22.0-cp313-cp313t-win_amd64.whl", hash = "sha256:ff86011bd159a9d2dfc89c34cfd8aff12875980e3bd6a39ff097887520e60249"}, + {file = "yarl-1.22.0-cp313-cp313t-win_arm64.whl", hash = "sha256:7861058d0582b847bc4e3a4a4c46828a410bca738673f35a29ba3ca5db0b473b"}, + {file = "yarl-1.22.0-cp314-cp314-macosx_10_13_universal2.whl", hash = "sha256:34b36c2c57124530884d89d50ed2c1478697ad7473efd59cfd479945c95650e4"}, + {file = "yarl-1.22.0-cp314-cp314-macosx_10_13_x86_64.whl", hash = "sha256:0dd9a702591ca2e543631c2a017e4a547e38a5c0f29eece37d9097e04a7ac683"}, + {file = "yarl-1.22.0-cp314-cp314-macosx_11_0_arm64.whl", hash = "sha256:594fcab1032e2d2cc3321bb2e51271e7cd2b516c7d9aee780ece81b07ff8244b"}, + {file = "yarl-1.22.0-cp314-cp314-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:f3d7a87a78d46a2e3d5b72587ac14b4c16952dd0887dbb051451eceac774411e"}, + {file = "yarl-1.22.0-cp314-cp314-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:852863707010316c973162e703bddabec35e8757e67fcb8ad58829de1ebc8590"}, + {file = "yarl-1.22.0-cp314-cp314-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:131a085a53bfe839a477c0845acf21efc77457ba2bcf5899618136d64f3303a2"}, + {file = "yarl-1.22.0-cp314-cp314-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:078a8aefd263f4d4f923a9677b942b445a2be970ca24548a8102689a3a8ab8da"}, + {file = "yarl-1.22.0-cp314-cp314-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:bca03b91c323036913993ff5c738d0842fc9c60c4648e5c8d98331526df89784"}, + {file = "yarl-1.22.0-cp314-cp314-musllinux_1_2_aarch64.whl", hash = "sha256:68986a61557d37bb90d3051a45b91fa3d5c516d177dfc6dd6f2f436a07ff2b6b"}, + {file = "yarl-1.22.0-cp314-cp314-musllinux_1_2_armv7l.whl", hash = "sha256:4792b262d585ff0dff6bcb787f8492e40698443ec982a3568c2096433660c694"}, + {file = "yarl-1.22.0-cp314-cp314-musllinux_1_2_ppc64le.whl", hash = "sha256:ebd4549b108d732dba1d4ace67614b9545b21ece30937a63a65dd34efa19732d"}, + {file = "yarl-1.22.0-cp314-cp314-musllinux_1_2_s390x.whl", hash = "sha256:f87ac53513d22240c7d59203f25cc3beac1e574c6cd681bbfd321987b69f95fd"}, + {file = "yarl-1.22.0-cp314-cp314-musllinux_1_2_x86_64.whl", hash = "sha256:22b029f2881599e2f1b06f8f1db2ee63bd309e2293ba2d566e008ba12778b8da"}, + {file = "yarl-1.22.0-cp314-cp314-win32.whl", hash = "sha256:6a635ea45ba4ea8238463b4f7d0e721bad669f80878b7bfd1f89266e2ae63da2"}, + {file = "yarl-1.22.0-cp314-cp314-win_amd64.whl", hash = "sha256:0d6e6885777af0f110b0e5d7e5dda8b704efed3894da26220b7f3d887b839a79"}, + {file = "yarl-1.22.0-cp314-cp314-win_arm64.whl", hash = "sha256:8218f4e98d3c10d683584cb40f0424f4b9fd6e95610232dd75e13743b070ee33"}, + {file = "yarl-1.22.0-cp314-cp314t-macosx_10_13_universal2.whl", hash = "sha256:45c2842ff0e0d1b35a6bf1cd6c690939dacb617a70827f715232b2e0494d55d1"}, + {file = "yarl-1.22.0-cp314-cp314t-macosx_10_13_x86_64.whl", hash = "sha256:d947071e6ebcf2e2bee8fce76e10faca8f7a14808ca36a910263acaacef08eca"}, + {file = "yarl-1.22.0-cp314-cp314t-macosx_11_0_arm64.whl", hash = "sha256:334b8721303e61b00019474cc103bdac3d7b1f65e91f0bfedeec2d56dfe74b53"}, + {file = "yarl-1.22.0-cp314-cp314t-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:1e7ce67c34138a058fd092f67d07a72b8e31ff0c9236e751957465a24b28910c"}, + {file = "yarl-1.22.0-cp314-cp314t-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:d77e1b2c6d04711478cb1c4ab90db07f1609ccf06a287d5607fcd90dc9863acf"}, + {file = "yarl-1.22.0-cp314-cp314t-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:c4647674b6150d2cae088fc07de2738a84b8bcedebef29802cf0b0a82ab6face"}, + {file = "yarl-1.22.0-cp314-cp314t-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:efb07073be061c8f79d03d04139a80ba33cbd390ca8f0297aae9cce6411e4c6b"}, + {file = "yarl-1.22.0-cp314-cp314t-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:e51ac5435758ba97ad69617e13233da53908beccc6cfcd6c34bbed8dcbede486"}, + {file = "yarl-1.22.0-cp314-cp314t-musllinux_1_2_aarch64.whl", hash = "sha256:33e32a0dd0c8205efa8e83d04fc9f19313772b78522d1bdc7d9aed706bfd6138"}, + {file = "yarl-1.22.0-cp314-cp314t-musllinux_1_2_armv7l.whl", hash = "sha256:bf4a21e58b9cde0e401e683ebd00f6ed30a06d14e93f7c8fd059f8b6e8f87b6a"}, + {file = "yarl-1.22.0-cp314-cp314t-musllinux_1_2_ppc64le.whl", hash = "sha256:e4b582bab49ac33c8deb97e058cd67c2c50dac0dd134874106d9c774fd272529"}, + {file = "yarl-1.22.0-cp314-cp314t-musllinux_1_2_s390x.whl", hash = "sha256:0b5bcc1a9c4839e7e30b7b30dd47fe5e7e44fb7054ec29b5bb8d526aa1041093"}, + {file = "yarl-1.22.0-cp314-cp314t-musllinux_1_2_x86_64.whl", hash = "sha256:c0232bce2170103ec23c454e54a57008a9a72b5d1c3105dc2496750da8cfa47c"}, + {file = "yarl-1.22.0-cp314-cp314t-win32.whl", hash = "sha256:8009b3173bcd637be650922ac455946197d858b3630b6d8787aa9e5c4564533e"}, + {file = "yarl-1.22.0-cp314-cp314t-win_amd64.whl", hash = "sha256:9fb17ea16e972c63d25d4a97f016d235c78dd2344820eb35bc034bc32012ee27"}, + {file = "yarl-1.22.0-cp314-cp314t-win_arm64.whl", hash = "sha256:9f6d73c1436b934e3f01df1e1b21ff765cd1d28c77dfb9ace207f746d4610ee1"}, + {file = "yarl-1.22.0-cp39-cp39-macosx_10_9_universal2.whl", hash = "sha256:3aa27acb6de7a23785d81557577491f6c38a5209a254d1191519d07d8fe51748"}, + {file = "yarl-1.22.0-cp39-cp39-macosx_10_9_x86_64.whl", hash = "sha256:af74f05666a5e531289cb1cc9c883d1de2088b8e5b4de48004e5ca8a830ac859"}, + {file = "yarl-1.22.0-cp39-cp39-macosx_11_0_arm64.whl", hash = "sha256:62441e55958977b8167b2709c164c91a6363e25da322d87ae6dd9c6019ceecf9"}, + {file = "yarl-1.22.0-cp39-cp39-manylinux2014_aarch64.manylinux_2_17_aarch64.manylinux_2_28_aarch64.whl", hash = "sha256:b580e71cac3f8113d3135888770903eaf2f507e9421e5697d6ee6d8cd1c7f054"}, + {file = "yarl-1.22.0-cp39-cp39-manylinux2014_armv7l.manylinux_2_17_armv7l.manylinux_2_31_armv7l.whl", hash = "sha256:e81fda2fb4a07eda1a2252b216aa0df23ebcd4d584894e9612e80999a78fd95b"}, + {file = "yarl-1.22.0-cp39-cp39-manylinux2014_ppc64le.manylinux_2_17_ppc64le.manylinux_2_28_ppc64le.whl", hash = "sha256:99b6fc1d55782461b78221e95fc357b47ad98b041e8e20f47c1411d0aacddc60"}, + {file = "yarl-1.22.0-cp39-cp39-manylinux2014_s390x.manylinux_2_17_s390x.manylinux_2_28_s390x.whl", hash = "sha256:088e4e08f033db4be2ccd1f34cf29fe994772fb54cfe004bbf54db320af56890"}, + {file = "yarl-1.22.0-cp39-cp39-manylinux2014_x86_64.manylinux_2_17_x86_64.manylinux_2_28_x86_64.whl", hash = "sha256:2e4e1f6f0b4da23e61188676e3ed027ef0baa833a2e633c29ff8530800edccba"}, + {file = "yarl-1.22.0-cp39-cp39-musllinux_1_2_aarch64.whl", hash = "sha256:84fc3ec96fce86ce5aa305eb4aa9358279d1aa644b71fab7b8ed33fe3ba1a7ca"}, + {file = "yarl-1.22.0-cp39-cp39-musllinux_1_2_armv7l.whl", hash = "sha256:5dbeefd6ca588b33576a01b0ad58aa934bc1b41ef89dee505bf2932b22ddffba"}, + {file = "yarl-1.22.0-cp39-cp39-musllinux_1_2_ppc64le.whl", hash = "sha256:14291620375b1060613f4aab9ebf21850058b6b1b438f386cc814813d901c60b"}, + {file = "yarl-1.22.0-cp39-cp39-musllinux_1_2_s390x.whl", hash = "sha256:a4fcfc8eb2c34148c118dfa02e6427ca278bfd0f3df7c5f99e33d2c0e81eae3e"}, + {file = "yarl-1.22.0-cp39-cp39-musllinux_1_2_x86_64.whl", hash = "sha256:029866bde8d7b0878b9c160e72305bbf0a7342bcd20b9999381704ae03308dc8"}, + {file = "yarl-1.22.0-cp39-cp39-win32.whl", hash = "sha256:4dcc74149ccc8bba31ce1944acee24813e93cfdee2acda3c172df844948ddf7b"}, + {file = "yarl-1.22.0-cp39-cp39-win_amd64.whl", hash = "sha256:10619d9fdee46d20edc49d3479e2f8269d0779f1b031e6f7c2aa1c76be04b7ed"}, + {file = "yarl-1.22.0-cp39-cp39-win_arm64.whl", hash = "sha256:dd7afd3f8b0bfb4e0d9fc3c31bfe8a4ec7debe124cfd90619305def3c8ca8cd2"}, + {file = "yarl-1.22.0-py3-none-any.whl", hash = "sha256:1380560bdba02b6b6c90de54133c81c9f2a453dee9912fe58c1dcced1edb7cff"}, + {file = "yarl-1.22.0.tar.gz", hash = "sha256:bebf8557577d4401ba8bd9ff33906f1376c877aa78d1fe216ad01b4d6745af71"}, ] [package.dependencies] @@ -8650,4 +9209,4 @@ gradio = ["gradio"] [metadata] lock-version = "2.1" python-versions = ">=3.11,<4.0" -content-hash = "95ca4b8902c8d665a5897c51ea728aa444953ca9a7789f2a2daa605fc90f3955" +content-hash = "21d4c3d4a120aaa56a92a20f6f9e9844139e1740269a5b1afb01341ec3118d26" diff --git a/pyproject.toml b/pyproject.toml index 2ab7d97..f2c1d62 100644 --- a/pyproject.toml +++ b/pyproject.toml @@ -18,7 +18,7 @@ python = ">=3.11,<4.0" click = "^8.2.1" aurelian = {git = "https://github.com/monarch-initiative/aurelian.git"} gradio = "^5.23.3" -pydantic-ai = ">=0.2.0" +pydantic-ai = "==0.2.0" logfire = ">=3.5.3" fastobo = ">=0.12.3" oaklib = ">=0.6.21" @@ -27,6 +27,7 @@ matplotlib = "^3.10.3" pymupdf = "^1.26.3" pdfminer-six = {optional=true, version="*"} PyPDF2 = {optional=true, version="*"} +openai = {optional=true, version="*"} [tool.poetry.group.dev.dependencies] pytest = "^8.2.0"