Integrated analysis of gene networks and cellular functions identifies novel heart failure biomarkers.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:40775796", "kind": "science-record", "revision": 4, "content_hash": "sha256:02318e2c0336b99cb771f0eaf0724d54530fedfef099e362244848c30673150d", "created_at": "2026-11-01T20:30:52Z", "updated_at": "2026-11-01T22:56:58Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Integrated analysis of gene networks and cellular functions identifies novel heart failure biomarkers.", "doi": "10.1186/s41065-025-00521-5", "pmid": "40775796", "authors": ["Jiang Juncheng", "Chen Lei", "Lin Hao", "Liang Fei"], "journal": "Hereditas", "year": 2025, "abstract": "INTRODUCTION: Heart failure (HF) is a complex clinical condition characterized by impaired cardiac function and progressive structural remodeling. To elucidate the molecular mechanisms driving HF, this study aimed to identify key regulatory hub genes, explore their functional relevance, and assess their diagnostic and therapeutic potential.\nMETHODS: Four public microarray datasets (GSE161472, GSE147236, GSE116250, and GSE46224) were retrieved from the Gene Expression Omnibus (GEO) database. Differential expression analysis using the limma package in R identified Differentially expressed genes (DEGs), which were further analyzed via Venn diagrams, STRING PPI networks, and Cytoscape's CytoHubba plugin to determine top hub genes. RT-qPCR and Western blotting were used to validate gene expression in HF and normal cardiomyocyte cell lines. Functional assays (proliferation, colony formation, and wound healing) were conducted following overexpression of COL9A1 and MTIF3. miRNA regulation and immune cell infiltration were analyzed using TargetScan and CIBERSORT, respectively. Enrichment analysis was performed via DAVID, and drug prediction was conducted using DGIdb.\nRESULTS: Four hub genes-COL9A1, MTIF3, MRPS25, and HMGN1-were consistently downregulated in HF and exhibited high diagnostic potential (AUC > 0.8). Overexpression of COL9A1 and MTIF3 significantly reduced cell proliferation, colony formation, and migration in HF cell lines. Immune infiltration analysis revealed strong negative correlations between hub gene expression and various immune cell types. Drug prediction identified Milrinone as a potential therapeutic candidate targeting COL9A1.\nCONCLUSION: COL9A1, MTIF3, MRPS25, and HMGN1 emerge as critical biomarkers and regulators in HF, offering promising avenues for diagnosis, mechanistic understanding, and targeted therapy development.", "claims": [{"id": "claim-method", "statement": "These datasets were analyzed using the limma package to identify DEGs between HF and normal control samples.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40775796", "locator": "sections[17] \"Identification of hub genes in HF\" paragraph 2", "quote": "These datasets were analyzed using the limma package to identify DEGs between HF and normal control samples."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Any type of the data will be provided by the corresponding author.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40775796", "locator": "sections[30] \"Data availability\" paragraph 2", "quote": "Any type of the data will be provided by the corresponding author."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Four hub genes—COL9A1, MTIF3, MRPS25, and HMGN1—were consistently downregulated in HF and exhibited high diagnostic potential (AUC > 0.8).", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:40775796", "locator": "sections[0] \"Abstract\" paragraph 3", "quote": "Four hub genes—COL9A1, MTIF3, MRPS25, and HMGN1—were consistently downregulated in HF and exhibited high diagnostic potential (AUC > 0.8)."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Four hub genes—COL9A1, MTIF3, MRPS25, and HMGN1—were consistently downregulated in HF and exhibited high diagnostic potential (AUC > 0.8).", "steps": [{"id": "read_published_estimate", "order": 1, "name": "Read the published estimate from the source", "kind": "other", "state": "complete", "blocked_on": null, "description": "The claim, method and evidence span published with the source article.", "duration_hours": null, "parameters": {}, "inputs": ["source:pmid:40775796"], "outputs": ["the published estimate and its evidence"], "instruments": [], "reagents": []}, {"id": "obtain_source_data", "order": 2, "name": "Obtain the source data from the named repository", "kind": "data-preparation", "state": "complete", "blocked_on": null, "description": "The GEO series accession resolves and its sample accessions are listed. This lane did not download the dataset or read its licence.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE116250"], "outputs": ["the source data with its repository provenance"], "instruments": [], "reagents": []}, {"id": "run_analysis", "order": 3, "name": "Run the published analysis", "kind": "analysis", "state": "complete", "blocked_on": null, "description": "Apply the paper's statistical method to the resolved series and compare the result with the published target.", "duration_hours": null, "parameters": {}, "inputs": ["data:geo:GSE116250"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:40775796", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1186/s41065-025-00521-5", "sha256": "sha256:bcde3826aaee4240fd9336bd495366d61282d65e1f2ce3d3976d613dd90de724", "bytes": 48454, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1186/s41065-025-00521-5", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC12333206", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE116250", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE116250", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE116250", "version": null, "note": "Any type of the data will be provided by the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Any type of the data will be provided by the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM3219558", "GSM3219559", "GSM3219560", "GSM3219561", "GSM3219562", "GSM3219563", "GSM3219564", "GSM3219565", "GSM3219566", "GSM3219567", "GSM3219568", "GSM3219569", "GSM3219570", "GSM3219571", "GSM3219572", "GSM3219573", "GSM3219574", "GSM3219575", "GSM3219576", "GSM3219577", "GSM3219578", "GSM3219579", "GSM3219580", "GSM3219581", "GSM3219582", "GSM3219583", "GSM3219584", "GSM3219585", "GSM3219586", "GSM3219587", "GSM3219588", "GSM3219589", "GSM3219590", "GSM3219591", "GSM3219592", "GSM3219593", "GSM3219594", "GSM3219595", "GSM3219596", "GSM3219597", "GSM3219598", "GSM3219599", "GSM3219600", "GSM3219601", "GSM3219602", "GSM3219603", "GSM3219604", "GSM3219605", "GSM3219606", "GSM3219607", "GSM3219608", "GSM3219609", "GSM3219610", "GSM3219611", "GSM3219612", "GSM3219613", "GSM3219614", "GSM3219615", "GSM3219616", "GSM3219617", "GSM3219618", "GSM3219619", "GSM3219620", "GSM3219621"], "sample_count": 64, "group_sizes": null, "group_sizes_basis": null, "platform": "16791", "taxon": "Homo sapiens", "title": "RNA-seq of heart failure in human left ventricles", "resolution_checked_at": "2026-11-01T15:39:54Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE147236", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE147236", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE147236", "version": null, "note": "Any type of the data will be provided by the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Any type of the data will be provided by the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM4421321", "GSM4421322", "GSM4421323", "GSM4421324", "GSM4421325", "GSM4421326", "GSM4421327", "GSM4421328", "GSM4421329", "GSM4421330", "GSM4421331", "GSM4421332", "GSM4421333", "GSM4421334"], "sample_count": 14, "group_sizes": null, "group_sizes_basis": null, "platform": "20301;18573", "taxon": "Homo sapiens", "title": "Altered Enhancer and Promoter Usage Leads to Differential Gene Expression in the Normal and Failed Human Heart ", "resolution_checked_at": "2026-11-01T20:16:08Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE161472", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE161472", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE161472", "version": null, "note": "Any type of the data will be provided by the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Any type of the data will be provided by the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM4907735", "GSM4907736", "GSM4907738", "GSM4907739", "GSM4907741", "GSM4907743", "GSM4907744", "GSM4907745", "GSM4907747", "GSM4907748", "GSM4907750", "GSM4907752", "GSM4907754", "GSM4907755", "GSM4907757", "GSM4907758", "GSM4907760", "GSM4907761", "GSM4907763", "GSM4907764", "GSM4907765", "GSM4907767", "GSM4907768", "GSM4907770", "GSM4907771", "GSM4907773", "GSM4907774", "GSM4907776", "GSM4907777", "GSM4907779", "GSM4907780", "GSM4907781", "GSM4907782", "GSM4907784", "GSM4907785", "GSM4907787", "GSM4907789", "GSM4907791", "GSM4907792", "GSM4907794", "GSM4907795", "GSM4907796", "GSM4907798", "GSM4907800", "GSM4907801", "GSM4907802", "GSM4907804", "GSM4907805", "GSM4907807", "GSM4907808", "GSM4907810", "GSM4907812", "GSM4907813", "GSM4907816", "GSM4907818", "GSM4907822", "GSM4907824", "GSM4907826", "GSM4907830", "GSM4907832", "GSM4907836", "GSM4907839", "GSM4907840", "GSM4907841", "GSM4907842", "GSM4907843", "GSM4907844", "GSM4907845", "GSM4907846", "GSM4907847", "GSM4907848", "GSM4907849", "GSM4907850", "GSM4907851", "GSM4907852", "GSM4907853", "GSM4907854", "GSM4907855", "GSM4907856", "GSM4907857", "GSM4907858", "GSM4907859", "GSM4907860", "GSM4907861"], "sample_count": 84, "group_sizes": null, "group_sizes_basis": null, "platform": "11154", "taxon": "Homo sapiens", "title": "Chamber-Enriched gene expression profiles in failing human hearts with reduced ejection fraction [RNA-Seq]", "resolution_checked_at": "2026-11-01T20:16:08Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}, {"id": "data:geo:GSE36074", "role": "raw", "format": "geo-series", "media_type": "application/vnd.ncbi.geo-series+json", "uri": "https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE36074", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE36074", "version": null, "note": "Any type of the data will be provided by the corresponding author.", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Any type of the data will be provided by the corresponding author.", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM880736", "GSM880737", "GSM880738", "GSM880739", "GSM880740", "GSM880741", "GSM880742", "GSM880743", "GSM880744", "GSM880745", "GSM880746", "GSM880747", "GSM880748", "GSM880749", "GSM880750", "GSM880751", "GSM880752", "GSM880753", "GSM880754"], "sample_count": 19, "group_sizes": null, "group_sizes_basis": null, "platform": "1261", "taxon": "Mus musculus", "title": "Differential regulation of extracellular matrix constituents in myocardial remodeling with and without heart failure following pressure overload", "resolution_checked_at": "2026-11-01T19:09:46Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}], "gaps": ["asset:data:geo:GSE116250 not downloaded", "asset:data:geo:GSE116250 licence not read", "asset:data:geo:GSE147236 not downloaded", "asset:data:geo:GSE147236 licence not read", "asset:data:geo:GSE161472 not downloaded", "asset:data:geo:GSE161472 licence not read", "asset:data:geo:GSE36074 not downloaded", "asset:data:geo:GSE36074 licence not read"]}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "family": "differential_expression", "specific": "limma_voom", "label": "Differential expression analysis", "dsl_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["count_matrix_with_condition"], "evidence": {"score": 1.0, "band": "verbatim", "quote": "These datasets were analyzed using the limma package to identify DEGs between HF and normal control samples."}}, {"id": "method-2", "family": "group_comparison", "specific": "anova", "label": "Group comparison", "dsl_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["two_or_more_groups_continuous"], "evidence": {"score": 0.8, "band": "high", "quote": "ANOVA"}}, {"id": "method-3", "family": "correlation_analysis", "specific": "pearson", "label": "Correlation analysis", "dsl_operations": ["pearson_r"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["paired_numeric_columns"], "evidence": {"score": 0.8, "band": "high", "quote": "Pearson correlation"}}, {"id": "method-4", "family": "network_analysis", "specific": "ppi_network", "label": "Network / pathway analysis", "dsl_operations": ["build_graph", "centrality_scores", "pathway_enrich"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["edge_list"], "evidence": {"score": 0.7, "band": "medium", "quote": "PPI"}}], "targets": [], "gaps": ["method.reader_differs_from_extractor"]}, "capability": {"state": "complete", "requirements": [{"capability_id": "capability:computational_analysis", "label": "Computational analysis platform", "assay_families": ["meta_analysis", "machine_learning", "survival_analysis", "statistical_regression", "pca", "molecular_docking", "network_analysis", "differential_expression", "gwas"], "availability_state": "owned", "tier_unlocked": "R1", "candidate": "Automated Assays Laravel application and simulated adapters"}], "gaps": []}, "readiness": {"state": "complete", "tier": "R1", "blocking_axis": "none", "blocked_on": "nothing:replicable_now", "axes": {"method": {"tier": "R1", "expressible": true, "required_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: limma_voom."}, "capability": {"tier": "R1", "capability_id": "capability:computational_analysis", "availability_state": "owned", "basis": "The computational analysis is owned. The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE161472", "GSE147236", "GSE116250", "and GSE46224", "GSE36074"], "resolved_accessions": ["GSE161472", "GSE147236", "GSE116250", "GSE36074"], "statements": ["Any type of the data will be provided by the corresponding author."], "basis": "The paper names GSE161472, GSE147236, GSE116250, GSE36074 in Gene Expression Omnibus (GEO) database and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "assets": ["source:pmid:40775796", "data:geo:GSE116250"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE116250"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T19:58:44Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 13338, "completion_tokens": 1701, "cached_tokens": 264}}, "human_critique": null, "stages": [{"id": "extraction", "state": "complete", "reader": "MiniMax-M3.1-Flash", "provider": "minimax"}], "gaps": ["review.independent_reader", "review.machine_critique", "review.human_critique"]}, "execution": {"state": "absent", "status": "not_run", "mode": null, "runs": [], "gaps": ["execution.not_run"]}, "provenance": {"entities": [{"id": "pmid:40775796", "type": "paper", "label": "pmid:40775796"}, {"id": "source:pmid:40775796", "type": "manuscript", "label": "PMID 40775796 full text"}, {"id": "data:geo:GSE116250", "type": "dataset", "label": "GEO GSE116250"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:40775796", "type": "paper", "label": "pmid:40775796"}, {"id": "source:pmid:40775796", "type": "manuscript", "label": "PMID 40775796 full text"}, {"id": "data:geo:GSE116250", "type": "dataset", "label": "GEO GSE116250"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-40775796", "type": "extraction", "used": ["source:pmid:40775796"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE116250", "type": "accession_resolution", "used": ["data:geo:GSE116250"], "agent": "agent:corpus-assay-engine"}], "agents": [{"id": "agent:corpus-assay-engine", "type": "software", "label": "Corpus assay engine"}, {"id": "agent:minimax-reader", "type": "software", "label": "MiniMax literature reader"}], "source_run_id": "reading-sci-2026-11-01", "dsl_catalogue_fingerprint": "343fb30756ba6ec3", "capability_table_fingerprint": "2cb3e42f047d2ecf", "snapshot_id": "ba34b49490d9bfaf"}, "lineage": {"parent_id": "pmid:40775796", "parent_hash": "sha256:d428256aed9d7803c40ca48b9948c9423d702eda1c8e016a96cf378021b189c9", "fork_of": null, "generation": 3}, "gaps": ["asset:data:geo:GSE116250 licence not read", "asset:data:geo:GSE116250 not downloaded", "asset:data:geo:GSE147236 licence not read", "asset:data:geo:GSE147236 not downloaded", "asset:data:geo:GSE161472 licence not read", "asset:data:geo:GSE161472 not downloaded", "asset:data:geo:GSE36074 licence not read", "asset:data:geo:GSE36074 not downloaded", "execution.not_run", "method.reader_differs_from_extractor", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "microarray", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["therapeutic potential. METHODS: Four public microarray datasets (GSE161472, GSE147236, GSE116250, a", "isons. Differential expression analysis from microarray datasets was conducted using the limma packa"], "order_basis": "paper_text_order:423", "id": "assay:1"}, {"role": "data_generation", "definition_id": "qpcr", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["CytoHubba plugin to determine top hub genes. RT-qPCR and Western blotting were used to validate g", "oHubba plugin to determine top hub genes. RT-qPCR and Western blotting were used to validate g"], "order_basis": "paper_text_order:795", "id": "assay:2"}, {"role": "data_generation", "definition_id": "western_blot", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["ugin to determine top hub genes. RT-qPCR and Western blotting were used to validate gene expression in HF"], "order_basis": "paper_text_order:807", "id": "assay:3"}, {"role": "analysis", "definition_id": "differential_expression", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["These datasets were analyzed using the limma package to identify DEGs between HF and normal control samples."], "order_basis": "consumes_earlier_output", "id": "assay:4"}]}