{"data":{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:40918148", "kind": "science-record", "revision": 4, "content_hash": "sha256:85fa2798382e7ec1e6b0048739d1ff5affd9eced0ad0b4ec78944d9368c84920", "created_at": "2026-11-01T20:31:01Z", "updated_at": "2026-11-01T22:57:09Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Exploring the biological functions and immune regulatory roles of IRAK3, TNFRSF1A, CX3CR1, and JUNB in T2DM combined with MAFLD: integrated bioinformatics and single-cell analysis.", "doi": "10.3389/fimmu.2025.1587225", "pmid": "40918148", "authors": ["Qin Wang", "Xiaoqi Li", "Kaidierdan Wushoulaji", "Jinyang Wang", "Li Wan", "Ye Yang", "Xueli Gong"], "journal": "Frontiers in immunology", "year": 2025, "abstract": "Objective: Diabetes mellitus combined with nonalcoholic fatty liver disease is a prevalent and intricate metabolic disorder that presents a significant global health challenge, imposing economic and emotional burdens on society and families. An in-depth understanding of the disease pathogenesis is crucial for enhancing diagnostic and therapeutic efficacy. Therefore, the study aims to identify and validate autophagy-related diagnostic biomarkers associated with T2DM-associated MAFLD, investigate regulatory mechanisms in disease progression, and explore cellular diversity within the same tissue using single-cell sequencing data.\nMethods: This study utilized four datasets retrieved from the Gene Expression Omnibus (GEO) database: GSE15653, GSE89632, GSE24807 and GSE23343. The analysis involved variance analysis, WGCNA analysis, PPI network construction, machine learning application, examination of autophagy-related gene sets, and diagnostic ROC analysis to identify and validate autophagy-related biomarkers in T2DM combined with MAFLD within an independent external dataset. Functional enrichment analysis, immune infiltration analysis, and validation of gene significance in T2DM combined with MAFLD progression were conducted using animal experiments to understand the biological functions and immunomodulatory roles of key biomarkers. Cellular diversity within liver tissues was characterized at the single-cell level, exploring interrelationships, differentiation, and developmental trajectories among cell populations through cellular communication and pseudo-temporal analyses.\nResults: The study identified four key biomarkers (IRAK3, TNFRSF1A, CX3CR1, JUNB). Real-time fluorescence quantitative PCR analysis in animal experiments demonstrated significantly higher mRNA expression levels of IRAK3, TNFRSF1A, CX3CR1, and JUNB in T2DM and MAFLD rat liver tissues compared to the control group. Quantitative immunohistochemical analysis revealed notably elevated protein expression levels of IRAK3, TNFRSF1A, CX3CR1, and JUNB in liver tissues of rats with T2DM and MAFLD when contrasted with the control group (P < 0.05). Enrichment analysis indicated associations of T2DM combined with MAFLD pathogenesis with pathways such as the NF-kappa B signaling pathway, MAPK signaling pathway, Fluid shear stress and atherosclerosis, Insulin resistance, and Cytokine-cytokine receptor interaction. Correlative analysis uncovered connections between immune infiltration and the identified genes. Single-cell transcriptomic analysis highlighted the differentiation of CX3CR1, JUNB, and TFRC in various single-cell-annotated populations. The pseudo-temporal analysis of epithelial cells identified enriched genes at crucial nodes related to \"Leukocyte transendothelial migration\", \"Lipid and atherosclerosis\", and \"Type II diabetes mellitus\" signaling pathways. Additionally, four cellular communication signaling pathways (TNF, CXCL, VEGF, and MIF) potentially significant in T2DM combined with MAFLD progression were identified through cell communication analysis.\nConclusion: This study unveiled potential associations and key biomarkers (IRAK3, TNFRSF1A, CX3CR1, JUNB) concerning T2DM combined with MAFLD and relevant pathways, offering novel insights for the investigation of these two conditions.", "claims": [{"id": "claim-method", "statement": "Difference analysis was performed separately to obtain the respective DEGs, using limma package (version 3.58.1), with screening criteria: |log2FC| > 0.5 and P < 0.05 (8, 9).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40918148", "locator": "sections[3] \"Identification of differential expression genes\" paragraph 2", "quote": "Difference analysis was performed separately to obtain the respective DEGs, using limma package (version 3.58.1), with screening criteria: |log2FC| > 0.5 and P < 0.05 (8, 9)."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The datasets generated and/or analysed during the current study are available in the NCBI repository, and the data used to support the findings of this study have been deposited in the GEO repository (GSE15653, GSE89632, and GSE24807 and GSE136103).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40918148", "locator": "sections[37] \"Data availability statement\" paragraph 2", "quote": "The datasets generated and/or analysed during the current study are available in the NCBI repository, and the data used to support the findings of this study have been deposited in the GEO repository (GSE15653, GSE89632, and GSE24807 and GSE136103)."}], "state": "complete"}, {"id": "claim-target-result", "statement": "In the GSE15653 training dataset, receiver operating characteristic analysis showed AUCs above 0.8 for IRAK3, TFRC, TNFRSF1A, CX3CR1, and JUNB.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:40918148", "locator": "sections[24] \"Performance of five diagnostic biomarkers\" paragraph 2", "quote": "In GSE15653, the AUCs for all five genes were above 0.8 ( Figure 4M )."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "In the GSE15653 training dataset, receiver operating characteristic analysis showed AUCs above 0.8 for IRAK3, TFRC, TNFRSF1A, CX3CR1, and JUNB.", "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:40918148"], "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. 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The physical bench the paper used is not, so a physical validation cannot be run here."}, "data": {"tier": "R1", "reachable": true, "accessions": ["GSE15653", "GSE89632", "GSE24807", "GSE23343", "GSE136103"], "resolved_accessions": ["GSE15653", "GSE89632", "GSE24807", "GSE23343", "GSE136103"], "statements": ["The datasets generated and/or analysed during the current study are available in the NCBI repository, and the data used to support the findings of this study have been deposited in the GEO repository (GSE15653, GSE89632, and GSE24807 and GSE136103)."], "basis": "The paper names GSE15653, GSE89632, GSE24807, GSE23343, GSE136103 in GEO 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:40918148", "data:geo:GSE136103"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE136103"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T20:01:08Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 20337, "completion_tokens": 2041, "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:40918148", "type": "paper", "label": "pmid:40918148"}, {"id": "source:pmid:40918148", "type": "manuscript", "label": "PMID 40918148 full text"}, {"id": "data:geo:GSE136103", "type": "dataset", "label": "GEO GSE136103"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:40918148", "type": "paper", "label": "pmid:40918148"}, {"id": "source:pmid:40918148", "type": "manuscript", "label": "PMID 40918148 full text"}, {"id": "data:geo:GSE136103", "type": "dataset", "label": "GEO GSE136103"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-40918148", "type": "extraction", "used": ["source:pmid:40918148"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE136103", "type": "accession_resolution", "used": ["data:geo:GSE136103"], "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:40918148", "parent_hash": "sha256:b41de55db2be7a5538ee09890e65a43189331cd55ecb571cbae63aa29affd820", "fork_of": null, "generation": 3}, "gaps": ["asset:data:geo:GSE136103 licence not read", "asset:data:geo:GSE136103 not downloaded", "asset:data:geo:GSE15653 licence not read", "asset:data:geo:GSE15653 not downloaded", "asset:data:geo:GSE23343 licence not read", "asset:data:geo:GSE23343 not downloaded", "asset:data:geo:GSE24807 licence not read", "asset:data:geo:GSE24807 not downloaded", "asset:data:geo:GSE89632 licence not read", "asset:data:geo:GSE89632 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.834, "evidence": ["TNFRSF1A, CX3CR1, and JUNB in T2DM and MAFLD rat liver tissues compared to the control group.", "FRSF1A, CX3CR1, and JUNB in liver tissues of rats with T2DM and MAFLD when contrasted with the"], "order_basis": "paper_text_order:1998", "id": "assay:1"}, {"role": "data_generation", "definition_id": "ihc", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["compared to the control group. Quantitative immunohistochemical analysis revealed notably elevated protein e"], "order_basis": "paper_text_order:2061", "id": "assay:2"}, {"role": "data_generation", "definition_id": "microarray", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["dentities. Supplementary Table 1A summary of Microarray Information. Supplementary Table 2List of Pr"], "order_basis": "paper_text_order:9939", "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": ["Difference analysis was performed separately to obtain the respective DEGs, using limma package (version 3.58.1), with screening criteria: |log2FC| > 0.5 and P < 0.05 (8, 9)."], "order_basis": "consumes_earlier_output", "id": "assay:4"}]},"meta":{"api_version":"v1","automation_ladder_snapshot":"ba34b49490d9bfaf","automation_ladder_caveats":["Method extraction is rule-based and has no hand-judged accuracy sample. Evidence bands order textual support; method agreement intervals are null (n=0), never probabilities. Work-type validation does not validate methods.","Operation coverage describes only explicitly named methods. It does not prove a complete protocol, compatible parameters, successful compilation or re-execution. Unrecognised or ambiguous methods require review.","Data reachability is a textual accession or public-data statement. No dataset was downloaded or checked for access, completeness or licence.","Capabilities are planning states seeded from the dated equipment register. No bench ownership, completed quote or partner booking is inferred. Procurement counts are dependencies, not guaranteed replications or financial returns.","Tier and blocker counts are deterministic assessments of this corpus, not measured agreement. R3 is reserved for procurement; unresolved methods and data require human work (R4). The most restrictive axis wins, with capability, method, data as tie-breaks. Resolving one blocker can leave another at the same tier."],"engine":"corpus_engine","engine_provider":"rule_based_v1+lex99e1195c7d6f","run_id":"run-20261023T122449232913","source":"esearch","source_detail":"PubMed mirror biomed_pubmed (read-only)","run_status":"complete","imported_at":"2026-11-03T20:16:52+00:00","generated_at":"2026-11-04T02:12:22+00:00","total_papers":5529,"total_assays_tracked":29,"automatable_assay_families":6,"validated":true,"caveat_count":9,"blocking_caveats":5,"caveats":[{"code":"low_evidence_dominates","basis":["4,152 of 5,529 classifications (75.1%) matched no cue evidence and sit at the 0.05 floor.","34 of 230 data_only calls (14.8%) are in that group."],"claim":"Work type and confidence bands","gloss":"Most records were classified from their title and framing alone, with assay-cue coverage at zero.","detail":"Most classifications in this run rest on no matched evidence at all. At the evidence floor the work type comes from title framing and a fixed prior, not from anything in the paper, so the published work-type split should be read as a rough triage signal rather than a measured distribution. The impact is bounded but not removed: since 2026-10-23 the engine excludes floor-confidence records from the shortlist entirely and publishes them separately as held out, so the recommendation is unaffected even though the census is.","status":"unverified","severity":"high"},{"code":"runtime_is_modelled","basis":["Runtime is summed from published per-assay hour figures. Timing awaits the first executed replication.","4,407 of 5,529 records (79.7%) model to 0.00 hours because no assay was matched, which the ranking then reads as \"cheapest\".","0 of 10 shortlisted records carry a 0.00-hour estimate."],"claim":"Estimated replication runtime","gloss":"The hour figures are estimates built from assay mentions; timing awaits the first executed replication.","detail":"The hour figures are a cost model derived from the bench steps implied by each matched assay family. The first executed replication will supply measured timing. Records without an assay match currently receive a zero-hour model value.","status":"unverified","severity":"high"},{"code":"signal_score_without_citations","basis":["5,529 of 5,529 records (100.0%) have no citation count from the source metadata."],"claim":"Signal score","gloss":"The signal score uses publication-type weight because the mirror supplied zero citation counts.","detail":"The source supplied no citation counts for any record in this run, so the signal score is publication-type weight only. The citation term of the ranking is inert here, and the shortlist is ordered by publication type alone.","status":"unverified","severity":"high"},{"code":"abstract_absent","basis":["1,667 of 5,529 records (30.2%) carry no abstract at all."],"claim":"Evidence base for classification","gloss":"Some records contain a title and publication type only, defining the available classification evidence.","detail":"Where the mirror contains a title and publication types only, those fields define the classifier evidence. A methods section is required for fuller automated and human review.","status":"unverified","severity":"medium"},{"code":"classifier_agreement_measured","basis":["Published two-way decision agreement 77.7% (310 of 399 decidable records) from a stratified hand-check of 438 real records.","Three-way diagnostic agreement 73.9% (288 of 390 decidable records).","data_only agreement 75.2% (100 of 133 decidable).","48 record(s) could not be decided from title and abstract and were excluded from the denominator.","56 analysis-only records were published under another work type, so the data_only share is not an upper bound."],"claim":"Published automatable decision","gloss":"This figure has been checked against a human reading the same papers, so we know how often it is right.","detail":"The published automatable / not-automatable distribution comes from a rule-based classifier that was hand-checked against a fixed ground-truth definition. The agreement rates below are measured, not estimated. The three-way work type remains a diagnostic and is reported separately.","status":"measured","severity":"high"},{"code":"llm_comparison_not_measured","basis":["rule_based_v1+lex99e1195c7d6f produced 5,529 of 5,529 classifications.","Measured on 438 labelled records; these are RULE-BASED figures, not model results."],"claim":"Rule-based versus LLM agreement","gloss":"Every number here is the rule engine’s own. Model comparison begins when a working API credential is connected and measured.","detail":"The published two-way decision agreed with a human reading on 310 of 399 decidable records (77.7%). The diagnostic three-way label agreed on 288 of 390 decidable records (73.9%). Every percentage in this run belongs to the rule engine. Model comparison begins when a working API credential is connected and measured.","status":"not_measured","severity":"high"},{"code":"confidence_is_a_band","basis":["low band: 135 of 210 hand-judged records were correct, 64.3% [57.6, 70.5] (95% CI).","medium band: 80 of 104 hand-judged records were correct, 76.9% [68.0, 84.0] (95% CI).","high band: 73 of 76 hand-judged records were correct, 96.0% [89.0, 98.7] (95% CI).","A fitted calibrated probability was built, measured and withdrawn: it overstated held-out accuracy and reorders nothing."],"claim":"Confidence band and evidence score","gloss":"The confidence band carries a measured accuracy interval; 0.85 represents relative rank strength.","detail":"Confidence on this run is a BAND plus its measured accuracy interval. The number stored alongside each record is a monotone evidence score that orders records; 0.85 represents relative rank strength. A fitted probability was withdrawn after it overstated held-out accuracy. Threshold on the band.","status":"measured","severity":"medium"},{"code":"three_way_split_is_diagnostic","basis":["The corpus is published at the two-way decision: automatable or not-automatable. The three-way split (data_only / physical / mixed) is published as a diagnostic with its measured reliability attached, not as a claim, because the rule engine's `mixed` call cannot be defended.","The engine called 22 record(s) mixed; 10 matched the human judgement (45.5%, 95% CI 26.9-65.3).","The engine's `mixed` call is right on 10/22 hand-judged records (45.5%, 95% CI 26.9%-65.3%); a constant `physical` guess scores 36.4%.","The engine's `mixed` call does not reliably beat a constant `physical` guess on the hand-judged records it labels mixed.","The sign of that difference flips between two independent samples, so the three-way refinement is not demonstrably informative.","The mixed stratum contributes a disproportionate share of errors relative to its size.","At title-only depth the physical/mixed split collapses: a title says that work was done, not whether it was also analysed."],"claim":"The published decision is two-way","gloss":"The three-way split is shown for diagnosis only. The published split is two ways.","detail":"Count and filter the corpus on automatable versus not-automatable. The data_only / physical / mixed split remains an internal engine diagnostic because the mixed call has lower measured reliability.","status":"measured","severity":"medium"},{"code":"automatable_flag_unproven","basis":["6 of 29 assay families are marked automatable now: meta_analysis, machine_learning, survival_analysis, pca, molecular_docking, differential_expression.","The flag is a rule over assay family and work type; validation begins with the first executed replication.","It inherits the 75.2% data_only agreement rate, because the flag requires the record to be analysis-only."],"claim":"Automatable now","gloss":"This flag marks assay families the rules classify as data-only. The first executed replication will validate it.","detail":"This flag marks families the rules consider replicable from data alone. Its validity depends on the analysis-only classification and will be measured through an executed replication.","status":"unverified","severity":"medium"}],"confidence_policy":"band_with_measured_interval","confidence_contract":{"policy":"band_with_measured_interval","summary":"Confidence is reported as a BAND with a measured accuracy interval. The raw evidence score supplies monotone ordering. A fitted point estimate was withdrawn after it overstated held-out accuracy.","evidence_score":"A monotone evidence score in [0,1] built from cue mass, axis separation and text coverage. Use it to order records. Interpret 0.85 as relative rank strength.","confidence_band":"low | medium | high. Consumers threshold on this value.","band_accuracy":"Wilson 95% interval on the measured agreement of the hand-judged records in this band.","calibrated_confidence":"WITHDRAWN. Reintroduction requires held-out evidence demonstrating reliable estimates across every bin."},"band_accuracy":{"low":{"n":210,"low":0.576,"band":"low","high":0.7046,"agree":135,"accuracy":0.6429},"high":{"n":76,"low":0.8903,"band":"high","high":0.9865,"agree":73,"accuracy":0.9605},"medium":{"n":104,"low":0.6795,"band":"medium","high":0.8397,"agree":80,"accuracy":0.7692}},"provider":"rule_based_v1+lex99e1195c7d6f","lexicon_id":"99e1195c7d6f","contract_published_at":"2026-10-23T12:25:29.022232+00:00","confidence_is_band":true,"confidence_is_probability":false,"decision_taxonomy":"two_way","decidable_fraction_two_way":0.8854,"decidable_fraction_two_way_low":0.8565,"decidable_fraction_two_way_high":0.9143,"decidable_fraction_three_way":0.8586,"decidable_fraction_three_way_low":0.8287,"decidable_fraction_three_way_high":0.8884,"decidable_population":5529,"validation_sample_size":438,"three_way_cost_fraction":0.0268,"three_way_cost_records":148,"decision_counts":{"automatable":230,"not_automatable":5299},"decision_split":{"automatable":{"count":230,"share":0.04159884246699222},"not_automatable":{"count":5299,"share":0.9584011575330078}},"diagnostic_work_type_counts":{"mixed":24,"physical":5275,"data_only":230}}}