{"data":{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:40487403", "kind": "science-record", "revision": 4, "content_hash": "sha256:3123935517d9beb6897a20800caa2be20d6cda168b054b15c5158595b1b2bc04", "created_at": "2026-11-01T20:30:36Z", "updated_at": "2026-11-01T22:56:38Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Identification of biomarkers and potential drug targets in DFU based on fundamental experiments and multi-omics joint analysis.", "doi": "10.3389/fphar.2025.1561179", "pmid": "40487403", "authors": ["Xudong Xin", "Haidong Zhou", "Song Huang", "Wenzhao Zhang", "Jiahou Xu", "Wei Wang", "Jihua Wei", "Liqing Li"], "journal": "Frontiers in pharmacology", "year": 2025, "abstract": "Objective: This study aims to investigate the molecular mechanisms by which quercetin facilitates the treatment of diabetic foot ulcers (DFU).\nMethods: Transcriptome sequencing datasets for DFU, specifically GSE80178, GSE134431, and GSE147890, along with single-cell dataset GSE165816, were retrieved from the Gene Expression Omnibus (GEO) online database (https://www.ncbi.nlm.nih.gov/geo/). The single-cell data were subjected to processing, annotation, differential gene expression analysis, and staining. The transcriptome sequencing data were analyzed using weighted gene co-expression network analysis (WGCNA), followed by assessment of immune infiltration. By integrating transcriptomic data and differentially expressed genes identified through WGCNA, co-expressed differentially expressed genes were obtained, and a protein-protein interaction (PPI) network was constructed followed by enrichment analysis. Core genes were screened using four machine learning models (Random Forest, Lasso, XGBoost, and SVM). Drug prediction was performed to identify potential therapeutic agents, and molecular docking simulations were conducted to assess the binding interactions between the macromolecular proteins encoded by the core genes and quercetin. A rat model of diabetic foot ulcer (DFU) was established and randomly divided into three groups: control, model, and treatment groups. Tissue samples were collected at 3, 7, and 14 days post-intervention for RT-qPCR, hematoxylin and eosin (H&E) staining, Masson's trichrome staining, and immunofluorescence staining to evaluate the therapeutic effects of quercetin via modulation of the core genes on DFU.\nResults: The analysis identified 275 differentially co-expressed genes that are extensively involved in the IL-17 signaling pathway, metabolic pathways, the PI3K/Akt signaling pathway, Staphylococcus aureus infection, complement and coagulation cascades, among others. From these, four core genes (CIB2, SAMHD1, DPYSL2, IFI44) were selected using machine learning techniques. Immune infiltration analysis demonstrated a strong correlation between SAMHD1, IFI44, DPYSL2, and macrophages. Molecular docking studies revealed that quercetin exhibits a lower binding energy with the target protein binding site, forming a stable structure. Single-cell analysis indicated that SAMHD1 is predominantly expressed in macrophages, whereas DPYSL2 is expressed not only in macrophages but also significantly in vascular endothelial cells and other cell types. This suggests that SAMHD1 and DPYSL2 may exert their effects by modulating these cells, as corroborated by basic experimental findings. The improvement in wound tissue morphology observed in the treatment group was more favorable compared to the model group. In comparison to the acute group, the gene expression profile in the model group aligned with bioinformatics predictions. Furthermore, the alterations in core gene expression following quercetin treatment were statistically significant.\nConclusion: Quercetin may enhance the healing of diabetic foot ulcers by modulating macrophage activity through the regulation of SAMHD1 and DPYSL2, thereby contributing to the recovery process.", "claims": [{"id": "claim-method", "statement": "Statistical analyses were conducted using SPSS version 26.0 to represent measurement data and to compare multiple samples through one-way analysis of variance (ANOVA). Based on the results of the homogeneity of variance test, the Least Significant Difference (LSD) method was employed when variances were equal, while the Tamhane’s T2 method was utilized in cases of unequal variances. A p-value of less than 0.05 was considered indicative of statistical significance.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40487403", "locator": "sections[23] \"2.2.2.8 Statistical methods\" paragraph 2", "quote": "Statistical analyses were conducted using SPSS version 26.0 to represent measurement data and to compare multiple samples through one-way analysis of variance (ANOVA). Based on the results of the homogeneity of variance test, the Least Significant Difference (LSD) method was employed when variances were equal, while the Tamhane’s T2 method was utilized in cases of unequal variances. A p-value of less than 0.05 was considered indicative of statistical significance."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:40487403", "locator": "sections[38] \"Data availability statement\" paragraph 2", "quote": "The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found in the article/supplementary material."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Quercetin may enhance the healing of diabetic foot ulcers by modulating macrophage activity through the regulation of SAMHD1 and DPYSL2, thereby contributing to the recovery process.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:40487403", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "Quercetin may enhance the healing of diabetic foot ulcers by modulating macrophage activity through the regulation of SAMHD1 and DPYSL2, thereby contributing to the recovery process."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Quercetin may enhance the healing of diabetic foot ulcers by modulating macrophage activity through the regulation of SAMHD1 and DPYSL2, thereby contributing to the recovery process.", "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:40487403"], "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:GSE134431"], "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:GSE134431"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:40487403", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.3389/fphar.2025.1561179", "sha256": "sha256:c609728ad0b6a0fac0f80534a38d04a8a6333ede1d5b1637841147005f8fa4e1", "bytes": 44879, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.3389/fphar.2025.1561179", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC12141248", "source": "europe_pmc_fulltext", "coverage": "whole_body_without_references", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE134431", "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=GSE134431", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE134431", "version": null, "note": "The datasets presented in this study can be found in online repositories. 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No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "assets": ["source:pmid:40487403", "data:geo:GSE134431"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE134431"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T19:54:01Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 12089, "completion_tokens": 2269, "cached_tokens": 128}}, "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:40487403", "type": "paper", "label": "pmid:40487403"}, {"id": "source:pmid:40487403", "type": "manuscript", "label": "PMID 40487403 full text"}, {"id": "data:geo:GSE134431", "type": "dataset", "label": "GEO GSE134431"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:40487403", "type": "paper", "label": "pmid:40487403"}, {"id": "source:pmid:40487403", "type": "manuscript", "label": "PMID 40487403 full text"}, {"id": "data:geo:GSE134431", "type": "dataset", "label": "GEO GSE134431"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-40487403", "type": "extraction", "used": ["source:pmid:40487403"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE134431", "type": "accession_resolution", "used": ["data:geo:GSE134431"], "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:40487403", "parent_hash": "sha256:b1fa65a4e3308d25ac38fce31b5f3b6b568915c74cd21a591b8f71cf14852969", "fork_of": null, "generation": 3}, "gaps": ["asset:data:geo:GSE134431 licence not read", "asset:data:geo:GSE134431 not downloaded", "asset:data:geo:GSE147890 licence not read", "asset:data:geo:GSE147890 not downloaded", "asset:data:geo:GSE165816 licence not read", "asset:data:geo:GSE165816 not downloaded", "asset:data:geo:GSE223964 licence not read", "asset:data:geo:GSE223964 not downloaded", "asset:data:geo:GSE80178 licence not read", "asset:data:geo:GSE80178 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": 0.99, "evidence": ["s encoded by the core genes and quercetin. A rat model of diabetic foot ulcer (DFU) was estab", "nvironment, 30 SPF-grade Sprague-Dawley male rats were randomly allocated into three groups: an acu", "stablish a rat model of type 1 diabetes, the rats were fasted for 12 h with unrestricted access to", "to water. On the day of model induction, the rats were weighed, and blood samples were collected fr"], "order_basis": "paper_text_order:1336", "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": ["d at 3, 7, and 14 days post-intervention for RT-qPCR, hematoxylin and eosin (H&E) staining, Masso", "t 3, 7, and 14 days post-intervention for RT-qPCR, hematoxylin and eosin (H&E) staining, Masso", "AMHD1 were subsequently quantified using the RT-qPCR method. A fluorescent quantitative PCR instr", "odel. 2.2.2.6 Real-time quantitative PCR (RT qPCR) method Total RNA was extracted from tissue"], "order_basis": "paper_text_order:1542", "id": "assay:2"}, {"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": [") staining, Masson's trichrome staining, and immunofluorescence staining to evaluate the therapeutic effects"], "order_basis": "paper_text_order:1622", "id": "assay:3"}, {"role": "analysis", "definition_id": "group_comparison", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Statistical analyses were conducted using SPSS version 26.0 to represent measurement data and to compare multiple samples through one-way analysis of variance (ANOVA). Based on the results of the homogeneity of variance test, the Least Significant Difference (LSD) method was employed when variances were equal, while the Tamhane’s T2 method was utilized in cases of unequal variances. A p-value of less than 0.05 was considered indicative of statistical significance."], "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":"2026-11-04T03:01:21+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}}}