{"data":{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:41408107", "kind": "science-record", "revision": 2, "content_hash": "sha256:fcba10a980ee0ee92284dfad0e808eab83dfb8b4e303f42cd4254b7ba4bda45d", "created_at": "2026-11-01T20:31:24Z", "updated_at": "2026-11-01T21:36:12Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Celastrol suppresses bone destruction in rheumatoid arthritis by inhibiting ALOX5 expression in macrophages via the NF-κB pathway.", "doi": "10.1038/s41598-025-33001-x", "pmid": "41408107", "authors": ["YiQing Chen", "Zihan Wang", "YanYu Chen", "XiaoJing Liu", "LongXiao Liu", "ZhiKun Tu", "Qingwen Tao", "Yuan Xu"], "journal": "Scientific reports", "year": 2025, "abstract": "Rheumatoid arthritis (RA) is a complex and highly disabling chronic autoimmune disease. As the disease progresses, patients often develop complications such as joint destruction and cardiovascular diseases, posing significant threats to human health. Celastrol, a major bioactive compound extracted from the traditional Chinese herb Tripterygium wilfordii Hook. f., exhibits potent immunomodulatory and anti-inflammatory properties. However, the specific mechanisms underlying its protective effects against bone destruction in RA remain poorly understood. To elucidate its potential therapeutic mechanisms, this study retrieved three gene expression datasets-GSE55235, GSE93777, and GSE200815-from the Gene Expression Omnibus (GEO) database. The primary molecular targets of celastrol were obtained from the HERB and TCMSP platforms. Functional mechanisms associated with these targets were explored using gene set variation analysis (GSVA) and weighted gene co-expression network analysis (WGCNA). Furthermore, molecular docking, immune infiltration analysis, and single-cell RNA sequencing analysis were employed to investigate the role of key target genes. In this study, thirteen potential target genes of celastrol in RA have been identified, including ADAMTS5, AGTR1, ALOX5, CTSB, MMP3, MMP9, MYC, TNF, ITGA4, ITGB7, MMP1, MMP13, and PPARG. Among these, ALOX5 was found to significantly promote MMP3 protein expression, based on which a regulatory model with high predictive power was constructed. GSVA analysis revealed that the TNF-NFκB pathway was significantly activated in RA and exhibited a strong positive correlation with ALOX5 expression. Further experimental analysis demonstrated that knockdown of ALOX5 and its shared transcription factor with MMP2 resulted in a significant downregulation of both genes and inhibition of TNF-NFκB pathway activity. Single-cell transcriptomic analysis showed that ALOX5 was predominantly expressed in macrophages, and the AddModuleScore of celastrol-targeted genes in this cell type was significantly higher than in other cell types, suggesting that macrophages may serve as key effector cells in celastrol-mediated treatment of RA. Celastrol might attenuate RA bone destruction by inhibiting the expression of the ALOX5 gene in macrophages, thereby suppressing the activation of the NF-κB pathway and subsequently reducing the production of matrix metalloproteinases.", "claims": [{"id": "claim-method", "statement": "Subsequently, multiple linear regression models were developed based on the correlation analysis findings to assess the impact of different factors on MMP3 protein expression levels.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41408107", "locator": "sections[7] \"Correlation analysis of key genes with clinical phenotypes\" paragraph 2", "quote": "Subsequently, multiple linear regression models were developed based on the correlation analysis findings to assess the impact of different factors on MMP3 protein expression levels."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Data is provided within the manuscript or supplementary information files.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41408107", "locator": "sections[35] \"notes\" paragraph 1", "quote": "Data is provided within the manuscript or supplementary information files."}], "state": "complete"}, {"id": "claim-target-result", "statement": "In this study, thirteen potential target genes of celastrol in RA have been identified, including ADAMTS5, AGTR1, ALOX5, CTSB, MMP3, MMP9, MYC, TNF, ITGA4, ITGB7, MMP1, MMP13, and PPARG.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:41408107", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "In this study, thirteen potential target genes of celastrol in RA have been identified, including ADAMTS5, AGTR1, ALOX5, CTSB, MMP3, MMP9, MYC, TNF, ITGA4, ITGB7, MMP1, MMP13, and PPARG."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "In this study, thirteen potential target genes of celastrol in RA have been identified, including ADAMTS5, AGTR1, ALOX5, CTSB, MMP3, MMP9, MYC, TNF, ITGA4, ITGB7, MMP1, MMP13, and PPARG.", "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:41408107"], "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:GSE200815"], "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:GSE200815"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:41408107", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1038/s41598-025-33001-x", "sha256": 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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": ["GSE55235", "GSE93777", "GSE200815"], "resolved_accessions": ["GSE55235", "GSE93777", "GSE200815"], "statements": ["Data is provided within the manuscript or supplementary information files."], "basis": "The paper names GSE55235, GSE93777, GSE200815 in Gene Expression Omnibus (GEO) and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["ols_fit"], "assets": ["source:pmid:41408107", "data:geo:GSE200815"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE200815"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T20:08:42Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 11266, "completion_tokens": 2638, "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:41408107", "type": "paper", "label": "pmid:41408107"}, {"id": "source:pmid:41408107", "type": "manuscript", "label": "PMID 41408107 full text"}, {"id": "data:geo:GSE200815", "type": "dataset", "label": "GEO GSE200815"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:41408107", "type": "paper", "label": "pmid:41408107"}, {"id": "source:pmid:41408107", "type": "manuscript", "label": "PMID 41408107 full text"}, {"id": "data:geo:GSE200815", "type": "dataset", "label": "GEO GSE200815"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-41408107", "type": "extraction", "used": ["source:pmid:41408107"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE200815", "type": "accession_resolution", "used": ["data:geo:GSE200815"], "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:41408107", "parent_hash": "sha256:fdaafb6586fcd1a85016b85e09a266bfa5d4b02e3a8215120ae4a59d3c08780a", "fork_of": null, "generation": 1}, "gaps": ["asset:data:geo:GSE200815 licence not read", "asset:data:geo:GSE200815 not downloaded", "asset:data:geo:GSE55235 licence not read", "asset:data:geo:GSE55235 not downloaded", "asset:data:geo:GSE93777 licence not read", "asset:data:geo:GSE93777 not downloaded", "execution.not_run", "review.human_critique", "review.independent_reader", "review.machine_critique"], "assays": [{"role": "data_generation", "definition_id": "scrna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "unsupported", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["r docking, immune infiltration analysis, and single-cell RNA sequencing analysis were employed to investigate the ro"], "order_basis": "paper_text_order:1152", "id": "assay:1"}, {"role": "data_generation", "definition_id": "rna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["mmune infiltration analysis, and single-cell RNA sequencing analysis were employed to investigate the ro", ".gpsadb.com/). This database integrates 3048 RNA-seq datasets covering 1458 genes subjected to ge", "on of TNF-NFκB pathway activity. Single-cell transcriptomic analysis showed that ALOX5 was predominantly"], "order_basis": "paper_text_order:1164", "id": "assay:2"}, {"role": "data_generation", "definition_id": "transfection", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["ther experimental analysis demonstrated that knockdown of ALOX5 and its shared transcription factor", "ferential expression matrices following gene knockdown. Differential expression analysis was perfor", "ed to genetic perturbation via siRNA, shRNA, CRISPR/Cas9, or CRISPRi technologies. A total of 60", "genes subjected to genetic perturbation via siRNA, shRNA, CRISPR/Cas9, or CRISPRi technologies"], "order_basis": "paper_text_order:1789", "id": "assay:3"}, {"role": "data_generation", "definition_id": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.69, "evidence": ["d regulatory relationships between human and mouse transcription factors and their target genes"], "order_basis": "paper_text_order:4585", "id": "assay:4"}, {"role": "analysis", "definition_id": "regression_modelling", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["ols_fit"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Subsequently, multiple linear regression models were developed based on the correlation analysis findings to assess the impact of different factors on MMP3 protein expression levels."], "order_basis": "consumes_earlier_output", "id": "assay:5"}]},"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":"2026-11-04T01:42:17+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}}}