{"data":{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:40826484", "kind": "science-record", "revision": 3, "content_hash": "sha256:ac7c2a34634b9282a06b271e5020daeaef6e73e2f1bccd6926ef2d2b7f1ba9bc", "created_at": "2026-11-01T20:30:55Z", "updated_at": "2026-11-01T22:14:34Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Unraveling the causal role of TGF-βRII in osteoporosis and the potential of its associated differential genes as novel targets.", "doi": "10.1186/s40001-025-02971-z", "pmid": "40826484", "authors": ["Xinyu Zhu", "Yueyang Fan", "Wenyu Wang", "Rui Wu", "Chen Zhang", "Ziquan Yang"], "journal": "European journal of medical research", "year": 2025, "abstract": "BACKGROUND: Osteoporosis (OP) is a common disorder associated with reduced density of the bones, increasing the likelihood of fractures and deformities. The global incidence of OP is rising rapidly due to aging populations and lifestyle changes, affecting not only older adults but, increasingly, younger and middle-aged individuals. The long-term care and rehabilitation required for OP-induced fractures and complications impose significant economic burdens on both individuals and society, as well as reducing their quality of life.\nMETHODS: Recent studies have demonstrated an association between transforming growth factor-beta type II receptor (TGF-βRII) and OP through analysis of gene expression data sets and Mendelian randomization, suggesting potential causal relationships. Differentially expressed genes (DEGs) were identified between mesenchymal stem cells (MSCs) from OP patients and healthy controls in the GEO database, and their functions were analyzed. The relationships between the identified genes and their effects on immune cells were examined in terms of ceRNAs and immune infiltration. Single-cell RNA-seq data of OP patients in GSE147287 was used to investigate effects on MSC differentiation from DEGs, and gene expression data were verified using RT-qPCR.\nRESULTS: The molecular pathways underlying OP were explored by focusing on the role of MSCs and TGF-β signaling, identifying a significant causal link between TGFBRII and OP. DEGs associated with the TGF-β pathway included ID2, ID4, LRRC32, and EMP3, which are closely related to bone homeostasis and the differentiation of bone marrow MSCs. In addition, analysis of immune infiltration showed the involvement of these genes in various immune cells, and potential non-coding RNA targeting ID2, ID4, and LRRC32 were investigated using ceRNA networks. Single-cell sequencing demonstrated the expression of ID2, ID4, LRRC32, and EMP3 in bone marrow MSCs and their effects on MSC differentiation.\nCONCLUSIONS: TGFBRII was found to be causally associated with OP. ID2, ID4, LRRC32, and EMP3 affect the differentiation and osteogenic function of bone marrow MSCs through the TGF-β pathway, suggesting the potential of ID2, ID4, LRRC32, and EMP3 as therapeutic targets for treating osteoporosis. In summary, targeting of ID2, ID4, LRRC32, and EMP3 holds significant promise for the treatment of OP, providing new targets and strategies, and precise treatment.", "claims": [{"id": "claim-method", "statement": "The causal relationships between pathways and OP were investigated using a bidirectional two-sample MR approach. 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Three methods, namely, IVW, MR–Egger, and weighted median (with weighted and simple modes as supplementary analyses) were used to assess the causal association between the TGF-β pathway and OP."}}, {"id": "method-2", "family": "principal_component_analysis", "specific": "pca", "label": "Principal component analysis", "dsl_operations": ["pca_fit"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["wide_numeric_matrix"], "evidence": {"score": 0.8, "band": "high", "quote": "PCA"}}, {"id": "method-3", "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": 0.8, "band": "high", "quote": "Limma"}}, {"id": "method-4", "family": "network_analysis", "specific": "pathway_enrichment", "label": "Network / pathway analysis", "dsl_operations": ["pathway_enrich"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["edge_list"], "evidence": {"score": 0.8, "band": "high", "quote": "GO enrichment"}}], "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": ["mr_estimate"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: mendelian_randomisation."}, "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": ["GSE35958", "GSE80614", "GSE20941", "GSE35956", "GSE147287", "GSE7158", "GSE56815", "GSE100609", "GSE230665"], "resolved_accessions": ["GSE35958", "GSE80614", "GSE20941", "GSE35956", "GSE147287", "GSE7158", "GSE56815", "GSE100609", "GSE230665"], "statements": ["No datasets were generated or analysed during the current study."], "basis": "The paper names GSE35958, GSE80614, GSE20941, GSE35956, GSE147287, GSE7158, GSE56815, GSE100609, GSE230665 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": ["mr_estimate"], "assets": ["source:pmid:40826484", "data:geo:GSE100609"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE100609"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T19:59:53Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 12764, "completion_tokens": 2386, "cached_tokens": 256}}, "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:40826484", "type": "paper", "label": "pmid:40826484"}, {"id": "source:pmid:40826484", "type": "manuscript", "label": "PMID 40826484 full text"}, {"id": "data:geo:GSE100609", "type": "dataset", "label": "GEO GSE100609"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:40826484", "type": "paper", "label": "pmid:40826484"}, {"id": "source:pmid:40826484", "type": "manuscript", "label": "PMID 40826484 full text"}, {"id": "data:geo:GSE100609", "type": "dataset", "label": "GEO GSE100609"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-40826484", "type": "extraction", "used": ["source:pmid:40826484"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE100609", "type": "accession_resolution", "used": ["data:geo:GSE100609"], "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:40826484", "parent_hash": "sha256:c9a45f32b8f2e2aea286b75d62467cc6ee1c6b81c6132e0d2df483e74a158cc2", "fork_of": null, "generation": 2}, "gaps": ["asset:data:geo:GSE100609 licence not read", "asset:data:geo:GSE100609 not downloaded", "asset:data:geo:GSE147287 licence not read", "asset:data:geo:GSE147287 not downloaded", "asset:data:geo:GSE20941 licence not read", "asset:data:geo:GSE20941 not downloaded", "asset:data:geo:GSE230665 licence not read", "asset:data:geo:GSE230665 not downloaded", "asset:data:geo:GSE35956 licence not read", "asset:data:geo:GSE35956 not downloaded", "asset:data:geo:GSE35958 licence not read", "asset:data:geo:GSE35958 not downloaded", "asset:data:geo:GSE56815 licence not read", "asset:data:geo:GSE56815 not downloaded", "asset:data:geo:GSE7158 licence not read", "asset:data:geo:GSE7158 not downloaded", "asset:data:geo:GSE80614 licence not read", "asset:data:geo:GSE80614 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": "scrna_seq", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "unsupported", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["in terms of ceRNAs and immune infiltration. Single-cell RNA-seq data of OP patients in GSE147287 was used to"], "order_basis": "paper_text_order:1195", "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": ["ceRNAs and immune infiltration. Single-cell RNA-seq data of OP patients in GSE147287 was used to", "loaded from the GEO database. These included transcriptome data from 38 OP samples and 40 normal MSC co"], "order_basis": "paper_text_order:1207", "id": "assay:2"}, {"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": ["and gene expression data were verified using RT-qPCR. RESULTS: The molecular pathways underlying", "gene expression data were verified using RT-qPCR. RESULTS: The molecular pathways underlying"], "order_basis": "paper_text_order:1358", "id": "assay:3"}, {"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": ["s with osteoporosis and healthy controls The microarray data sets GSE35958 and GSE80614 were downloa"], "order_basis": "paper_text_order:2673", "id": "assay:4"}, {"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": ["in CD8 effector T cells and TRAF6-deficient mouse macrophages and monocytes following LPS trea"], "order_basis": "paper_text_order:5189", "id": "assay:5"}, {"role": "analysis", "definition_id": "genetic_association", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["mr_estimate"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["The causal relationships between pathways and OP were investigated using a bidirectional two-sample MR approach. Three methods, namely, IVW, MR–Egger, and weighted median (with weighted and simple modes as supplementary analyses) were used to assess the causal association between the TGF-β pathway and OP."], "order_basis": "consumes_earlier_output", "id": "assay:6"}]},"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":"2026-11-04T02:19:30+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}}}