{"data":{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:41609946", "kind": "science-record", "revision": 3, "content_hash": "sha256:edd74fe6bf35beb97d60b2335ac66284fe3535a068e3f40ddb41992065690c3b", "created_at": "2026-11-01T20:31:42Z", "updated_at": "2026-11-01T22:15:31Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Unraveling heterogeneity in LUAD via multi-omics integration: molecular classification and therapeutic implications.", "doi": "10.1007/s12672-026-04498-z", "pmid": "41609946", "authors": ["Shijian Zhen", "Xiuying Zhang", "Qunying Li", "Zhihuan Liu", "Dongdong Wang", "Shuxue Xi", "Shufang Shi", "Geng Tian", "Jialiang Yang", "Haiwen Zhao", "Jinyang Liu"], "journal": "Discover oncology", "year": 2026, "abstract": "Lung adenocarcinoma (LUAD) displays significant morphological and molecular heterogeneity both within and between tumors. This heterogeneity, coupled with the complexities of the tumor microenvironment (TME), notably influences LUAD progression and patient prognosis. Integrating mass-spectrometry-based proteomic data from human tumors with corresponding multi-omics data opens significant opportunities for comprehensive and systematic cancer proteogenomic analyses. In our study, we analyzed LUAD proteogenomic data from the Cancer Proteome Atlas Program (CPTAC) to conduct a systematic molecular classification by integrating multi-omics data (genomic, transcriptomic, and proteomic) using ten clustering algorithms. This approach successfully identified three distinct molecular subtypes with notable biological heterogeneity: metabolic pathway activation, cell cycle pathway activation, and immune modulation. The metabolic pathway activation subtype was characterized by significant upregulation of metabolic pathways, this subtype showed enhanced mRNA expression and protein abundance of genes related to fatty acid and bile acid metabolism (e.g., MLYCD, ACSM3, ACSL5, ACSS1, and MAOA). It also exhibited a notably higher frequency of EGFR mutations compared to other subtypes. The cell cycle pathway activation subtype was defined by the activation of cell cycle signaling pathways, this subtype demonstrated amplification of the PCNA gene and significantly increased mRNA and protein expression levels of key cell cycle-related genes, such as CCNB1 and CDK1. Importantly, a high mutation frequency, copy number deletions, and downregulation of the tumor suppressor gene STK11 were observed, leading to the inactivation of its tumor suppressor function. This subtype also showed potential sensitivity to various cell cycle inhibitors. The immune modulation subtype was characterized by high immune cell infiltration and low tumor purity. This subtype exhibited multi-omics activation of the Ras signaling pathway, including MET amplification, increased GRB2 expression, decreased PEBP1 expression, and RET activating mutations. These findings suggest that this subtype may benefit from a combination of immunotherapy and targeted therapy against the Ras signaling pathway. Based on the expression profiles of 300 subtype-specific marker genes, we validated the molecular characteristics and clinical relevance of these three subtypes in the TCGA-LUAD and GSE50081 cohorts. Moreover, to enhance clinical applicability, we developed a rapid and cost-effective multi-instance model based on pathological images combined with deep learning techniques. This deep learning model demonstrated excellent performance in multi-omics subtype predictions. In, conclusion, this study systematically elucidates the molecular heterogeneity of LUAD through a multi-omics integration strategy, establishes a clinically relevant molecular classification system, and provides a theoretical foundation for developing personalized treatment plans for LUAD.", "claims": [{"id": "claim-method", "statement": "Subsequently, we use the “MOVICS\" [35] R package for ten state-of-the-art multi-omics integrative clustering algorithms (including iClusterBayes, moCluster, CIMLR, IntNMF, ConsensusClustering, COCA, NEMO, PINSPlus, SNF, and LRA) to establish the final classification model, and further integrate the clustering results of the above algorithms to generate robust clustering.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41609946", "locator": "sections[4] \"Multi-omics molecular subtype classification\" paragraph 2", "quote": "Subsequently, we use the “MOVICS\" [35] R package for ten state-of-the-art multi-omics integrative clustering algorithms (including iClusterBayes, moCluster, CIMLR, IntNMF, ConsensusClustering, COCA, NEMO, PINSPlus, SNF, and LRA) to establish the final classification model, and further integrate the clustering results of the above algorithms to generate robust clustering."}], "state": "complete"}, {"id": "claim-data-access", "statement": "The sequencing data, hematoxylin-eosin (H&E)-stained whole-slide images, and clinical datasets utilized in this study are publicly available, with specific access details as follows: CPTAC Lung Adenocarcinoma (CPTAC-LUAD) dataset: Accessible through the Proteomic Data Commons (PDC) at https://pdc.cancer.gov/pdc/cptac-pancancer. Gene Expression Omnibus (GEO) datasets: Including GSE50081 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE50081) and GSE176307 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE176307). TCGA Lung Adenocarcinoma (TCGA-LUAD) dataset: Retrievable from the Genomic Data Commons (GDC) under project ID: TCGA-LUAD, via https://portal.gdc.cancer.gov/projects/TCGA-LUAD. Molecular Signatures Database (MSigDB) resources: Accessible at https://www.gsea-msigdb.org/.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:41609946", "locator": "sections[29] \"Data availability\" paragraph 2", "quote": "The sequencing data, hematoxylin-eosin (H&E)-stained whole-slide images, and clinical datasets utilized in this study are publicly available, with specific access details as follows: CPTAC Lung Adenocarcinoma (CPTAC-LUAD) dataset: Accessible through the Proteomic Data Commons (PDC) at https://pdc.cancer.gov/pdc/cptac-pancancer. Gene Expression Omnibus (GEO) datasets: Including GSE50081 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE50081) and GSE176307 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE176307). TCGA Lung Adenocarcinoma (TCGA-LUAD) dataset: Retrievable from the Genomic Data Commons (GDC) under project ID: TCGA-LUAD, via https://portal.gdc.cancer.gov/projects/TCGA-LUAD. Molecular Signatures Database (MSigDB) resources: Accessible at https://www.gsea-msigdb.org/."}], "state": "complete"}, {"id": "claim-target-result", "statement": "The study identified three LUAD molecular subtypes characterized by metabolic pathway activation, cell cycle pathway activation, and immune modulation.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:41609946", "locator": "sections[0] \"Abstract\" paragraph 1", "quote": "This approach successfully identified three distinct molecular subtypes with notable biological heterogeneity: metabolic pathway activation, cell cycle pathway activation, and immune modulation."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "partial", "objective": "The study identified three LUAD molecular subtypes characterized by metabolic pathway activation, cell cycle pathway activation, and immune modulation.", "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:41609946"], "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": ["GSE50081", "GSE176307"], "resolved_accessions": ["GSE50081", "GSE176307"], "statements": ["The sequencing data, hematoxylin-eosin (H&E)-stained whole-slide images, and clinical datasets utilized in this study are publicly available, with specific access details as follows: CPTAC Lung Adenocarcinoma (CPTAC-LUAD) dataset: Accessible through the Proteomic Data Commons (PDC) at https://pdc.cancer.gov/pdc/cptac-pancancer. Gene Expression Omnibus (GEO) datasets: Including GSE50081 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE50081) and GSE176307 (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi? acc=GSE176307). TCGA Lung Adenocarcinoma (TCGA-LUAD) dataset: Retrievable from the Genomic Data Commons (GDC) under project ID: TCGA-LUAD, via https://portal.gdc.cancer.gov/projects/TCGA-LUAD. Molecular Signatures Database (MSigDB) resources: Accessible at https://www.gsea-msigdb.org/."], "basis": "The paper names GSE50081, GSE176307 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": [], "assets": ["source:pmid:41609946", "data:geo:GSE176307"], "steps": []}, "must_build": {"dsl_operations": [{"operation": "group_comparison_wilcoxon", "unlocks_papers": null, "priority": null}], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE176307"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T20:11:34Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 17623, "completion_tokens": 2999, "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:41609946", "type": "paper", "label": "pmid:41609946"}, {"id": "source:pmid:41609946", "type": "manuscript", "label": "PMID 41609946 full text"}, {"id": "data:geo:GSE176307", "type": "dataset", "label": "GEO GSE176307"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:41609946", "type": "paper", "label": "pmid:41609946"}, {"id": "source:pmid:41609946", "type": "manuscript", "label": "PMID 41609946 full text"}, {"id": "data:geo:GSE176307", "type": "dataset", "label": "GEO GSE176307"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-41609946", "type": "extraction", "used": ["source:pmid:41609946"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE176307", "type": "accession_resolution", "used": ["data:geo:GSE176307"], "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:41609946", "parent_hash": "sha256:8dc8b39c5f51e8b31e18dff9673f784dca41c3ca37acaab7a4dbb87d119d7f2c", "fork_of": null, "generation": 2}, "gaps": ["asset:data:geo:GSE176307 licence not read", "asset:data:geo:GSE176307 not downloaded", "asset:data:geo:GSE50081 licence not read", "asset:data:geo:GSE50081 not downloaded", "execution.not_run", "method.group_comparison_wilcoxon", "method.reader_named_unmapped", "review.human_critique", "review.independent_reader", "review.machine_critique", "step:run_analysis blocked on method:group_comparison_wilcoxon"], "assays": [{"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": ["ll culture and small interfering RNA (siRNA) transfection The human LUAD cell line A549 was obtained f", "n (Gibco). The following day, the cells were transfected with siRNAs using Lipomaster 3000 Transfecti", "ransfected with siRNAs using Lipomaster 3000 Transfection Reagent (Vazyme, Nanjing, China) according t", "ficiency of the siRNAs. The effects of ACSM3 knockdown on cell proliferation and migration were eva"], "order_basis": "paper_text_order:3179", "id": "assay:1"}, {"role": "data_generation", "definition_id": "cell_culture", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["iology Research Institute, China. Cells were cultured in RPMI-1640 medium supplemented with 10% fetal", "siRNA) transfection The human LUAD cell line A549 was obtained from the Shanghai Cell Biology"], "order_basis": "paper_text_order:3224", "id": "assay:2"}, {"role": "data_generation", "definition_id": "western_blot", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["ccording to the manufacturer’s instructions. Western blotting was subsequently performed to assess the eff"], "order_basis": "paper_text_order:3606", "id": "assay:3"}, {"role": "data_generation", "definition_id": "apoptosis_assay", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.93, "evidence": ["ation and migration were evaluated using the CCK-8 assay and the wound healing assay, respectiv"], "order_basis": "paper_text_order:3782", "id": "assay:4"}, {"role": "analysis", "definition_id": "group_comparison", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 0.8, "evidence": ["Wilcoxon"], "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":"2026-11-04T02:15:11+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}}}