Temporal Transcript Profiling Identifies a Role for Unfolded Protein Stress in Human Gut Ischemia-Reperfusion Injury.

{"sci_version": "1.2", "schema": "https://corpus.bntrg.co.uk/sci/1.0/sci.schema.json", "id": "pmid:34774803", "kind": "science-record", "revision": 5, "content_hash": "sha256:cc8031343464839bc5931978d60fea4d1cff965b897f5584f9199991de316614", "created_at": "2026-11-01T17:36:28Z", "updated_at": "2026-11-01T22:47:52Z", "generator": {"name": "corpus-assay-engine", "run_id": "reading-sci-2026-11-01"}, "paper": {"state": "complete", "title": "Temporal Transcript Profiling Identifies a Role for Unfolded Protein Stress in Human Gut Ischemia-Reperfusion Injury.", "doi": "10.1016/j.jcmgh.2021.11.001", "pmid": "34774803", "authors": ["Anna M Kip", "Joep Grootjans", "Marco Manca", "M'hamed Hadfoune", "Bas Boonen", "Joep P M Derikx", "Erik A L Biessen", "Steven W M Olde Damink", "Cornelis H C Dejong", "Wim A Buurman", "Kaatje Lenaerts"], "journal": "Cellular and molecular gastroenterology and hepatology", "year": 2022, "abstract": "BACKGROUND & AIMS: Intestinal ischemia-reperfusion injury is a serious and life-threatening condition. A better understanding of molecular mechanisms related to intestinal ischemia-reperfusion injury in human beings is imperative to find therapeutic targets and improve patient outcome.\nMETHODS: First, the in vivo dynamic modulation of mucosal gene expression of the ischemia-reperfusion-injured human small intestine was studied. Based on functional enrichment analysis of the changing transcriptome, one of the predominantly regulated pathways was selected for further investigation in an in vitro human intestinal organoid model.\nRESULTS: Ischemia-reperfusion massively changed the transcriptional landscape of the human small intestine. Functional enrichment analysis based on gene ontology and pathways pointed to the response to unfolded protein as a predominantly regulated process. In addition, regulatory network analysis identified hypoxia-inducing factor 1A as one of the key mediators of ischemia-reperfusion-induced changes, including the unfolded protein response (UPR). Differential expression of genes involved in the UPR was confirmed using quantitative polymerase chain reaction analysis. Electron microscopy showed signs of endoplasmic reticulum stress. Collectively, these findings point to a critical role for unfolded protein stress in intestinal ischemia-reperfusion injury in human beings. In a human intestinal organoid model exposed to hypoxia-reoxygenation, attenuation of UPR activation with integrated stress response inhibitor strongly reduced pro-apoptotic activating transcription factor 4 (ATF4)-CCAAT/enhancer-binding protein homologous protein (CHOP) signaling.\nCONCLUSIONS: Transcriptome analysis showed a crucial role for unfolded protein stress in the response to ischemia-reperfusion in human small intestine. UPR inhibition during hypoxia-reoxygenation in an intestinal organoid model suggests that downstream protein kinase R-like ER kinase (PERK) signaling may be a promising target to reduce intestinal ischemia-reperfusion injury. Microarray data are available in GEO (https://www.ncbi.nlm.nih.gov/gds, accession number GSE37013).", "claims": [{"id": "claim-method", "statement": "Time-course differential analysis was performed using Bioconductor package limma with time points as factors, and corrections for patient-IDs effect.", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34774803", "locator": "sections[19] \"Differential expression analysis\" paragraph 2", "quote": "Time-course differential analysis was performed using Bioconductor package limma with time points as factors, and corrections for patient-IDs effect."}], "state": "complete"}, {"id": "claim-data-access", "statement": "Microarray data are available in GEO (https://www.ncbi.nlm.nih.gov/gds, accession number GSE37013).", "kind": "methodological", "target": null, "evidence": [{"asset": "source:pmid:34774803", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "Microarray data are available in GEO (https://www.ncbi.nlm.nih.gov/gds, accession number GSE37013)."}], "state": "complete"}, {"id": "claim-target-result", "statement": "Ischemia-reperfusion activates unfolded protein stress in the human small intestine, and inhibition of downstream PERK signaling with ISRIB strongly reduces pro-apoptotic ATF4-CHOP signaling during hypoxia-reoxygenation in intestinal organoids.", "kind": "qualitative", "target": null, "evidence": [{"asset": "source:pmid:34774803", "locator": "sections[0] \"Abstract\" paragraph 4", "quote": "Transcriptome analysis showed a crucial role for unfolded protein stress in the response to ischemia-reperfusion in human small intestine."}], "state": "complete"}], "gaps": []}, "experiment": {"state": "complete", "objective": "Ischemia-reperfusion activates unfolded protein stress in the human small intestine, and inhibition of downstream PERK signaling with ISRIB strongly reduces pro-apoptotic ATF4-CHOP signaling during hypoxia-reoxygenation in intestinal organoids.", "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:34774803"], "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:GSE37013"], "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:GSE37013"], "outputs": ["the replicated result and its comparison"], "instruments": [], "reagents": []}], "materials": [], "instruments": [], "reagents": [], "conditions": {}, "gaps": []}, "data": {"state": "partial", "assets": [{"id": "source:pmid:34774803", "role": "manuscript", "format": "xml", "media_type": "application/xml", "uri": "https://doi.org/10.1016/j.jcmgh.2021.11.001", "sha256": "sha256:55937edf32a2f1c27344be5828263043c55a1d8ed1ee8d9465313954e3573636", "bytes": 67675, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "10.1016/j.jcmgh.2021.11.001", "version": null, "note": "Full article fetched from PMC; the checksum covers the rendered section body, not the original XML bytes.", "structure": {"pmcid": "PMC8761776", "source": "europe_pmc_fulltext", "coverage": "whole_body", "text_hash_scope": "rendered_section_body"}}, {"id": "data:geo:GSE37013", "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=GSE37013", "sha256": null, "bytes": null, "access": "open", "state": "resolved", "reader": null, "reader_status": "reader_required", "identifier": "GSE37013", "version": null, "note": "Microarray data are available in GEO (https://www.ncbi.nlm.nih.gov/gds, accession number GSE37013).", "structure": {"repository": "GEO", "access_route": "GEO accession URL", "access_statement_verbatim": "Microarray data are available in GEO (https://www.ncbi.nlm.nih.gov/gds, accession number GSE37013).", "access_statement_kind": "data_availability_statement", "sample_accessions": ["GSM908514", "GSM908515", "GSM908516", "GSM908517", "GSM908518", "GSM908519", "GSM908520", "GSM908521", "GSM908522", "GSM908523", "GSM908524", "GSM908525", "GSM908526", "GSM908527", "GSM908528", "GSM908529", "GSM908530", "GSM908531", "GSM908532", "GSM908533", "GSM908534", "GSM908535", "GSM908536", "GSM908537", "GSM908538", "GSM908539", "GSM908540", "GSM908541"], "sample_count": 28, "group_sizes": null, "group_sizes_basis": null, "platform": "6947", "taxon": "Homo sapiens", "title": "Genome-wide analysis of Ischaemia-Reperfusion damage in human bowel", "resolution_checked_at": "2026-11-01T17:30:42Z", "resolution_check": "identifier_resolution_only_no_download_no_licence_read", "downloaded": false, "licence_read": false}}], "gaps": ["asset:data:geo:GSE37013 not downloaded", "asset:data:geo:GSE37013 licence not read"]}, "analysis": {"state": "partial", "methods": [{"id": "method-1", "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": 1.0, "band": "verbatim", "quote": "Time-course differential analysis was performed using Bioconductor package limma with time points as factors, and corrections for patient-IDs effect."}}, {"id": "method-2", "family": "group_comparison", "specific": "anova", "label": "Group comparison", "dsl_operations": ["group_summary", "welch_t", "bootstrap_mean_difference", "group_comparison_anova"], "missing_operations": [], "expressible": true, "parameters": {}, "data_shapes": ["two_or_more_groups_continuous"], "evidence": {"score": 0.8, "band": "high", "quote": "analysis of variance"}}], "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": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "missing_operations": [], "basis": "The paper names the method it used and the corpus's method extractor maps it onto the DSL catalogue: limma_voom."}, "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": ["GSE37013"], "resolved_accessions": ["GSE37013"], "statements": ["Microarray data are available in GEO (https://www.ncbi.nlm.nih.gov/gds, accession number GSE37013)."], "basis": "The paper names GSE37013 in GEO and the accession resolves in the repository. No dataset was downloaded and no licence was read."}}, "can_run": {"dsl_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "assets": ["source:pmid:34774803", "data:geo:GSE37013"], "steps": ["run_analysis"]}, "must_build": {"dsl_operations": [], "converters": [], "readers": [], "capabilities": [], "data_gaps": ["data:geo:GSE37013"]}, "gaps": []}, "review": {"state": "partial", "machine_critique": {"kind": "extraction_review", "reader": {"model": "MiniMax-M3.1-Flash", "provider": "minimax", "provider_family": "minimax", "read_at": "2026-11-01T17:07:09Z", "independence": "single_reader"}, "evidence_check": {"method": "verbatim", "availability": "verbatim"}, "calls": 5, "usage": {"prompt_tokens": 18243, "completion_tokens": 1054, "cached_tokens": 188}}, "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:34774803", "type": "paper", "label": "pmid:34774803"}, {"id": "source:pmid:34774803", "type": "manuscript", "label": "PMID 34774803 full text"}, {"id": "data:geo:GSE37013", "type": "dataset", "label": "GEO GSE37013"}], "activities": [{"id": "activity-reading-sci-2026-11-01", "type": "classification", "used": [{"id": "pmid:34774803", "type": "paper", "label": "pmid:34774803"}, {"id": "source:pmid:34774803", "type": "manuscript", "label": "PMID 34774803 full text"}, {"id": "data:geo:GSE37013", "type": "dataset", "label": "GEO GSE37013"}], "agent": "agent:corpus-assay-engine"}, {"id": "activity-read-34774803", "type": "extraction", "used": ["source:pmid:34774803"], "agent": "agent:minimax-reader"}, {"id": "activity-resolve-GSE37013", "type": "accession_resolution", "used": ["data:geo:GSE37013"], "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:34774803", "parent_hash": "sha256:5acfa12a775349540ceb216479a4c3b868e4cdee7f2b9425c95cd606240d5b7f", "fork_of": null, "generation": 4}, "gaps": ["asset:data:geo:GSE37013 licence not read", "asset:data:geo:GSE37013 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": "animal_model", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.77, "evidence": ["improve patient outcome. METHODS: First, the in vivo dynamic modulation of mucosal gene expressio"], "order_basis": "paper_text_order:380", "id": "assay:1"}, {"role": "data_generation", "definition_id": "microarray", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.99, "evidence": ["duce intestinal ischemia-reperfusion injury. Microarray data are available in GEO (https://www.ncbi.", "Statistical Analysis Statistical analysis of microarray data were performed in R as described in the"], "order_basis": "paper_text_order:2149", "id": "assay:2"}, {"role": "data_generation", "definition_id": "apoptosis_assay", "definition_version": "99e1195c7d6f", "definition_digest": null, "required_operations": [], "support_state": "partial", "source_hashes": {"assay_lexicon": "99e1195c7d6f"}, "confidence": 0.69, "evidence": ["Statistical analysis of gene expression and apoptosis data was performed using GraphPad Prism vers"], "order_basis": "paper_text_order:3923", "id": "assay:3"}, {"role": "analysis", "definition_id": "differential_expression", "definition_version": "f2132e96ae6c7a4e", "definition_digest": null, "required_operations": ["normalise_counts", "differential_expression_fit", "fdr_bh"], "support_state": "supported", "source_hashes": {"dsl_catalogue": "f2132e96ae6c7a4e"}, "confidence": 1.0, "evidence": ["Time-course differential analysis was performed using Bioconductor package limma with time points as factors, and corrections for patient-IDs effect."], "order_basis": "consumes_earlier_output", "id": "assay:4"}]}