{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:33:08Z","timestamp":1790094788353,"version":"4.0.1"},"reference-count":55,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"3","license":[{"start":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:00:00Z","timestamp":1639526400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2021,12,15]],"date-time":"2021-12-15T00:00:00Z","timestamp":1639526400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["lww.com","ovid.com"],"crossmark-restriction":true},"short-container-title":["Hepatology"],"published-print":{"date-parts":[[2022,3]]},"abstract":"<jats:title>Abstract<\/jats:title>\n          <jats:sec>\n            <jats:title>Background and Aims<\/jats:title>\n            <jats:p>Alagille Syndrome (ALGS) is a congenital disorder caused by mutations in the Notch ligand gene <jats:italic toggle=\"yes\">JAGGED1<\/jats:italic>, leading to neonatal loss of intrahepatic duct (IHD) cells and cholestasis. Cholestasis can resolve in certain patients with ALGS, suggesting regeneration of IHD cells. However, the mechanisms driving IHD cell regeneration following Jagged loss remains unclear. Here, we show that cholestasis due to developmental loss of IHD cells can be consistently phenocopied in zebrafish with compound <jats:italic toggle=\"yes\">jagged1b<\/jats:italic> and <jats:italic toggle=\"yes\">jagged2b<\/jats:italic> mutations or knockdown.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Approach and Results<\/jats:title>\n            <jats:p>Leveraging the transience of <jats:italic toggle=\"yes\">jagged<\/jats:italic> knockdown in juvenile zebrafish, we find that resumption of Jagged expression leads to robust regeneration of IHD cells through a Notch\u2010dependent mechanism. Combining multiple lineage tracing strategies with whole\u2010liver three\u2010dimensional imaging, we demonstrate that the extrahepatic duct (EHD) is the primary source of multipotent progenitors that contribute to the regeneration, but not to the development, of IHD cells. Hepatocyte\u2010to\u2010IHD cell transdifferentiation is possible but rarely detected. Progenitors in the EHD proliferate and migrate into the liver with Notch signaling loss and differentiate into IHD cells if Notch signaling increases. Tissue\u2010specific mosaic analysis with an inducible dominant\u2010negative Fgf receptor suggests that Fgf signaling from the surrounding mesenchymal cells maintains this extrahepatic niche by directly preventing premature differentiation and allocation of EHD progenitors to the liver. Indeed, transcriptional profiling and functional analysis of adult mouse EHD organoids uncover their distinct differentiation and proliferative potential relative to IHD organoids.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our data show that IHD cells regenerate upon resumption of Jagged\/Notch signaling, from multipotent progenitors originating from an Fgf\u2010dependent extrahepatic stem cell niche. We posit that if Jagged\/Notch signaling is augmented, through normal stochastic variation, gene therapy, or a Notch agonist, regeneration of IHD cells in patients with ALGS may be enhanced.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1002\/hep.32173","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T14:50:54Z","timestamp":1632754254000},"page":"567-583","update-policy":"https:\/\/doi.org\/10.1097\/lww.0000000000001000","source":"Crossref","is-referenced-by-count":18,"title":["Intrahepatic cholangiocyte regeneration from an Fgf\u2010dependent extrahepatic progenitor niche in a zebrafish\u00a0model of Alagille Syndrome"],"prefix":"10.1097","volume":"75","author":[{"given":"Chengjian","family":"Zhao","sequence":"first","affiliation":[{"name":"Human Genetics Program,Sanford Burnham Prebys Medical Discovery Institute,La Jolla,California,USA"},{"name":"State Key Laboratory of Biotherapy and Cancer Center,West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy,Sichuan,People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joseph J.","family":"Lancman","sequence":"additional","affiliation":[{"name":"Human Genetics Program,Sanford Burnham Prebys Medical Discovery Institute,La Jolla,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center,West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy,Sichuan,People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keith P.","family":"Gates","sequence":"additional","affiliation":[{"name":"Human Genetics Program,Sanford Burnham Prebys Medical Discovery Institute,La Jolla,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan","family":"Cao","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center,West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy,Sichuan,People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lindsey","family":"Barske","sequence":"additional","affiliation":[{"name":"Department of Pediatrics,College of Medicine & Division of Human Genetics,Cincinnati Children\u2019s Hospital Medical Center,University of Cincinnati,Cincinnati,Ohio,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Matalonga","sequence":"additional","affiliation":[{"name":"Human Genetics Program,Sanford Burnham Prebys Medical Discovery Institute,La Jolla,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiangyu","family":"Pan","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center,West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy,Sichuan,People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaye","family":"He","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research,Madison,Wisconsin,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alyssa","family":"Graves","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research,Madison,Wisconsin,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jan","family":"Huisken","sequence":"additional","affiliation":[{"name":"Morgridge Institute for Research,Madison,Wisconsin,USA"},{"name":"Department of Integrative Biology,University of Wisconsin\u2010Madison,Madison,Wisconsin,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chong","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Biotherapy and Cancer Center,West China Hospital, Sichuan University, and Collaborative Innovation Center for Biotherapy,Sichuan,People\u2019s Republic of China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8755-2777","authenticated-orcid":false,"given":"P.\u00a0Duc\u00a0Si","family":"Dong","sequence":"additional","affiliation":[{"name":"Human Genetics Program,Sanford Burnham Prebys Medical Discovery Institute,La Jolla,California,USA"},{"name":"Graduate School of Biomedical Sciences,Sanford Burnham Prebys Medical Discovery Institute,La Jolla,California,USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","published-online":{"date-parts":[[2021,12,15]]},"reference":[{"key":"hep32173-bib-0001-20250824","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1111\/iep.12272","article-title":"The many ways to mend your liver: A critical appraisal","volume":"99","year":"2018","journal-title":"Int J Exp Pathol"},{"key":"hep32173-bib-0002-20250824","doi-asserted-by":"crossref","first-page":"1348","DOI":"10.1053\/j.gastro.2018.08.016","article-title":"Reserve stem cells in intestinal homeostasis and injury","volume":"155","year":"2018","journal-title":"Gastroenterology"},{"key":"hep32173-bib-0003-20250824","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1146\/annurev-pathmechdis-012419-032824","article-title":"Liver progenitors and adult cell plasticity in hepatic injury and repair: knowns and unknowns","volume":"15","year":"2020","journal-title":"Annu Rev Pathol"},{"key":"hep32173-bib-0004-20250824","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1038\/nrgastro.2016.97","article-title":"Liver regeneration\u2014mechanisms and models to clinical application","volume":"13","year":"2016","journal-title":"Nat Rev Gastroenterol Hepatol"},{"key":"hep32173-bib-0005-20250824","doi-asserted-by":"crossref","first-page":"350","DOI":"10.1038\/nature23015","article-title":"Cholangiocytes act as facultative liver stem cells during impaired hepatocyte regeneration","volume":"547","year":"2017","journal-title":"Nature"},{"key":"hep32173-bib-0006-20250824","doi-asserted-by":"crossref","first-page":"1361","DOI":"10.1053\/j.gastro.2015.08.034","article-title":"Zebrafish: an important tool for liver disease research","volume":"149","year":"2015","journal-title":"Gastroenterology"},{"key":"hep32173-bib-0007-20250824","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1016\/bs.ctdb.2016.10.005","article-title":"Zebrafish pancreas development and regeneration: fishing for diabetes therapies","volume":"124","year":"2017","journal-title":"Curr Top Dev Biol"},{"key":"hep32173-bib-0008-20250824","first-page":"435","article-title":"Clinical utility gene card for: Alagille syndrome (ALGS)","volume":"22","year":"2014","journal-title":"Eur J Hum Genet"},{"key":"hep32173-bib-0009-20250824","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1002\/hep4.1468","article-title":"Outcomes of childhood cholestasis in Alagille syndrome: results of a multicenter observational study","volume":"4","year":"2020","journal-title":"Hepatol Commun"},{"key":"hep32173-bib-0010-20250824","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1002\/hep.510290331","article-title":"Features of Alagille syndrome in 92 patients: frequency and relation to prognosis","volume":"29","year":"1999","journal-title":"Hepatology"},{"key":"hep32173-bib-0011-20250824","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1038\/ng0797-243","article-title":"Alagille syndrome is caused by mutations in human Jagged1, which encodes a ligand for Notch1","volume":"16","year":"1997","journal-title":"Nat Genet"},{"key":"hep32173-bib-0012-20250824","doi-asserted-by":"crossref","first-page":"169","DOI":"10.1086\/505332","article-title":"NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway","volume":"79","year":"2006","journal-title":"Am J Hum Genet"},{"key":"hep32173-bib-0013-20250824","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1038\/ng0797-235","article-title":"Mutations in the human Jagged1 gene are responsible for Alagille syndrome","volume":"16","year":"1997","journal-title":"Nat Genet"},{"key":"hep32173-bib-0014-20250824","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1038\/ejhg.2011.181","article-title":"Alagille syndrome: pathogenesis, diagnosis and management","volume":"20","year":"2012","journal-title":"Eur J Hum Genet"},{"key":"hep32173-bib-0015-20250824","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1038\/s41467-017-00666-6","article-title":"Endoderm Jagged induces liver and pancreas duct lineage in zebrafish","volume":"8","year":"2017","journal-title":"Nat Commun"},{"key":"hep32173-bib-0016-20250824","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/ng1961","article-title":"Fgf10 regulates hepatopancreatic ductal system patterning and differentiation","volume":"39","year":"2007","journal-title":"Nat Genet"},{"key":"hep32173-bib-0017-20250824","doi-asserted-by":"crossref","first-page":"1531","DOI":"10.1002\/hep.29632","article-title":"Zebrafish abcb11b mutant reveals strategies to restore bile excretion impaired by bile salt export pump deficiency","volume":"67","year":"2018","journal-title":"Hepatology"},{"key":"hep32173-bib-0018-20250824","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1111\/j.1600-0676.1989.tb00377.x","article-title":"Liver cell rosettes: structural differences in cholestasis and hepatitis","volume":"9","year":"1989","journal-title":"Liver"},{"key":"hep32173-bib-0019-20250824","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1002\/hep.510270318","article-title":"Rearrangement of hepatocellular F\u2010actin precedes the formation of rosette\u2010like structures in parenchyma of cholestatic rat liver","volume":"27","year":"1998","journal-title":"Hepatology"},{"key":"hep32173-bib-0020-20250824","doi-asserted-by":"crossref","first-page":"5753","DOI":"10.1242\/dev.01411","article-title":"Inhibition of Jagged\u2010mediated Notch signaling disrupts zebrafish biliary development and generates multi\u2010organ defects compatible with an Alagille syndrome phenocopy","volume":"131","year":"2004","journal-title":"Development"},{"key":"hep32173-bib-0021-20250824","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/j.ydbio.2008.01.011","article-title":"Pdx\u20101 and Ptf1a concurrently determine fate specification of pancreatic multipotent progenitor cells","volume":"316","year":"2008","journal-title":"Dev Biol"},{"key":"hep32173-bib-0022-20250824","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1101\/gad.1663208","article-title":"Graded levels of Ptf1a differentially regulate endocrine and exocrine fates in the developing pancreas","volume":"22","year":"2008","journal-title":"Genes Dev"},{"key":"hep32173-bib-0023-20250824","doi-asserted-by":"crossref","first-page":"724","DOI":"10.1002\/dvdy.24271","article-title":"Fate mapping of ptf1a\u2010expressing cells during pancreatic organogenesis and regeneration in zebrafish","volume":"244","year":"2015","journal-title":"Dev Dyn"},{"key":"hep32173-bib-0024-20250824","doi-asserted-by":"crossref","first-page":"463","DOI":"10.1126\/science.aba4767","article-title":"Lineage analysis reveals an endodermal contribution to the vertebrate pituitary","volume":"370","year":"2020","journal-title":"Science"},{"key":"hep32173-bib-0025-20250824","article-title":"Evolution of the hypoxia\u2010sensitive cells involved in amniote respiratory reflexes","volume":"6","year":"2017","journal-title":"Elife"},{"key":"hep32173-bib-0026-20250824","doi-asserted-by":"crossref","first-page":"247","DOI":"10.1038\/s41586-018-0075-5","article-title":"De novo formation of the biliary system by TGFbeta\u2010mediated hepatocyte transdifferentiation","volume":"557","year":"2018","journal-title":"Nature"},{"key":"hep32173-bib-0027-20250824","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1016\/j.cell.2009.03.045","article-title":"The canonical Notch signaling pathway: unfolding the activation mechanism","volume":"137","year":"2009","journal-title":"Cell"},{"key":"hep32173-bib-0028-20250824","doi-asserted-by":"crossref","first-page":"1819","DOI":"10.1242\/dev.129.8.1819","article-title":"The onecut transcription factor HNF6 is required for normal development of the biliary tract","volume":"129","year":"2002","journal-title":"Development"},{"key":"hep32173-bib-0029-20250824","doi-asserted-by":"crossref","first-page":"174","DOI":"10.1016\/j.stem.2019.07.002","article-title":"Defining adult stem cell function at its simplest: the ability to replace lost cells through mitosis","volume":"25","year":"2019","journal-title":"Cell Stem Cell"},{"key":"hep32173-bib-0030-20250824","doi-asserted-by":"crossref","first-page":"2469","DOI":"10.1002\/hep.26254","article-title":"Canonical Notch2 signaling determines biliary cell fates of embryonic hepatoblasts and adult hepatocytes independent of Hes1","volume":"57","year":"2013","journal-title":"Hepatology"},{"key":"hep32173-bib-0031-20250824","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1242\/jcs.03330","article-title":"Beta cells occur naturally in extrahepatic bile ducts of mice","volume":"120","year":"2007","journal-title":"J Cell Sci"},{"key":"hep32173-bib-0032-20250824","first-page":"2159","article-title":"Multipotent stem\/progenitor cells in human biliary tree give rise to hepatocytes, cholangiocytes, and pancreatic islets","volume":"54","year":"2011","journal-title":"Hepatology"},{"key":"hep32173-bib-0033-20250824","doi-asserted-by":"crossref","first-page":"1719","DOI":"10.1002\/hep.30365","article-title":"Peribiliary glands are key in regeneration of the human biliary epithelium after severe bile duct injury","volume":"69","year":"2019","journal-title":"Hepatology"},{"key":"hep32173-bib-0034-20250824","doi-asserted-by":"crossref","first-page":"2917","DOI":"10.3390\/ijms19102917","article-title":"Contribution of resident stem cells to liver and biliary tree regeneration in human diseases","volume":"19","year":"2018","journal-title":"Int J Mol Sci"},{"key":"hep32173-bib-0035-20250824","doi-asserted-by":"crossref","first-page":"244","DOI":"10.1038\/s41586-018-0004-7","article-title":"Distributed hepatocytes expressing telomerase repopulate the liver in homeostasis and injury","volume":"556","year":"2018","journal-title":"Nature"},{"key":"hep32173-bib-0036-20250824","article-title":"Generation of organoids from mouse extrahepatic bile ducts","year":"2019","journal-title":"J Vis Exp"},{"key":"hep32173-bib-0037-20250824","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1002\/hep.21814","article-title":"Fibroblast growth factor 10 is critical for liver growth during embryogenesis and controls hepatoblast survival via beta\u2010catenin activation","volume":"46","year":"2007","journal-title":"Hepatology"},{"key":"hep32173-bib-0038-20250824","doi-asserted-by":"crossref","first-page":"4011","DOI":"10.1242\/dev.007823","article-title":"Reciprocal endoderm\u2013mesoderm interactions mediated by fgf24 and fgf10 govern pancreas development","volume":"134","year":"2007","journal-title":"Development"},{"key":"hep32173-bib-0039-20250824","doi-asserted-by":"crossref","first-page":"955","DOI":"10.1126\/science.276.5314.955","article-title":"Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors","volume":"276","year":"1997","journal-title":"Science"},{"key":"hep32173-bib-0040-20250824","doi-asserted-by":"crossref","first-page":"5173","DOI":"10.1242\/dev.02101","article-title":"Fgf signaling instructs position\u2010dependent growth rate during zebrafish fin regeneration","volume":"132","year":"2005","journal-title":"Development"},{"key":"hep32173-bib-0041-20250824","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1126\/science.1177319","article-title":"Identification of a primary target of thalidomide teratogenicity","volume":"327","year":"2010","journal-title":"Science"},{"key":"hep32173-bib-0042-20250824","doi-asserted-by":"crossref","first-page":"491","DOI":"10.1016\/j.ydbio.2004.07.001","article-title":"Differential requirement for ptf1a in endocrine and exocrine lineages of developing zebrafish pancreas","volume":"274","year":"2004","journal-title":"Dev Biol"},{"key":"hep32173-bib-0043-20250824","doi-asserted-by":"crossref","first-page":"4639","DOI":"10.1242\/dev.00671","article-title":"Zebrafish fgf24 functions with fgf8 to promote posterior mesodermal development","volume":"130","year":"2003","journal-title":"Development"},{"key":"hep32173-bib-0044-20250824","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1002\/dvdy.24491","article-title":"Fibroblast growth factors in the gastrointestinal tract: twists and turns","volume":"246","year":"2017","journal-title":"Dev Dyn"},{"key":"hep32173-bib-0045-20250824","doi-asserted-by":"crossref","first-page":"1316","DOI":"10.1016\/j.ajpath.2018.03.008","article-title":"Understanding liver regeneration: from mechanisms to regenerative medicine","volume":"188","year":"2018","journal-title":"Am J Pathol"},{"key":"hep32173-bib-0046-20250824","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1038\/nrm3272","article-title":"A family business: stem cell progeny join the niche to regulate homeostasis","volume":"13","year":"2012","journal-title":"Nat Rev Mol Cell Biol"},{"key":"hep32173-bib-0047-20250824","article-title":"scRNA\u2010Seq reveals distinct stem cell populations that drive hair cell regeneration after loss of Fgf and Notch signaling","volume":"8","year":"2019","journal-title":"Elife"},{"key":"hep32173-bib-0048-20250824","first-page":"630","article-title":"Molecular pathways and targeted therapy in cholangiocarcinoma","volume":"17","year":"2019","journal-title":"Clin Adv Hematol Oncol"},{"key":"hep32173-bib-0049-20250824","doi-asserted-by":"crossref","first-page":"1758835920940948","DOI":"10.1177\/1758835920940948","article-title":"Targeting the FGFR signaling pathway in cholangiocarcinoma: promise or delusion?","volume":"12","year":"2020","journal-title":"Ther Adv Med Oncol"},{"key":"hep32173-bib-0050-20250824","doi-asserted-by":"crossref","first-page":"755","DOI":"10.1111\/liv.12920","article-title":"Early life predictive markers of liver disease outcome in an international, multicentre cohort of children with Alagille syndrome","volume":"36","year":"2016","journal-title":"Liver Int"},{"key":"hep32173-bib-0051-20250824","first-page":"471","article-title":"Discordant clinical phenotype in monozygotic twins with Alagille syndrome: possible influence of non\u2010genetic factors","volume":"170A","year":"2016","journal-title":"Am J Med Genet A"},{"key":"hep32173-bib-0052-20250824","doi-asserted-by":"crossref","first-page":"194","DOI":"10.1002\/ajmg.10610","article-title":"Monozygotic twins with a severe form of Alagille syndrome and phenotypic discordance","volume":"112","year":"2002","journal-title":"Am J Med Genet"},{"key":"hep32173-bib-0053-20250824","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1017\/S1047951114002753","article-title":"Variable expression of Alagille syndrome in a family with a new JAG1 gene mutation","volume":"26","year":"2016","journal-title":"Cardiol Young"},{"key":"hep32173-bib-0054-20250824","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/978-3-319-89512-3_5","article-title":"Modeling the Notch response","volume":"1066","year":"2018","journal-title":"Adv Exp Med Biol"},{"key":"hep32173-bib-0055-20250824","doi-asserted-by":"crossref","first-page":"929","DOI":"10.3389\/fphys.2020.00929","article-title":"Understanding the principles of pattern formation driven by Notch signaling by integrating experiments and theoretical models","volume":"11","year":"2020","journal-title":"Front Physiol"}],"container-title":["Hepatology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/hep.32173","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/hep.32173","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.32173","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,8,25]],"date-time":"2025-08-25T00:04:12Z","timestamp":1756080252000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.lww.com\/10.1002\/hep.32173"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,15]]},"references-count":55,"journal-issue":{"issue":"3","published-print":{"date-parts":[[2022]]}},"URL":"https:\/\/doi.org\/10.1002\/hep.32173","relation":{},"ISSN":["0270-9139","1527-3350"],"issn-type":[{"value":"0270-9139","type":"print"},{"value":"1527-3350","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,15]]},"assertion":[{"value":"2021-06-06","name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-09-22","name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}}]}}