{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T20:28:55Z","timestamp":1790713735886,"version":"4.1.0"},"reference-count":59,"publisher":"Oxford University Press (OUP)","issue":"22","license":[{"start":{"date-parts":[[2021,7,7]],"date-time":"2021-07-07T00:00:00Z","timestamp":1625616000000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Hospital for Sick Children Research Training Competition Award"},{"DOI":"10.13039\/501100000024","name":"Canadian Institute of Health Research","doi-asserted-by":"crossref","award":["GSD-157899"],"award-info":[{"award-number":["GSD-157899"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100000024","name":"Canadian Institute of Health Research","doi-asserted-by":"crossref","award":["FDN-154273"],"award-info":[{"award-number":["FDN-154273"]}],"id":[{"id":"10.13039\/501100000024","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2021,11,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Severe respiratory impairment is a prominent feature of Rett syndrome, an X-linked disorder caused by mutations in methyl CpG-binding protein 2 (MECP2). Despite MECP2\u2019s ubiquitous expression, respiratory anomalies are attributed to neuronal dysfunction. Here, we show that neutral lipids accumulate in mouse Mecp2-mutant lungs, whereas surfactant phospholipids decrease. Conditional deletion of Mecp2 from lipid-producing alveolar epithelial 2 (AE2) cells causes aberrant lung lipids and respiratory symptoms, whereas deletion of Mecp2 from hindbrain neurons results in distinct respiratory abnormalities. Single-cell RNA sequencing of AE2 cells suggests lipid production and storage increase at the expense of phospholipid synthesis. Lipid production enzymes are confirmed as direct targets of MECP2-directed nuclear receptor co-repressor 1\/2 transcriptional repression. Remarkably, lipid-lowering fluvastatin improves respiratory anomalies in Mecp2-mutant mice. These data implicate autonomous pulmonary loss of MECP2 in respiratory symptoms for the first time and have immediate impacts on patient care.<\/jats:p>","DOI":"10.1093\/hmg\/ddab182","type":"journal-article","created":{"date-parts":[[2021,7,2]],"date-time":"2021-07-02T19:17:55Z","timestamp":1625253475000},"page":"2161-2176","source":"Crossref","is-referenced-by-count":9,"title":["Aberrant lung lipids cause respiratory impairment in a <i>Mecp2<\/i>-deficient mouse model of Rett syndrome"],"prefix":"10.1093","volume":"30","author":[{"given":"Neeti","family":"Vashi","sequence":"first","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A1, Canada"},{"name":"Genetics and Genome Biology Program, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario M5G 0A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cameron","family":"Ackerley","sequence":"additional","affiliation":[{"name":"Translational Medicine Program, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario M5G 0A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin","family":"Post","sequence":"additional","affiliation":[{"name":"Translational Medicine Program, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario M5G 0A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica J","family":"Justice","sequence":"additional","affiliation":[{"name":"Department of Molecular Genetics, University of Toronto, Toronto, Ontario M5S 1A1, Canada"},{"name":"Genetics and Genome Biology Program, Hospital for Sick Children, Peter Gilgan Centre for Research and Learning, Toronto, Ontario M5G 0A4, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2021,7,6]]},"reference":[{"key":"2021110209345259100_ref1","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1513\/AnnalsATS.201411-507FR","article-title":"The role of surfactant in lung disease and host defense against pulmonary infections","volume":"12","author":"Han","year":"2015","journal-title":"Ann. Am. Thorac. Soc."},{"key":"2021110209345259100_ref2","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1016\/S0005-2736(00)00256-X","article-title":"Role of pulmonary surfactant components in surface film formation and dynamics","volume":"1467","author":"Veldhuizen","year":"2000","journal-title":"Biochim. Biophys. Acta Biomembr."},{"key":"2021110209345259100_ref3","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1146\/annurev.med.60.041807.123500","article-title":"Alveolar surfactant homeostasis and the pathogenesis of pulmonary disease","volume":"61","author":"Whitsett","year":"2010","journal-title":"Annu. Rev. Med."},{"key":"2021110209345259100_ref4","doi-asserted-by":"crossref","first-page":"324","DOI":"10.1002\/ajmg.a.20058","article-title":"Analysis of 40 sporadic or familial neonatal and pediatric cases with severe unexplained respiratory distress: relationship to SFTPB","volume":"119","author":"Tredano","year":"2003","journal-title":"Am. J. Med. Genet."},{"key":"2021110209345259100_ref5","doi-asserted-by":"crossref","first-page":"10562","DOI":"10.1073\/pnas.1107559108","article-title":"Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs","volume":"108","author":"Lawson","year":"2011","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021110209345259100_ref6","doi-asserted-by":"crossref","first-page":"9628","DOI":"10.1074\/jbc.M611767200","article-title":"ABCA3 as a lipid transporter in pulmonary surfactant biogenesis","volume":"282","author":"Ban","year":"2007","journal-title":"J. Biol. Chem."},{"key":"2021110209345259100_ref7","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0091376","article-title":"Epithelial SCAP\/INSIG\/SREBP signaling regulates multiple biological processes during perinatal lung maturation","volume":"9","author":"Bridges","year":"2014","journal-title":"PLoS One"},{"key":"2021110209345259100_ref8","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S0387-7604(85)80039-5","article-title":"Abnormal breathing in the Rett syndrome","volume":"7","author":"Lugaresi","year":"1985","journal-title":"Brain Dev."},{"key":"2021110209345259100_ref9","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/13810","article-title":"Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2","volume":"23","author":"Amir","year":"1999","journal-title":"Nat. Genet."},{"key":"2021110209345259100_ref10","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1002\/ana.22124","article-title":"Rett syndrome: revised diagnostic criteria and nomenclature","volume":"68","author":"Neul","year":"2010","journal-title":"Ann. Neurol."},{"key":"2021110209345259100_ref11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1750-1172-9-87","article-title":"Twenty years of surveillance in Rett syndrome: what does this tell us?","volume":"9","author":"Anderson","year":"2014","journal-title":"Orphanet J. Rare Dis."},{"key":"2021110209345259100_ref12","doi-asserted-by":"crossref","first-page":"384","DOI":"10.1136\/adc.80.4.384","article-title":"Recent insights into hyperventilation from the study of Rett syndrome","volume":"80","author":"Kerr","year":"1999","journal-title":"Arch. Dis. Child."},{"key":"2021110209345259100_ref13","doi-asserted-by":"crossref","first-page":"122","DOI":"10.1016\/S0387-7604(01)00358-8","article-title":"Reduced expression of neuropeptides can be related to respiratory disturbances in Rett syndrome","volume":"23","author":"Saito","year":"2001","journal-title":"Brain Dev."},{"key":"2021110209345259100_ref14","doi-asserted-by":"crossref","first-page":"11521","DOI":"10.1523\/JNEUROSCI.4373-05.2005","article-title":"Mecp2 deficiency disrupts norepinephrine and respiratory systems in mice","volume":"25","author":"Viemari","year":"2005","journal-title":"J. Neurosci."},{"key":"2021110209345259100_ref15","doi-asserted-by":"crossref","first-page":"443","DOI":"10.1203\/01.pdr.0000238302.84552.d0","article-title":"Autonomic nervous system dysregulation: breathing and heart rate perturbation during wakefulness in young girls with Rett syndrome","volume":"60","author":"Weese-Mayer","year":"2006","journal-title":"Pediatr. Res."},{"key":"2021110209345259100_ref16","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1152\/japplphysiol.01361.2011","article-title":"7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome","volume":"112","author":"Johnson","year":"2012","journal-title":"J. Appl. Physiol."},{"key":"2021110209345259100_ref17","doi-asserted-by":"crossref","first-page":"1047","DOI":"10.1242\/dmm.016030","article-title":"A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome","volume":"7","author":"Kron","year":"2014","journal-title":"DMM Dis. Model. Mech."},{"key":"2021110209345259100_ref18","doi-asserted-by":"crossref","first-page":"18208","DOI":"10.1073\/pnas.1012104107","article-title":"Correction of respiratory disorders in a mouse model of Rett syndrome","volume":"107","author":"Abdala","year":"2010","journal-title":"Proc. Natl. Acad. Sci."},{"key":"2021110209345259100_ref19","doi-asserted-by":"crossref","first-page":"1626","DOI":"10.1152\/japplphysiol.00889.2013","article-title":"A selective 5-HT1a receptor agonist improves respiration in a mouse model of Rett syndrome","volume":"115","author":"Levitt","year":"2013","journal-title":"J. Appl. Physiol."},{"key":"2021110209345259100_ref20","doi-asserted-by":"crossref","first-page":"2846","DOI":"10.1038\/npp.2014.136","article-title":"Improvement of the Rett syndrome phenotype in a mecp2 mouse model upon treatment with levodopa and a DOPA-decarboxylase inhibitor","volume":"39","author":"Szczesna","year":"2014","journal-title":"Neuropsychopharmacology"},{"key":"2021110209345259100_ref21","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/j.resp.2011.02.002","article-title":"The benzodiazepine Midazolam mitigates the breathing defects of Mecp2-deficient mice","volume":"177","author":"Voituron","year":"2011","journal-title":"Respir. Physiol. Neurobiol."},{"key":"2021110209345259100_ref22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s11689-016-9169-2","article-title":"Effects of early-life exposure to THIP on phenotype development in a mouse model of Rett syndrome","volume":"8","author":"Zhong","year":"2016","journal-title":"J. Neurodev. Disord."},{"key":"2021110209345259100_ref23","doi-asserted-by":"crossref","first-page":"898","DOI":"10.1038\/nn.3434","article-title":"Rett syndrome mutations abolish the interaction of MeCP2 with the NCoR\/SMRT co-repressor","volume":"16","author":"Lyst","year":"2013","journal-title":"Nat. Neurosci."},{"key":"2021110209345259100_ref24","doi-asserted-by":"crossref","first-page":"398","DOI":"10.1038\/nature24058","article-title":"Radically truncated MeCP2 rescues Rett syndrome-like neurological defects","volume":"550","author":"Tillotson","year":"2017","journal-title":"Nature"},{"key":"2021110209345259100_ref25","doi-asserted-by":"crossref","first-page":"341","DOI":"10.1038\/nature12348","article-title":"Activity-dependent phosphorylation of MeCP2 threonine 308 regulates interaction with NCoR","volume":"499","author":"Ebert","year":"2013","journal-title":"Nature"},{"key":"2021110209345259100_ref26","doi-asserted-by":"crossref","first-page":"E3243","DOI":"10.1073\/pnas.1700731114","article-title":"Structure of the MeCP2\u2013TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders","volume":"114","author":"Kruusvee","year":"2017","journal-title":"Proc. Natl. Acad. Sci."},{"key":"2021110209345259100_ref27","doi-asserted-by":"crossref","first-page":"1497","DOI":"10.1038\/nn.4347","article-title":"Histone deacetylase 3 associates with MeCP2 to regulate FOXO and social behavior","volume":"19","author":"Nott","year":"2016","journal-title":"Nat. Neurosci."},{"key":"2021110209345259100_ref28","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1101\/gad.214023.113","article-title":"Emerging roles of the corepressors NCoR1 and SMRT in homeostasis","volume":"27","author":"Mottis","year":"2013","journal-title":"Genes Dev."},{"key":"2021110209345259100_ref29","doi-asserted-by":"crossref","first-page":"1315","DOI":"10.1126\/science.1198125","article-title":"A circadian rhythm orchestrated by histone deacetylase 3 controls hepatic lipid metabolism","volume":"331","author":"Feng","year":"2011","journal-title":"Science"},{"key":"2021110209345259100_ref30","first-page":"3029","article-title":"MeCP2 co-ordinates liver lipid metabolism with the NCoR1\/HDAC3 corepressor complex","volume":"25","author":"Kyle","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"2021110209345259100_ref31","doi-asserted-by":"crossref","first-page":"115","DOI":"10.1093\/hmg\/11.2.115","article-title":"Insight into Rett syndrome: MeCP2 levels display tissue- and cell-specific differences and correlate with neuronal maturation","volume":"11","author":"Shahbazian","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"2021110209345259100_ref32","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1038\/nbt1210-1248","article-title":"Towards a knowledge-based Human Protein Atlas","volume":"28","author":"Uhlen","year":"2010","journal-title":"Nat. Biotechnol."},{"key":"2021110209345259100_ref33","doi-asserted-by":"crossref","first-page":"1013","DOI":"10.1038\/ng.2714","article-title":"A suppressor screen in Mecp2 mutant mice implicates cholesterol metabolism in Rett syndrome","volume":"45","author":"Buchovecky","year":"2013","journal-title":"Nat. Genet."},{"key":"2021110209345259100_ref34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41598-017-12293-8","article-title":"Pathogenesis of lethal aspiration pneumonia in Mecp2-null mouse model for Rett syndrome","volume":"7","author":"Kida","year":"2017","journal-title":"Sci. Rep."},{"key":"2021110209345259100_ref35","doi-asserted-by":"crossref","first-page":"5033","DOI":"10.1128\/MCB.01665-05","article-title":"Gene expression analysis exposes mitochondrial abnormalities in a mouse model of Rett syndrome","volume":"26","author":"Kriaucionis","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"2021110209345259100_ref36","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1155\/2013\/137629","article-title":"Genes related to mitochondrial functions, protein degradation, and chromatin folding are differentially expressed in lymphomonocytes of Rett syndrome patients","volume":"2013","author":"Pecorelli","year":"2013","journal-title":"Mediat. Inflamm."},{"key":"2021110209345259100_ref37","doi-asserted-by":"crossref","first-page":"58","DOI":"10.3389\/fncel.2017.00058","article-title":"Mitochondrial dysfunction in the pathogenesis of Rett syndrome: implications for mitochondria-targeted therapies","volume":"11","author":"Shulyakova","year":"2017","journal-title":"Front. Cell. Neurosci."},{"key":"2021110209345259100_ref38","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.cell.2005.12.022","article-title":"Protein sensors for membrane sterols","volume":"124","author":"Goldstein","year":"2006","journal-title":"Cell"},{"key":"2021110209345259100_ref39","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1172\/JCI0215593","article-title":"SREBPs: activators of the complete program of cholesterol and fatty acid synthesis in the liver","volume":"109","author":"Horton","year":"2002","journal-title":"J. Clin. Invest."},{"key":"2021110209345259100_ref40","doi-asserted-by":"crossref","first-page":"11603","DOI":"10.1073\/pnas.90.24.11603","article-title":"SREBP-2, a second basic-helix-loop-helix-leucine zipper protein that stimulates transcription by binding to a sterol regulatory element","volume":"90","author":"Hua","year":"1993","journal-title":"Proc. Natl. Acad. Sci. U. S. A."},{"key":"2021110209345259100_ref41","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1038\/s41467-019-09152-7","article-title":"Sterol regulatory element binding protein 1 couples mechanical cues and lipid metabolism","volume":"10","author":"Bertolio","year":"2019","journal-title":"Nat. Commun."},{"key":"2021110209345259100_ref42","doi-asserted-by":"crossref","first-page":"737","DOI":"10.1111\/j.1471-4159.2005.03056.x","article-title":"Regulation of cholesterol\/lipid biosynthetic genes by Egr2\/Krox20 during peripheral nerve myelination","volume":"93","author":"LeBlanc","year":"2005","journal-title":"J. Neurochem."},{"key":"2021110209345259100_ref43","doi-asserted-by":"crossref","first-page":"29069","DOI":"10.1074\/jbc.M110.120386","article-title":"Sterol regulatory element-binding protein (SREBP)-1-mediated lipogenesis is involved in cell senescence","volume":"285","author":"Kim","year":"2010","journal-title":"J. Biol. Chem."},{"key":"2021110209345259100_ref44","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1136\/thoraxjnl-2016-208649","article-title":"Lung disease caused by ABCA3 mutations","volume":"72","author":"Kr\u00f6ner","year":"2017","journal-title":"Thorax"},{"key":"2021110209345259100_ref45","doi-asserted-by":"crossref","first-page":"12799","DOI":"10.1074\/jbc.M601019200","article-title":"24(S)-hydroxycholesterol participates in a liver X receptor-controlled pathway in astrocytes that regulates apolipoprotein E-mediated cholesterol efflux","volume":"281","author":"Abildayeva","year":"2006","journal-title":"J. Biol. Chem."},{"key":"2021110209345259100_ref46","doi-asserted-by":"crossref","DOI":"10.7554\/eLife.22409","article-title":"Lovastatin fails to improve motor performance and survival in methyl-CpG-binding protein2-null mice","volume":"5","author":"Villani","year":"2016","journal-title":"elife"},{"key":"2021110209345259100_ref47","article-title":"A role for metabolism in Rett syndrome pathogenesis: new clinical findings and potential treatment targets","volume":"1","author":"Justice","year":"2013","journal-title":"Rare Dis."},{"key":"2021110209345259100_ref48","doi-asserted-by":"crossref","DOI":"10.1371\/journal.pone.0104834","article-title":"Cholesterol metabolism is altered in Rett syndrome: a study on plasma and primary cultured fibroblasts derived from patients","volume":"9","author":"Segatto","year":"2014","journal-title":"PLoS One"},{"key":"2021110209345259100_ref49","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s12944-020-01278-8","article-title":"Alveolar lipids in pulmonary disease. A review","volume":"19","author":"Agudelo","year":"2020","journal-title":"Lipids Health Dis."},{"key":"2021110209345259100_ref50","doi-asserted-by":"crossref","first-page":"386","DOI":"10.1378\/chest.09-3021","article-title":"Unrecognized lung disease in classic Rett syndrome: a physiologic and high-resolution CT imaging study","volume":"138","author":"De Felice","year":"2010","journal-title":"Chest"},{"key":"2021110209345259100_ref51","first-page":"4389","article-title":"Exclusive expression of MeCP2 in the nervous system distinguishes between brain and peripheral Rett syndrome-like phenotypes","volume":"25","author":"Ross","year":"2016","journal-title":"Hum. Mol. Genet."},{"key":"2021110209345259100_ref52","doi-asserted-by":"crossref","first-page":"515","DOI":"10.1016\/j.braindev.2018.03.010","article-title":"The course of awake breathing disturbances across the lifespan in Rett syndrome","volume":"40","author":"Tarquinio","year":"2018","journal-title":"Brain Dev."},{"key":"2021110209345259100_ref53","doi-asserted-by":"crossref","first-page":"27","DOI":"10.1016\/j.cellimm.2018.01.020","article-title":"Macrophages and lipid metabolism","volume":"330","author":"Remmerie","year":"2018","journal-title":"Cell. Immunol."},{"key":"2021110209345259100_ref54","doi-asserted-by":"crossref","first-page":"177","DOI":"10.1007\/s11248-013-9764-x","article-title":"Rapid conversion of EUCOMM\/KOMP-CSD alleles in mouse embryos using a cell-permeable Cre recombinase","volume":"23","author":"Ryder","year":"2014","journal-title":"Transgenic Res."},{"key":"2021110209345259100_ref55","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1126\/science.1138389","article-title":"Reversal of neurological defects in a mouse model of Rett syndrome","volume":"315","author":"Guy","year":"2007","journal-title":"Science"},{"key":"2021110209345259100_ref56","doi-asserted-by":"crossref","first-page":"L796","DOI":"10.1152\/ajplung.00334.2015","article-title":"Flow-cytometric method for simultaneous analysis of mouse lung epithelial, endothelial, and hematopoietic lineage cells","volume":"310","author":"Singer","year":"2016","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2021110209345259100_ref57","doi-asserted-by":"crossref","first-page":"1202","DOI":"10.1016\/j.cell.2015.05.002","article-title":"Highly parallel genome-wide expression profiling of individual cells using nanoliter droplets","volume":"161","author":"Macosko","year":"2015","journal-title":"Cell"},{"key":"2021110209345259100_ref58","first-page":"1","article-title":"Pooling across cells to normalize single-cell RNA sequencing data with many zero counts","volume":"17","author":"Lun","year":"2016","journal-title":"Genome Biol."},{"key":"2021110209345259100_ref59","doi-asserted-by":"crossref","first-page":"240","DOI":"10.1016\/j.ymeth.2009.03.001","article-title":"ChIP-seq: using high-throughput sequencing to discover protein-DNA interactions","volume":"48","author":"Schmidt","year":"2009","journal-title":"Methods"}],"container-title":["Human Molecular Genetics"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/academic.oup.com\/hmg\/advance-article-pdf\/doi\/10.1093\/hmg\/ddab182\/39523890\/ddab182.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/30\/22\/2161\/41029025\/ddab182.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"http:\/\/academic.oup.com\/hmg\/article-pdf\/30\/22\/2161\/41029025\/ddab182.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,2]],"date-time":"2021-11-02T09:36:08Z","timestamp":1635845768000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/hmg\/article\/30\/22\/2161\/6316235"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,6]]},"references-count":59,"journal-issue":{"issue":"22","published-online":{"date-parts":[[2021,7,6]]},"published-print":{"date-parts":[[2021,11,1]]}},"URL":"https:\/\/doi.org\/10.1093\/hmg\/ddab182","relation":{},"ISSN":["0964-6906","1460-2083"],"issn-type":[{"value":"0964-6906","type":"print"},{"value":"1460-2083","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2021,11,15]]},"published":{"date-parts":[[2021,7,6]]}}}