{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T06:39:01Z","timestamp":1790836741835,"version":"4.1.0"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T00:00:00Z","timestamp":1639353600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Cardiovasc. Med."],"abstract":"<jats:p><jats:bold>Background:<\/jats:bold> Dilated cardiomyopathy (DCM) is a major cause of heart failure worldwide. The Z-line protein Cypher\/Z-band alternatively spliced PDZ-motif protein (ZASP) is closely associated with DCM, both clinically and in animal models. Our earlier work revealed Cypher\/ZASP as a PKA-anchoring protein (AKAP) that tethers PKA to phosphorylate target substrates. However, the downstream PKA effectors regulated by AKAP Cypher\/ZASP and their relevance to DCM remain largely unknown.<\/jats:p><jats:p><jats:bold>Methods and Results:<\/jats:bold> For the identification of candidate PKA substrates, global quantitative phosphoproteomics was performed on cardiac tissue from wild-type and Cypher-knockout mice with PKA activation. A total of 216 phosphopeptides were differentially expressed in the Cypher-knockout mice; 31 phosphorylation sites were selected as candidates using the PKA consensus motifs. Bioinformatic analysis indicated that differentially expressed proteins were enriched mostly in cell adhesion and mRNA processing. Furthermore, the phosphorylation of \u03b2-catenin Ser675 was verified to be facilitated by Cypher. This phosphorylation promoted the transcriptional activity of \u03b2-catenin, and also the proliferative capacity of cardiomyocytes. Immunofluorescence staining demonstrated that Cypher colocalised with \u03b2-catenin in the intercalated discs (ICD) and altered the cytoplasmic distribution of \u03b2-catenin. Moreover, the phosphorylation of two other PKA substrates, vimentin Ser72 and troponin I Ser23\/24, was suppressed by Cypher deletion.<\/jats:p><jats:p><jats:bold>Conclusions:<\/jats:bold> Cypher\/ZASP plays an essential role in \u03b2-catenin activation <jats:italic>via<\/jats:italic> Ser675 phosphorylation, which modulates cardiomyocyte proliferation. Additionally, Cypher\/ZASP regulates other PKA effectors, such as vimentin Ser72 and troponin I Ser23\/24. These findings establish the AKAP Cypher\/ZASP as a signalling hub in the progression of DCM.<\/jats:p>","DOI":"10.3389\/fcvm.2021.753072","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T06:55:37Z","timestamp":1639378537000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":8,"title":["Phosphoproteomic Analysis Reveals Downstream PKA Effectors of AKAP Cypher\/ZASP in the Pathogenesis of Dilated Cardiomyopathy"],"prefix":"10.3389","volume":"8","author":[{"given":"Jialan","family":"Lv","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhicheng","family":"Pan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jian","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rui","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongfei","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiaqi","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yang","family":"Dong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jing","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiang","family":"Yin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongqiang","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaogang","family":"Guo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,13]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1038\/s41572-019-0084-1","article-title":"Dilated cardiomyopathy","volume":"5","author":"Schultheiss","year":"2019","journal-title":"Nat Rev Dis Primers."},{"key":"B2","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1111\/cge.12458","article-title":"A mutation in the Z-line cypher\/ZASP protein is associated with arrhythmogenic right ventricular cardiomyopathy","volume":"88","author":"Lopez-Ayala","year":"2015","journal-title":"Clin Genet."},{"key":"B3","doi-asserted-by":"publisher","first-page":"2014","DOI":"10.1016\/j.jacc.2003.10.021","article-title":"Mutations in Cypher\/ZASP in patients with dilated cardiomyopathy and left ventricular non-compaction","volume":"42","author":"Vatta","year":"2003","journal-title":"J Am Coll Cardiol."},{"key":"B4","doi-asserted-by":"publisher","first-page":"355","DOI":"10.1038\/s42003-021-01864-1","article-title":"Myopathy associated LDB3 mutation causes Z-disc disassembly and protein aggregation through PKC\u03b1 and TSC2-mTOR downregulation","volume":"4","author":"Pathak","year":"2021","journal-title":"Commun Biol."},{"key":"B5","doi-asserted-by":"publisher","first-page":"766","DOI":"10.1631\/jzus.B1900017","article-title":"Impact of LDB3 gene polymorphisms on clinical presentation and implantable cardioverter defibrillator (ICD) implantation in Chinese patients with idiopathic dilated cardiomyopathy","volume":"20","author":"Wang","year":"2019","journal-title":"J Zhejiang Univ Sci B."},{"key":"B6","doi-asserted-by":"publisher","first-page":"3058","DOI":"10.3390\/ijms22063058","article-title":"The role of Z-disc proteins in myopathy and cardiomyopathy","volume":"22","author":"Wadmore","year":"2021","journal-title":"Int J Mol Sci"},{"key":"B7","doi-asserted-by":"publisher","first-page":"605","DOI":"10.1083\/jcb.200107092","article-title":"Ablation of Cypher, a PDZ-LIM domain Z-line protein, causes a severe form of congenital myopathy","volume":"155","author":"Zhou","year":"2001","journal-title":"J Cell Biol."},{"key":"B8","doi-asserted-by":"publisher","first-page":"701","DOI":"10.1093\/hmg\/ddn400","article-title":"Cardiac-specific ablation of Cypher leads to a severe form of dilated cardiomyopathy with premature death","volume":"18","author":"Zheng","year":"2009","journal-title":"Hum Mol Genet."},{"key":"B9","doi-asserted-by":"publisher","first-page":"96","DOI":"10.1093\/jmcb\/mjp038","article-title":"ALP\/Enigma PDZ-LIM domain proteins in the heart","volume":"2","author":"Zheng","year":"2010","journal-title":"J. Mol. Cell Biol"},{"key":"B10","doi-asserted-by":"publisher","first-page":"5647","DOI":"10.1242\/jcs.103291","article-title":"Zasp regulates integrin activation","volume":"125","author":"Bouaouina","year":"2012","journal-title":"J Cell Sci."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1583","DOI":"10.1083\/jcb.200707045","article-title":"Zasp is required for the assembly of functional integrin adhesion sites","volume":"179","author":"Jani","year":"2007","journal-title":"J Cell Biol."},{"key":"B12","doi-asserted-by":"publisher","first-page":"2328","DOI":"10.7150\/ijms.48872","article-title":"Downregulation of cypher induces apoptosis in cardiomyocytes via Akt\/p38 MAPK signaling pathway","volume":"17","author":"Xuan","year":"2020","journal-title":"Int J Med Sci."},{"key":"B13","doi-asserted-by":"publisher","first-page":"112","DOI":"10.1016\/j.yjmcc.2019.04.020","article-title":"cAMP\/PKA signaling compartmentalization in cardiomyocytes: Lessons from FRET-based biosensors","volume":"131","author":"Ghigo","year":"2019","journal-title":"J Mol Cell Cardiol."},{"key":"B14","doi-asserted-by":"publisher","first-page":"218","DOI":"10.3390\/ijms16010218","article-title":"Compartmentalization role of A-kinase anchoring proteins (AKAPs) in mediating protein kinase A (PKA) signaling and cardiomyocyte hypertrophy","volume":"16","author":"Rababa'h","year":"2014","journal-title":"Int J Mol Sci"},{"key":"B15","doi-asserted-by":"publisher","first-page":"933","DOI":"10.1016\/j.tips.2020.09.007","article-title":"AKAP Signaling islands: venues for precision pharmacology","volume":"41","author":"Omar","year":"2020","journal-title":"Trends Pharmacol Sci."},{"key":"B16","doi-asserted-by":"publisher","first-page":"29403","DOI":"10.1074\/jbc.M113.470708","article-title":"Cypher\/ZASP is a novel A-kinase anchoring protein","volume":"288","author":"Lin","year":"2013","journal-title":"J Biol Chem."},{"key":"B17","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1085\/jgp.201711818","article-title":"Catterall WA. The AKAP cypher\/Zasp contributes to \u03b2-adrenergic\/PKA stimulation of cardiac Ca12 calcium channels","volume":"150","author":"Yu","year":"2018","journal-title":"J Gen Physiol."},{"key":"B18","doi-asserted-by":"publisher","first-page":"D253","DOI":"10.1093\/nar\/gkq1159","article-title":"PHOSIDA 2011: the posttranslational modification database","volume":"39","author":"Gnad","year":"2011","journal-title":"Nucleic Acids Res."},{"key":"B19","doi-asserted-by":"publisher","first-page":"1912","DOI":"10.1126\/science.1075762","article-title":"The protein kinase complement of the human genome","volume":"298","author":"Manning","year":"2002","journal-title":"Science."},{"key":"B20","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1007\/s00395-010-0101-8","article-title":"Stabilised beta-catenin in postnatal ventricular myocardium leads to dilated cardiomyopathy and premature death","volume":"105","author":"Hirschy","year":"2010","journal-title":"Basic Res Cardiol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"333","DOI":"10.1093\/hmg\/ddw389","article-title":"Decreased WNT\/\u03b2-catenin signalling contributes to the pathogenesis of dilated cardiomyopathy caused by mutations in the lamin a\/C gene","volume":"26","author":"Le Dour","year":"2017","journal-title":"Hum Mol Genet."},{"key":"B22","doi-asserted-by":"publisher","first-page":"e003010","DOI":"10.1161\/CIRCHEARTFAILURE.116.003010","article-title":"Transcription Factor 7-like 2 Mediates Canonical Wnt\/\u03b2-Catenin Signaling and c-Myc Upregulation in heart failure","volume":"9","author":"Hou","year":"2016","journal-title":"Circ Heart Fail"},{"key":"B23","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1007\/s10741-018-9743-7","article-title":"Intercalated discs: cellular adhesion and signaling in heart health and diseases","volume":"24","author":"Zhao","year":"2019","journal-title":"Heart Fail Rev."},{"key":"B24","doi-asserted-by":"publisher","first-page":"2309","DOI":"10.1002\/hep.26775","article-title":"Tri-iodothyronine induces hepatocyte proliferation by protein kinase A-dependent \u03b2-catenin activation in rodents","volume":"59","author":"Fanti","year":"2014","journal-title":"Hepatology."},{"key":"B25","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1161\/ATVBAHA.116.308587","article-title":"E-Prostanoid 3 Receptor mediates sprouting angiogenesis through suppression of the protein kinase A\/\u03b2-catenin\/notch pathway","volume":"37","author":"Chen","year":"2017","journal-title":"Arterioscler Thromb Vasc Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"234","DOI":"10.14348\/molcells.2018.2340","article-title":"Liraglutide inhibits the apoptosis of MC3T3-E1 cells induced by serum deprivation through cAMP\/PKA\/\u03b2-Catenin and PI3K\/AKT\/GSK3\u03b2 signaling pathways","volume":"41","author":"Wu","year":"2018","journal-title":"Mol Cells."},{"key":"B27","doi-asserted-by":"publisher","first-page":"1713","DOI":"10.1002\/hep.26554","article-title":"Protein kinase A-dependent pSer(675) -\u03b2-catenin, a novel signaling defect in a mouse model of congenital hepatic fibrosis","volume":"58","author":"Spirli","year":"2013","journal-title":"Hepatology."},{"key":"B28","doi-asserted-by":"publisher","first-page":"101063","DOI":"10.1016\/j.arr.2020.101063","article-title":"Wnt signaling pathway in aging-related tissue fibrosis and therapies","volume":"60","author":"Hu","year":"2020","journal-title":"Ageing Res Rev."},{"key":"B29","doi-asserted-by":"publisher","first-page":"41","DOI":"10.1093\/jmcb\/mjaa046","article-title":"Induction of Wnt signaling antagonists and p21-activated kinase enhances cardiomyocyte proliferation during zebrafish heart regeneration","volume":"13","author":"Peng","year":"2021","journal-title":"J Mol Cell Biol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"2342","DOI":"10.1161\/CIRCULATIONAHA.117.028752","article-title":"Fibroblast primary cilia are required for cardiac fibrosis","volume":"139","author":"Villalobos","year":"2019","journal-title":"Circulation."},{"key":"B31","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/j.lfs.2016.10.021","article-title":"Cardioprotective effects of monocyte locomotion inhibitory factor on myocardial ischemic injury by targeting vimentin","volume":"167","author":"Jiang","year":"2016","journal-title":"Life Sci."},{"key":"B32","doi-asserted-by":"publisher","first-page":"1331","DOI":"10.1039\/C5MT00094G","article-title":"The involvement of vimentin in copper-induced regression of cardiomyocyte hypertrophy","volume":"7","author":"Li","year":"2015","journal-title":"Metallomics."},{"key":"B33","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1016\/j.ppedcard.2011.02.003","article-title":"The costamere bridges sarcomeres to the sarcolemma in striated muscle","volume":"31","author":"Peter","year":"2011","journal-title":"Prog Pediatr Cardiol."},{"key":"B34","doi-asserted-by":"publisher","first-page":"10053","DOI":"10.1074\/jbc.M109.044420","article-title":"Regulation of microtubule dynamics through phosphorylation on stathmin by Epstein-Barr virus kinase BGLF4","volume":"285","author":"Chen","year":"2010","journal-title":"J Biol Chem."},{"key":"B35","doi-asserted-by":"publisher","first-page":"7817","DOI":"10.18632\/aging.102290","article-title":"PRL-3 exerts oncogenic functions in myeloid leukemia cells via aberrant dephosphorylation of stathmin and activation of STAT3 signaling","volume":"11","author":"Xu","year":"2019","journal-title":"Aging."},{"key":"B36","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/j.abb.2019.01.025","article-title":"Troponin I modulation of cardiac performance: plasticity in the survival switch","volume":"664","author":"Biesiadecki","year":"2019","journal-title":"Arch Biochem Biophys"},{"key":"B37","doi-asserted-by":"publisher","first-page":"8588","DOI":"10.1074\/jbc.RA117.001292","article-title":"Monophosphorylation of cardiac troponin-I at Ser-23\/24 is sufficient to regulate cardiac myofibrillar Ca sensitivity and calpain-induced proteolysis","volume":"293","author":"Martin-Garrido","year":"2018","journal-title":"J Biol Chem."},{"key":"B38","doi-asserted-by":"publisher","first-page":"362","DOI":"10.1111\/eci.12598","article-title":"\u03b2-adrenergic receptor signalling and its functional consequences in the diseased heart.","volume":"46","author":"Najafi","year":"2016","journal-title":"Eur J Clin Invest."},{"key":"B39","doi-asserted-by":"publisher","first-page":"24691","DOI":"10.1073\/pnas.2006764117","article-title":"Distinct hypertrophic cardiomyopathy genotypes result in convergent sarcomeric proteoform profiles revealed by top-down proteomics","volume":"117","author":"Tucholski","year":"2020","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B40","doi-asserted-by":"publisher","first-page":"6746","DOI":"10.1074\/jbc.M311849200","article-title":"A Cypher\/ZASP mutation associated with dilated cardiomyopathy alters the binding affinity to protein kinase C","volume":"279","author":"Arimura","year":"2004","journal-title":"J Biol Chem."},{"key":"B41","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1161\/CIRCULATIONAHA.120.052384","article-title":"Cooperative Binding of ETS2 and NFAT Links Erk1\/2 and calcineurin signaling in the pathogenesis of cardiac hypertrophy","volume":"144","author":"Luo","year":"2021","journal-title":"Circulation."},{"key":"B42","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1016\/j.yjmcc.2010.10.021","article-title":"The p38 mitogen-activated protein kinase pathway\u2013a potential target for intervention in infarction, hypertrophy, and heart failure","volume":"51","author":"Marber","year":"2011","journal-title":"J Mol Cell Cardiol."},{"key":"B43","doi-asserted-by":"publisher","first-page":"2714","DOI":"10.1038\/emboj.2012.150","article-title":"The many faces and functions of \u03b2-catenin","volume":"31","author":"Valenta","year":"2012","journal-title":"EMBO J."},{"key":"B44","doi-asserted-by":"publisher","first-page":"200267","DOI":"10.1098\/rsob.200267","article-title":"Walking the tight wire between cell adhesion and WNT signalling: a balancing act for \u03b2-catenin","volume":"10","author":"van der Wal","year":"2020","journal-title":"Open Biol."},{"key":"B45","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.ajpath.2017.10.016","article-title":"Overexpression of MUC13, a poor prognostic predictor, promotes cell growth by activating Wnt signaling in hepatocellular carcinoma","volume":"188","author":"Dai","year":"2018","journal-title":"Am J Pathol."},{"key":"B46","doi-asserted-by":"publisher","first-page":"E1263","DOI":"10.1152\/ajpendo.00600.2012","article-title":"GLP-1(28-36) improves \u03b2-cell mass and glucose disposal in streptozotocin-induced diabetic mice and activates cAMP\/PKA\/\u03b2-catenin signaling in \u03b2-cells in vitro","volume":"304","author":"Shao","year":"2013","journal-title":"Am J Physiol Endocrinol Metab."},{"key":"B47","doi-asserted-by":"publisher","first-page":"9971","DOI":"10.1074\/jbc.M508778200","article-title":"Phosphorylation of beta-catenin by cyclic AMP-dependent protein kinase","volume":"281","author":"Taurin","year":"2006","journal-title":"J Biol Chem."},{"key":"B48","doi-asserted-by":"publisher","first-page":"123","DOI":"10.1016\/j.bone.2016.01.023","article-title":"Prostaglandin-mediated inhibition of PTH-stimulated \u03b2-catenin signaling in osteoblasts by bone marrow macrophages","volume":"85","author":"Estus","year":"2016","journal-title":"Bone."},{"key":"B49","doi-asserted-by":"publisher","first-page":"639148","DOI":"10.3389\/fcvm.2021.639148","article-title":"Cardiomyocyte proliferative capacity is restricted in mice with mutation","volume":"8","author":"Onoue","year":"2021","journal-title":"Front Cardiovasc Med."},{"key":"B50","doi-asserted-by":"publisher","first-page":"4666","DOI":"10.1038\/s41467-020-18379-8","article-title":"Intercalated disc protein Xin\u03b2 is required for Hippo-YAP signaling in the heart","volume":"11","author":"Guo","year":"2020","journal-title":"Nat Commun."},{"key":"B51","doi-asserted-by":"publisher","first-page":"250","DOI":"10.1111\/jnc.15014","article-title":"Truncating mutations in SHANK3 associated with global developmental delay interfere with nuclear \u03b2-catenin signaling","volume":"155","author":"Hassani Nia","year":"2020","journal-title":"J Neurochem."},{"key":"B52","doi-asserted-by":"publisher","first-page":"919","DOI":"10.1242\/jcs.00906","article-title":"Specific in vivo phosphorylation sites determine the assembly dynamics of vimentin intermediate filaments","volume":"117","author":"Eriksson","year":"2004","journal-title":"J Cell Sci."},{"key":"B53","doi-asserted-by":"publisher","first-page":"jcs254359","DOI":"10.1242\/jcs.254359","article-title":"Vimentin tunes cell migration on collagen by controlling \u03b21 integrin activation and clustering","volume":"134","author":"Ostrowska-Podhorodecka","year":"2021","journal-title":"J Cell Sci"},{"key":"B54","doi-asserted-by":"publisher","first-page":"2401","DOI":"10.1096\/fj.11-199018","article-title":"Vimentin phosphorylation by Cdc2 in schwann cell controls axon growth via \u03b21-integrin activation","volume":"26","author":"Chang","year":"2012","journal-title":"FASEB J."},{"key":"B55","doi-asserted-by":"publisher","first-page":"61","DOI":"10.3390\/cells10010061","article-title":"Master regulators of muscle atrophy: role of costamere components","volume":"10","author":"Gorza","year":"2021","journal-title":"Cells"},{"key":"B56","doi-asserted-by":"publisher","first-page":"2690","DOI":"10.1161\/CIRCULATIONAHA.111.028498","article-title":"Absence of SOCS3 in the cardiomyocyte increases mortality in a gp130-dependent manner accompanied by contractile dysfunction and ventricular arrhythmias","volume":"124","author":"Yajima","year":"2011","journal-title":"Circulation."},{"key":"B57","doi-asserted-by":"publisher","first-page":"669","DOI":"10.1113\/JP270959","article-title":"The contributions of cardiac myosin binding protein C and troponin I phosphorylation to \u03b2-adrenergic enhancement of in vivo cardiac function","volume":"594","author":"Gresham","year":"2016","journal-title":"J Physiol."},{"key":"B58","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1093\/cvr\/cvt144","article-title":"Differential changes in titin domain phosphorylation increase myofilament stiffness in failing human hearts","volume":"99","author":"K\u00f6tter","year":"2013","journal-title":"Cardiovasc Res."},{"key":"B59","doi-asserted-by":"publisher","first-page":"1305","DOI":"10.1161\/CIRCRESAHA.116.309631","article-title":"Adrenergic signaling strengthens cardiac myocyte cohesion","volume":"120","author":"Schinner","year":"2017","journal-title":"Circ Res."},{"key":"B60","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1007\/s00395-010-0131-2","article-title":"EH-myomesin splice isoform is a novel marker for dilated cardiomyopathy","volume":"106","author":"Schoenauer","year":"2011","journal-title":"Basic Res Cardiol."}],"container-title":["Frontiers in Cardiovascular Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.753072\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T06:55:44Z","timestamp":1639378544000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fcvm.2021.753072\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,13]]},"references-count":60,"alternative-id":["10.3389\/fcvm.2021.753072"],"URL":"https:\/\/doi.org\/10.3389\/fcvm.2021.753072","relation":{},"ISSN":["2297-055X"],"issn-type":[{"value":"2297-055X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,13]]},"article-number":"753072"}}