{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T03:20:13Z","timestamp":1790824813404,"version":"4.1.0"},"reference-count":47,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2019,1,23]],"date-time":"2019-01-23T00:00:00Z","timestamp":1548201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Biomolecules"],"abstract":"<jats:p>Macrophage migration inhibitory factor (MIF) is a pleiotropic cytokine known to play a major role in inflammatory diseases such as myocardial infarction (MI), where its expression increases. Cardio-protective functions of MIF during ischemia have been reported. Recently, the structurally related MIF-2 was identified and similar effects are assumed. We wanted to further investigate the role of MIF and MIF-2 on inflammatory processes during MI. Therefore, we subjected mice to experimentally induced MI by coronary occlusion for one and five days. During the acute phase of MI, the gene expression of Mif was upregulated in the infarct zone, whereas Mif-2 was downregulated, suggesting a minor role of MIF-2. Simulating ischemic conditions or mechanical stress in vitro, we demonstrated that Mif expression was induced in resident cardiac cells. To investigate possible auto-\/paracrine effects, cardiomyocytes and cardiac fibroblasts were individually treated with recombinant murine MIF, which in turn induced Mif expression and the expression of pro-inflammatory genes in cardiac fibroblasts. Cardiomyocytes did not respond to recombinant MIF with pro-inflammatory gene expression. While MIF stimulation alone did not change the expression of pro-fibrotic genes in cardiac fibroblasts, ischemia reduced their expression. Mimicking the increased MIF levels during MI, we exposed cardiac fibroblasts to simulated ischemia in the presence of MIF, which led to further reduced expression of pro-fibrotic genes. The presented data show that MIF was expressed by resident cardiac cells during MI. In vitro, Mif expression was induced by different external stimuli in cardiomyocytes and cardiac fibroblasts. Addition of recombinant MIF protein increased the expression of pro-inflammatory genes in cardiac fibroblasts including Mif expression itself. Thereby, cardiac fibroblasts may amplify Mif expression during ischemia promoting cardiomyocyte survival.<\/jats:p>","DOI":"10.3390\/biom9020038","type":"journal-article","created":{"date-parts":[[2019,1,24]],"date-time":"2019-01-24T11:12:48Z","timestamp":1548328368000},"page":"38","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Macrophage Migration Inhibitory Factor (MIF) Expression Increases during Myocardial Infarction and Supports Pro-Inflammatory Signaling in Cardiac Fibroblasts"],"prefix":"10.3390","volume":"9","author":[{"given":"Svenja","family":"Voss","sequence":"first","affiliation":[{"name":"Clinic for General and Interventional Cardiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany"},{"name":"Partner Site Hamburg\/Kiel\/L\u00fcbeck, DZHK (German Center for Cardiovascular Research), 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0807-4851","authenticated-orcid":false,"given":"Saskia","family":"Kr\u00fcger","sequence":"additional","affiliation":[{"name":"Clinic for General and Interventional Cardiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany"},{"name":"Partner Site Hamburg\/Kiel\/L\u00fcbeck, DZHK (German Center for Cardiovascular Research), 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3237-140X","authenticated-orcid":false,"given":"Katharina","family":"Scherschel","sequence":"additional","affiliation":[{"name":"Partner Site Hamburg\/Kiel\/L\u00fcbeck, DZHK (German Center for Cardiovascular Research), 20246 Hamburg, Germany"},{"name":"Clinic for Cardiology\u2014Electrophysiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Svenja","family":"Warnke","sequence":"additional","affiliation":[{"name":"Clinic for General and Interventional Cardiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael","family":"Schwarzl","sequence":"additional","affiliation":[{"name":"Clinic for General and Interventional Cardiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany"},{"name":"Partner Site Hamburg\/Kiel\/L\u00fcbeck, DZHK (German Center for Cardiovascular Research), 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benedikt","family":"Schrage","sequence":"additional","affiliation":[{"name":"Clinic for General and Interventional Cardiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany"},{"name":"Partner Site Hamburg\/Kiel\/L\u00fcbeck, DZHK (German Center for Cardiovascular Research), 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Evaldas","family":"Girdauskas","sequence":"additional","affiliation":[{"name":"Partner Site Hamburg\/Kiel\/L\u00fcbeck, DZHK (German Center for Cardiovascular Research), 20246 Hamburg, Germany"},{"name":"Clinic for Cardiovascular Surgery, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian","family":"Meyer","sequence":"additional","affiliation":[{"name":"Partner Site Hamburg\/Kiel\/L\u00fcbeck, DZHK (German Center for Cardiovascular Research), 20246 Hamburg, Germany"},{"name":"Clinic for Cardiology\u2014Electrophysiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Blankenberg","sequence":"additional","affiliation":[{"name":"Clinic for General and Interventional Cardiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany"},{"name":"Partner Site Hamburg\/Kiel\/L\u00fcbeck, DZHK (German Center for Cardiovascular Research), 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dirk","family":"Westermann","sequence":"additional","affiliation":[{"name":"Clinic for General and Interventional Cardiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany"},{"name":"Partner Site Hamburg\/Kiel\/L\u00fcbeck, DZHK (German Center for Cardiovascular Research), 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5477-769X","authenticated-orcid":false,"given":"Diana","family":"Lindner","sequence":"additional","affiliation":[{"name":"Clinic for General and Interventional Cardiology, University Heart Center Hamburg, University Hospital Hamburg-Eppendorf, 20246 Hamburg, Germany"},{"name":"Partner Site Hamburg\/Kiel\/L\u00fcbeck, DZHK (German Center for Cardiovascular Research), 20246 Hamburg, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,1,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2551","DOI":"10.1093\/eurheartj\/ehs184","article-title":"Third universal definition of myocardial infarction","volume":"33","author":"Thygesen","year":"2012","journal-title":"Eur. Heart J."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1016\/S0140-6736(06)68770-9","article-title":"Global and regional burden of disease and risk factors, 2001: Systematic analysis of population health data","volume":"367","author":"Lopez","year":"2006","journal-title":"Lancet"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"255","DOI":"10.1038\/nrcardio.2014.28","article-title":"The inflammatory response in myocardial injury, repair, and remodelling","volume":"11","author":"Frangogiannis","year":"2014","journal-title":"Nat. Rev. Cardiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"E8727","DOI":"10.1073\/pnas.1721635115","article-title":"Precursor proadrenomedullin influences cardiomyocyte survival and local inflammation related to myocardial infarction","volume":"115","author":"Hinrichs","year":"2018","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"White, D.A., Fang, L., Chan, W., Morand, E.F., Kiriazis, H., Duffy, S.J., Taylor, A.J., Dart, A.M., Du, X.J., and Gao, X.M. (2013). Pro-inflammatory action of MIF in acute myocardial infarction via activation of peripheral blood mononuclear cells. PLoS ONE, 8.","DOI":"10.1371\/annotation\/6e24b7bb-83c7-4887-9621-96b64acfb1c1"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"428","DOI":"10.1007\/s00395-014-0428-7","article-title":"Cardiac fibroblasts support cardiac inflammation in heart failure","volume":"109","author":"Lindner","year":"2014","journal-title":"Basic Res. Cardiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1161\/CIRCHEARTFAILURE.109.931451","article-title":"Cardiac inflammation contributes to changes in the extracellular matrix in patients with heart failure and normal ejection fraction","volume":"4","author":"Westermann","year":"2011","journal-title":"Circ. Heart Fail."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1080\/14728222.2017.1336227","article-title":"MIF family cytokines in cardiovascular diseases and prospects for precision-based therapeutics","volume":"21","author":"Tilstam","year":"2017","journal-title":"Expert Opin. Ther. Targets"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1007\/s10557-014-6568-z","article-title":"Post-myocardial infarct inflammation and the potential role of cell therapy","volume":"29","author":"Geutskens","year":"2015","journal-title":"Cardiovasc. Drugs Ther."},{"key":"ref_10","first-page":"415","article-title":"Crystal structure of macrophage migration inhibitory factor (MIF), a glucocorticoid-induced regulator of cytokine production, reveals a unique architecture","volume":"108","author":"Lolis","year":"1996","journal-title":"Proc. Assoc. Am. Physicians"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1002\/pro.5560051016","article-title":"NMR characterization of structure, backbone dynamics, and glutathione binding of the human macrophage migration inhibitory factor (MIF)","volume":"5","author":"Muhlhahn","year":"1996","journal-title":"Protein Sci."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"170","DOI":"10.1038\/sj.gene.6363867","article-title":"A functional promoter polymorphism in the macrophage migration inhibitory factor (MIF) gene associated with disease severity in rheumatoid arthritis","volume":"3","author":"Baugh","year":"2002","journal-title":"Genes Immun."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1038\/72262","article-title":"Protection from septic shock by neutralization of macrophage migration inhibitory factor","volume":"6","author":"Calandra","year":"2000","journal-title":"Nat. Med."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1002\/art.10728","article-title":"Macrophage migration inhibitory factor: An emerging therapeutic target in rheumatoid arthritis","volume":"48","author":"Morand","year":"2003","journal-title":"Arthritis Rheum."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"399","DOI":"10.1038\/nrd2029","article-title":"MIF: A new cytokine link between rheumatoid arthritis and atherosclerosis","volume":"5","author":"Morand","year":"2006","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1073\/pnas.56.1.72","article-title":"Delayed hypersensitivity in vitro: Its mediation by cell-free substances formed by lymphoid cell-antigen interaction","volume":"56","author":"David","year":"1966","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"80","DOI":"10.1126\/science.153.3731.80","article-title":"Mechanism of a reaction in vitro associated with delayed-type hypersensitivity","volume":"153","author":"Bloom","year":"1966","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"438","DOI":"10.1016\/S0008-6363(01)00408-4","article-title":"Macrophage migration inhibitory factor as a redox-sensitive cytokine in cardiac myocytes","volume":"52","author":"Takahashi","year":"2001","journal-title":"Cardiovasc. Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"920","DOI":"10.1038\/414920a","article-title":"MIF regulates innate immune responses through modulation of Toll-like receptor 4","volume":"414","author":"Roger","year":"2001","journal-title":"Nature"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"132","DOI":"10.1016\/j.cca.2009.04.016","article-title":"Increase of macrophage migration inhibitory factor (MIF) expression in cardiomyocytes during chronic hypoxia","volume":"405","author":"Jian","year":"2009","journal-title":"Clin. Chim. Acta"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"3023","DOI":"10.1002\/art.20470","article-title":"Reduced leukocyte-endothelial cell interactions in the inflamed microcirculation of macrophage migration inhibitory factor-deficient mice","volume":"50","author":"Gregory","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1084\/jem.185.8.1455","article-title":"The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat","volume":"185","author":"Lan","year":"1997","journal-title":"J. Exp. Med."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1038\/nm1567","article-title":"MIF is a noncognate ligand of CXC chemokine receptors in inflammatory and atherogenic cell recruitment","volume":"13","author":"Bernhagen","year":"2007","journal-title":"Nat. Med."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1467","DOI":"10.1084\/jem.20030286","article-title":"MIF signal transduction initiated by binding to CD74","volume":"197","author":"Leng","year":"2003","journal-title":"J. Exp. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"595","DOI":"10.1016\/j.immuni.2006.08.020","article-title":"CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complex","volume":"25","author":"Shi","year":"2006","journal-title":"Immunity"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1016\/j.cyto.2012.03.014","article-title":"D-dopachrome tautomerase (D-DT or MIF-2): Doubling the MIF cytokine family","volume":"59","author":"Merk","year":"2012","journal-title":"Cytokine"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"E577","DOI":"10.1073\/pnas.1102941108","article-title":"The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF)","volume":"108","author":"Merk","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1016\/S0002-9149(01)02251-2","article-title":"Elevation of plasma levels of macrophage migration inhibitory factor in patients with acute myocardial infarction","volume":"89","author":"Takahashi","year":"2002","journal-title":"Am. J. Cardiol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"774","DOI":"10.1016\/S0002-9149(01)01850-1","article-title":"Elevation of plasma level of macrophage migration inhibitory factor in patients with acute myocardial infarction","volume":"88","author":"Yu","year":"2001","journal-title":"Am. J. Cardiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e000226","DOI":"10.1161\/JAHA.113.000226","article-title":"Macrophage migration inhibitory factor for the early prediction of infarct size","volume":"2","author":"Chan","year":"2013","journal-title":"J. Am. Heart Assoc."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"578","DOI":"10.1038\/nature06504","article-title":"Macrophage migration inhibitory factor stimulates AMP-activated protein kinase in the ischaemic heart","volume":"451","author":"Miller","year":"2008","journal-title":"Nature"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"991","DOI":"10.1016\/j.yjmcc.2010.12.022","article-title":"Deletion of macrophage migration inhibitory factor protects the heart from severe ischemia-reperfusion injury: A predominant role of anti-inflammation","volume":"50","author":"Gao","year":"2011","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"321","DOI":"10.1093\/cvr\/cvu071","article-title":"Macrophage migration inhibitory factor in myocardial ischaemia\/reperfusion injury","volume":"102","author":"Rassaf","year":"2014","journal-title":"Cardiovasc. Res."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1068","DOI":"10.1161\/HYPERTENSIONAHA.108.116350","article-title":"Renin inhibition improves cardiac function and remodeling after myocardial infarction independent of blood pressure","volume":"52","author":"Westermann","year":"2008","journal-title":"Hypertension"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1073\/pnas.95.6.2979","article-title":"Hl-1 cells: A cardiac muscle cell line that contracts and retains phenotypic characteristics of the adult cardiomyocyte","volume":"95","author":"Claycomb","year":"1998","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"14155","DOI":"10.1038\/ncomms14155","article-title":"Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias","volume":"8","author":"Jungen","year":"2017","journal-title":"Nat. Commun."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2013\u0394\u0394CTmethod","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1042\/CS20130828","article-title":"Role of MIF in myocardial ischaemia and infarction: Insight from recent clinical and experimental findings","volume":"127","author":"Dayawansa","year":"2014","journal-title":"Clin. Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"3807","DOI":"10.1172\/JCI39738","article-title":"Cardiac macrophage migration inhibitory factor inhibits JNK pathway activation and injury during ischemia\/reperfusion","volume":"119","author":"Qi","year":"2009","journal-title":"J. Clin. Investig."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1191","DOI":"10.1089\/ars.2010.3163","article-title":"Macrophage migration inhibitory factor provides cardioprotection during ischemia\/reperfusion by reducing oxidative stress","volume":"14","author":"Koga","year":"2011","journal-title":"Antioxid. Redox Signal."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"490","DOI":"10.1161\/HYPERTENSIONAHA.113.02219","article-title":"Macrophage migration inhibitory factor deletion exacerbates pressure overload-induced cardiac hypertrophy through mitigating autophagy","volume":"63","author":"Xu","year":"2014","journal-title":"Hypertension"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"267","DOI":"10.1111\/j.1753-0407.2010.00088.x","article-title":"Macrophage migration inhibitory factor deficiency augments cardiac dysfunction in type 1 diabetic murine cardiomyocytes","volume":"2","author":"Tong","year":"2010","journal-title":"J. Diabetes"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"e000439","DOI":"10.1161\/JAHA.113.000439","article-title":"Macrophage migration inhibitory factor deficiency augments doxorubicin-induced cardiomyopathy","volume":"2","author":"Xu","year":"2013","journal-title":"J. Am. Heart Assoc."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.yjmcc.2014.01.015","article-title":"Differential roles of cardiac and leukocyte derived macrophage migration inhibitory factor in inflammatory responses and cardiac remodelling post myocardial infarction","volume":"69","author":"White","year":"2014","journal-title":"J. Mol. Cell. Cardiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1111\/jcmm.12936","article-title":"D-dopachrome tautomerase in adipose tissue inflammation and wound repair","volume":"21","author":"Kim","year":"2017","journal-title":"J. Cell. Mol. Med."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Kim, B.S., Rongisch, R., Hager, S., Grieb, G., Nourbakhsh, M., Rennekampff, H.O., Bucala, R., Bernhagen, J., and Pallua, N. (2015). Macrophage migration inhibitory factor in acute adipose tissue inflammation. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0137366"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"7446","DOI":"10.1074\/jbc.M111.329664","article-title":"Neutralization of macrophage migration inhibitory factor (MIF) by fully human antibodies correlates with their specificity for the beta-sheet structure of MIF","volume":"287","author":"Kerschbaumer","year":"2012","journal-title":"J. Biol. Chem."}],"container-title":["Biomolecules"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/2\/38\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:28:11Z","timestamp":1760185691000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-273X\/9\/2\/38"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,1,23]]},"references-count":47,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2019,2]]}},"alternative-id":["biom9020038"],"URL":"https:\/\/doi.org\/10.3390\/biom9020038","relation":{},"ISSN":["2218-273X"],"issn-type":[{"value":"2218-273X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,1,23]]}}}