{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T13:43:30Z","timestamp":1790171010542,"version":"4.1.0"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,6,12]],"date-time":"2018-06-12T00:00:00Z","timestamp":1528761600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,6,12]],"date-time":"2018-06-12T00:00:00Z","timestamp":1528761600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Activation of the renin-angiotensin system (RAS) is associated with hypertension and heart disease. However, how RAS activation causes cardiac lesions remains elusive. Here we report the involvement of Wnt\/\u03b2-catenin signaling in this process. In rats with chronic infusion of angiotensin II (Ang II), eight Wnt ligands were induced and \u03b2-catenin activated in both cardiomyocytes and cardiac fibroblasts. Blockade of Wnt\/\u03b2-catenin signaling by small molecule inhibitor ICG-001 restrained Ang II-induced cardiac hypertrophy by normalizing heart size and inhibiting hypertrophic marker genes. ICG-001 also attenuated myocardial fibrosis and inhibited \u03b1-smooth muscle actin, fibronectin and collagen I expression. These changes were accompanied by a reduced expression of atrial natriuretic peptide and B-type natriuretic peptide. Interestingly, ICG-001 also lowered blood pressure induced by Ang II. <jats:italic>In vitro<\/jats:italic>, Ang II induced multiple Wnt ligands and activated \u03b2-catenin in rat primary cardiomyocytes and fibroblasts. ICG-001 inhibited myocyte hypertrophy and Snail1, c-Myc and atrial natriuretic peptide expression, and abolished the fibrogenic effect of Ang II in cardiac fibroblasts. Finally, recombinant Wnt3a was sufficient to induce cardiomyocyte injury and fibroblast activation <jats:italic>in vitro<\/jats:italic>. Taken together, these results illustrate an essential role for Wnt\/\u03b2-catenin in mediating hypertension, cardiac hypertrophy and myocardial fibrosis. Therefore, blockade of this pathway may be a novel strategy for ameliorating hypertensive heart disease.<\/jats:p>","DOI":"10.1038\/s41598-018-27064-2","type":"journal-article","created":{"date-parts":[[2018,6,6]],"date-time":"2018-06-06T15:46:52Z","timestamp":1528300012000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":81,"title":["An essential role for Wnt\/\u03b2-catenin signaling in mediating hypertensive heart disease"],"prefix":"10.1038","volume":"8","author":[{"given":"Yue","family":"Zhao","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunhong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cong","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xue","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinhua","family":"Miao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulin","family":"Liao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lili","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youhua","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,6,12]]},"reference":[{"key":"27064_CR1","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1007\/s10741-016-9581-4","volume":"22","author":"CM Alpert","year":"2017","unstructured":"Alpert, C. M., Smith, M. A., Hummel, S. L. & Hummel, E. K. Symptom burden in heart failure: assessment, impact on outcomes, and management. Heart Fail Rev 22, 25\u201339 (2017).","journal-title":"Heart Fail Rev"},{"key":"27064_CR2","doi-asserted-by":"publisher","first-page":"163","DOI":"10.1016\/j.ijcard.2016.07.256","volume":"223","author":"EB Reyes","year":"2016","unstructured":"Reyes, E. B. et al. Heart failure across Asia: Same healthcare burden but differences in organization of care. Int J Cardiol 223, 163\u2013167 (2016).","journal-title":"Int J Cardiol"},{"key":"27064_CR3","doi-asserted-by":"publisher","first-page":"884","DOI":"10.1002\/ejhf.319","volume":"17","author":"H Shimokawa","year":"2015","unstructured":"Shimokawa, H., Miura, M., Nochioka, K. & Sakata, Y. Heart failure as a general pandemic in Asia. Eur J Heart Fail 17, 884\u2013892 (2015).","journal-title":"Eur J Heart Fail"},{"key":"27064_CR4","doi-asserted-by":"publisher","first-page":"245","DOI":"10.1016\/j.yjmcc.2016.06.001","volume":"97","author":"I Shimizu","year":"2016","unstructured":"Shimizu, I. & Minamino, T. Physiological and pathological cardiac hypertrophy. J Mol Cell Cardiol 97, 245\u2013262 (2016).","journal-title":"J Mol Cell Cardiol"},{"key":"27064_CR5","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1038\/ajh.2012.86","volume":"25","author":"AC Larstorp","year":"2012","unstructured":"Larstorp, A. C. et al. Regression of ECG-LVH is associated with lower risk of new-onset heart failure and mortality in patients with isolated systolic hypertension; The LIFE study. Am J Hypertens 25, 1101\u20131109 (2012).","journal-title":"American journal of hypertension"},{"key":"27064_CR6","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1097\/HCO.0000000000000299","volume":"31","author":"S Garg","year":"2016","unstructured":"Garg, S. & Drazner, M. H. Refining the classification of left ventricular hypertrophy to provide new insights into the progression from hypertension to heart failure. Curr Opin Cardiol 31, 387\u2013393 (2016).","journal-title":"Curr Opin Cardiol"},{"key":"27064_CR7","doi-asserted-by":"publisher","first-page":"37","DOI":"10.1172\/JCI62839","volume":"123","author":"JH van Berlo","year":"2013","unstructured":"van Berlo, J. H., Maillet, M. & Molkentin, J. D. Signaling effectors underlying pathologic growth and remodeling of the heart. J Clin Invest 123, 37\u201345 (2013).","journal-title":"J Clin Invest"},{"key":"27064_CR8","doi-asserted-by":"publisher","first-page":"214","DOI":"10.1093\/cvr\/cvu054","volume":"102","author":"A Deb","year":"2014","unstructured":"Deb, A. Cell-cell interaction in the heart via Wnt\/beta-catenin pathway after cardiac injury. Cardiovasc Res 102, 214\u2013223 (2014).","journal-title":"Cardiovasc Res"},{"key":"27064_CR9","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1161\/01.HYP.0000255947.79237.61","volume":"49","author":"OH Cingolani","year":"2007","unstructured":"Cingolani, O. H. Cardiac hypertrophy and the Wnt\/Frizzled pathway. Hypertension 49, 427\u2013428 (2007).","journal-title":"Hypertension"},{"key":"27064_CR10","doi-asserted-by":"publisher","first-page":"38","DOI":"10.1038\/nrm3495","volume":"14","author":"M Maillet","year":"2013","unstructured":"Maillet, M., van Berlo, J. H. & Molkentin, J. D. Molecular basis of physiological heart growth: fundamental concepts and new players. Nat Rev Mol Cell Biol 14, 38\u201348 (2013).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"27064_CR11","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1007\/s12265-015-9646-0","volume":"8","author":"D Sorriento","year":"2015","unstructured":"Sorriento, D. et al. Integrating GRK2 and NFkappaB in the pathophysiology of cardiac hypertrophy. J Cardiovasc Transl Res 8, 493\u2013502 (2015).","journal-title":"J Cardiovasc Transl Res"},{"key":"27064_CR12","doi-asserted-by":"publisher","first-page":"e0130477","DOI":"10.1371\/journal.pone.0130477","volume":"10","author":"E Cipolletta","year":"2015","unstructured":"Cipolletta, E. et al. Targeting the CaMKII\/ERK interaction in the heart prevents cardiac hypertrophy. PLoS One 10, e0130477 (2015).","journal-title":"PLoS One"},{"key":"27064_CR13","doi-asserted-by":"publisher","first-page":"215","DOI":"10.1161\/HYPERTENSIONAHA.113.02382","volume":"63","author":"G Santulli","year":"2014","unstructured":"Santulli, G. Adrenal signaling in heart failure: something more than a distant ship\u2019s smoke on the horizon. Hypertension 63, 215\u2013216 (2014).","journal-title":"Hypertension"},{"key":"27064_CR14","doi-asserted-by":"publisher","first-page":"848","DOI":"10.1161\/HYPERTENSIONAHA.115.06689","volume":"67","author":"T Tsuruda","year":"2016","unstructured":"Tsuruda, T. et al. Angiotensin II stimulation of cardiac hypertrophy and functional decompensation in osteoprotegerin-deficient mice. Hypertension 67, 848\u2013856 (2016).","journal-title":"Hypertension"},{"key":"27064_CR15","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1111\/bph.12825","volume":"172","author":"PM Snijder","year":"2015","unstructured":"Snijder, P. M. et al. Exogenous administration of thiosulfate, a donor of hydrogen sulfide, attenuates angiotensin II-induced hypertensive heart disease in rats. Br J Pharmacol 172, 1494\u20131504 (2015).","journal-title":"Br J Pharmacol"},{"key":"27064_CR16","doi-asserted-by":"publisher","first-page":"1192","DOI":"10.1016\/j.cell.2012.05.012","volume":"149","author":"H Clevers","year":"2012","unstructured":"Clevers, H. & Nusse, R. Wnt\/beta-catenin signaling and disease. Cell 149, 1192\u20131205 (2012).","journal-title":"Cell"},{"key":"27064_CR17","doi-asserted-by":"publisher","first-page":"468","DOI":"10.1038\/nrm2717","volume":"10","author":"S Angers","year":"2009","unstructured":"Angers, S. & Moon, R. T. Proximal events in Wnt signal transduction. Nat Rev Mol Cell Biol 10, 468\u2013477 (2009).","journal-title":"Nat Rev Mol Cell Biol"},{"key":"27064_CR18","doi-asserted-by":"publisher","first-page":"156","DOI":"10.1038\/labinvest.2015.153","volume":"96","author":"D Zhou","year":"2016","unstructured":"Zhou, D., Tan, R. J., Fu, H. & Liu, Y. Wnt\/beta-catenin signaling in kidney injury and repair: a double-edged sword. Lab Invest 96, 156\u2013167 (2016).","journal-title":"Lab Invest"},{"key":"27064_CR19","doi-asserted-by":"publisher","first-page":"985","DOI":"10.1016\/j.cell.2017.05.016","volume":"169","author":"R Nusse","year":"2017","unstructured":"Nusse, R. & Clevers, H. Wnt\/b-catenin signaling, disease, and emerging theapeutic modalities. Cell 169, 985\u2013999 (2017).","journal-title":"Cell"},{"key":"27064_CR20","doi-asserted-by":"publisher","first-page":"565","DOI":"10.1007\/s10735-013-9507-6","volume":"44","author":"Q Zheng","year":"2013","unstructured":"Zheng, Q., Chen, P., Xu, Z., Li, F. & Yi, X. P. Expression and redistribution of beta-catenin in the cardiac myocytes of left ventricle of spontaneously hypertensive rat. J Mol Histol 44, 565\u2013573 (2013).","journal-title":"J Mol Histol"},{"key":"27064_CR21","doi-asserted-by":"publisher","first-page":"444","DOI":"10.1007\/s11684-015-0421-z","volume":"9","author":"SC Gitau","year":"2015","unstructured":"Gitau, S. C. et al. Acetyl salicylic acid attenuates cardiac hypertrophy through Wnt signaling. Front Med 9, 444\u2013456 (2015).","journal-title":"Front Med"},{"key":"27064_CR22","doi-asserted-by":"publisher","first-page":"939","DOI":"10.1161\/HYPERTENSIONAHA.109.141127","volume":"55","author":"P Malekar","year":"2010","unstructured":"Malekar, P. et al. Wnt signaling is critical for maladaptive cardiac hypertrophy and accelerates myocardial remodeling. Hypertension 55, 939\u2013945 (2010).","journal-title":"Hypertension"},{"key":"27064_CR23","doi-asserted-by":"publisher","first-page":"30","DOI":"10.1016\/j.metabol.2015.10.013","volume":"65","author":"H Tao","year":"2016","unstructured":"Tao, H., Yang, J. J., Shi, K. H. & Li, J. Wnt signaling pathway in cardiac fibrosis: New insights and directions. Metabolism 65, 30\u201340 (2016).","journal-title":"Metabolism"},{"key":"27064_CR24","doi-asserted-by":"publisher","first-page":"473","DOI":"10.1161\/01.HYP.0000255946.55091.24","volume":"49","author":"VA van de Schans","year":"2007","unstructured":"van de Schans, V. A. et al. Interruption of Wnt signaling attenuates the onset of pressure overload-induced cardiac hypertrophy. Hypertension 49, 473\u2013480 (2007).","journal-title":"Hypertension"},{"key":"27064_CR25","doi-asserted-by":"crossref","unstructured":"Uitterdijk, A. et al. UM206, a selective Frizzled antagonist, attenuates adverse remodeling after myocardial infarction in swine. Lab Invest 96, 168\u2013176 (2016).","DOI":"10.1038\/labinvest.2015.139"},{"key":"27064_CR26","doi-asserted-by":"publisher","first-page":"1177","DOI":"10.1161\/HYPERTENSIONAHA.111.00391","volume":"61","author":"M Hagenmueller","year":"2013","unstructured":"Hagenmueller, M. et al. Dapper-1 induces myocardial remodeling through activation of canonical Wnt signaling in cardiomyocytes. Hypertension 61, 1177\u20131183 (2013).","journal-title":"Hypertension"},{"key":"27064_CR27","doi-asserted-by":"publisher","first-page":"24665","DOI":"10.1074\/jbc.M109.091256","volume":"285","author":"W He","year":"2010","unstructured":"He, W. et al. Plasminogen activator inhibitor-1 is a transcriptional target of the canonical pathway of Wnt\/beta-catenin signaling. J Biol Chem 285, 24665\u201324675 (2010).","journal-title":"J Biol Chem"},{"key":"27064_CR28","doi-asserted-by":"publisher","first-page":"1997","DOI":"10.1681\/ASN.2009010019","volume":"20","author":"C Dai","year":"2009","unstructured":"Dai, C. et al. Wnt\/beta-catenin signaling promotes podocyte dysfunction and albuminuria. J Am Soc Nephrol 20, 1997\u20132008 (2009).","journal-title":"J Am Soc Nephrol"},{"key":"27064_CR29","first-page":"1413","volume":"38","author":"P Blyszczuk","year":"2017","unstructured":"Blyszczuk, P. et al. Transforming growth factor-beta-dependent Wnt secretion controls myofibroblast formation and myocardial fibrosis progression in experimental autoimmune myocarditis. Eur Heart J 38, 1413\u20131425 (2017).","journal-title":"Eur Heart J"},{"key":"27064_CR30","doi-asserted-by":"publisher","first-page":"e75010","DOI":"10.1371\/journal.pone.0075010","volume":"8","author":"T Sasaki","year":"2013","unstructured":"Sasaki, T., Hwang, H., Nguyen, C., Kloner, R. A. & Kahn, M. The small molecule Wnt signaling modulator ICG-001 improves contractile function in chronically infarcted rat myocardium. PLoS One 8, e75010 (2013).","journal-title":"PLoS One"},{"key":"27064_CR31","doi-asserted-by":"publisher","first-page":"1642","DOI":"10.1681\/ASN.2010101079","volume":"22","author":"S Hao","year":"2011","unstructured":"Hao, S. et al. Targeted inhibition of beta-catenin\/CBP signaling ameliorates renal interstitial fibrosis. J Am Soc Nephrol 22, 1642\u20131653 (2011).","journal-title":"J Am Soc Nephrol"},{"key":"27064_CR32","doi-asserted-by":"crossref","unstructured":"Kumar, N. et al. Thymosin beta4 deficiency exacerbates renal and cardiac injury in angiotensin-II-induced hypertension. Hypertension 71, 1133\u20131142 (2018).","DOI":"10.1161\/HYPERTENSIONAHA.118.10952"},{"key":"27064_CR33","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1016\/j.bbrc.2016.03.029","volume":"473","author":"L Yu","year":"2016","unstructured":"Yu, L., Meng, W., Ding, J. & Cheng, M. Klotho inhibits angiotensin II-induced cardiomyocyte hypertrophy through suppression of the AT1R\/beta catenin pathway. Biochem Biophys Res Commun 473, 455\u2013461 (2016).","journal-title":"Biochem Biophys Res Commun"},{"key":"27064_CR34","doi-asserted-by":"publisher","first-page":"1737","DOI":"10.1002\/jcp.25275","volume":"231","author":"L Li","year":"2016","unstructured":"Li, L. et al. Thymosin beta4 prevents angiotensin II-induced cardiomyocyte growth by regulating Wnt\/WISP signaling. J Cell Physiol 231, 1737\u20131744 (2016).","journal-title":"J Cell Physiol"},{"key":"27064_CR35","doi-asserted-by":"publisher","first-page":"1040","DOI":"10.1681\/ASN.2016070734","volume":"28","author":"T Yang","year":"2017","unstructured":"Yang, T. & Xu, C. Physiology and pathophysiology of the intrarenal renin-angiotensin system: An update. J Am Soc Nephrol 28, 1040\u20131049 (2017).","journal-title":"J Am Soc Nephrol"},{"key":"27064_CR36","doi-asserted-by":"crossref","unstructured":"Munoz-Durango, N. et al. Role of the renin-angiotensin-aldosterone system beyond blood pressure regulation: Molecular and Cellular mechanisms involved in end-organ damage during arterial hypertension. Int J Mol Sci 17 (2016).","DOI":"10.3390\/ijms17070797"},{"key":"27064_CR37","doi-asserted-by":"publisher","first-page":"107","DOI":"10.1681\/ASN.2014010085","volume":"26","author":"L Zhou","year":"2015","unstructured":"Zhou, L. et al. Multiple genes of the renin-angiotensin system are novel targets of Wnt\/beta-catenin signaling. J Am Soc Nephrol 26, 107\u2013120 (2015).","journal-title":"J Am Soc Nephrol"},{"key":"27064_CR38","doi-asserted-by":"publisher","first-page":"100","DOI":"10.1097\/MNH.0000000000000205","volume":"25","author":"L Zhou","year":"2016","unstructured":"Zhou, L. & Liu, Y. Wnt\/beta-catenin signaling and renin-angiotensin system in chronic kidney disease. Curr Opin Nephrol Hypertens 25, 100\u2013106 (2016).","journal-title":"Curr Opin Nephrol Hypertens"},{"key":"27064_CR39","doi-asserted-by":"publisher","first-page":"1727","DOI":"10.1681\/ASN.2015040449","volume":"27","author":"L Xiao","year":"2016","unstructured":"Xiao, L. et al. Sustained activation of Wnt\/beta-catenin signaling drives AKI to CKD progression. J Am Soc Nephrol 27, 1727\u20131740 (2016).","journal-title":"J Am Soc Nephrol"},{"key":"27064_CR40","doi-asserted-by":"publisher","first-page":"429","DOI":"10.1038\/emboj.2011.418","volume":"31","author":"J Duan","year":"2012","unstructured":"Duan, J. et al. Wnt1\/beta-catenin injury response activates the epicardium and cardiac fibroblasts to promote cardiac repair. EMBO J 31, 429\u2013442 (2012).","journal-title":"EMBO J"},{"key":"27064_CR41","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1038\/kisup.2014.16","volume":"4","author":"RJ Tan","year":"2014","unstructured":"Tan, R. J., Zhou, D., Zhou, L. L. & Liu, Y. H. Wnt\/beta-catenin signaling and kidney fibrosis. Kidney Int Suppl. 4, 84\u201390 (2014).","journal-title":"Kidney Int Suppl."},{"key":"27064_CR42","doi-asserted-by":"publisher","first-page":"e104040","DOI":"10.1371\/journal.pone.0104040","volume":"9","author":"C Chen","year":"2014","unstructured":"Chen, C. et al. Cytosolic CARP promotes angiotensin II- or pressure overload-induced cardiomyocyte hypertrophy through calcineurin accumulation. PLoS One 9, e104040 (2014).","journal-title":"PLoS One"},{"key":"27064_CR43","doi-asserted-by":"publisher","first-page":"3211","DOI":"10.1016\/j.ajpath.2015.08.004","volume":"185","author":"L Zhou","year":"2015","unstructured":"Zhou, L. et al. Klotho ameliorates kidney injury and fibrosis and normalizes blood pressure by targeting the renin-angiotensin system. Am J Pathol 185, 3211\u20133223 (2015).","journal-title":"Am J Pathol"},{"key":"27064_CR44","doi-asserted-by":"publisher","first-page":"H2408","DOI":"10.1152\/ajpheart.01089.2003","volume":"286","author":"SE Whitesall","year":"2004","unstructured":"Whitesall, S. E., Hoff, J. B., Vollmer, A. P. & D\u2019Alecy, L. G. Comparison of simultaneous measurement of mouse systolic arterial blood pressure by radiotelemetry and tail-cuff methods. Am J Physiol Heart Circ Physiol 286, H2408\u20132415 (2004).","journal-title":"Am J Physiol Heart Circ Physiol"},{"key":"27064_CR45","doi-asserted-by":"publisher","first-page":"1288","DOI":"10.1038\/ajh.2008.301","volume":"21","author":"M Feng","year":"2008","unstructured":"Feng, M. et al. Validation of volume-pressure recording tail-cuff blood pressure measurements. Am J Hypertens 21, 1288\u20131291 (2008).","journal-title":"Am J Hypertens"},{"key":"27064_CR46","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1681\/ASN.2013101033","volume":"26","author":"X Zhou","year":"2015","unstructured":"Zhou, X., Chen, K., Lei, H. & Sun, Z. Klotho gene deficiency causes salt-sensitive hypertension via monocyte chemotactic protein-1\/CC chemokine receptor 2-mediated inflammation. J Am Soc Nephrol 26, 121\u2013132 (2015).","journal-title":"J Am Soc Nephrol"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-27064-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-27064-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-27064-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T06:26:30Z","timestamp":1671603990000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-27064-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,12]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["27064"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-27064-2","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,12]]},"assertion":[{"value":"14 February 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 May 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 June 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"8996"}}