{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,23]],"date-time":"2025-09-23T14:28:56Z","timestamp":1758637736164,"version":"3.37.3"},"reference-count":35,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,8,12]],"date-time":"2019-08-12T00:00:00Z","timestamp":1565568000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,8,12]],"date-time":"2019-08-12T00:00:00Z","timestamp":1565568000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001659","name":"Deutsche Forschungsgemeinschaft","doi-asserted-by":"publisher","award":["SFB TRR57 P18"],"award-info":[{"award-number":["SFB TRR57 P18"]}],"id":[{"id":"10.13039\/501100001659","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100008050","name":"Fundaci&amp;#x00F3;n Cellex","doi-asserted-by":"publisher","award":["PREDICT"],"award-info":[{"award-number":["PREDICT"]}],"id":[{"id":"10.13039\/100008050","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007601","name":"EC | Horizon 2020","doi-asserted-by":"publisher","award":["668031"],"award-info":[{"award-number":["668031"]}],"id":[{"id":"10.13039\/501100007601","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Prevalence of non-alcoholic fatty liver disease (NAFLD) is increasing. Resulting fibrosis and portal hypertension, as a possible secondary event, may necessitate treatment. Overexpression of mouse renin in the transgenic rat model, TGR(mREN2)27, leads to spontaneous development of NAFLD. Therefore, we used TGR(mREN2)27 rats as a model of NAFLD where we hypothesized increased susceptibility and investigated fibrosis and portal hypertension and associated pathways. 12-week old TGR(mREN2)27 rats received either cholestatic (BDL) or toxic injury (CCl<jats:sub>4<\/jats:sub> inhalation). Portal and systemic hemodynamic assessments were performed using microsphere technique with and without injection of the Janus-Kinase 2 (JAK2) inhibitor AG490 or the non-peptidic Ang(1-7) agonist, AVE0991. The extent of liver fibrosis was assessed in TGR(mREN2)27 and wild-type rats using standard techniques. Protein and mRNA levels of profibrotic, renin-angiotensin system components were assessed in liver and primary hepatic stellate cells (HSC) and hepatocytes. TGR(mREN2)27 rats developed spontaneous, but mild fibrosis and portal hypertension due to the activation of the JAK2\/Arhgef1\/ROCK pathway. AG490 decreased migration of HSC and portal pressure in isolated liver perfusions and <jats:italic>in vivo<\/jats:italic>. Fibrosis or portal hypertension after cholestatic (BDL) or toxic injury (CCl<jats:sub>4<\/jats:sub>) was not aggravated in TGR(mREN2)27 rats, probably due to decreased mouse renin expression in hepatocytes. Interestingly, portal hypertension was even blunted in TGR(mREN2)27 rats (with or without additional injury) by AVE0991. TGR(mREN2)27 rats are a suitable model of spontaneous liver fibrosis and portal hypertension but not with increased susceptibility to liver damage. After additional injury, the animals can be used to evaluate novel therapeutic strategies targeting Mas.<\/jats:p>","DOI":"10.1038\/s41598-019-48024-4","type":"journal-article","created":{"date-parts":[[2019,8,12]],"date-time":"2019-08-12T10:03:02Z","timestamp":1565604182000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["TGR(mREN2)27 rats develop non-alcoholic fatty liver disease-associated portal hypertension responsive to modulations of Janus-kinase 2 and Mas receptor"],"prefix":"10.1038","volume":"9","author":[{"given":"Sabine","family":"Klein","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carola-Ellen","family":"Kleine","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Pieper","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michaela","family":"Granzow","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sebastian","family":"Gautsch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mimoun","family":"Himmit","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Katharina","family":"Kahrmann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2195-3666","authenticated-orcid":false,"given":"Robert","family":"Schierwagen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Frank Erhard","family":"Uschner","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4121-6743","authenticated-orcid":false,"given":"Fernando","family":"Magdaleno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Eleni","family":"Naoum","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Glen","family":"Kristiansen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Thomas","family":"Walther","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Bader","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tilman","family":"Sauerbruch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7028-3881","authenticated-orcid":false,"given":"Jonel","family":"Trebicka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,8,12]]},"reference":[{"key":"48024_CR1","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1016\/j.jhep.2010.04.008","volume":"53","author":"V Ratziu","year":"2010","unstructured":"Ratziu, V., Bellentani, S., Cortez-Pinto, H., Day, C. & Marchesini, G. A position statement on NAFLD\/NASH based on the EASL 2009 special conference. Journal of hepatology 53, 372\u2013384 (2010).","journal-title":"Journal of hepatology"},{"key":"48024_CR2","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1016\/j.cgh.2012.05.008","volume":"10","author":"FD Mendes","year":"2012","unstructured":"Mendes, F. D., Suzuki, A., Sanderson, S. O., Lindor, K. D. & Angulo, P. Prevalence and indicators of portal hypertension in patients with nonalcoholic fatty liver disease. Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association 10, 1028\u20131033 e1022 (2012).","journal-title":"Clinical gastroenterology and hepatology: the official clinical practice journal of the American Gastroenterological Association"},{"key":"48024_CR3","doi-asserted-by":"publisher","first-page":"2102","DOI":"10.1007\/s10620-016-4124-3","volume":"61","author":"SJ Nagpal","year":"2016","unstructured":"Nagpal, S. J. et al. Portal Hypertension Complications Are Frequently the First Presentation of NAFLD in Patients Undergoing Liver Transplantation Evaluation. Digestive diseases and sciences 61, 2102\u20132107 (2016).","journal-title":"Digestive diseases and sciences"},{"key":"48024_CR4","doi-asserted-by":"publisher","first-page":"180","DOI":"10.1136\/gutjnl-2016-312431","volume":"66","author":"Y Rotman","year":"2017","unstructured":"Rotman, Y. & Sanyal, A. J. Current and upcoming pharmacotherapy for non-alcoholic fatty liver disease. Gut 66, 180\u2013190 (2017).","journal-title":"Gut"},{"key":"48024_CR5","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms3823","volume":"4","author":"I Mederacke","year":"2013","unstructured":"Mederacke, I. et al. Fate tracing reveals hepatic stellate cells as dominant contributors to liver fibrosis independent of its aetiology. Nature communications 4, 2823, https:\/\/doi.org\/10.1038\/ncomms3823 (2013).","journal-title":"Nature communications"},{"key":"48024_CR6","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1053\/j.gastro.2008.03.003","volume":"134","author":"SL Friedman","year":"2008","unstructured":"Friedman, S. L. Mechanisms of hepatic fibrogenesis. Gastroenterology 134, 1655\u20131669 (2008).","journal-title":"Gastroenterology"},{"key":"48024_CR7","doi-asserted-by":"publisher","first-page":"141","DOI":"10.1016\/S0168-8278(00)80422-5","volume":"32","author":"J Bosch","year":"2000","unstructured":"Bosch, J. & Garcia-Pagan, J. C. Complications of cirrhosis. I. Portal hypertension. Journal of hepatology 32, 141\u2013156 (2000).","journal-title":"Journal of hepatology"},{"key":"48024_CR8","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1002\/hep.27117","volume":"60","author":"M Granzow","year":"2014","unstructured":"Granzow, M. et al. Angiotensin-II type 1 receptor-mediated Janus kinase 2 activation induces liver fibrosis. Hepatology 60, 334\u2013348 (2014).","journal-title":"Hepatology"},{"key":"48024_CR9","doi-asserted-by":"publisher","first-page":"145","DOI":"10.1136\/gutjnl-2015-309600","volume":"66","author":"S Klein","year":"2017","unstructured":"Klein, S. et al. Janus-kinase-2 relates directly to portal hypertension and to complications in rodent and human cirrhosis. Gut 66, 145\u2013155 (2017).","journal-title":"Gut"},{"key":"48024_CR10","doi-asserted-by":"publisher","first-page":"744","DOI":"10.1136\/gut.2003.020263","volume":"53","author":"L Benvegnu","year":"2004","unstructured":"Benvegnu, L., Gios, M., Boccato, S. & Alberti, A. Natural history of compensated viral cirrhosis: a prospective study on the incidence and hierarchy of major complications. Gut 53, 744\u2013749 (2004).","journal-title":"Gut"},{"key":"48024_CR11","doi-asserted-by":"publisher","first-page":"95","DOI":"10.12703\/P6-95","volume":"6","author":"T Sauerbruch","year":"2014","unstructured":"Sauerbruch, T. & Trebicka, J. Future therapy of portal hypertension in liver cirrhosis - a guess. F1000prime reports 6, 95 (2014).","journal-title":"F1000prime reports"},{"key":"48024_CR12","doi-asserted-by":"publisher","first-page":"417","DOI":"10.1016\/j.jhep.2008.03.018","volume":"49","author":"Y Wei","year":"2008","unstructured":"Wei, Y. et al. Angiotensin II-induced non-alcoholic fatty liver disease is mediated by oxidative stress in transgenic TG(mRen2)27(Ren2) rats. Journal of hepatology 49, 417\u2013428 (2008).","journal-title":"Journal of hepatology"},{"key":"48024_CR13","doi-asserted-by":"publisher","first-page":"505","DOI":"10.1152\/physrev.00023.2016","volume":"98","author":"RAS Santos","year":"2018","unstructured":"Santos, R. A. S. et al. The ACE2\/Angiotensin-(1-7)\/MAS Axis of the Renin-Angiotensin System: Focus on Angiotensin-(1-7). Physiol Rev 98, 505\u2013553 (2018).","journal-title":"Physiol Rev"},{"key":"48024_CR14","doi-asserted-by":"publisher","first-page":"375","DOI":"10.1042\/CS20080647","volume":"117","author":"JS Lubel","year":"2009","unstructured":"Lubel, J. S. et al. Angiotensin-(1-7), an alternative metabolite of the renin-angiotensin system, is up-regulated in human liver disease and has antifibrotic activity in the bile-duct-ligated rat. Clinical science 117, 375\u2013386 (2009).","journal-title":"Clinical science"},{"key":"48024_CR15","doi-asserted-by":"publisher","first-page":"874","DOI":"10.1053\/j.gastro.2013.06.036","volume":"145","author":"JA Grace","year":"2013","unstructured":"Grace, J. A. et al. Activation of the MAS receptor by angiotensin-(1-7) in the renin-angiotensin system mediates mesenteric vasodilatation in cirrhosis. Gastroenterology 145, 874\u2013884 e875 (2013).","journal-title":"Gastroenterology"},{"key":"48024_CR16","doi-asserted-by":"publisher","first-page":"e0138732","DOI":"10.1371\/journal.pone.0138732","volume":"10","author":"S Klein","year":"2015","unstructured":"Klein, S. et al. Hemodynamic Effects of the Non-Peptidic Angiotensin-(1-7) Agonist AVE0991 in Liver Cirrhosis. PloS one 10, e0138732 (2015).","journal-title":"PloS one"},{"key":"48024_CR17","doi-asserted-by":"publisher","first-page":"638","DOI":"10.1002\/jcb.25313","volume":"117","author":"SS Karcioglu","year":"2016","unstructured":"Karcioglu, S. S. et al. The Role of RAAS Inhibition by Aliskiren on Paracetamol-Induced Hepatotoxicity Model in Rats. J Cell Biochem 117, 638\u2013646 (2016).","journal-title":"J Cell Biochem"},{"key":"48024_CR18","doi-asserted-by":"publisher","first-page":"e77817","DOI":"10.1371\/journal.pone.0077817","volume":"8","author":"KC Lee","year":"2013","unstructured":"Lee, K. C. et al. Aliskiren attenuates steatohepatitis and increases turnover of hepatic fat in mice fed with a methionine and choline deficient diet. PloS one 8, e77817 (2013).","journal-title":"PloS one"},{"key":"48024_CR19","doi-asserted-by":"publisher","first-page":"1241","DOI":"10.1111\/hepr.12081","volume":"43","author":"Y Aihara","year":"2013","unstructured":"Aihara, Y. et al. Direct renin inhibitor, aliskiren, attenuates the progression of non-alcoholic steatohepatitis in the rat model. Hepatology research: the official journal of the Japan Society of Hepatology 43, 1241\u20131250 (2013).","journal-title":"Hepatology research: the official journal of the Japan Society of Hepatology"},{"key":"48024_CR20","doi-asserted-by":"publisher","first-page":"501","DOI":"10.1016\/j.jcma.2012.07.001","volume":"75","author":"YC Hsieh","year":"2012","unstructured":"Hsieh, Y. C. et al. Aliskiren reduces portal pressure and intrahepatic resistance in biliary cirrhotic rats. J Chin Med Assoc 75, 501\u2013508 (2012).","journal-title":"J Chin Med Assoc"},{"key":"48024_CR21","doi-asserted-by":"publisher","first-page":"526","DOI":"10.1111\/j.1365-2362.2011.02611.x","volume":"42","author":"CC Chang","year":"2012","unstructured":"Chang, C. C. et al. Aliskiren reduces portal pressure in portal hypertensive rats. European journal of clinical investigation 42, 526\u2013533 (2012).","journal-title":"European journal of clinical investigation"},{"key":"48024_CR22","doi-asserted-by":"publisher","first-page":"1261","DOI":"10.1111\/j.1365-2362.2012.02725.x","volume":"42","author":"KC Lee","year":"2012","unstructured":"Lee, K. C. et al. Aliskiren attenuates chronic carbon tetrachloride-induced liver injury in mice. European journal of clinical investigation 42, 1261\u20131271 (2012).","journal-title":"European journal of clinical investigation"},{"key":"48024_CR23","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1053\/gast.2001.26295","volume":"121","author":"M Schepke","year":"2001","unstructured":"Schepke, M. et al. Hemodynamic effects of the angiotensin II receptor antagonist irbesartan in patients with cirrhosis and portal hypertension. Gastroenterology 121, 389\u2013395 (2001).","journal-title":"Gastroenterology"},{"key":"48024_CR24","doi-asserted-by":"publisher","first-page":"1152","DOI":"10.1111\/j.1572-0241.2007.01759.x","volume":"103","author":"M Schepke","year":"2008","unstructured":"Schepke, M. et al. Irbesartan plus low-dose propranolol versus low-dose propranolol alone in cirrhosis: a placebo-controlled, double-blind study. The American journal of gastroenterology 103, 1152\u20131158 (2008).","journal-title":"The American journal of gastroenterology"},{"key":"48024_CR25","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/S0168-8278(97)80427-8","volume":"26","author":"G Fernandez-Esparrach","year":"1997","unstructured":"Fernandez-Esparrach, G. et al. Diuretic requirements after therapeutic paracentesis in non-azotemic patients with cirrhosis. A randomized double-blind trial of spironolactone versus placebo. Journal of hepatology 26, 614\u2013620 (1997).","journal-title":"Journal of hepatology"},{"key":"48024_CR26","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1007\/BF01477293","volume":"56","author":"H Wernze","year":"1978","unstructured":"Wernze, H., Spech, H. J. & Muller, G. Studies on the activity of the renin-angiotensin-aldosterone system (RAAS) in patients with cirrhosis of the liver. Klinische Wochenschrift 56, 389\u2013397 (1978).","journal-title":"Klinische Wochenschrift"},{"key":"48024_CR27","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1111\/liv.12611","volume":"35","author":"GB Goh","year":"2015","unstructured":"Goh, G. B. et al. Renin-angiotensin system and fibrosis in non-alcoholic fatty liver disease. Liver international: official journal of the International Association for the Study of the Liver 35, 979\u2013985 (2015).","journal-title":"Liver international: official journal of the International Association for the Study of the Liver"},{"key":"48024_CR28","doi-asserted-by":"publisher","first-page":"e0163069","DOI":"10.1371\/journal.pone.0163069","volume":"11","author":"S Pelusi","year":"2016","unstructured":"Pelusi, S. et al. Renin-Angiotensin System Inhibitors, Type 2 Diabetes and Fibrosis Progression: An Observational Study in Patients with Nonalcoholic Fatty Liver Disease. PloS one 11, e0163069 (2016).","journal-title":"PloS one"},{"key":"48024_CR29","doi-asserted-by":"publisher","first-page":"e32785","DOI":"10.1371\/journal.pone.0032785","volume":"7","author":"M Pasarin","year":"2012","unstructured":"Pasarin, M. et al. Sinusoidal endothelial dysfunction precedes inflammation and fibrosis in a model of NAFLD. PloS one 7, e32785 (2012).","journal-title":"PloS one"},{"key":"48024_CR30","doi-asserted-by":"publisher","first-page":"1428","DOI":"10.1038\/labinvest.2012.103","volume":"92","author":"S Francque","year":"2012","unstructured":"Francque, S. et al. Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture. Laboratory investigation; a journal of technical methods and pathology 92, 1428\u20131439 (2012).","journal-title":"Laboratory investigation; a journal of technical methods and pathology"},{"issue":"10","key":"48024_CR31","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1038\/s41374-017-0018-z","volume":"98","author":"Denise Van der Graaff","year":"2018","unstructured":"Van der Graaff, D. et al. Severe steatosis induces portal hypertension by systemic arterial hyporeactivity and hepatic vasoconstrictor hyperreactivity in rats. Laboratory investigation; a journal of technical methods and pathology, https:\/\/doi.org\/10.1038\/s41374-017-0018-z (2018).","journal-title":"Laboratory Investigation"},{"key":"48024_CR32","doi-asserted-by":"publisher","first-page":"743","DOI":"10.1016\/j.jhep.2015.05.022","volume":"63","author":"R de Franchis","year":"2015","unstructured":"de Franchis, R. & Faculty, B. V. Expanding consensus in portal hypertension: Report of the Baveno VI Consensus Workshop: Stratifying risk and individualizing care for portal hypertension. Journal of hepatology 63, 743\u2013752 (2015).","journal-title":"Journal of hepatology"},{"issue":"4","key":"48024_CR33","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.dld.2014.12.017","volume":"47","author":"Dong Wang","year":"2015","unstructured":"Wang, D. et al. Inhibition of Janus kinase-2 signalling pathway ameliorates portal hypertensive syndrome in partial portal hypertensive and liver cirrhosis rats. Digestive and liver disease: official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver, https:\/\/doi.org\/10.1016\/j.dld.2014.12.017 (2015).","journal-title":"Digestive and Liver Disease"},{"key":"48024_CR34","doi-asserted-by":"publisher","first-page":"91","DOI":"10.1007\/978-1-4939-7113-8_7","volume":"1627","author":"S Klein","year":"2017","unstructured":"Klein, S., Schierwagen, R., Uschner, F. E. & Trebicka, J. Mouse and Rat Models of Induction of Hepatic Fibrosis and Assessment of Portal Hypertension. Methods Mol Biol 1627, 91\u2013116 (2017).","journal-title":"Methods Mol Biol"},{"key":"48024_CR35","doi-asserted-by":"publisher","first-page":"702","DOI":"10.1016\/j.jhep.2010.04.025","volume":"53","author":"J Trebicka","year":"2010","unstructured":"Trebicka, J. et al. Atorvastatin attenuates hepatic fibrosis in rats after bile duct ligation via decreased turnover of hepatic stellate cells. Journal of hepatology 53, 702\u2013712 (2010).","journal-title":"Journal of hepatology"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-48024-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-48024-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-48024-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T12:27:02Z","timestamp":1671280022000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-48024-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,8,12]]},"references-count":35,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["48024"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-48024-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2019,8,12]]},"assertion":[{"value":"5 October 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 July 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 August 2019","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"This study was supported by grants from the Deutsche Forschungsgemeinschaft (SFB TRR57 P18), Cellex Foundation (PREDICT), European Union\u2019s Horizon 2020 Research and Innovation Programme (No. 668031) and Societal Challenges - Health, Demographic Change and Wellbeing (No. 731875). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"11598"}}