{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T12:13:21Z","timestamp":1788178401957,"version":"build-2803163510"},"reference-count":34,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T00:00:00Z","timestamp":1788134400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"National Science and Technology Council, R.O.C.","award":["NSTC 114-2314-B-038-059"],"award-info":[{"award-number":["NSTC 114-2314-B-038-059"]}]},{"DOI":"10.13039\/501100022600","name":"Wan Fang Hospital","doi-asserted-by":"publisher","award":["111-wf-f-8"],"award-info":[{"award-number":["111-wf-f-8"]}],"id":[{"id":"10.13039\/501100022600","id-type":"DOI","asserted-by":"publisher"}]},{"name":"the Foundation for the Development of Internal Medicine in Okinawa, Japan","award":["07-02-005 and 07-02-006"],"award-info":[{"award-number":["07-02-005 and 07-02-006"]}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Biomed Sci"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>Cardiac fibrosis is a pathological remodeling process that contributes to the development and progression of heart failure. Although glucose-dependent insulinotropic polypeptide (GIP) may exert antifibrotic effects, how GIP receptor activation regulates cardiac fibrogenesis and modulates cardiac function in heart failure remains unclear. This study investigated whether GIP receptor agonism suppresses cardiac fibroblast activity and improves heart failure and explored the underlying mechanisms by using cellular and animal models.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      Human cardiac fibroblasts were treated with [D-Ala\n                      <jats:sup>2<\/jats:sup>\n                      ]GIP (DA-GIP; 10, 100, or 300\u00a0nM) for 24\u00a0h or left untreated (control). Fibroblast migration, collagen production, and intracellular signaling were examined using wound healing, immunoblotting, enzyme-linked immunosorbent, and fluorometric assays. Cardiac structure, function, and fibrosis were assessed through echocardiography and Masson\u2019s trichrome staining in rats with isoproterenol-induced heart failure with and without DA-GIP (24\u00a0nM\/kg, twice daily for 2\u00a0weeks) administration.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Compared with control cells, DA-GIP (300\u00a0nM)-treated cardiac fibroblasts exhibited a significantly lower migratory activity and reduced expression levels of pro-collagen IA1, pro-collagen III, and transforming growth factor-\u03b21 proteins. Additionally, DA-GIP increased nitric oxide (NO) production and promoted endothelial NO synthase (eNOS) and protein kinase B (Akt) activation in cardiac fibroblasts. Notably, Akt inhibition blocked DA-GIP-induced eNOS activation, and treatment with\n                      <jats:italic>N<\/jats:italic>\n                      <jats:sup>\n                        <jats:italic>\u03c9<\/jats:italic>\n                      <\/jats:sup>\n                      -nitro-L-arginine methyl ester (a NO synthase inhibitor, 100\u00a0\u03bcM) attenuated the antifibrotic effect of DA-GIP. In heart failure rats, DA-GIP reduced myocardial fibrosis, chamber dilatation, and systolic dysfunction.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>DA-GIP suppresses cardiac fibroblast activity through Akt-dependent eNOS activation and subsequent NO production, thereby improving cardiac remodeling and function in experimental heart failure.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s12929-026-01288-1","type":"journal-article","created":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:13:14Z","timestamp":1788174794000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Glucose-dependent insulinotropic polypeptide receptor agonism improves heart failure with antifibrosis through Akt-dependent nitric oxide signaling"],"prefix":"10.1186","volume":"33","author":[{"given":"Ting-Wei","family":"Lee","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ting-I","family":"Lee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Satoshi","family":"Higa","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8687-5091","authenticated-orcid":false,"given":"Yu-Hsun","family":"Kao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yi-Jen","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,8,31]]},"reference":[{"issue":"4","key":"1288_CR1","doi-asserted-by":"publisher","first-page":"201","DOI":"10.1038\/s41574-022-00783-3","volume":"19","author":"R Hammoud","year":"2023","unstructured":"Hammoud R, Drucker DJ. Beyond the pancreas: contrasting cardiometabolic actions of GIP and GLP1. Nat Rev Endocrinol. 2023;19(4):201\u201316.","journal-title":"Nat Rev Endocrinol"},{"key":"1288_CR2","doi-asserted-by":"publisher","DOI":"10.1016\/j.molmet.2025.102118","volume":"95","author":"TD M\u00fcller","year":"2025","unstructured":"M\u00fcller TD, Adriaenssens A, Ahr\u00e9n B, Bl\u00fcher M, Birkenfeld AL, Campbell JE, et al. Glucose-dependent insulinotropic polypeptide (GIP). Mol Metab. 2025;95:102118.","journal-title":"Mol Metab"},{"issue":"4","key":"1288_CR3","doi-asserted-by":"publisher","first-page":"479","DOI":"10.1210\/endrev\/bnaf006","volume":"46","author":"MM Wolfe","year":"2025","unstructured":"Wolfe MM, Boylan MO, Chin WW. Glucose-dependent insulinotropic polypeptide in incretin physiology: role in health and disease. Endocr Rev. 2025;46(4):479\u2013500.","journal-title":"Endocr Rev"},{"issue":"1","key":"1288_CR4","doi-asserted-by":"publisher","first-page":"169","DOI":"10.1186\/s12933-022-01604-7","volume":"21","author":"MA Nauck","year":"2022","unstructured":"Nauck MA, D\u2019Alessio DA. Tirzepatide, a dual GIP\/GLP-1 receptor co-agonist for the treatment of type 2 diabetes with unmatched effectiveness regrading glycaemic control and body weight reduction. Cardiovasc Diabetol. 2022;21(1):169.","journal-title":"Cardiovasc Diabetol"},{"issue":"1","key":"1288_CR5","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1056\/NEJMoa2416394","volume":"393","author":"LJ Aronne","year":"2025","unstructured":"Aronne LJ, Horn DB, le Roux CW, Ho W, Falcon BL, Gomez Valderas E, et al. Tirzepatide as compared with semaglutide for the treatment of obesity. N Engl J Med. 2025;393(1):26\u201336.","journal-title":"N Engl J Med"},{"key":"1288_CR6","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2019.170228","volume":"125","author":"AA Greenwell","year":"2020","unstructured":"Greenwell AA, Chahade JJ, Ussher JR. Cardiovascular biology of the GIP receptor. Peptides. 2020;125:170228.","journal-title":"Peptides"},{"issue":"12","key":"1288_CR7","doi-asserted-by":"publisher","first-page":"2773","DOI":"10.1007\/s00125-021-05564-7","volume":"64","author":"V Karhunen","year":"2021","unstructured":"Karhunen V, Daghlas I, Zuber V, Vujkovic M, Olsen AK, Knudsen LB, et al. Leveraging human genetic data to investigate the cardiometabolic effects of glucose-dependent insulinotropic polypeptide signalling. Diabetologia. 2021;64(12):2773\u20138.","journal-title":"Diabetologia"},{"issue":"13","key":"1288_CR8","doi-asserted-by":"publisher","DOI":"10.1161\/JAHA.120.019477","volume":"10","author":"F Kahles","year":"2021","unstructured":"Kahles F, R\u00fcckbeil MV, Arrivas MC, Mertens RW, Moellmann J, Biener M, et al. Association of glucose-dependent insulinotropic polypeptide levels with cardiovascular mortality in patients with acute myocardial infarction. J Am Heart Assoc. 2021;10(13):e019477.","journal-title":"J Am Heart Assoc"},{"key":"1288_CR9","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.yjmcc.2015.12.016","volume":"91","author":"JK Lighthouse","year":"2016","unstructured":"Lighthouse JK, Small EM. Transcriptional control of cardiac fibroblast plasticity. J Mol Cell Cardiol. 2016;91:52\u201360.","journal-title":"J Mol Cell Cardiol"},{"issue":"6","key":"1288_CR10","doi-asserted-by":"publisher","first-page":"1021","DOI":"10.1161\/CIRCRESAHA.115.306565","volume":"118","author":"JG Travers","year":"2016","unstructured":"Travers JG, Kamal FA, Robbins J, Yutzey KE, Blaxall BC. Cardiac fibrosis: the fibroblast awakens. Circ Res. 2016;118(6):1021\u201340.","journal-title":"Circ Res"},{"key":"1288_CR11","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1016\/j.yjmcc.2015.11.029","volume":"93","author":"RS Nagalingam","year":"2016","unstructured":"Nagalingam RS, Safi HA, Czubryt MP. Gaining myocytes or losing fibroblasts: challenges in cardiac fibroblast reprogramming for infarct repair. J Mol Cell Cardiol. 2016;93:108\u201314.","journal-title":"J Mol Cell Cardiol"},{"issue":"9","key":"1288_CR12","doi-asserted-by":"publisher","first-page":"1988","DOI":"10.1253\/circj.CJ-16-0152","volume":"80","author":"M Hiromura","year":"2016","unstructured":"Hiromura M, Mori Y, Kohashi K, Terasaki M, Shinmura K, Negoro T, et al. Suppressive effects of glucose-dependent insulinotropic polypeptide on cardiac hypertrophy and fibrosis in angiotensin II-infused mouse models. Circ J. 2016;80(9):1988\u201397.","journal-title":"Circ J"},{"issue":"2","key":"1288_CR13","doi-asserted-by":"publisher","DOI":"10.1177\/1479164121999034","volume":"18","author":"M Hiromura","year":"2021","unstructured":"Hiromura M, Mori Y, Terasaki M, Kushima H, Saito T, Osaka N, et al. Glucose-dependent insulinotropic polypeptide inhibits cardiac hypertrophy and fibrosis in diabetic mice via suppression of TGF-\u03b22. Diab Vasc Dis Res. 2021;18(2):1479164121999034.","journal-title":"Diab Vasc Dis Res"},{"issue":"5","key":"1288_CR14","doi-asserted-by":"publisher","DOI":"10.1016\/j.jacadv.2025.101740","volume":"4","author":"SS Dani","year":"2025","unstructured":"Dani SS, Makwana B, Khadke S, Kumar A, Jhund P, Nasir K, et al. An observational study of cardiovascular outcomes of tirzepatide vs glucagon-like peptide-1 receptor agonists. JACC Adv. 2025;4(5):101740.","journal-title":"JACC Adv"},{"issue":"2","key":"1288_CR15","doi-asserted-by":"publisher","first-page":"450","DOI":"10.1016\/j.cmet.2017.11.003","volume":"27","author":"JR Ussher","year":"2018","unstructured":"Ussher JR, Campbell JE, Mulvihill EE, Baggio LL, Bates HE, McLean BA, et al. Inactivation of the glucose-dependent insulinotropic polypeptide receptor improves outcomes following experimental myocardial infarction. Cell Metab. 2018;27(2):450-60.e6.","journal-title":"Cell Metab"},{"key":"1288_CR16","doi-asserted-by":"publisher","DOI":"10.1016\/j.peptides.2019.170174","volume":"125","author":"SM Heimb\u00fcrger","year":"2020","unstructured":"Heimb\u00fcrger SM, Bergmann NC, Augustin R, Gasbjerg LS, Christensen MB, Knop FK. Glucose-dependent insulinotropic polypeptide (GIP) and cardiovascular disease. Peptides. 2020;125:170174.","journal-title":"Peptides"},{"issue":"3","key":"1288_CR17","doi-asserted-by":"publisher","first-page":"216","DOI":"10.1016\/j.pharmthera.2009.02.009","volume":"122","author":"EJ Tsai","year":"2009","unstructured":"Tsai EJ, Kass DA. Cyclic GMP signaling in cardiovascular pathophysiology and therapeutics. Pharmacol Ther. 2009;122(3):216\u201338.","journal-title":"Pharmacol Ther"},{"issue":"8","key":"1288_CR18","doi-asserted-by":"publisher","first-page":"1996","DOI":"10.1111\/bph.12959","volume":"172","author":"J Inserte","year":"2015","unstructured":"Inserte J, Garcia-Dorado D. The cGMP\/PKG pathway as a common mediator of cardioprotection: translatability and mechanism. Br J Pharmacol. 2015;172(8):1996\u20132009.","journal-title":"Br J Pharmacol"},{"issue":"2","key":"1288_CR19","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1161\/CIRCRESAHA.107.157677","volume":"102","author":"P Li","year":"2008","unstructured":"Li P, Wang D, Lucas J, Oparil S, Xing D, Cao X, et al. Atrial natriuretic peptide inhibits transforming growth factor beta-induced Smad signaling and myofibroblast transformation in mouse cardiac fibroblasts. Circ Res. 2008;102(2):185\u201392.","journal-title":"Circ Res"},{"issue":"6","key":"1288_CR20","doi-asserted-by":"publisher","first-page":"584","DOI":"10.1161\/CIRCULATIONAHA.110.971853","volume":"123","author":"J Chen","year":"2011","unstructured":"Chen J, Shearer GC, Chen Q, Healy CL, Beyer AJ, Nareddy VB, et al. Omega-3 fatty acids prevent pressure overload-induced cardiac fibrosis through activation of cyclic GMP\/protein kinase G signaling in cardiac fibroblasts. Circulation. 2011;123(6):584\u201393.","journal-title":"Circulation"},{"issue":"5","key":"1288_CR21","doi-asserted-by":"publisher","first-page":"2469","DOI":"10.1172\/JCI118305","volume":"96","author":"J Hou","year":"1995","unstructured":"Hou J, Kato H, Cohen RA, Chobanian AV, Brecher P. Angiotensin II-induced cardiac fibrosis in the rat is increased by chronic inhibition of nitric oxide synthase. J Clin Invest. 1995;96(5):2469\u201377.","journal-title":"J Clin Invest"},{"issue":"1","key":"1288_CR22","doi-asserted-by":"publisher","first-page":"46","DOI":"10.14336\/AD.2022.0523","volume":"14","author":"Z Cai","year":"2023","unstructured":"Cai Z, Wu C, Xu Y, Cai J, Zhao M, Zu L. The NO-cGMP-PKG axis in HFpEF: from pathological mechanisms to potential therapies. Aging Dis. 2023;14(1):46\u201362.","journal-title":"Aging Dis"},{"issue":"1","key":"1288_CR23","doi-asserted-by":"publisher","first-page":"474","DOI":"10.1016\/0006-291X(90)91417-Q","volume":"171","author":"UC Garg","year":"1990","unstructured":"Garg UC, Hassid A. Nitric oxide-generating vasodilators inhibit mitogenesis and proliferation of BALB\/C 3T3 fibroblasts by a cyclic GMP-independent mechanism. Biochem Biophys Res Commun. 1990;171(1):474\u20139.","journal-title":"Biochem Biophys Res Commun"},{"issue":"3","key":"1288_CR24","doi-asserted-by":"publisher","first-page":"652","DOI":"10.2337\/diabetes.51.3.652","volume":"51","author":"SA Hinke","year":"2002","unstructured":"Hinke SA, Gelling RW, Pederson RA, Manhart S, Nian C, Demuth HU, et al. Dipeptidyl peptidase IV-resistant [D-Ala(2)]glucose-dependent insulinotropic polypeptide (GIP) improves glucose tolerance in normal and obese diabetic rats. Diabetes. 2002;51(3):652\u201361.","journal-title":"Diabetes"},{"key":"1288_CR25","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejphar.2025.177858","volume":"1002","author":"TW Lee","year":"2025","unstructured":"Lee TW, Lee TI, Higa S, Kao YH, Chen YJ. Calcitriol deficiency reduces myocardial ATP production with disturbed mitochondrial dynamics and increased uncoupling protein 2 expression. Eur J Pharmacol. 2025;1002:177858.","journal-title":"Eur J Pharmacol"},{"key":"1288_CR26","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23010166","author":"TW Lee","year":"2021","unstructured":"Lee TW, Chung CC, Lee TI, Lin YK, Kao YH, Chen YJ. Fibroblast growth factor 23 stimulates cardiac fibroblast activity through phospholipase C-mediated calcium signaling. Int J Mol Sci. 2021. https:\/\/doi.org\/10.3390\/ijms23010166.","journal-title":"Int J Mol Sci"},{"issue":"1","key":"1288_CR27","doi-asserted-by":"publisher","DOI":"10.1186\/s12933-023-01756-0","volume":"22","author":"CC Chung","year":"2023","unstructured":"Chung CC, Lin YK, Chen YC, Kao YH, Yeh YH, Trang NN, et al. Empagliflozin suppressed cardiac fibrogenesis through sodium-hydrogen exchanger inhibition and modulation of the calcium homeostasis. Cardiovasc Diabetol. 2023;22(1):27.","journal-title":"Cardiovasc Diabetol"},{"issue":"4","key":"1288_CR28","doi-asserted-by":"publisher","first-page":"323","DOI":"10.1016\/j.trsl.2014.05.001","volume":"164","author":"M Cavalera","year":"2014","unstructured":"Cavalera M, Wang J, Frangogiannis NG. Obesity, metabolic dysfunction, and cardiac fibrosis: pathophysiological pathways, molecular mechanisms, and therapeutic opportunities. Transl Res. 2014;164(4):323\u201335.","journal-title":"Transl Res"},{"issue":"2","key":"1288_CR29","doi-asserted-by":"publisher","first-page":"437","DOI":"10.1073\/pnas.0408704102","volume":"102","author":"JS Swaney","year":"2005","unstructured":"Swaney JS, Roth DM, Olson ER, Naugle JE, Meszaros JG, Insel PA. Inhibition of cardiac myofibroblast formation and collagen synthesis by activation and overexpression of adenylyl cyclase. Proc Natl Acad Sci. 2005;102(2):437\u201342.","journal-title":"Proc Natl Acad Sci"},{"issue":"6","key":"1288_CR30","doi-asserted-by":"publisher","first-page":"787","DOI":"10.1124\/mol.113.087742","volume":"84","author":"D Lu","year":"2013","unstructured":"Lu D, Aroonsakool N, Yokoyama U, Patel HH, Insel PA. Increase in cellular cyclic AMP concentrations reverses the profibrogenic phenotype of cardiac myofibroblasts: a novel therapeutic approach for cardiac fibrosis. Mol Pharmacol. 2013;84(6):787\u201393.","journal-title":"Mol Pharmacol"},{"issue":"1","key":"1288_CR31","doi-asserted-by":"publisher","first-page":"191","DOI":"10.1007\/s11010-009-0219-x","volume":"333","author":"S Umar","year":"2010","unstructured":"Umar S, van der Laarse A. Nitric oxide and nitric oxide synthase isoforms in the normal, hypertrophic, and failing heart. Mol Cell Biochem. 2010;333(1):191\u2013201.","journal-title":"Mol Cell Biochem"},{"issue":"2","key":"1288_CR32","doi-asserted-by":"publisher","first-page":"211","DOI":"10.1093\/cvr\/cvt181","volume":"100","author":"A Kazakov","year":"2013","unstructured":"Kazakov A, Hall R, Jagoda P, Bachelier K, M\u00fcller-Best P, Semenov A, et al. Inhibition of endothelial nitric oxide synthase induces and enhances myocardial fibrosis. Cardiovasc Res. 2013;100(2):211\u201321.","journal-title":"Cardiovasc Res"},{"issue":"7","key":"1288_CR33","doi-asserted-by":"publisher","first-page":"2717","DOI":"10.1210\/en.2018-00336","volume":"159","author":"Y Mori","year":"2018","unstructured":"Mori Y, Kushima H, Koshibu M, Saito T, Hiromura M, Kohashi K, et al. Glucose-dependent insulinotropic polypeptide suppresses peripheral arterial remodeling in male mice. Endocrinology. 2018;159(7):2717\u201332.","journal-title":"Endocrinology"},{"issue":"6736","key":"1288_CR34","doi-asserted-by":"publisher","first-page":"597","DOI":"10.1038\/21218","volume":"399","author":"D Fulton","year":"1999","unstructured":"Fulton D, Gratton JP, McCabe TJ, Fontana J, Fujio Y, Walsh K, et al. Regulation of endothelium-derived nitric oxide production by the protein kinase Akt. Nature. 1999;399(6736):597\u2013601.","journal-title":"Nature"}],"container-title":["Journal of Biomedical Science"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12929-026-01288-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1186\/s12929-026-01288-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1186\/s12929-026-01288-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,31]],"date-time":"2026-08-31T11:13:17Z","timestamp":1788174797000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1186\/s12929-026-01288-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,31]]},"references-count":34,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,12]]}},"alternative-id":["1288"],"URL":"https:\/\/doi.org\/10.1186\/s12929-026-01288-1","relation":{},"ISSN":["1423-0127"],"issn-type":[{"value":"1423-0127","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,31]]},"assertion":[{"value":"10 March 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"31 August 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"All animal experiment protocols adhered to the guidelines issued by the Institutional Animal Care and Use Committee of Taipei Medical University and were approved by the local animal ethics review board\u00a0LAC2023-0458.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}],"article-number":"88"}}