{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T13:11:30Z","timestamp":1790946690567,"version":"4.1.0"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T00:00:00Z","timestamp":1606953600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T00:00:00Z","timestamp":1606953600000},"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>Osteogenesis imperfecta (OI) type V is an autosomal dominant disorder caused by the c.-14C\u2009&gt;\u2009T mutation in the interferon-induced transmembrane protein 5 gene (<jats:italic>IFITM5<\/jats:italic>), however, its onset mechanism remains unclear. In this study, heterozygous c.-14C\u2009&gt;\u2009T mutant mice were developed to investigate the effect of immunosuppressants (FK506 and rapamycin) on OI type V. Among the mosaic mice generated by Crispr\/Cas9-based technology, mice with less than 40% mosaic ratio of c.-14C\u2009&gt;\u2009T mutation survived, whereas those with more than 48% mosaic ratio exhibited lethal skeletal abnormalities with one exception. All heterozygous mutants obtained by mating mosaic mice with wild-type mice exhibited a perinatal lethal phenotype due to severe skeletal abnormalities. Administration of FK506, a calcineurin inhibitor, in the heterozygous fetuses improved bone mineral content (BMC) of the neonates, although it did not save the neonates from the lethal effects of the mutation, whereas rapamycin, an mTOR inhibitor, reduced BMC, suggesting that mTOR signaling is involved in the bone mineralization of heterozygous mutants. These findings could clarify certain aspects of the onset mechanism of OI type V and enable development of therapeutics for this condition.<\/jats:p>","DOI":"10.1038\/s41598-020-78403-1","type":"journal-article","created":{"date-parts":[[2020,12,3]],"date-time":"2020-12-03T11:02:35Z","timestamp":1606993355000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Effect of immunosuppressants on a mouse model of osteogenesis imperfecta type V harboring a heterozygous Ifitm5 c.-14C\u2009&gt;\u2009T mutation"],"prefix":"10.1038","volume":"10","author":[{"given":"Nobutaka","family":"Hanagata","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Taro","family":"Takemura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Keiko","family":"Kamimura","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshiaki","family":"Koda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,12,3]]},"reference":[{"key":"78403_CR1","doi-asserted-by":"publisher","first-page":"2004","DOI":"10.1002\/jbmr.2243","volume":"29","author":"A Patoine","year":"2014","unstructured":"Patoine, A. et al. Topological mapping of BRIL reveals a type II orientation and effects of osteogenesis imperfect mutations on its cellular destination. J. Bone Miner. Res. 29, 2004\u20132016 (2014).","journal-title":"J. Bone Miner. Res."},{"key":"78403_CR2","doi-asserted-by":"publisher","first-page":"1497","DOI":"10.1359\/jbmr.080412","volume":"23","author":"P Moffatt","year":"2008","unstructured":"Moffatt, P. et al. Bril: A novel bone-specific modulator of mineralization. J. Bone Miner. Res. 23, 1497\u20131508 (2008).","journal-title":"J. Bone Miner. Res."},{"key":"78403_CR3","doi-asserted-by":"publisher","first-page":"279","DOI":"10.1007\/s00774-010-0221-0","volume":"29","author":"N Hanagata","year":"2011","unstructured":"Hanagata, N. et al. Characterization of the osteoblast-specific transmembrane protein IFITM5 and analysis of IFITM5-deficient mice. J. Bone Miner. Metab. 29, 279\u2013290 (2011).","journal-title":"J. Bone Miner. Metab."},{"key":"78403_CR4","doi-asserted-by":"publisher","first-page":"e0184568","DOI":"10.1371\/journal.pone.0184568","volume":"12","author":"A Patoine","year":"2017","unstructured":"Patoine, A., Husseini, A., Kasaai, B., Gaumond, M.-H. & Moffatt, P. The osteogenic cell surface marker BRIL\/IFITM5 is dispensable for bone development and homeostasis in mice. PLoS ONE 12, e0184568 (2017).","journal-title":"PLoS ONE"},{"key":"78403_CR5","doi-asserted-by":"publisher","first-page":"343","DOI":"10.1016\/j.ajhg.2012.06.005","volume":"91","author":"TJ Cho","year":"2012","unstructured":"Cho, T. J. et al. A single recurrent mutation in the 5\u2019-UTR of IFITM5 causes osteogenesis imperfecta type V. Am. J. Hum. Genet. 91, 343\u2013348 (2012).","journal-title":"Am. J. Hum. Genet."},{"key":"78403_CR6","doi-asserted-by":"publisher","first-page":"349","DOI":"10.1016\/j.ajhg.2012.06.011","volume":"91","author":"O Semler","year":"2012","unstructured":"Semler, O. et al. A mutation in the 5\u2019-UTR of IFITM5 creates an in-frame start codon and causes autosomal-dominant osteogenesis imperfecta type V with hyperplastic callus. Am. J. Hum. Genet. 91, 349\u2013357 (2012).","journal-title":"Am. J. Hum. Genet."},{"key":"78403_CR7","doi-asserted-by":"publisher","first-page":"1387","DOI":"10.1002\/jbmr.2156","volume":"29","author":"H Koyer-Kuhn","year":"2014","unstructured":"Koyer-Kuhn, H. et al. A nonclassical IFITM5 mutation located in the coding region causes severe osteogenesis imperfect with prenatal onset. J. Bone Miner. Res. 29, 1387\u20131391 (2014).","journal-title":"J. Bone Miner. Res."},{"key":"78403_CR8","doi-asserted-by":"crossref","unstructured":"Rauch, F. et al. Osteogenesis imperfecta type V: Marker phenotypic variability despite the presence of the IFITM5 c.-14C>T mutation in all patients. J. Med. Genet. 50, 21\u201324 (2013)","DOI":"10.1136\/jmedgenet-2012-101307"},{"key":"78403_CR9","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1002\/jbmr.1891","volume":"28","author":"JR Shapiro","year":"2013","unstructured":"Shapiro, J. R. et al. Phenotypic variability of osteogenesis imperfecta type V caused by an IFITM5 mutation. J. Bone Miner. Res. 28, 1523\u20131530 (2013).","journal-title":"J. Bone Miner. Res."},{"key":"78403_CR10","first-page":"37","volume":"1","author":"J Fitzgerald","year":"2013","unstructured":"Fitzgerald, J. et al. Phenotypic variability in individuals with type V osteogenesis imperfecta with identical IFITM5 mutations. J. Rare Disord. 1, 37\u201342 (2013).","journal-title":"J. Rare Disord."},{"key":"78403_CR11","doi-asserted-by":"publisher","first-page":"1523","DOI":"10.1002\/jbmr.1891","volume":"28","author":"PM Campeau","year":"2013","unstructured":"Campeau, P. M. & Lee, B. H. Phenotypic variability of osteogenesis imperfect type V caused by an IFITM5 mutation. J. Bone Miner. Res. 28, 1523\u20131530 (2013).","journal-title":"J. Bone Miner. Res."},{"key":"78403_CR12","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1097\/MCD.0b013e32836032f0","volume":"22","author":"M Balasubramanian","year":"2013","unstructured":"Balasubramanian, M. et al. Genotype-phenotype study in type V osteogenesis imperfecta. Clin. Dysmorphol. 22, 93\u2013101 (2013).","journal-title":"Clin. Dysmorphol."},{"key":"78403_CR13","doi-asserted-by":"publisher","first-page":"1980","DOI":"10.1002\/ajmg.a.36025","volume":"161A","author":"M Takagi","year":"2013","unstructured":"Takagi, M. et al. A recurrent mutation in the 5\u2032-UTR of IFITM5 causes osteogenesis imperfecta type V. Am. J. Med. Genet. A 161A, 1980\u20131982 (2013).","journal-title":"Am. J. Med. Genet. A"},{"key":"78403_CR14","doi-asserted-by":"publisher","first-page":"e72337","DOI":"10.1371\/journal.pone.0072337","volume":"8","author":"Z Zhang","year":"2013","unstructured":"Zhang, Z. et al. Phenotype and genotype analysis of Chinese patients with osteogenesis imperfect type V. PLoS ONE 8, e72337 (2013).","journal-title":"PLoS ONE"},{"key":"78403_CR15","doi-asserted-by":"publisher","first-page":"2333","DOI":"10.1002\/jbmr.1983","volume":"28","author":"M Grover","year":"2013","unstructured":"Grover, M. et al. Osteogenesis imperfecta type without features of type V caused by a mutation in the IFITM5 gene. J. Bone Miner. Res. 28, 2333\u20132337 (2013).","journal-title":"J. Bone Miner. Res."},{"key":"78403_CR16","doi-asserted-by":"publisher","first-page":"1972","DOI":"10.1002\/ajmg.a.36024","volume":"161A","author":"OH Kim","year":"2013","unstructured":"Kim, O. H. et al. Osteogenesis imperfecta type V: Clinical and radiographic manifestations in mutation confirmed patients. Am. J. Med. Genet. A. 161A, 1972\u20131979 (2013).","journal-title":"Am. J. Med. Genet. A."},{"key":"78403_CR17","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.trsl.2016.11.005","volume":"181","author":"H Kang","year":"2017","unstructured":"Kang, H., Aryal, A. C. S. & Marini, J. C. Osteogenesis imperfecta: New genes reveal novel mechanisms in bone dysplasia. Transl. Res. 181, 27\u201348 (2017).","journal-title":"Transl. Res."},{"key":"78403_CR18","doi-asserted-by":"publisher","first-page":"1650","DOI":"10.1359\/jbmr.2000.15.9.1650","volume":"15","author":"FH Glorieux","year":"2000","unstructured":"Glorieux, F. H. et al. Type V osteogenesis imperfecta: A new form of brittle bone disease. J. Bone Miner. Res. 15, 1650\u20131658 (2000).","journal-title":"J. Bone Miner. Res."},{"key":"78403_CR19","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1016\/j.bone.2005.07.020","volume":"38","author":"L Zeitlin","year":"2006","unstructured":"Zeitlin, L., Rauch, F., Travers, R., Munns, C. & Glorieux, F. H. The effect of cyclical intravenous pamidronate in children and adolescents with osteogenesis imperfecta type V. Bone 38, 13\u201320 (2006).","journal-title":"Bone"},{"key":"78403_CR20","doi-asserted-by":"publisher","first-page":"1181","DOI":"10.1359\/jbmr.070418","volume":"22","author":"MS Cheung","year":"2007","unstructured":"Cheung, M. S., Glorieux, F. H. & Rauch, F. Natural history of hyperplastic callus formation in osteogenesis imperfecta type V. J. Bone Miner. Res. 22, 1181\u20131186 (2007).","journal-title":"J. Bone Miner. Res."},{"key":"78403_CR21","doi-asserted-by":"publisher","first-page":"1136","DOI":"10.1002\/ajmg.a.36409","volume":"164A","author":"E Guillen-Navarro","year":"2014","unstructured":"Guillen-Navarro, E. et al. Two mutations in IFITM5 causing distinct form of osteogenesis imperfecta. Am. J. Med. Genet. A 164A, 1136\u20131142 (2014).","journal-title":"Am. J. Med. Genet. A"},{"key":"78403_CR22","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.bbrc.2011.04.136","volume":"409","author":"N Hanagata","year":"2011","unstructured":"Hanagata, N. & Li, X. Osteoblast-enriched membrane protein IFITM5 regulates the association of CD9 with an FKBP11-CD81-FPRP complex and stimulates expression of interferon-induced genes. Biochem. Biophys. Res. Commun. 409, 378\u2013384 (2011).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"78403_CR23","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1007\/s00335-005-0127-7","volume":"17","author":"SL Rulten","year":"2006","unstructured":"Rulten, S. L. et al. The human FK506-binding proteins: Characterization of human FKBP19. Mamm. Genome 17, 322\u2013331 (2006).","journal-title":"Mamm. Genome"},{"key":"78403_CR24","doi-asserted-by":"publisher","first-page":"131","DOI":"10.1016\/j.bone.2017.11.013","volume":"107","author":"F Rauch","year":"2018","unstructured":"Rauch, F. et al. Crispr-Cas9 engineered osteogenesis imperfecta type V leads to severe skeletal deformities and perinatal lethality in mice. Bone 107, 131\u2013142 (2018).","journal-title":"Bone"},{"key":"78403_CR25","first-page":"1002","volume":"7","author":"JD Powell","year":"2006","unstructured":"Powell, J. D. & Zheng, Y. Dissecting the mechanism of T-cell anergy with immunophilin ligands. Curr. Opin. Investig. Drugs 7, 1002\u20131007 (2006).","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"78403_CR26","doi-asserted-by":"publisher","first-page":"428","DOI":"10.1093\/embo-reports\/kvd090","volume":"1","author":"S Matsuda","year":"2000","unstructured":"Matsuda, S. et al. Two distinct action mechanisms of immunophilin-ligand complexes for the blockade of T-cell activation. EMBO Rep. 1, 428\u2013434 (2000).","journal-title":"EMBO Rep."},{"key":"78403_CR27","doi-asserted-by":"publisher","first-page":"9575","DOI":"10.1073\/pnas.161299698","volume":"98","author":"MP Santini","year":"2001","unstructured":"Santini, M. P., Talora, C., Seki, T., Bolgan, L. & Dotto, G. P. Cross talk among calcineurin, Sp1\/Sp3, and NFAT in control of p21WAF1\/CIP1 expression in keratinocyte differentiation. Proc. Natl. Acad. Sci. U.S.A. 98, 9575\u20139580 (2001).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"78403_CR28","doi-asserted-by":"publisher","first-page":"880","DOI":"10.1038\/nm1270","volume":"11","author":"T Koga","year":"2005","unstructured":"Koga, T. et al. NFAT and Osterix cooperatively regulate bone formation. Nat. Med. 11, 880\u2013885 (2005).","journal-title":"Nat. Med."},{"key":"78403_CR29","doi-asserted-by":"publisher","first-page":"13278","DOI":"10.1074\/jbc.M113.457010","volume":"288","author":"B Kasaai","year":"2013","unstructured":"Kasaai, B., Gaumond, M. H. & Moffatt, P. Regulation of the bone-restricted IFITM5-like (Bril) gene transcription by Sp and Gli family members and CpG methylation. J. Biol. Chem. 288, 13278\u201313294 (2013).","journal-title":"J. Biol. Chem."},{"key":"78403_CR30","doi-asserted-by":"publisher","first-page":"3600","DOI":"10.1172\/JCI65592","volume":"123","author":"E Spiekerkoetter","year":"2013","unstructured":"Spiekerkoetter, E. et al. FK506 activates BMPR2, rescues endothelial dysfunction, and reverses pulmonary hypertension. J. Clin. Invest. 123, 3600\u20133613 (2013).","journal-title":"J. Clin. Invest."},{"key":"78403_CR31","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1016\/j.mce.2009.08.012","volume":"314","author":"JF Zhang","year":"2010","unstructured":"Zhang, J. F. et al. Flavonoids of Herba Epimedii regulate osteogenesis of human mesenchymal stem cells through BMP and Wnt\/\u03b2-catenin signaling pathway. Mol. Cellul. Endocrinol. 314, 70\u201374 (2010).","journal-title":"Mol. Cellul. Endocrinol."},{"key":"78403_CR32","doi-asserted-by":"publisher","first-page":"2511","DOI":"10.1002\/jbmr.477","volume":"26","author":"M Okamoto","year":"2011","unstructured":"Okamoto, M. et al. Conditional deletion of Bmpr1a in differentiated osteoclasts increases osteoblastic bone formation, increasing volume of remodeling bone in mice. J. Bone Miner. Res. 26, 2511\u20132522 (2011).","journal-title":"J. Bone Miner. Res."},{"key":"78403_CR33","doi-asserted-by":"publisher","first-page":"27560","DOI":"10.1074\/jbc.M404222200","volume":"279","author":"Y Mishina","year":"2004","unstructured":"Mishina, Y. et al. Bone morphogenetic protein type IA receptor signaling regulates postnatal osteoblast function and bone remodeling. J. Biol. Chem. 279, 27560\u201327566 (2004).","journal-title":"J. Biol. Chem."},{"key":"78403_CR34","doi-asserted-by":"publisher","first-page":"836","DOI":"10.1038\/nature02041","volume":"425","author":"J Zhang","year":"2003","unstructured":"Zhang, J. et al. Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425, 836\u2013841 (2003).","journal-title":"Nature"},{"key":"78403_CR35","doi-asserted-by":"publisher","first-page":"2007","DOI":"10.1359\/jbmr.080809","volume":"23","author":"N Kamiya","year":"2008","unstructured":"Kamiya, N. et al. Disruption of BMP signaling in osteoblasts through type IA receptor (BMPRIA) increases bone mass. J. Bone Miner. Res. 23, 2007\u20132017 (2008).","journal-title":"J. Bone Miner. Res."},{"key":"78403_CR36","doi-asserted-by":"publisher","first-page":"3801","DOI":"10.1242\/dev.025825","volume":"135","author":"N Kamiya","year":"2008","unstructured":"Kamiya, N. et al. BMP signaling negatively regulates bone mass through sclerostin by inhibiting the canonical Wnt pathway. Development 135, 3801\u20133811 (2008).","journal-title":"Development"},{"key":"78403_CR37","doi-asserted-by":"publisher","first-page":"1227","DOI":"10.1016\/0092-8674(92)90643-Q","volume":"69","author":"J Chung","year":"1992","unstructured":"Chung, J., Kuo, C. J., Crabtree, G. R. & Blenis, J. Rapamycin-FKBP specifically blocks growth-dependent activation of and signaling by the 70 kd S6 protein kinases. Cell 69, 1227\u20131236 (1992).","journal-title":"Cell"},{"key":"78403_CR38","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/0092-8674(94)90570-3","volume":"78","author":"DM Sabatini","year":"1994","unstructured":"Sabatini, D. M., Erdjument-Bromage, H., Lui, M., Tempst, P. & Snyder, S. H. RAFT1: A mammalian protein that binds to FKBP12 in a rapamycin-dependent fashion and is homologous to yeast TORs. Cell 78, 35\u201343 (1994).","journal-title":"Cell"},{"key":"78403_CR39","doi-asserted-by":"publisher","first-page":"868","DOI":"10.1038\/nrd3531","volume":"10","author":"D Benjamin","year":"2011","unstructured":"Benjamin, D., Colombi, M., Moroni, C. & Hall, M. N. Rapamycin passes the torch: a new generation of mTOR inhibitors. Nat. Rev. Drug Discov. 10, 868\u2013880 (2011).","journal-title":"Nat. Rev. Drug Discov."},{"key":"78403_CR40","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1172\/JCI73937","volume":"125","author":"H Vakifahmetoglu-Norberg","year":"2015","unstructured":"Vakifahmetoglu-Norberg, H., Xia, H. G. & Yuan, J. Pharmacologic agents targeting autophagy. J Clin Invest. 125, 5\u201313 (2015).","journal-title":"J Clin Invest."},{"key":"78403_CR41","doi-asserted-by":"publisher","first-page":"3339","DOI":"10.1172\/JCI93521","volume":"127","author":"K Hino","year":"2017","unstructured":"Hino, K. et al. Activin-A enhances mTOR signaling to promote aberrant chondrogenesis in fibrodysplasia ossificans progressiva. J. Clin. Invest. 127, 3339\u20133352 (2017).","journal-title":"J. Clin. Invest."},{"key":"78403_CR42","doi-asserted-by":"publisher","first-page":"15438","DOI":"10.1073\/pnas.1510540112","volume":"112","author":"K Hino","year":"2015","unstructured":"Hino, K. et al. Neofunction of ACVR1 in fibrodysplasia ossificans progressiva. Proc. Natl. Acad. Sci. U.S.A. 112, 15438\u201315443 (2015).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."},{"key":"78403_CR43","doi-asserted-by":"crossref","unstructured":"Hatsell, S. J. et al. ACVR1R206H receptor mutation causes fibrodysplasia ossificans progressiva by imparting responsiveness to activin A. Sci. Transl. Med. 7, 303ra137 (2015)","DOI":"10.1126\/scitranslmed.aac4358"},{"key":"78403_CR44","doi-asserted-by":"crossref","unstructured":"Cheung, M. S, Glorieux, F. H. & Rauch, F. Natural history of hyperplastic callus formation in osteogenesis imperfecta type V. J. Bone Miner. Res. 22, 1181\u20131186 (2007)","DOI":"10.1359\/jbmr.070418"},{"key":"78403_CR45","doi-asserted-by":"publisher","first-page":"E10069","DOI":"10.1073\/pnas.1811892115","volume":"115","author":"G Shi","year":"2018","unstructured":"Shi, G., Ozog, S., Torbett, B. E. & Compton, A. A. mTOR inhibitors lower an intrinsic barrier to virus infection mediated by IFITM3. Proc. Natl. Acad. Sci. U.S.A. 115, E10069\u2013E10078 (2018).","journal-title":"Proc. Natl. Acad. Sci. U.S.A."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-78403-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-78403-1","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-78403-1.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,7]],"date-time":"2022-12-07T00:10:47Z","timestamp":1670371847000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-78403-1"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,12,3]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["78403"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-78403-1","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,12,3]]},"assertion":[{"value":"7 May 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"19 November 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 December 2020","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":"21197"}}