{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,21]],"date-time":"2026-09-21T09:05:41Z","timestamp":1789981541108,"version":"4.0.1"},"reference-count":43,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,11,17]],"date-time":"2017-11-17T00:00:00Z","timestamp":1510876800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,11,17]],"date-time":"2017-11-17T00:00:00Z","timestamp":1510876800000},"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>One of the major challenges of the current Zika virus (ZIKV) epidemic is to prevent congenital foetal abnormalities, including microcephaly, following ZIKV infection of pregnant women. Given the urgent need for ZIKV prophylaxis and treatment, repurposing of approved drugs appears to be a viable and immediate solution. We demonstrate that the common anti-malaria drug chloroquine (CQ) extends the lifespan of ZIKV-infected interferon signalling-deficient AG129 mice. However, the severity of ZIKV infection in these mice precludes the study of foetal (vertical) viral transmission. Here, we show that interferon signalling-competent SJL mice support chronic ZIKV infection. Infected dams and sires are both able to transmit ZIKV to the offspring, making this an ideal model for <jats:italic>in vivo<\/jats:italic> validation of compounds shown to suppress ZIKV in cell culture. Administration of CQ to ZIKV-infected pregnant SJL mice during mid-late gestation significantly attenuated vertical transmission, reducing the ZIKV load in the foetal brain more than 20-fold. Given the limited side effects of CQ, its lack of contraindications in pregnant women, and its worldwide availability and low cost, we suggest that CQ could be considered for the treatment and prophylaxis of ZIKV.<\/jats:p>","DOI":"10.1038\/s41598-017-15467-6","type":"journal-article","created":{"date-parts":[[2017,11,13]],"date-time":"2017-11-13T10:06:46Z","timestamp":1510567606000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":115,"title":["Repurposing of the anti-malaria drug chloroquine for Zika Virus treatment and prophylaxis"],"prefix":"10.1038","volume":"7","author":[{"given":"Sergey A.","family":"Shiryaev","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pinar","family":"Mesci","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonella","family":"Pinto","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Fernandes","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicholas","family":"Sheets","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sujan","family":"Shresta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen","family":"Farhy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chun-Teng","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex Y.","family":"Strongin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alysson R.","family":"Muotri","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexey V.","family":"Terskikh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,11,17]]},"reference":[{"key":"15467_CR1","doi-asserted-by":"publisher","first-page":"1885","DOI":"10.3201\/eid2110.150847","volume":"21","author":"GS Campos","year":"2015","unstructured":"Campos, G. S., Bandeira, A. C. & Sardi, S. I. Zika Virus Outbreak, Bahia, Brazil. Emerg Infect Dis \n                           21, 1885\u20131886, https:\/\/doi.org\/10.3201\/eid2110.150847 (2015).","journal-title":"Emerg Infect Dis"},{"key":"15467_CR2","doi-asserted-by":"publisher","DOI":"10.1186\/s12879-017-2394-9","volume":"17","author":"LA Castro","year":"2017","unstructured":"Castro, L. A. et al. Assessing real-time Zika risk in the United States. BMC Infect Dis \n                           17, 284, https:\/\/doi.org\/10.1186\/s12879-017-2394-9 (2017).","journal-title":"BMC Infect Dis"},{"key":"15467_CR3","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.jcv.2016.10.024","volume":"85","author":"RS Azevedo","year":"2016","unstructured":"Azevedo, R. S. et al. Zika virus epidemic in Brazil. I. Fatal disease in adults: Clinical and laboratorial aspects. J Clin Virol \n                           85, 56\u201364, https:\/\/doi.org\/10.1016\/j.jcv.2016.10.024 (2016).","journal-title":"J Clin Virol"},{"key":"15467_CR4","doi-asserted-by":"publisher","first-page":"267","DOI":"10.1038\/nature18296","volume":"534","author":"FR Cugola","year":"2016","unstructured":"Cugola, F. R. et al. The Brazilian Zika virus strain causes birth defects in experimental models. Nature \n                           534, 267\u2013271, https:\/\/doi.org\/10.1038\/nature18296 (2016).","journal-title":"Nature"},{"key":"15467_CR5","doi-asserted-by":"publisher","unstructured":"Li, C. et al. Zika Virus Disrupts Neural Progenitor Development and Leads to Microcephaly in Mice. Cell Stem Cell, https:\/\/doi.org\/10.1016\/j.stem.2016.04.017 (2016).","DOI":"10.1016\/j.stem.2016.04.017"},{"key":"15467_CR6","doi-asserted-by":"publisher","first-page":"951","DOI":"10.1056\/NEJMoa1600651","volume":"374","author":"J Mlakar","year":"2016","unstructured":"Mlakar, J. et al. Zika Virus Associated with Microcephaly. N Engl J Med \n                           374, 951\u2013958, https:\/\/doi.org\/10.1056\/NEJMoa1600651 (2016).","journal-title":"N Engl J Med"},{"key":"15467_CR7","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1001\/jamaneurol.2016.3720","volume":"73","author":"AS Melo","year":"2016","unstructured":"Melo, A. S. et al. Congenital Zika Virus Infection: Beyond Neonatal Microcephaly. JAMA Neurol \n                           73, 1407\u20131416, https:\/\/doi.org\/10.1001\/jamaneurol.2016.3720 (2016).","journal-title":"JAMA Neurol"},{"key":"15467_CR8","doi-asserted-by":"publisher","first-page":"219","DOI":"10.15585\/mmwr.mm6608a4","volume":"66","author":"JD Cragan","year":"2017","unstructured":"Cragan, J. D. et al. Baseline Prevalence of Birth Defects Associated with Congenital Zika Virus Infection - Massachusetts, North Carolina, and Atlanta, Georgia, 2013-2014. MMWR Morb Mortal Wkly Rep \n                           66, 219\u2013222, https:\/\/doi.org\/10.15585\/mmwr.mm6608a4 (2017).","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"15467_CR9","doi-asserted-by":"publisher","unstructured":"Beckham, J. D., Pastula, D. M., Massey, A. & Tyler, K. L. Zika Virus as an Emerging Global Pathogen: Neurological Complications of Zika Virus. JAMA Neurol, https:\/\/doi.org\/10.1001\/jamaneurol.2016.0800 (2016).","DOI":"10.1001\/jamaneurol.2016.0800"},{"key":"15467_CR10","doi-asserted-by":"publisher","first-page":"910","DOI":"10.15585\/mmwr.mm6534e1","volume":"65","author":"E Dirlikov","year":"2016","unstructured":"Dirlikov, E. et al. Guillain-Barr\u00e9 Syndrome During Ongoing Zika Virus Transmission - Puerto Rico, January 1-July 31, 2016. MMWR Morb Mortal Wkly Rep \n                           65, 910\u2013914, https:\/\/doi.org\/10.15585\/mmwr.mm6534e1 (2016).","journal-title":"MMWR Morb Mortal Wkly Rep"},{"key":"15467_CR11","first-page":"1466","volume-title":"Br Med J (Clin ResEd)","author":"MS Wolfe","year":"1985","unstructured":"Wolfe, M. S. & Cordero, J. F. Safety of chloroquine in chemosuppression of malaria during pregnancy. Br Med J (Clin ResEd) 290, (1466\u20131467 (1985)."},{"key":"15467_CR12","doi-asserted-by":"publisher","unstructured":"Delvecchio, R. et al. Chloroquine, an Endocytosis Blocking Agent, Inhibits Zika Virus Infection in Different Cell Models. Viruses \n                           8, https:\/\/doi.org\/10.3390\/v8120322 (2016).","DOI":"10.3390\/v8120322"},{"key":"15467_CR13","doi-asserted-by":"publisher","unstructured":"Cao, B., Parnell, L. A., Diamond, M. S. & Mysorekar, I. U. Inhibition of autophagy limits vertical transmission of Zika virus in pregnant mice. J Exp Med, https:\/\/doi.org\/10.1084\/jem.20170957 (2017).","DOI":"10.1084\/jem.20170957"},{"key":"15467_CR14","doi-asserted-by":"publisher","first-page":"218","DOI":"10.1016\/j.antiviral.2017.04.015","volume":"143","author":"SA Shiryaev","year":"2017","unstructured":"Shiryaev, S. A. et al. Characterization of the Zika virus two-component NS2B-NS3 protease and structure-assisted identification of allosteric small-molecule antagonists. Antiviral Res \n                           143, 218\u2013229, https:\/\/doi.org\/10.1016\/j.antiviral.2017.04.015 (2017).","journal-title":"Antiviral Res"},{"key":"15467_CR15","doi-asserted-by":"publisher","first-page":"587","DOI":"10.1016\/j.stem.2016.02.016","volume":"18","author":"H Tang","year":"2016","unstructured":"Tang, H. et al. Zika Virus Infects Human Cortical Neural Progenitors and Attenuates Their Growth. Cell Stem Cell \n                           18, 587\u2013590, https:\/\/doi.org\/10.1016\/j.stem.2016.02.016 (2016).","journal-title":"Cell Stem Cell"},{"key":"15467_CR16","doi-asserted-by":"publisher","unstructured":"Morrison, T. E. & Diamond, M. S. Animal Models of Zika Virus Infection, Pathogenesis, and Immunity. J Virol \n                           91, https:\/\/doi.org\/10.1128\/JVI.00009-17 (2017).","DOI":"10.1128\/JVI.00009-17"},{"key":"15467_CR17","doi-asserted-by":"publisher","first-page":"1362","DOI":"10.4269\/ajtmh.16-0111","volume":"94","author":"SL Rossi","year":"2016","unstructured":"Rossi, S. L. et al. Characterization of a Novel Murine Model to Study Zika Virus. Am J Trop Med Hyg \n                           94, 1362\u20131369, https:\/\/doi.org\/10.4269\/ajtmh.16-0111 (2016).","journal-title":"Am J Trop Med Hyg"},{"key":"15467_CR18","doi-asserted-by":"publisher","first-page":"438","DOI":"10.1038\/nature20556","volume":"540","author":"J Govero","year":"2016","unstructured":"Govero, J. et al. Zika virus infection damages the testes in mice. Nature \n                           540, 438\u2013442, https:\/\/doi.org\/10.1038\/nature20556 (2016).","journal-title":"Nature"},{"key":"15467_CR19","doi-asserted-by":"publisher","unstructured":"Paz-Bailey, G. et al. Persistence of Zika Virus in Body Fluids - Preliminary Report. N Engl J Med, https:\/\/doi.org\/10.1056\/NEJMoa1613108 (2017).","DOI":"10.1056\/NEJMoa1613108"},{"key":"15467_CR20","doi-asserted-by":"publisher","unstructured":"Frank, C. et al. Sexual transmission of Zika virus in Germany, April 2016. Euro surveillance: bulletin Europ\u00e9en sur les maladies transmissibles\u2009=\u2009European communicable disease bulletin \n                           21, https:\/\/doi.org\/10.2807\/1560-7917.ES.2016.21.23.30252 (2016).","DOI":"10.2807\/1560-7917.ES.2016.21.23.30252"},{"key":"15467_CR21","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1016\/j.cmi.2016.12.027","volume":"23","author":"J Moreira","year":"2017","unstructured":"Moreira, J., Peixoto, T. M., Siqueira, A. M. & Lamas, C. C. Sexually acquired Zika virus: a systematic review. Clin Microbiol Infect \n                           23, 296\u2013305, https:\/\/doi.org\/10.1016\/j.cmi.2016.12.027 (2017).","journal-title":"Clin Microbiol Infect"},{"key":"15467_CR22","doi-asserted-by":"publisher","unstructured":"Cao, B., Diamond, M. S. & Mysorekar, I. U. Maternal-Fetal Transmission of Zika Virus: Routes and Signals for Infection. J Interferon Cytokine Res, https:\/\/doi.org\/10.1089\/jir.2017.0011 (2017).","DOI":"10.1089\/jir.2017.0011"},{"key":"15467_CR23","first-page":"286","volume":"21","author":"TO Fakeye","year":"2002","unstructured":"Fakeye, T. O., Fehintola, F. A., Ademowo, O. G. & Walker, O. Therapeutic monitoring of chloroquine in pregnant women with malaria. West Afr J Med \n                           21, 286\u2013287 (2002).","journal-title":"West Afr J Med"},{"key":"15467_CR24","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1007\/s00228-008-0500-z","volume":"64","author":"SJ Lee","year":"2008","unstructured":"Lee, S. J. et al. Chloroquine pharmacokinetics in pregnant and nonpregnant women with vivax malaria. Eur J Clin Pharmacol \n                           64, 987\u2013992, https:\/\/doi.org\/10.1007\/s00228-008-0500-z (2008).","journal-title":"Eur J Clin Pharmacol"},{"key":"15467_CR25","doi-asserted-by":"publisher","DOI":"10.1186\/1475-2875-12-122","volume":"12","author":"RS Chandra","year":"2013","unstructured":"Chandra, R. S. et al. Creative solutions to extraordinary challenges in clinical trials: methodology of a phase III trial of azithromycin and chloroquine fixed-dose combination in pregnant women in Africa. Malar J \n                           12, 122, https:\/\/doi.org\/10.1186\/1475-2875-12-122 (2013).","journal-title":"Malar J"},{"key":"15467_CR26","doi-asserted-by":"publisher","unstructured":"Radeva-Petrova, D., Kayentao, K., ter Kuile, F. O., Sinclair, D. & Garner, P. Drugs for preventing malaria in pregnant women in endemic areas: any drug regimen versus placebo or no treatment. Cochrane Database Syst Rev, CD000169, https:\/\/doi.org\/10.1002\/14651858.CD000169.pub3 (2014).","DOI":"10.1002\/14651858.CD000169.pub3"},{"key":"15467_CR27","doi-asserted-by":"publisher","first-page":"674","DOI":"10.1111\/j.1365-2125.2008.03111.x","volume":"65","author":"I Law","year":"2008","unstructured":"Law, I. et al. Transfer of chloroquine and desethylchloroquine across the placenta and into milk in Melanesian mothers. Br J Clin Pharmacol \n                           65, 674\u2013679, https:\/\/doi.org\/10.1111\/j.1365-2125.2008.03111.x (2008).","journal-title":"Br J Clin Pharmacol"},{"key":"15467_CR28","doi-asserted-by":"publisher","first-page":"174","DOI":"10.1055\/s-2007-999371","volume":"8","author":"M Levy","year":"1991","unstructured":"Levy, M., Buskila, D., Gladman, D. D., Urowitz, M. B. & Koren, G. Pregnancy outcome following first trimester exposure to chloroquine. Am J Perinatol \n                           8, 174\u2013178, https:\/\/doi.org\/10.1055\/s-2007-999371 (1991).","journal-title":"Am J Perinatol"},{"key":"15467_CR29","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1097\/00007691-198907000-00001","volume":"11","author":"EO Titus","year":"1989","unstructured":"Titus, E. O. Recent developments in the understanding of the pharmacokinetics and mechanism of action of chloroquine. Ther Drug Monit \n                           11, 369\u2013379 (1989).","journal-title":"Ther Drug Monit"},{"key":"15467_CR30","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/0002-9343(83)91269-X","volume":"75","author":"AH Mackenzie","year":"1983","unstructured":"Mackenzie, A. H. Dose refinements in long-term therapy of rheumatoid arthritis with antimalarials. Am J Med \n                           75, 40\u201345 (1983).","journal-title":"Am J Med"},{"key":"15467_CR31","doi-asserted-by":"crossref","unstructured":"Browning, D. J. In Hydroxychloroquine and Chloroquine Retinopathy 35\u201363 (Springer, 2014).","DOI":"10.1007\/978-1-4939-0597-3_2"},{"key":"15467_CR32","doi-asserted-by":"publisher","first-page":"160","DOI":"10.3390\/v3020160","volume":"3","author":"JM Smit","year":"2011","unstructured":"Smit, J. M., Moesker, B., Rodenhuis-Zybert, I. & Wilschut, J. Flavivirus cell entry and membrane fusion. Viruses \n                           3, 160\u2013171, https:\/\/doi.org\/10.3390\/v3020160 (2011).","journal-title":"Viruses"},{"key":"15467_CR33","unstructured":"Maramorosch, K., Shatkin, A. J., Murphy, F. A., Chambers, T. J. & Monath, T. P. The flaviviruses: structure, replication and evolution. Vol. 59 (Academic Press, 2003)."},{"key":"15467_CR34","doi-asserted-by":"publisher","first-page":"33149","DOI":"10.1074\/jbc.M114.610428","volume":"289","author":"SC Hsieh","year":"2014","unstructured":"Hsieh, S. C. et al. Highly conserved residues in the helical domain of dengue virus type 1 precursor membrane protein are involved in assembly, precursor membrane (prM) protein cleavage, and entry. J Biol Chem \n                           289, 33149\u201333160, https:\/\/doi.org\/10.1074\/jbc.M114.610428 (2014).","journal-title":"J Biol Chem"},{"key":"15467_CR35","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1016\/j.chom.2016.07.004","volume":"20","author":"NJ Barrows","year":"2016","unstructured":"Barrows, N. J. et al. A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection. Cell Host Microbe \n                           20, 259\u2013270, https:\/\/doi.org\/10.1016\/j.chom.2016.07.004 (2016).","journal-title":"Cell Host Microbe"},{"key":"15467_CR36","doi-asserted-by":"publisher","first-page":"134","DOI":"10.1016\/j.antiviral.2016.11.023","volume":"137","author":"KM Bullard-Feibelman","year":"2017","unstructured":"Bullard-Feibelman, K. M. et al. The FDA-approved drug sofosbuvir inhibits Zika virus infection. Antiviral Res \n                           137, 134\u2013140, https:\/\/doi.org\/10.1016\/j.antiviral.2016.11.023 (2017).","journal-title":"Antiviral Res"},{"key":"15467_CR37","doi-asserted-by":"publisher","DOI":"10.1038\/srep40920","volume":"7","author":"CQ Sacramento","year":"2017","unstructured":"Sacramento, C. Q. et al. The clinically approved antiviral drug sofosbuvir inhibits Zika virus replication. Sci Rep \n                           7, 40920, https:\/\/doi.org\/10.1038\/srep40920 (2017).","journal-title":"Sci Rep"},{"key":"15467_CR38","doi-asserted-by":"publisher","first-page":"446","DOI":"10.1016\/j.immuni.2017.02.012","volume":"46","author":"C Li","year":"2017","unstructured":"Li, C. et al. 25-Hydroxycholesterol Protects Host against Zika Virus Infection and Its Associated Microcephaly in a Mouse Model. Immunity \n                           46, 446\u2013456, https:\/\/doi.org\/10.1016\/j.immuni.2017.02.012 (2017).","journal-title":"Immunity"},{"key":"15467_CR39","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1038\/nm.4184","volume":"22","author":"M Xu","year":"2016","unstructured":"Xu, M. et al. Identification of small-molecule inhibitors of Zika virus infection and induced neural cell death via a drug repurposing screen. Nat Med \n                           22, 1101\u20131107, https:\/\/doi.org\/10.1038\/nm.4184 (2016).","journal-title":"Nat Med"},{"key":"15467_CR40","doi-asserted-by":"publisher","first-page":"14408","DOI":"10.1073\/pnas.1618029113","volume":"113","author":"H Retallack","year":"2016","unstructured":"Retallack, H. et al. Zika virus cell tropism in the developing human brain and inhibition by azithromycin. Proc Natl Acad Sci USA \n                           113, 14408\u201314413, https:\/\/doi.org\/10.1073\/pnas.1618029113 (2016).","journal-title":"Proc Natl Acad Sci USA"},{"key":"15467_CR41","doi-asserted-by":"publisher","first-page":"e0004695","DOI":"10.1371\/journal.pntd.0004695","volume":"10","author":"J Zmurko","year":"2016","unstructured":"Zmurko, J. et al. The Viral Polymerase Inhibitor 7-Deaza-2\u2032-C-Methyladenosine Is a Potent Inhibitor of In Vitro Zika Virus Replication and Delays Disease Progression in a Robust Mouse Infection Model. PLoS Negl Trop Dis \n                           10, e0004695, https:\/\/doi.org\/10.1371\/journal.pntd.0004695 (2016).","journal-title":"PLoS Negl Trop Dis"},{"key":"15467_CR42","doi-asserted-by":"publisher","first-page":"29","DOI":"10.1016\/j.ijid.2016.12.011","volume":"55","author":"SE Reznik","year":"2017","unstructured":"Reznik, S. E. & Ashby, C. R. Jr. Sofosbuvir: an antiviral drug with potential efficacy against Zika infection. Int J Infect Dis \n                           55, 29\u201330, https:\/\/doi.org\/10.1016\/j.ijid.2016.12.011 (2017).","journal-title":"Int J Infect Dis"},{"key":"15467_CR43","doi-asserted-by":"publisher","first-page":"1232","DOI":"10.3201\/eid1408.080287","volume":"14","author":"RS Lanciotti","year":"2008","unstructured":"Lanciotti, R. S. et al. Genetic and serologic properties of Zika virus associated with an epidemic, Yap State, Micronesia, 2007. Emerg Infect Dis \n                           14, 1232\u20131239, https:\/\/doi.org\/10.3201\/eid1408.080287 (2008).","journal-title":"Emerg Infect Dis"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15467-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15467-6","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15467-6.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T13:43:12Z","timestamp":1671802992000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-15467-6"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,11,17]]},"references-count":43,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["15467"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-15467-6","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,11,17]]},"assertion":[{"value":"14 July 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 October 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"17 November 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no\u00a0competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"15771"}}