{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,20]],"date-time":"2026-10-20T11:46:42Z","timestamp":1792496802183,"version":"4.5.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,6,5]],"date-time":"2018-06-05T00:00:00Z","timestamp":1528156800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,6,5]],"date-time":"2018-06-05T00:00:00Z","timestamp":1528156800000},"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>\n                  <jats:p>Hepatitis E is the most common type of acute hepatitis prevalent worldwide. The open reading frame 3 protein of HEV (HEV ORF3) is proposed to create a favorable environment for viral replication and pathogenesis. However, the mechanisms by which HEV overcomes the effects of host immunity, particularly the role of ORF3, remain to be established. Expression of IFN\u03b1 and IFN\u03b2 in supernatant and cell samples was examined via ELISA and quantitative RT-PCR. The protein levels of specific signaling factors in cells overexpressing HEV ORF3 were examined via western blot. Analyses of cells transfected with vectors expressing ORF3 demonstrated that HEV ORF3 significantly impairs the generation of endogenous type I interferon through downregulating TLR3 and TLR7 as well as their corresponding downstream signaling pathways. Moreover, inhibition of NF\u03baB, JAK\/STAT and JNK\/MAPK signaling pathways contributed significantly to suppression of increased levels of TLR7. Levels of p-P65, p-STAT1 and p-JNK were markedly impaired in ORF3-expressing cells, even upon treatment with the respective agonists. HEV ORF3 inhibits the production of endogenous type I interferon through downregulation of TLR3 and TLR7. Furthermore, suppression of TLR7 is achieved through impairment of multiple signaling pathways, including NF\u03baB, JAK\/STAT and JNK\/MAPK.<\/jats:p>","DOI":"10.1038\/s41598-018-26975-4","type":"journal-article","created":{"date-parts":[[2018,5,30]],"date-time":"2018-05-30T05:43:29Z","timestamp":1527659009000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":38,"title":["HEV ORF3 downregulates TLR7 to inhibit the generation of type I interferon via impairment of multiple signaling pathways"],"prefix":"10.1038","volume":"8","author":[{"given":"Qingsong","family":"Lei","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lin","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shujun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tianju","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaomei","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaolin","family":"Ding","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,6,5]]},"reference":[{"key":"26975_CR1","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.meegid.2014.01.002","volume":"22","author":"MT Perez-Gracia","year":"2014","unstructured":"Perez-Gracia, M. T., Suay, B. & Mateos-Lindemann, M. L. Hepatitis E: an emerging disease. Infect Genet Evol 22, 40\u201359, https:\/\/doi.org\/10.1016\/j.meegid.2014.01.002 (2014).","journal-title":"Infect Genet Evol"},{"key":"26975_CR2","doi-asserted-by":"publisher","first-page":"116","DOI":"10.1128\/CMR.00057-13","volume":"27","author":"N Kamar","year":"2014","unstructured":"Kamar, N., Dalton, H. R., Abravanel, F. & Izopet, J. Hepatitis E virus infection. Clin Microbiol Rev 27, 116\u2013138, https:\/\/doi.org\/10.1128\/CMR.00057-13 (2014).","journal-title":"Clin Microbiol Rev"},{"key":"26975_CR3","doi-asserted-by":"publisher","first-page":"213","DOI":"10.1016\/j.jceh.2013.08.009","volume":"3","author":"Shalimar","year":"2013","unstructured":"Shalimar & Acharya, S. K. Hepatitis e and acute liver failure in pregnancy. J Clin Exp Hepatol 3, 213\u2013224, https:\/\/doi.org\/10.1016\/j.jceh.2013.08.009 (2013).","journal-title":"J Clin Exp Hepatol"},{"key":"26975_CR4","doi-asserted-by":"publisher","first-page":"12081","DOI":"10.1128\/JVI.79.18.12081-12087.2005","volume":"79","author":"S Tyagi","year":"2005","unstructured":"Tyagi, S., Surjit, M. & Lal, S. K. The 41-amino-acid C-terminal region of the hepatitis E virus ORF3 protein interacts with bikunin, a kunitz-type serine protease inhibitor. J Virol 79, 12081\u201312087, https:\/\/doi.org\/10.1128\/JVI.79.18.12081-12087.2005 (2005).","journal-title":"J Virol"},{"key":"26975_CR5","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1007\/s00535-012-0682-0","volume":"48","author":"H Okamoto","year":"2013","unstructured":"Okamoto, H. Culture systems for hepatitis E virus. J Gastroenterol 48, 147\u2013158, https:\/\/doi.org\/10.1007\/s00535-012-0682-0 (2013).","journal-title":"J Gastroenterol"},{"key":"26975_CR6","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1055\/s-0033-1338110","volume":"33","author":"RP Holla","year":"2013","unstructured":"Holla, R. P., Ahmad, I., Ahmad, Z. & Jameel, S. Molecular virology of hepatitis E virus. Semin Liver Dis 33, 3\u201314, https:\/\/doi.org\/10.1055\/s-0033-1338110 (2013).","journal-title":"Semin Liver Dis"},{"key":"26975_CR7","doi-asserted-by":"publisher","DOI":"10.1038\/emi.2012.7","volume":"1","author":"D Cao","year":"2012","unstructured":"Cao, D. & Meng, X. J. Molecular biology and replication of hepatitis E virus. Emerg Microbes Infect 1, e17, https:\/\/doi.org\/10.1038\/emi.2012.7 (2012).","journal-title":"Emerg Microbes Infect"},{"key":"26975_CR8","doi-asserted-by":"publisher","first-page":"e22412","DOI":"10.1371\/journal.pone.0022412","volume":"6","author":"V Chandra","year":"2011","unstructured":"Chandra, V. et al. The hepatitis E virus ORF3 protein regulates the expression of liver-specific genes by modulating localization of hepatocyte nuclear factor 4. PLoS One 6, e22412, https:\/\/doi.org\/10.1371\/journal.pone.0022412 (2011).","journal-title":"PLoS One"},{"key":"26975_CR9","doi-asserted-by":"publisher","first-page":"e100787","DOI":"10.1371\/journal.pone.0100787","volume":"9","author":"J Xu","year":"2014","unstructured":"Xu, J. et al. Open reading frame 3 of genotype 1 hepatitis E virus inhibits nuclear factor-kappaappa B signaling induced by tumor necrosis factor-alpha in human A549 lung epithelial cells. PLoS One 9, e100787, https:\/\/doi.org\/10.1371\/journal.pone.0100787 (2014).","journal-title":"PLoS One"},{"key":"26975_CR10","doi-asserted-by":"publisher","first-page":"e63793","DOI":"10.1371\/journal.pone.0063793","volume":"8","author":"PB Devhare","year":"2013","unstructured":"Devhare, P. B., Chatterjee, S. N., Arankalle, V. A. & Lole, K. S. Analysis of antiviral response in human epithelial cells infected with hepatitis E virus. PLoS One 8, e63793, https:\/\/doi.org\/10.1371\/journal.pone.0063793 (2013).","journal-title":"PLoS One"},{"key":"26975_CR11","doi-asserted-by":"publisher","first-page":"373","DOI":"10.1038\/ni.1863","volume":"11","author":"T Kawai","year":"2010","unstructured":"Kawai, T. & Akira, S. The role of pattern-recognition receptors in innate immunity: update on Toll-like receptors. Nat Immunol 11, 373\u2013384, https:\/\/doi.org\/10.1038\/ni.1863 (2010).","journal-title":"Nat Immunol"},{"key":"26975_CR12","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1038\/nri3581","volume":"14","author":"LB Ivashkiv","year":"2014","unstructured":"Ivashkiv, L. B. & Donlin, L. T. Regulation of type I interferon responses. Nat Rev Immunol 14, 36\u201349, https:\/\/doi.org\/10.1038\/nri3581 (2014).","journal-title":"Nat Rev Immunol"},{"key":"26975_CR13","doi-asserted-by":"publisher","first-page":"3413","DOI":"10.4049\/jimmunol.177.5.3413","volume":"177","author":"SA Steer","year":"2006","unstructured":"Steer, S. A. et al. Role of MAPK in the regulation of double-stranded RNA- and encephalomyocarditis virus-induced cyclooxygenase-2 expression by macrophages. J Immunol 177, 3413\u20133420 (2006).","journal-title":"J Immunol"},{"key":"26975_CR14","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1016\/j.immuni.2013.05.007","volume":"38","author":"D Goubau","year":"2013","unstructured":"Goubau, D., Deddouche, S. & Reis e Sousa, C. Cytosolic sensing of viruses. Immunity 38, 855\u2013869, https:\/\/doi.org\/10.1016\/j.immuni.2013.05.007 (2013).","journal-title":"Immunity"},{"key":"26975_CR15","doi-asserted-by":"publisher","first-page":"687","DOI":"10.1038\/nri3295","volume":"12","author":"NK Duggal","year":"2012","unstructured":"Duggal, N. K. & Emerman, M. Evolutionary conflicts between viruses and restriction factors shape immunity. Nat Rev Immunol 12, 687\u2013695, https:\/\/doi.org\/10.1038\/nri3295 (2012).","journal-title":"Nat Rev Immunol"},{"key":"26975_CR16","doi-asserted-by":"publisher","first-page":"11924","DOI":"10.1128\/JVI.01935-14","volume":"88","author":"Y Nan","year":"2014","unstructured":"Nan, Y. et al. Hepatitis E virus inhibits type I interferon induction by ORF1 products. J Virol 88, 11924\u201311932, https:\/\/doi.org\/10.1128\/JVI.01935-14 (2014).","journal-title":"J Virol"},{"key":"26975_CR17","doi-asserted-by":"publisher","first-page":"914","DOI":"10.1056\/NEJMoa1406011","volume":"372","author":"J Zhang","year":"2015","unstructured":"Zhang, J. et al. Long-term efficacy of a hepatitis E vaccine. N Engl J Med 372, 914\u2013922, https:\/\/doi.org\/10.1056\/NEJMoa1406011 (2015).","journal-title":"N Engl J Med"},{"key":"26975_CR18","doi-asserted-by":"publisher","first-page":"82","DOI":"10.1053\/j.gastro.2015.09.011","volume":"150","author":"VL Dao Thi","year":"2016","unstructured":"Dao Thi, V. L. et al. Sofosbuvir Inhibits Hepatitis E Virus Replication In Vitro and Results in an Additive Effect When Combined With Ribavirin. Gastroenterology 150, 82\u201385 e84, https:\/\/doi.org\/10.1053\/j.gastro.2015.09.011 (2016).","journal-title":"Gastroenterology"},{"key":"26975_CR19","doi-asserted-by":"publisher","first-page":"105","DOI":"10.1089\/vim.2015.0107","volume":"29","author":"Q Lei","year":"2016","unstructured":"Lei, Q. et al. ORF3 of Hepatitis E Virus Inhibits the Expression of Proinflammatory Cytokines and Chemotactic Factors in LPS-Stimulated Human PMA-THP1 Cells by Inhibiting NF-kappaB Pathway. Viral Immunol 29, 105\u2013111, https:\/\/doi.org\/10.1089\/vim.2015.0107 (2016).","journal-title":"Viral Immunol"},{"key":"26975_CR20","doi-asserted-by":"publisher","DOI":"10.1038\/srep27597","volume":"6","author":"M He","year":"2016","unstructured":"He, M. et al. The ORF3 Protein of Genotype 1 Hepatitis E Virus Suppresses TLR3-induced NF-kappaB Signaling via TRADD and RIP1. Sci Rep 6, 27597, https:\/\/doi.org\/10.1038\/srep27597 (2016).","journal-title":"Sci Rep"},{"key":"26975_CR21","first-page":"1991","volume":"139","author":"S Gessani","year":"1987","unstructured":"Gessani, S., Belardelli, F., Borghi, P., Boraschi, D. & Gresser, I. Correlation between the lipopolysaccharide response of mice and the capacity of mouse peritoneal cells to transfer an antiviral state. Role of endogenous interferon. J Immunol 139, 1991\u20131998 (1987).","journal-title":"Role of endogenous interferon. J Immunol"},{"key":"26975_CR22","doi-asserted-by":"publisher","first-page":"443","DOI":"10.1016\/j.jhep.2017.06.016","volume":"67","author":"U Protzer","year":"2017","unstructured":"Protzer, U. & Visualizing, H. E. V. infection In human liver tissue. J Hepatol 67, 443\u2013445, https:\/\/doi.org\/10.1016\/j.jhep.2017.06.016 (2017).","journal-title":"J Hepatol"},{"key":"26975_CR23","doi-asserted-by":"publisher","first-page":"200","DOI":"10.1016\/j.jhep.2016.02.045","volume":"65","author":"Y Debing","year":"2016","unstructured":"Debing, Y., Moradpour, D., Neyts, J. & Gouttenoire, J. Update on hepatitis E virology: Implications for clinical practice. J Hepatol 65, 200\u2013212, https:\/\/doi.org\/10.1016\/j.jhep.2016.02.045 (2016).","journal-title":"J Hepatol"},{"key":"26975_CR24","doi-asserted-by":"publisher","first-page":"84","DOI":"10.1111\/tme.12405","volume":"27","author":"MJ Ankcorn","year":"2017","unstructured":"Ankcorn, M. J. & Tedder, R. S. Hepatitis E: the current state of play. Transfus Med 27, 84\u201395, https:\/\/doi.org\/10.1111\/tme.12405 (2017).","journal-title":"Transfus Med"},{"key":"26975_CR25","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1038\/nri2038","volume":"7","author":"G Trinchieri","year":"2007","unstructured":"Trinchieri, G. & Sher, A. Cooperation of Toll-like receptor signals in innate immune defence. Nat Rev Immunol 7, 179\u2013190, https:\/\/doi.org\/10.1038\/nri2038 (2007).","journal-title":"Nat Rev Immunol"},{"key":"26975_CR26","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1016\/j.cell.2006.02.016","volume":"124","author":"M Karin","year":"2006","unstructured":"Karin, M., Lawrence, T. & Nizet, V. Innate immunity gone awry: linking microbial infections to chronic inflammation and cancer. Cell 124, 823\u2013835, https:\/\/doi.org\/10.1016\/j.cell.2006.02.016 (2006).","journal-title":"Cell"},{"key":"26975_CR27","doi-asserted-by":"publisher","first-page":"1324","DOI":"10.1002\/hep.25530","volume":"55","author":"C Dong","year":"2012","unstructured":"Dong, C. et al. Suppression of interferon-alpha signaling by hepatitis E virus. Hepatology 55, 1324\u20131332, https:\/\/doi.org\/10.1002\/hep.25530 (2012).","journal-title":"Hepatology"},{"key":"26975_CR28","doi-asserted-by":"publisher","first-page":"57","DOI":"10.5501\/wjv.v2.i2.57","volume":"2","author":"MD Audsley","year":"2013","unstructured":"Audsley, M. D. & Moseley, G. W. Paramyxovirus evasion of innate immunity: Diverse strategies for common targets. World J Virol 2, 57\u201370, https:\/\/doi.org\/10.5501\/wjv.v2.i2.57 (2013).","journal-title":"World J Virol"},{"key":"26975_CR29","doi-asserted-by":"publisher","first-page":"693","DOI":"10.1146\/annurev.immunol.021908.132641","volume":"27","author":"S Vallabhapurapu","year":"2009","unstructured":"Vallabhapurapu, S. & Karin, M. Regulation and function of NF-kappaB transcription factors in the immune system. Annu Rev Immunol 27, 693\u2013733, https:\/\/doi.org\/10.1146\/annurev.immunol.021908.132641 (2009).","journal-title":"Annu Rev Immunol"},{"key":"26975_CR30","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1111\/j.1600-065X.2011.01092.x","volume":"246","author":"S Basak","year":"2012","unstructured":"Basak, S., Behar, M. & Hoffmann, A. Lessons from mathematically modeling the NF-kappaB pathway. Immunol Rev 246, 221\u2013238, https:\/\/doi.org\/10.1111\/j.1600-065X.2011.01092.x (2012).","journal-title":"Immunol Rev"},{"key":"26975_CR31","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1002\/wsbm.1331","volume":"8","author":"S Mitchell","year":"2016","unstructured":"Mitchell, S., Vargas, J. & Hoffmann, A. Signaling via the NFkappaB system. Wiley Interdiscip Rev Syst Biol Med 8, 227\u2013241, https:\/\/doi.org\/10.1002\/wsbm.1331 (2016).","journal-title":"Wiley Interdiscip Rev Syst Biol Med"},{"key":"26975_CR32","doi-asserted-by":"publisher","unstructured":"Fleming, S. B. Viral Inhibition of the IFN-Induced JAK\/STAT Signalling Pathway: Development of Live Attenuated Vaccines by Mutation of Viral-Encoded IFN-Antagonists. Vaccines (Basel) 4, https:\/\/doi.org\/10.3390\/vaccines4030023 (2016).","DOI":"10.3390\/vaccines4030023"},{"key":"26975_CR33","doi-asserted-by":"publisher","first-page":"793","DOI":"10.1128\/MMBR.00043-14","volume":"80","author":"A Zeke","year":"2016","unstructured":"Zeke, A., Misheva, M., Remenyi, A. & Bogoyevitch, M. A. JNK Signaling: Regulation and Functions Based on Complex Protein-Protein Partnerships. Microbiol Mol Biol Rev 80, 793\u2013835, https:\/\/doi.org\/10.1128\/MMBR.00043-14 (2016).","journal-title":"Microbiol Mol Biol Rev"},{"key":"26975_CR34","doi-asserted-by":"publisher","first-page":"e1003622","DOI":"10.1371\/journal.ppat.1003622","volume":"9","author":"LS Garver","year":"2013","unstructured":"Garver, L. S., de Almeida Oliveira, G. & Barillas-Mury, C. The JNK pathway is a key mediator of Anopheles gambiae antiplasmodial immunity. PLoS Pathog 9, e1003622, https:\/\/doi.org\/10.1371\/journal.ppat.1003622 (2013).","journal-title":"PLoS Pathog"},{"key":"26975_CR35","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1080\/15384101.2015.1119492","volume":"15","author":"B Mollereau","year":"2016","unstructured":"Mollereau, B. & Ma, D. Rb-mediated apoptosis or proliferation: It\u2019s up to JNK. Cell Cycle 15, 11\u201312, https:\/\/doi.org\/10.1080\/15384101.2015.1119492 (2016).","journal-title":"Cell Cycle"},{"key":"26975_CR36","doi-asserted-by":"publisher","first-page":"101042831771165","DOI":"10.1177\/1010428317711659","volume":"39","author":"I Gkouveris","year":"2017","unstructured":"Gkouveris, I. & Nikitakis, N. G. Role of JNK signaling in oral cancer: A mini review. Tumour Biol 39, 1010428317711659, https:\/\/doi.org\/10.1177\/1010428317711659 (2017).","journal-title":"Tumour Biol"},{"key":"26975_CR37","doi-asserted-by":"publisher","first-page":"679","DOI":"10.1038\/nri3495","volume":"13","author":"JS Arthur","year":"2013","unstructured":"Arthur, J. S. & Ley, S. C. Mitogen-activated protein kinases in innate immunity. Nat Rev Immunol 13, 679\u2013692, https:\/\/doi.org\/10.1038\/nri3495 (2013).","journal-title":"Nat Rev Immunol"},{"key":"26975_CR38","doi-asserted-by":"publisher","first-page":"e85715","DOI":"10.1371\/journal.pone.0085715","volume":"9","author":"AA Filardy","year":"2014","unstructured":"Filardy, A. A. et al. Infection with Leishmania major induces a cellular stress response in macrophages. PLoS One 9, e85715, https:\/\/doi.org\/10.1371\/journal.pone.0085715 (2014).","journal-title":"PLoS One"},{"key":"26975_CR39","doi-asserted-by":"publisher","first-page":"1273","DOI":"10.1073\/pnas.1423586112","volume":"112","author":"UN Ramphul","year":"2015","unstructured":"Ramphul, U. N., Garver, L. S., Molina-Cruz, A., Canepa, G. E. & Barillas-Mury, C. Plasmodium falciparum evades mosquito immunity by disrupting JNK-mediated apoptosis of invaded midgut cells. Proc Natl Acad Sci USA 112, 1273\u20131280, https:\/\/doi.org\/10.1073\/pnas.1423586112 (2015).","journal-title":"Proc Natl Acad Sci USA"},{"key":"26975_CR40","doi-asserted-by":"publisher","first-page":"28345","DOI":"10.1074\/jbc.M400457200","volume":"279","author":"A Kar-Roy","year":"2004","unstructured":"Kar-Roy, A., Korkaya, H., Oberoi, R., Lal, S. K. & Jameel, S. The hepatitis E virus open reading frame 3 protein activates ERK through binding and inhibition of the MAPK phosphatase. J Biol Chem 279, 28345\u201328357, https:\/\/doi.org\/10.1074\/jbc.M400457200 (2004).","journal-title":"J Biol Chem"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-26975-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-26975-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-26975-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,21]],"date-time":"2022-12-21T00:57:34Z","timestamp":1671584254000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-26975-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,6,5]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["26975"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-26975-4","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,6,5]]},"assertion":[{"value":"10 January 2018","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 May 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 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":"8585"}}