{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,25]],"date-time":"2026-03-25T02:45:40Z","timestamp":1774406740589,"version":"3.50.1"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2018,3,15]],"date-time":"2018-03-15T00:00:00Z","timestamp":1521072000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,3,15]],"date-time":"2018-03-15T00:00:00Z","timestamp":1521072000000},"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>Influenza A viruses cause seasonal epidemics and occasional pandemics. The emergence of viruses resistant to neuraminidase (NA) inhibitors and M2 ion channel inhibitors underlines the need for alternate anti-influenza drugs with novel mechanisms of action. Here, we report the discovery of a host factor as a potential target of anti-influenza drugs. By using cell-based virus replication screening of a chemical library and several additional assays, we identified clonidine as a new anti-influenza agent<jats:italic>in vitro<\/jats:italic>. We found that clonidine, which is an agonist of the alpha2-adrenergic receptor (\u03b12-AR), has an inhibitory effect on the replication of various influenza virus strains. \u03b12-AR is a Gi-type G protein-coupled receptor that reduces intracellular cyclic AMP (cAMP) levels. In-depth analysis showed that stimulation of \u03b12-ARs leads to impairment of influenza virus replication and that \u03b12-AR agonists inhibit the virus assembly step, likely via a cAMP-mediated pathway. Although clonidine administration did not reduce lung virus titers or prevent body weight loss, it did suppress lung edema and improve survival in a murine lethal infection model. Clonidine may thus protect against lung damage caused by influenza virus infection. Our results identify \u03b12-AR-mediated signaling as a key pathway to exploit in the development of anti-influenza agents.<\/jats:p>","DOI":"10.1038\/s41598-018-22927-0","type":"journal-article","created":{"date-parts":[[2018,3,9]],"date-time":"2018-03-09T14:59:16Z","timestamp":1520607556000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Stimulation of alpha2-adrenergic receptors impairs influenza virus infection"],"prefix":"10.1038","volume":"8","author":[{"given":"Ken","family":"Matsui","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Ozawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maki","family":"Kiso","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Makoto","family":"Yamashita","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toshihiko","family":"Maekawa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Minoru","family":"Kubota","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sumio","family":"Sugano","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yoshihiro","family":"Kawaoka","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2018,3,15]]},"reference":[{"key":"22927_CR1","doi-asserted-by":"publisher","first-page":"1188","DOI":"10.1038\/ni1530","volume":"8","author":"R Ahmed","year":"2007","unstructured":"Ahmed, R., Oldstone, M. B. & Palese, P. Protective immunity and susceptibility to infectious diseases: lessons from the 1918 influenza pandemic. Nat. Immunol. 8, 1188\u20131193 (2007).","journal-title":"Nat. Immunol."},{"key":"22927_CR2","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1016\/j.cell.2009.05.032","volume":"137","author":"TT Wang","year":"2009","unstructured":"Wang, T. T. & Palese, P. Unraveling the mystery of swine influenza virus. Cell 137, 983\u2013985 (2009).","journal-title":"Cell"},{"issue":"3","key":"22927_CR3","doi-asserted-by":"crossref","first-page":"495","DOI":"10.18388\/abp.2014_1870","volume":"61","author":"E Kr\u00f3l","year":"2014","unstructured":"Kr\u00f3l, E., Rych\u0142owska, M. & Szewczyk, B. Antivirals - current trends in fighting influenza. Acta Biochim. Pol. 61(3), 495\u2013504 (2014).","journal-title":"Acta Biochim. Pol."},{"key":"22927_CR4","doi-asserted-by":"publisher","first-page":"977","DOI":"10.1128\/AAC.46.4.977-981.2002","volume":"46","author":"Y Furuta","year":"2002","unstructured":"Furuta, Y. et al. In vitro and in vivo activities of anti-influenza virus compound T-705. Antimicrob. Agents Chemother. 46, 977\u2013981 (2002).","journal-title":"Antimicrob. Agents Chemother."},{"key":"22927_CR5","doi-asserted-by":"publisher","first-page":"5202","DOI":"10.1128\/AAC.00649-13","volume":"57","author":"H Sangawa","year":"2013","unstructured":"Sangawa, H. et al. Mechanism of action of T-705 ribosyl triphosphate against influenza virus RNA polymerase. Antimicrob. Agents Chemother. 57, 5202\u20135208 (2013).","journal-title":"Antimicrob. Agents Chemother."},{"issue":"6","key":"22927_CR6","doi-asserted-by":"publisher","first-page":"966","DOI":"10.3201\/eid1506.081357","volume":"15","author":"PK Cheng","year":"2009","unstructured":"Cheng, P. K. et al. Oseltamivir- and amantadine-resistant influenza viruses A (H1N1). Emerg. Infect. Dis. 15(6), 966\u2013968 (2009).","journal-title":"Emerg. Infect. Dis."},{"issue":"9846","key":"22927_CR7","doi-asserted-by":"publisher","first-page":"986","DOI":"10.1016\/S0140-6736(12)61080-0","volume":"380","author":"AH Diacon","year":"2012","unstructured":"Diacon, A. H. et al. 14-day bactericidal activity of PA-824, bedaquiline, pyrazinamide, and moxifloxacin combinations: a randomised trial. Lancet 380(9846), 986\u2013993 (2012).","journal-title":"Lancet"},{"issue":"21","key":"22927_CR8","doi-asserted-by":"publisher","first-page":"1522","DOI":"10.1056\/NEJMoa011157","volume":"345","author":"SL Gortmaker","year":"2001","unstructured":"Gortmaker, S. L. et al. Effect of combination therapy including protease inhibitors on mortality among children and adolescents infected with HIV-1. N. Engl. J. Med. 345(21), 1522\u20131528 (2001).","journal-title":"N. Engl. J. Med."},{"issue":"3","key":"22927_CR9","doi-asserted-by":"publisher","first-page":"239","DOI":"10.1038\/nbt0310-239","volume":"28","author":"JY Min","year":"2010","unstructured":"Min, J. Y. & Subbarao, K. Cellular targets for influenza drugs. Nat. Biotechnol. 28(3), 239\u2013240 (2010).","journal-title":"Nat. Biotechnol."},{"issue":"4","key":"22927_CR10","doi-asserted-by":"publisher","first-page":"2038","DOI":"10.1074\/jbc.274.4.2038","volume":"274","author":"P Scheiffele","year":"1999","unstructured":"Scheiffele, P., Rietveld, A., Wilk, T. & Simons, K. Influenza viruses select ordered lipid domains during budding from the plasma membrane. J. Biol. Chem. 274(4), 2038\u20132044 (1999).","journal-title":"J. Biol. Chem."},{"issue":"25","key":"22927_CR11","doi-asserted-by":"publisher","first-page":"14610","DOI":"10.1073\/pnas.2235620100","volume":"100","author":"M Takeda","year":"2003","unstructured":"Takeda, M., Leser, G. P., Russell, C. J. & Lamb, R. A. Influenza virus hemagglutinin concentrates in lipid raft microdomains for efficient viral fusion. Proc. Natl. Acad. Sci. USA 100(25), 14610\u201314617 (2003).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"22927_CR12","doi-asserted-by":"publisher","first-page":"818","DOI":"10.1038\/nature08760","volume":"463","author":"A Karlas","year":"2010","unstructured":"Karlas, A. et al. Genome-wide RNAi screen identifies human host factors crucial for influenza virus replication. Nature 463, 818\u2013822 (2010).","journal-title":"Nature"},{"key":"22927_CR13","doi-asserted-by":"publisher","first-page":"813","DOI":"10.1038\/nature08699","volume":"463","author":"R K\u00f6nig","year":"2010","unstructured":"K\u00f6nig, R. et al. Human host factors required for influenza virus replication. Nature 463, 813\u2013817 (2010).","journal-title":"Nature"},{"key":"22927_CR14","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1038\/35060098","volume":"3","author":"S Pleschka","year":"2001","unstructured":"Pleschka, S. et al. Influenza virus propagation is impaired by inhibition of the Raf\/MEK\/ERK signaling cascade. Nat. Cell Biol. 3, 301\u2013305 (2001).","journal-title":"Nat. Cell Biol."},{"issue":"6","key":"22927_CR15","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/j.chom.2014.11.002","volume":"16","author":"T Watanabe","year":"2014","unstructured":"Watanabe, T. et al. Influenza virus-host interactome screen as a platform for antiviral drug development. Cell Host Microbe 16(6), 795\u2013805 (2014).","journal-title":"Cell Host Microbe"},{"key":"22927_CR16","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.antiviral.2011.08.002","volume":"92","author":"K Droebner","year":"2011","unstructured":"Droebner, K., Pleschka, S., Ludwig, S. & Planz, O. Antiviral activity of the MEK-inhibitor U0126 against pandemic H1N1v and highly pathogenic avian influenza virus in vitro and in vivo. Antiviral Res. 92, 195\u2013203 (2011).","journal-title":"Antiviral Res."},{"issue":"7","key":"22927_CR17","doi-asserted-by":"publisher","first-page":"507","DOI":"10.1038\/nrd3480","volume":"10","author":"DC Swinney","year":"2011","unstructured":"Swinney, D. C. & Anthony, J. How were new medicines discovered? Nat. Rev. Drug Discov. 10(7), 507\u2013519 (2011).","journal-title":"Nat. Rev. Drug Discov."},{"key":"22927_CR18","doi-asserted-by":"publisher","first-page":"2879","DOI":"10.1099\/vir.0.037648-0","volume":"92","author":"M Ozawa","year":"2011","unstructured":"Ozawa, M. et al. Replication-incompetent influenza A viruses that stably express a foreign gene. J. Gen. Virol. 92, 2879\u20132888 (2011).","journal-title":"J. Gen. Virol."},{"issue":"8","key":"22927_CR19","doi-asserted-by":"publisher","first-page":"4139","DOI":"10.1128\/JCM.43.8.4139-4146.2005","volume":"43","author":"S Hatakeyama","year":"2005","unstructured":"Hatakeyama, S. et al. Enhanced expression of analpha2,6-linked sialic acid on MDCK cells improves isolation of human influenza viruses and evaluation of their sensitivity to a neuraminidase inhibitor. J. Clin. Microbiol. 43(8), 4139\u20134146 (2005).","journal-title":"J. Clin. Microbiol."},{"issue":"3","key":"22927_CR20","doi-asserted-by":"publisher","first-page":"981","DOI":"10.1128\/AAC.49.3.981-986.2005","volume":"49","author":"Y Furuta","year":"2005","unstructured":"Furuta, Y. et al. Mechanism of action of T-705 against influenza virus. Antimicrob. Agents Chemother. 49(3), 981\u2013986 (2005).","journal-title":"Antimicrob. Agents Chemother."},{"issue":"44","key":"22927_CR21","doi-asserted-by":"publisher","first-page":"17959","DOI":"10.1021\/ja207892q","volume":"133","author":"JJ Shie","year":"2011","unstructured":"Shie, J. J. et al. A practical synthesis of zanamivir phosphonate congeners with potent anti-influenza activity. J. Am. Chem. Soc. 133(44), 17959\u201317965 (2011).","journal-title":"J. Am. Chem. Soc."},{"issue":"3","key":"22927_CR22","doi-asserted-by":"publisher","first-page":"247","DOI":"10.1177\/1087057105285610","volume":"11","author":"PW Iversen","year":"2006","unstructured":"Iversen, P. W., Eastwood, B. J., Sittampalam, G. S. & Cox, K. L. A comparison of assay performance measures in screening assays: signal window, Z\u2019 factor, and assay variability ratio. J. Biomol. Screen. 11(3), 247\u2013252 (2006).","journal-title":"J. Biomol. Screen."},{"key":"22927_CR23","doi-asserted-by":"publisher","DOI":"10.1038\/srep01106","volume":"3","author":"M Ozawa","year":"2013","unstructured":"Ozawa, M. et al. A cell-based screening system for influenza A viral RNA transcription\/replication inhibitors. Sci. Rep. 3, 1106, https:\/\/doi.org\/10.1038\/srep01106 (2013).","journal-title":"Sci. Rep."},{"issue":"1","key":"22927_CR24","doi-asserted-by":"publisher","first-page":"7","DOI":"10.1016\/0014-2999(81)90426-X","volume":"70","author":"PB Timmermans","year":"1981","unstructured":"Timmermans, P. B., Schoop, A. M., Kwa, H. Y. & Van Zwieten, P. A. Characterization of alpha-adrenoceptors participating in the central hypotensive and sedative effects of clonidine using yohimbine, rauwolscine and corynanthine. Eur. J. Pharmacol. 70(1), 7\u201315 (1981).","journal-title":"Eur. J. Pharmacol."},{"key":"22927_CR25","first-page":"190","volume":"297","author":"R Virtanen","year":"1989","unstructured":"Virtanen, R., Savola, J. M. & Saano, V. Highly selective and specific antagonism of central and peripheral alpha 2-adrenoceptors by atipamezole. Arch. Int. Pharmacodyn. Ther. 297, 190\u2013204 (1989).","journal-title":"Arch. Int. Pharmacodyn. Ther."},{"issue":"9","key":"22927_CR26","doi-asserted-by":"publisher","first-page":"1193","DOI":"10.1017\/S1461145709991088","volume":"13","author":"JM Dwyer","year":"2010","unstructured":"Dwyer, J. M. et al. Preclinical characterization of BRL 44408: antidepressant- and analgesic-like activity through selective alpha2A-adrenoceptor antagonism. Int. J. Neuropsychopharmacol. 13(9), 1193\u20131205 (2010).","journal-title":"Int. J. Neuropsychopharmacol."},{"key":"22927_CR27","first-page":"F347","volume":"267","author":"MD Okusa","year":"1994","unstructured":"Okusa, M. D., Lynch, K. R., Rosin, D. L., Huang, L. & Wei, Y. Y. Apical membrane and intracellular distribution of endogenous alpha 2A-adrenergic receptors in MDCK cells. Am. J. Physiol. 267, F347\u2013353 (1994).","journal-title":"Am. J. Physiol."},{"issue":"5","key":"22927_CR28","doi-asserted-by":"publisher","first-page":"1287","DOI":"10.1016\/j.micinf.2005.12.008","volume":"8","author":"M Ohuchi","year":"2006","unstructured":"Ohuchi, M., Asaoka, N., Sakai, T. & Ohuchi, R. Roles of neuraminidase in the initial stage of influenza virus infection. Microbes Infect. 8(5), 1287\u20131293 (2006).","journal-title":"Microbes Infect."},{"key":"22927_CR29","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1016\/S0026-895X(25)13171-4","volume":"44","author":"MG Eason","year":"1993","unstructured":"Eason, M. G. & Liggett, S. B. Human alpha 2-adrenergic receptor subtype distribution: widespread and subtype-selective expression of alpha 2C10, alpha 2C4, and alpha 2C2 mRNA in multiple tissues. Mol. Pharmacol. 44, 70\u201375 (1993).","journal-title":"Mol. Pharmacol."},{"key":"22927_CR30","first-page":"241","volume":"67","author":"SA Babhair","year":"1990","unstructured":"Babhair, S. A., Tariq, M. & Abdullah, M. E. Comparison of intravenous and nasal bioavailability of clonidine in rodents. Res. Commun. Chem. Pathol. Pharmacol. 67, 241\u2013248 (1990).","journal-title":"Res. Commun. Chem. Pathol. Pharmacol."},{"issue":"Suppl 1","key":"22927_CR31","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2165\/00003088-199936001-00001","volume":"36","author":"LM Cass","year":"1999","unstructured":"Cass, L. M., Efthymiopoulos, C. & Bye, A. Pharmacokinetics of zanamivir after intravenous, oral, inhaled or intranasal administration to healthy volunteers. Clin. Pharmacokinet. 36(Suppl 1), 1\u201311 (1999).","journal-title":"Clin. Pharmacokinet."},{"issue":"4","key":"22927_CR32","doi-asserted-by":"publisher","first-page":"1216","DOI":"10.1128\/AAC.45.4.1216-1224.2001","volume":"45","author":"IA Leneva","year":"2001","unstructured":"Leneva, I. A., Goloubeva, O., Fenton, R. J., Tisdale, M. & Webster, R. G. Efficacy of zanamivir against avian influenza A viruses that possess genes encoding H5N1 internal proteins and are pathogenic in mammals. Antimicrob. Agents Chemother. 45(4), 1216\u20131224 (2001).","journal-title":"Antimicrob. Agents Chemother."},{"issue":"2","key":"22927_CR33","doi-asserted-by":"publisher","first-page":"L366","DOI":"10.1152\/ajplung.00011.2004","volume":"287","author":"XJ Chen","year":"2004","unstructured":"Chen, X. J. et al. Influenza virus inhibits ENaC and lung fluid clearance. Am. J. Physiol. Lung Cell. Mol. Physiol. 287(2), L366\u2013373 (2004).","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"issue":"2","key":"22927_CR34","doi-asserted-by":"publisher","first-page":"400","DOI":"10.1213\/00000539-200002000-00030","volume":"90","author":"T Asano","year":"2000","unstructured":"Asano, T., Dohi, S., Ohta, S., Shimonaka, H. & Iida, H. Antinociception by epidural and systemic alpha(2)-adrenoceptor agonists and their binding affinity in rat spinal cord and brain. Anesth. Analg. 90(2), 400\u2013407 (2000).","journal-title":"Anesth. Analg."},{"issue":"1","key":"22927_CR35","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/0014-2999(87)90125-7","volume":"134","author":"P Ernsberger","year":"1987","unstructured":"Ernsberger, P., Meeley, M. P., Mann, J. J. & Reis, D. J. Clonidine binds to imidazole binding sites as well as alpha 2-adrenoceptors in the ventrolateral medulla. Eur. J. Pharmacol. 134(1), 1\u201313 (1987).","journal-title":"Eur. J. Pharmacol."},{"key":"22927_CR36","doi-asserted-by":"publisher","first-page":"S59","DOI":"10.1097\/00005344-199512020-00011","volume":"26","author":"C Gargalidis-Moudanos","year":"1995","unstructured":"Gargalidis-Moudanos, C. & Parini, A. Selectivity of rilmenidine for I1-imidazoline-binding sites in rabbit proximal tubule cells. J. Cardiovasc. Pharmacol. 26, S59\u201362 (1995).","journal-title":"J. Cardiovasc. Pharmacol."},{"key":"22927_CR37","doi-asserted-by":"crossref","first-page":"1931","DOI":"10.1242\/jcs.108.5.1931","volume":"108","author":"M Brignoni","year":"1995","unstructured":"Brignoni, M. et al. Cyclic AMP modulates the rate of \u2018constitutive\u2019 exocytosis of apical membrane proteins in Madin-Darby canine kidney cells. J. Cell Sci. 108, 1931\u20131943 (1995).","journal-title":"J. Cell Sci."},{"issue":"6","key":"22927_CR38","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.1016\/S0026-895X(24)23223-5","volume":"57","author":"H Greney","year":"2000","unstructured":"Greney, H. et al. Coupling of I(1) imidazoline receptors to the cAMP pathway: studies with a highly selective ligand, benazoline. Mol. Pharmacol. 57(6), 1142\u20131151 (2000).","journal-title":"Mol. Pharmacol."},{"issue":"11","key":"22927_CR39","doi-asserted-by":"publisher","first-page":"2794","DOI":"10.1073\/pnas.68.11.2794","volume":"68","author":"A Peterkofsky","year":"1971","unstructured":"Peterkofsky, A. & Gazdar, C. Glucose and the metabolism of adenosine 3\u2032:-cyclic monophosphate in Escherichia coli. Proc. Natl. Acad. Sci. USA 68(11), 2794\u20132798 (1971).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"issue":"9","key":"22927_CR40","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1164\/rccm.200803-455OC","volume":"178","author":"KE Wolk","year":"2008","unstructured":"Wolk, K. E. et al. Influenza A virus inhibits alveolar fluid clearance in BALB\/c mice. Am. J. Respir. Crit. Care Med. 178(9), 969\u2013976 (2008).","journal-title":"Am. J. Respir. Crit. Care Med."},{"issue":"6","key":"22927_CR41","doi-asserted-by":"publisher","DOI":"10.1186\/cc9324","volume":"14","author":"N Hagau","year":"2010","unstructured":"Hagau, N. et al. Clinical aspects and cytokine response in severe H1N1 influenza A virus infection. Crit. Care 14(6), R203 (2010).","journal-title":"Crit. Care"},{"issue":"3","key":"22927_CR42","doi-asserted-by":"publisher","first-page":"1410","DOI":"10.4049\/jimmunol.0901709","volume":"184","author":"M Seki","year":"2010","unstructured":"Seki, M. et al. Critical role of IL-1 receptor-associated kinase-M in regulating chemokine-dependent deleterious inflammation in murine influenza pneumonia. J. Immunol. 184(3), 1410\u20138 (2010).","journal-title":"J. Immunol."},{"issue":"6","key":"22927_CR43","doi-asserted-by":"publisher","first-page":"e53","DOI":"10.1371\/journal.ppat.0020053","volume":"2","author":"R Le Goffic","year":"2006","unstructured":"Le Goffic, R. et al. Detrimental contribution of the Toll-like receptor (TLR)3 to influenza A virus-induced acute pneumonia. PLoS Pathog. 2(6), e53 (2006).","journal-title":"PLoS Pathog."},{"key":"22927_CR44","doi-asserted-by":"publisher","first-page":"9345","DOI":"10.1073\/pnas.96.16.9345","volume":"96","author":"G Neumann","year":"1999","unstructured":"Neumann, G. et al. Generation of influenza A viruses entirely from cloned cDNAs. Proc. Natl. Acad. Sci. USA 96, 9345\u20139350 (1999).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"issue":"5","key":"22927_CR45","doi-asserted-by":"publisher","first-page":"1067","DOI":"10.1007\/s00705-013-1932-z","volume":"159","author":"W Fonseca","year":"2014","unstructured":"Fonseca, W. et al. A recombinant influenza virus vaccine expressing the F protein of respiratory syncytial virus. Arch. Virol. 159(5), 1067\u201377 (2014).","journal-title":"Arch. Virol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-22927-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-22927-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-22927-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T17:08:28Z","timestamp":1751476108000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-018-22927-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,3,15]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2018,12]]}},"alternative-id":["22927"],"URL":"https:\/\/doi.org\/10.1038\/s41598-018-22927-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,3,15]]},"assertion":[{"value":"5 March 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 February 2018","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 March 2018","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Ken Matsui, Toshihiko Maekawa, and Minoru Kubota are employees of Fujifilm Corporation. The other authors declare that they have no conflicts of interest associated with this manuscript. Yoshihiro Kawaoka is a founder of FluGen. This study was funded, in part, by Fujifilm Corporation. The funder had no role in the study design, data collection and interpretation, or the decision to submit the work for publication.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"4631"}}