{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T16:40:14Z","timestamp":1782837614331,"version":"3.54.5"},"reference-count":61,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2019,9,26]],"date-time":"2019-09-26T00:00:00Z","timestamp":1569456000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000057","name":"National Institute of General Medical Sciences","doi-asserted-by":"publisher","award":["P20GM103423"],"award-info":[{"award-number":["P20GM103423"]}],"id":[{"id":"10.13039\/100000057","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["R15AI144686"],"award-info":[{"award-number":["R15AI144686"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>JC polyomavirus (JCPyV), a ubiquitous human pathogen, is the etiological agent of the fatal neurodegenerative disease progressive multifocal leukoencephalopathy (PML). Like most viruses, JCPyV infection requires the activation of host-cell signaling pathways in order to promote viral replication processes. Previous works have established the necessity of the extracellular signal-regulated kinase (ERK), the terminal core kinase of the mitogen-activated protein kinase (MAPK) cascade (MAPK-ERK) for facilitating transcription of the JCPyV genome. However, the underlying mechanisms by which the MAPK-ERK pathway becomes activated and induces viral transcription are poorly understood. Treatment of cells with siRNAs specific for Raf and MAP kinase kinase (MEK) targets proteins in the MAPK-ERK cascade, significantly reducing JCPyV infection. MEK, the dual-specificity kinase responsible for the phosphorylation of ERK, is phosphorylated at times congruent with early events in the virus infectious cycle. Moreover, a MAPK-specific signaling array revealed that transcription factors downstream of the MAPK cascade, including cMyc and SMAD4, are upregulated within infected cells. Confocal microscopy analysis demonstrated that cMyc and SMAD4 shuttle to the nucleus during infection, and nuclear localization is reduced when ERK is inhibited. These findings suggest that JCPyV induction of the MAPK-ERK pathway is mediated by Raf and MEK and leads to the activation of downstream transcription factors during infection. This study further defines the role of the MAPK cascade during JCPyV infection and the downstream signaling consequences, illuminating kinases as potential therapeutic targets for viral infection.<\/jats:p>","DOI":"10.3390\/ijms20194779","type":"journal-article","created":{"date-parts":[[2019,9,27]],"date-time":"2019-09-27T03:03:15Z","timestamp":1569553395000},"page":"4779","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["JCPyV-Induced MAPK Signaling Activates Transcription Factors during Infection"],"prefix":"10.3390","volume":"20","author":[{"given":"Jeanne K.","family":"DuShane","sequence":"first","affiliation":[{"name":"Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME 04469, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Colleen L.","family":"Mayberry","sequence":"additional","affiliation":[{"name":"Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME 04469, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michael P.","family":"Wilczek","sequence":"additional","affiliation":[{"name":"Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME 04469, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L.","family":"Nichols","sequence":"additional","affiliation":[{"name":"Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME 04469, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Melissa S.","family":"Maginnis","sequence":"additional","affiliation":[{"name":"Department of Molecular and Biomedical Sciences, The University of Maine, Orono, ME 04469, USA"},{"name":"Graduate School in Biomedical Sciences and Engineering, The University of Maine, Orono, ME 04469, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,9,26]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"839","DOI":"10.1515\/hsz-2016-0345","article-title":"The biology of JC polyomavirus","volume":"398","author":"Assetta","year":"2017","journal-title":"Biol. Chem."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Kean, J.M., Rao, S., Wang, M., and Garcea, R.L. (2009). Seroepidemiology of human polyomaviruses. PLoS Pathog., 5.","DOI":"10.1371\/journal.ppat.1000363"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"837","DOI":"10.1086\/597126","article-title":"Prevalence of polyomavirus BK and JC infection and replication in 400 healthy blood donors","volume":"199","author":"Egli","year":"2009","journal-title":"J. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"103","DOI":"10.1093\/infdis\/jir198","article-title":"Progressive multifocal leukoencephalopathy (PML) development is associated with mutations in JC virus capsid protein VP1 that change its receptor specificity","volume":"204","author":"Gorelik","year":"2011","journal-title":"J. Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"2288","DOI":"10.1128\/jcm.35.9.2288-2292.1997","article-title":"Latency and reactivation of JC virus in peripheral blood of human immunodeficiency virus type 1-infected patients","volume":"35","author":"Dubois","year":"1997","journal-title":"J. Clin. Microbiol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/S1470-2045(09)70161-5","article-title":"Monoclonal antibody-associated progressive multifocal leucoencephalopathy in patients treated with rituximab, natalizumab, and efalizumab: A Review from the Research on Adverse Drug Events and Reports (RADAR) Project","volume":"10","author":"Carson","year":"2009","journal-title":"Lancet. Oncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1007\/BF00686519","article-title":"Electron microscopic observations on a case of progressive multifocal leukoencephalopathy","volume":"5","author":"Silverman","year":"1965","journal-title":"Acta Neuropathol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1016\/S0140-6736(71)91777-6","article-title":"Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy","volume":"1","author":"Padgett","year":"1971","journal-title":"Lancet"},{"key":"ref_9","first-page":"93","article-title":"Progressive multifocal leuko-encephalopathy; a hitherto unrecognized complication of chronic lymphatic leukaemia and Hodgkin\u2019s disease","volume":"81","author":"Astrom","year":"1958","journal-title":"Brain"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"471","DOI":"10.1128\/CMR.05031-11","article-title":"Molecular biology, epidemiology, and pathogenesis of progressive multifocal leukoencephalopathy, the JC virus-induced demyelinating disease of the human brain","volume":"25","author":"Ferenczy","year":"2012","journal-title":"Clin. Microbiol. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"S8","DOI":"10.3949\/ccjm.78.s2.03","article-title":"The clinical features of PML","volume":"78","author":"Berger","year":"2011","journal-title":"Cleve. Clin. J. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"685","DOI":"10.1111\/apm.12128","article-title":"The human JC polyomavirus (JCPyV): Virological background and clinical implications","volume":"121","author":"Hirsch","year":"2013","journal-title":"APMIS"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e00247-13","DOI":"10.1128\/mBio.00247-13","article-title":"Progressive multifocal leukoencephalopathy-associated mutations in the JC polyomavirus capsid disrupt lactoseries tetrasaccharide c binding","volume":"4","author":"Maginnis","year":"2013","journal-title":"MBio"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6364","DOI":"10.1128\/JVI.00489-15","article-title":"The Greater Affinity of JC Polyomavirus Capsid for alpha2,6-Linked Lactoseries Tetrasaccharide c than for Other Sialylated Glycans Is a Major Determinant of Infectivity","volume":"89","author":"Stroh","year":"2015","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"309","DOI":"10.1016\/j.chom.2010.09.004","article-title":"Structure-function analysis of the human JC polyomavirus establishes the LSTc pentasaccharide as a functional receptor motif","volume":"8","author":"Neu","year":"2010","journal-title":"Cell Host Microbe"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"13490","DOI":"10.1128\/JVI.02252-13","article-title":"5-HT2 receptors facilitate JC polyomavirus entry","volume":"87","author":"Assetta","year":"2013","journal-title":"J. Virol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1380","DOI":"10.1126\/science.1103492","article-title":"The human polyomavirus, JCV, uses serotonin receptors to infect cells","volume":"306","author":"Elphick","year":"2004","journal-title":"Science"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1128\/JVI.78.1.250-256.2004","article-title":"A JC virus-induced signal is required for infection of glial cells by a clathrin- and eps15-dependent pathway","volume":"78","author":"Querbes","year":"2004","journal-title":"J. Virol."},{"key":"ref_19","doi-asserted-by":"crossref","unstructured":"Mayberry, C.L., Soucy, A.N., Lajoie, C.R., DuShane, J.K., and Maginnis, M.S. (2019). JC Polyomavirus Entry by Clathrin-Mediated Endocytosis Is Driven by beta-Arrestin. J. Virol., 93.","DOI":"10.1128\/JVI.01948-18"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.virol.2012.03.014","article-title":"The VP1 subunit of JC polyomavirus recapitulates early events in viral trafficking and is a novel tool to study polyomavirus entry","volume":"428","author":"Nelson","year":"2012","journal-title":"Virology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"264","DOI":"10.1038\/nrmicro2992","article-title":"A cornucopia of human polyomaviruses","volume":"11","author":"DeCaprio","year":"2013","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1016\/j.tim.2004.08.005","article-title":"The evolution of large DNA viruses: Combining genomic information of viruses and their hosts","volume":"12","author":"Shackelton","year":"2004","journal-title":"Trends Microbiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"6412","DOI":"10.1128\/JVI.02658-06","article-title":"MEK1\/2 inhibitors block basal and transforming growth factor 1beta1-stimulated JC virus multiplication","volume":"81","author":"Ravichandran","year":"2007","journal-title":"J. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","unstructured":"DuShane, J.K., Wilczek, M.P., Mayberry, C.L., and Maginnis, M.S. (2018). ERK Is a Critical Regulator of JC Polyomavirus Infection. J. Virol., 92.","DOI":"10.1128\/JVI.01529-17"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"783","DOI":"10.3389\/fmicb.2019.00783","article-title":"High-Throughput Characterization of Viral and Cellular Protein Expression Patterns During JC Polyomavirus Infection","volume":"10","author":"DuShane","year":"2019","journal-title":"Front. Microbiol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/j.bbamcr.2006.10.005","article-title":"The MEK\/ERK cascade: From signaling specificity to diverse functions","volume":"1773","author":"Shaul","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"195","DOI":"10.1177\/1947601911407328","article-title":"The ERK Cascade: Distinct Functions within Various Subcellular Organelles","volume":"2","author":"Wortzel","year":"2011","journal-title":"Genes Cancer"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1385\/MB:31:2:151","article-title":"The ERK cascade: A prototype of MAPK signaling","volume":"31","author":"Rubinfeld","year":"2005","journal-title":"Mol. Biotechnol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1839","DOI":"10.1074\/jbc.273.4.1839","article-title":"The pathways connecting G protein-coupled receptors to the nucleus through divergent mitogen-activated protein kinase cascades","volume":"273","author":"Gutkind","year":"1998","journal-title":"J. Biol. Chem."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1016\/S0898-6568(02)00007-4","article-title":"Modulation of the Ras\/Raf\/MEK\/ERK pathway by Ca(2+), and calmodulin","volume":"14","author":"Agell","year":"2002","journal-title":"Cell. Signal."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1016\/S0065-230X(08)60765-4","article-title":"Signal transduction through MAP kinase cascades","volume":"74","author":"Lewis","year":"1998","journal-title":"Adv. Cancer Res."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/978-1-4939-6424-6_13","article-title":"The Nuclear Translocation of ERK","volume":"1487","author":"Berti","year":"2017","journal-title":"Methods Mol. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","unstructured":"Maik-Rachline, G., Hacohen-Lev-Ran, A., and Seger, R. (2019). Nuclear ERK: Mechanism of Translocation, Substrates, and Role in Cancer. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20051194"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"665","DOI":"10.1128\/JVI.77.1.665-672.2003","article-title":"Regulation of human polyomavirus JC virus gene transcription by AP-1 in glial cells","volume":"77","author":"Sadowska","year":"2003","journal-title":"J. Virol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"12079","DOI":"10.1128\/JVI.01456-06","article-title":"NFAT4 is required for JC virus infection of glial cells","volume":"80","author":"Manley","year":"2006","journal-title":"J. Virol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"10506","DOI":"10.1128\/JVI.01355-06","article-title":"Interactions between c-Jun, nuclear factor 1, and JC virus promoter sequences: Implications for viral tropism","volume":"80","author":"Ravichandran","year":"2006","journal-title":"J. Virol."},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Ripple, M.J., Parker Struckhoff, A., Trillo-Tinoco, J., Li, L., Margolin, D.A., McGoey, R., and Del Valle, L. (2014). Activation of c-Myc and Cyclin D1 by JCV T-Antigen and beta-catenin in colon cancer. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0106257"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"9687","DOI":"10.1128\/JVI.75.20.9687-9695.2001","article-title":"JC virus multiplication in human hematopoietic progenitor cells requires the NF-1 class D transcription factor","volume":"75","author":"Monaco","year":"2001","journal-title":"J. Virol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/s12985-017-0707-7","article-title":"The DNA damage response promotes polyomavirus JC infection by nucleus to cytoplasm NF- kappaB activation","volume":"14","author":"White","year":"2017","journal-title":"Virol. J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"4378","DOI":"10.1074\/jbc.272.7.4378","article-title":"Differential regulation of Raf-1, A-Raf, and B-Raf by oncogenic ras and tyrosine kinases","volume":"272","author":"Marais","year":"1997","journal-title":"J. Biol. Chem."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"407","DOI":"10.1002\/biof.52","article-title":"The ERK signaling cascade--views from different subcellular compartments","volume":"35","author":"Yao","year":"2009","journal-title":"Biofactors"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1677\/erc.0.0080219","article-title":"Discovery of a novel Raf kinase inhibitor","volume":"8","author":"Lyons","year":"2001","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"7099","DOI":"10.1158\/0008-5472.CAN-04-1443","article-title":"BAY 43\u20139006 exhibits broad spectrum oral antitumor activity and targets the RAF\/MEK\/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis","volume":"64","author":"Wilhelm","year":"2004","journal-title":"Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"DuShane, J.K., and Maginnis, M.S. (2019). Human DNA Virus Exploitation of the MAPK-ERK Cascade. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20143427"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1779","DOI":"10.1101\/gad.523909","article-title":"Specific phosphorylation and activation of ERK1c by MEK1b: A unique route in the ERK cascade","volume":"23","author":"Shaul","year":"2009","journal-title":"Genes Dev."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1263","DOI":"10.1038\/sj.leu.2402945","article-title":"Signal transduction mediated by the Ras\/Raf\/MEK\/ERK pathway from cytokine receptors to transcription factors: Potential targeting for therapeutic intervention","volume":"17","author":"Chang","year":"2003","journal-title":"Leukemia"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1007\/BF02976565","article-title":"Transcriptional regulation of the glial cell-specific JC virus by p53","volume":"25","author":"Kim","year":"2002","journal-title":"Arch. Pharm. Res."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/sj.cr.7290105","article-title":"MAPK signal pathways in the regulation of cell proliferation in mammalian cells","volume":"12","author":"Zhang","year":"2002","journal-title":"Cell Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"5241","DOI":"10.1128\/JVI.77.9.5241-5252.2003","article-title":"Members of the AP-1 family, c-Jun and c-Fos, functionally interact with JC virus early regulatory protein large T antigen","volume":"77","author":"Kim","year":"2003","journal-title":"J. Virol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1016\/j.ymeth.2018.11.002","article-title":"Fluorescence-based quantification of nucleocytoplasmic transport","volume":"157","author":"Kelley","year":"2019","journal-title":"Methods"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"283","DOI":"10.1038\/sj.bjc.6601488","article-title":"Conferring specificity on the ubiquitous Raf\/MEK signalling pathway","volume":"90","author":"Kolch","year":"2004","journal-title":"Br. J. Cancer"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"947","DOI":"10.1083\/jcb.200709069","article-title":"Essential role of B-Raf in oligodendrocyte maturation and myelination during postnatal central nervous system development","volume":"180","author":"Catalanotti","year":"2008","journal-title":"J. Cell Biol."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"2262","DOI":"10.1128\/MCB.26.6.2262-2272.2006","article-title":"Regulation and role of Raf-1\/B-Raf heterodimerization","volume":"26","author":"Rushworth","year":"2006","journal-title":"Mol. Cell. Biol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"3207","DOI":"10.1038\/onc.2012.330","article-title":"ARAF acts as a scaffold to stabilize BRAF:CRAF heterodimers","volume":"32","author":"Rebocho","year":"2013","journal-title":"Oncogene"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"11022","DOI":"10.1073\/pnas.0901590106","article-title":"Signaling dynamics of the KSR1 scaffold complex","volume":"106","author":"McKay","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"81","DOI":"10.1101\/gad.6.1.81","article-title":"Max: Functional domains and interaction with c-Myc","volume":"6","author":"Kato","year":"1992","journal-title":"Genes Dev."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Thul, P.J., Akesson, L., Wiking, M., Mahdessian, D., Geladaki, A., Ait Blal, H., Alm, T., Asplund, A., Bjork, L., and Breckels, L.M. (2017). A subcellular map of the human proteome. Science, 356.","DOI":"10.1126\/science.aal3321"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"e3457","DOI":"10.7717\/peerj.3457","article-title":"Cytoplasmic expression of C-MYC protein is associated with risk stratification of mantle cell lymphoma","volume":"5","author":"Gong","year":"2017","journal-title":"PeerJ."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1257","DOI":"10.1073\/pnas.82.4.1257","article-title":"Establishment of a line of human fetal glial cells that supports JC virus multiplication","volume":"82","author":"Major","year":"1985","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"3910","DOI":"10.1128\/JVI.00089-15","article-title":"Modulation of a pore in the capsid of JC polyomavirus reduces infectivity and prevents exposure of the minor capsid proteins","volume":"89","author":"Nelson","year":"2015","journal-title":"J. Virol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/19\/4779\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:24:29Z","timestamp":1760189069000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/19\/4779"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,9,26]]},"references-count":61,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2019,10]]}},"alternative-id":["ijms20194779"],"URL":"https:\/\/doi.org\/10.3390\/ijms20194779","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,9,26]]}}}