{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:51:44Z","timestamp":1790394704011,"version":"4.1.0"},"reference-count":46,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,6,15]],"date-time":"2017-06-15T00:00:00Z","timestamp":1497484800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,6,15]],"date-time":"2017-06-15T00:00:00Z","timestamp":1497484800000},"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>As concerns increase about adenovirus type 5 (Ad5) being a safe gene transfer vector, it is important to evaluate its distribution, residence time, and possible toxicity in immunodeficient populations. To characterize the potential risk associated with different Ad5 vector delivery modes, we used immunocompetent and immunodeficient <jats:italic>Rag2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> animals to establish mouse and rat models that could be monitored with bioluminescent imaging following intramuscular or intravascular infection with an engineered replication-incompetent Ad5 virus carrying the firefly luciferase gene (Ad5-Fluc). The Ad5 vector was less well-tolerated by <jats:italic>Rag2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> animals than by wildtype ones, with delayed residence time, wider virus dissemination, less weight gain, and relatively severe pathological changes. In intravascularly Ad5-Fluc-infected <jats:italic>Rag2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice, systemic virus dissemination extended from the abdomen to the limbs and head on day 9 post-infection. Additionally, significant increases in plasma TNF-\u03b1 and IFN-\u03b3, which may be important factors in the heightened immunopathology in the liver and brain, were detected in the <jats:italic>Rag2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice 30 days after intravascular delivery. The Ad5 vector was better tolerated after intramuscular delivery than after intravascular delivery. Ad5-Fluc\/<jats:italic>Rag2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup> mice and rats can be used as reliable models of an immunodeficient population in which to evaluate the safety of Ad5-vectored vaccines or gene therapy products.<\/jats:p>","DOI":"10.1038\/s41598-017-03852-0","type":"journal-article","created":{"date-parts":[[2017,6,9]],"date-time":"2017-06-09T11:25:54Z","timestamp":1497007554000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":14,"title":["Biodistribution and residence time of adenovector serotype 5 in normal and immunodeficient mice and rats detected with bioluminescent imaging"],"prefix":"10.1038","volume":"7","author":[{"given":"Qiang","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shuya","family":"Zhou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Changfa","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weijin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianqian","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xi","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Baowen","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youchun","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2017,6,15]]},"reference":[{"key":"3852_CR1","doi-asserted-by":"publisher","first-page":"910","DOI":"10.1002\/jgm.1096","volume":"9","author":"EA Schenk-Braat","year":"2007","unstructured":"Schenk-Braat, E. A., van Mierlo, M. M., Wagemaker, G., Bangma, C. H. & Kaptein, L. C. An inventory of shedding data from clinical gene therapy trials. J Gene Med \n                           9, 910\u2013921 (2007).","journal-title":"J Gene Med"},{"key":"3852_CR2","doi-asserted-by":"publisher","first-page":"979","DOI":"10.1038\/sj.cgt.7700539","volume":"9","author":"T Reid","year":"2002","unstructured":"Reid, T., Warren, R. & Kirn, D. Intravascular adenoviral agents in cancer patients: lessons from clinical trials. Cancer Gene Ther \n                           9, 979\u2013986 (2002).","journal-title":"Cancer Gene Ther"},{"key":"3852_CR3","doi-asserted-by":"publisher","first-page":"2083","DOI":"10.1056\/NEJMoa1310566","volume":"369","author":"SM Hammer","year":"2013","unstructured":"Hammer, S. M. et al. Efficacy trial of a DNA\/rAd5 HIV-1 preventive vaccine. N Engl J Med \n                           369, 2083\u20132092 (2013).","journal-title":"N Engl J Med"},{"key":"3852_CR4","doi-asserted-by":"publisher","first-page":"301","DOI":"10.1089\/hum.2013.235","volume":"25","author":"D Majhen","year":"2014","unstructured":"Majhen, D. et al. Adenovirus-based vaccines for fighting infectious diseases and cancer: progress in the field. Hum Gene Ther \n                           25, 301\u2013317 (2014).","journal-title":"Hum Gene Ther"},{"key":"3852_CR5","doi-asserted-by":"publisher","first-page":"148","DOI":"10.1016\/j.ymgme.2003.08.016","volume":"80","author":"SE Raper","year":"2003","unstructured":"Raper, S. E. et al. Fatal systemic inflammatory response syndrome in a ornithine transcarbamylase deficient patient following adenoviral gene transfer. Mol Genet Metab \n                           80, 148\u2013158 (2003).","journal-title":"Mol Genet Metab"},{"key":"3852_CR6","first-page":"105","volume":"108","author":"N Teich","year":"2011","unstructured":"Teich, N. et al. Vaccination coverage in immunosuppressed patients: results of a regional health services research study. Dtsch Arztebl Int \n                           108, 105\u2013111 (2011).","journal-title":"Dtsch Arztebl Int"},{"key":"3852_CR7","doi-asserted-by":"publisher","first-page":"1557","DOI":"10.1126\/science.1176062","volume":"324","author":"C Fraser","year":"2009","unstructured":"Fraser, C. et al. Pandemic potential of a strain of influenza A (H1N1): early findings. Science. \n                           324, 1557\u20131561 (2009).","journal-title":"Science."},{"issue":"Suppl 4","key":"3852_CR8","doi-asserted-by":"publisher","first-page":"S211","DOI":"10.1513\/AnnalsATS.201401-038PL","volume":"11","author":"MP George","year":"2014","unstructured":"George, M. P. et al. Infections in the immunosuppressed host. Ann Am Thorac Soc. \n                           11(Suppl 4), S211\u2013220 (2014).","journal-title":"Ann Am Thorac Soc."},{"key":"3852_CR9","doi-asserted-by":"publisher","first-page":"11397","DOI":"10.1038\/srep11397","volume":"5","author":"Q Liu","year":"2015","unstructured":"Liu, Q. et al. Bioluminescent imaging of vaccinia virus infection in immunocompetent and immunodeficient rats as a model for human smallpox. Sci Rep \n                           5, 11397 (2015).","journal-title":"Sci Rep"},{"key":"3852_CR10","doi-asserted-by":"crossref","first-page":"2369","DOI":"10.1038\/ncomms3369","volume":"4","author":"W Pan","year":"2013","unstructured":"Pan, W. et al. Visualizing influenza virus infection in living mice. Nat Commun. \n                           4, 2369 (2013).","journal-title":"Nat Commun."},{"key":"3852_CR11","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1016\/0092-8674(92)90029-C","volume":"68","author":"Y Shinkai","year":"1992","unstructured":"Shinkai, Y. et al. RAG-2-deficient mice lack mature lymphocytes owing to inability to initiate V(D)J rearrangement. Cell. \n                           68, 855\u2013867 (1992).","journal-title":"Cell."},{"key":"3852_CR12","doi-asserted-by":"publisher","first-page":"464","DOI":"10.1038\/428464a","volume":"428","author":"A Abbott","year":"2004","unstructured":"Abbott, A. Laboratory animals: the Renaissance rat. Nature. \n                           428, 464\u2013466 (2004).","journal-title":"Nature."},{"key":"3852_CR13","doi-asserted-by":"publisher","first-page":"7171","DOI":"10.1128\/AAC.03860-14","volume":"58","author":"B Ying","year":"2014","unstructured":"Ying, B. et al. Ganciclovir inhibits human adenovirus replication and pathogenicity in permissive immunosuppressed Syrian hamsters. Antimicrob Agents Chemother \n                           58, 7171\u20137181 (2014).","journal-title":"Antimicrob Agents Chemother"},{"key":"3852_CR14","doi-asserted-by":"publisher","first-page":"7293","DOI":"10.1073\/pnas.0800200105","volume":"105","author":"K Toth","year":"2008","unstructured":"Toth, K. et al. Hexadecyloxypropyl-cidofovir, CMX001, prevents adenovirus-induced mortality in a permissive, immunosuppressed animal model. Proc Natl Acad Sci USA \n                           105, 7293\u20137297 (2008).","journal-title":"Proc Natl Acad Sci USA"},{"key":"3852_CR15","doi-asserted-by":"publisher","first-page":"2605","DOI":"10.1099\/0022-1317-81-11-2605","volume":"81","author":"R Alemany","year":"2000","unstructured":"Alemany, R., Suzuki, K. & Curiel, D. T. Blood clearance rates of adenovirus type 5 in mice. J Gen Virol \n                           81, 2605\u20132609 (2000).","journal-title":"J Gen Virol"},{"key":"3852_CR16","doi-asserted-by":"publisher","first-page":"2635","DOI":"10.4049\/jimmunol.164.5.2635","volume":"164","author":"K Mozdzanowska","year":"2000","unstructured":"Mozdzanowska, K., Maiese, K. & Gerhard, W. Th cell-deficient mice control influenza virus infection more effectively than Th- and B cell-deficient mice: evidence for a Th-independent contribution by B cells to virus clearance. J Immunol. \n                           164, 2635\u20132643 (2000).","journal-title":"J Immunol."},{"key":"3852_CR17","doi-asserted-by":"publisher","first-page":"5827","DOI":"10.4049\/jimmunol.175.9.5827","volume":"175","author":"BO Lee","year":"2005","unstructured":"Lee, B. O. et al. CD4 T cell-independent antibody response promotes resolution of primary influenza infection and helps to prevent reinfection. J Immunol. \n                           175, 5827\u20135838 (2005).","journal-title":"J Immunol."},{"key":"3852_CR18","doi-asserted-by":"publisher","first-page":"5368","DOI":"10.1128\/JVI.78.10.5368-5381.2004","volume":"78","author":"DM Shayakhmetov","year":"2004","unstructured":"Shayakhmetov, D. M., Li, Z. Y., Ni, S. & Lieber, A. Analysis of Adenovirus Sequestration in the Liver, Transduction of Hepatic Cells, and Innate Toxicity after Injection of Fiber-Modified Vectors. J Virol. \n                           78, 5368\u20135381 (2004).","journal-title":"J Virol."},{"key":"3852_CR19","doi-asserted-by":"publisher","first-page":"2729","DOI":"10.1016\/j.vaccine.2016.04.029","volume":"34","author":"S Zhou","year":"2016","unstructured":"Zhou, S. et al. A safe and sensitive enterovirus A71 infection model based on human SCARB2 knock-in mice. Vaccine. \n                           34, 2729\u20132736 (2016).","journal-title":"Vaccine."},{"key":"3852_CR20","doi-asserted-by":"publisher","first-page":"902","DOI":"10.1038\/sj.gt.3302949","volume":"14","author":"K Guse","year":"2007","unstructured":"Guse, K. et al. Luciferase imaging for evaluation of oncolytic adenovirus replication in vivo. Gene Ther \n                           14, 902\u2013911 (2007).","journal-title":"Gene Ther"},{"key":"3852_CR21","doi-asserted-by":"publisher","first-page":"1916","DOI":"10.1182\/blood-2007-02-062117","volume":"110","author":"N Tatsis","year":"2007","unstructured":"Tatsis, N. et al. Adenoviral vectors persist in vivo and maintain activated CD8+ T cells: implications for their use as vaccines. Blood. \n                           110, 1916\u20131923 (2007).","journal-title":"Blood."},{"key":"3852_CR22","doi-asserted-by":"publisher","first-page":"2230","DOI":"10.1096\/fj.00-0145com","volume":"14","author":"MO Hiltunen","year":"2000","unstructured":"Hiltunen, M. O. et al. Biodistribution of adenoviral vector to nontarget tissues after local in vivo gene transfer to arterial wall using intravascular and periadventitial gene delivery methods. FASEB J \n                           14, 2230\u20132236 (2000).","journal-title":"FASEB J"},{"key":"3852_CR23","doi-asserted-by":"publisher","first-page":"4866","DOI":"10.1128\/JVI.02819-06","volume":"81","author":"D Stone","year":"2007","unstructured":"Stone, D. et al. Adenovirus-platelet interaction in blood causes virus sequestration to the reticuloendothelial system of the liver. J Virol. \n                           81, 4866\u20134871 (2007).","journal-title":"J Virol."},{"key":"3852_CR24","doi-asserted-by":"publisher","first-page":"7836","DOI":"10.1128\/IAI.73.12.7836-7843.2005","volume":"73","author":"JL Kadurugamuwa","year":"2005","unstructured":"Kadurugamuwa, J. L. et al. Reduction of astrogliosis by early treatment of pneumococcal meningitis measured by simultaneous imaging, in vivo, of the pathogen and host response. Infect Immun. \n                           73, 7836\u20137843 (2005).","journal-title":"Infect Immun."},{"key":"3852_CR25","doi-asserted-by":"publisher","first-page":"357","DOI":"10.2217\/fvl.11.6","volume":"6","author":"SM Gregory","year":"2011","unstructured":"Gregory, S. M., Nazir, S. A. & Metcalf, J. P. Implications of the innate immune response to adenovirus and adenoviral vectors. Future Virol. \n                           6, 357\u2013374 (2011).","journal-title":"Future Virol."},{"key":"3852_CR26","doi-asserted-by":"publisher","first-page":"8692","DOI":"10.1128\/JVI.00527-07","volume":"81","author":"MJ Cameron","year":"2007","unstructured":"Cameron, M. J. et al. Interferon-mediated immunopathological events are associated with atypical innate and adaptive immune responses in patients with severe acute respiratory syndrome. J Virol. \n                           81, 8692\u20138706 (2007).","journal-title":"J Virol."},{"key":"3852_CR27","doi-asserted-by":"publisher","first-page":"1203","DOI":"10.1038\/nm1477","volume":"12","author":"MD de Jong","year":"2006","unstructured":"de Jong, M. D. et al. Fatal outcome of human influenza A (H5N1) is associated with high viral load and hypercytokinemia. Nat Med \n                           12, 1203\u20131207 (2006).","journal-title":"Nat Med"},{"key":"3852_CR28","doi-asserted-by":"publisher","first-page":"5368","DOI":"10.1128\/JVI.78.10.5368-5381.2004","volume":"78","author":"DM Shayakhmetov","year":"2004","unstructured":"Shayakhmetov, D. M., Li, Z. Y., Ni, S. & Lieber, A. Analysis of adenovirus sequestration in the liver, transduction of hepatic cells, and innate toxicity after injection of fiber-modified vectors. J Virol. \n                           78, 5368\u20135381 (2004).","journal-title":"J Virol."},{"key":"3852_CR29","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1089\/10430340152712665","volume":"13","author":"JN Lozier","year":"2002","unstructured":"Lozier, J. N. et al. Toxicity of a first-generation adenoviral vector in rhesus macaques. Hum Gene Ther \n                           13, 113\u2013124 (2002).","journal-title":"Hum Gene Ther"},{"key":"3852_CR30","doi-asserted-by":"publisher","first-page":"52","DOI":"10.1016\/j.virol.2004.06.043","volume":"328","author":"H Engler","year":"2004","unstructured":"Engler, H. et al. Acute hepatotoxicity of oncolytic adenoviruses in mouse models is associated with expression of wild-type E1a and induction of TNF-alpha. Virology. \n                           328, 52\u201361 (2004).","journal-title":"Virology."},{"key":"3852_CR31","doi-asserted-by":"publisher","first-page":"1685","DOI":"10.1056\/NEJMoa050333","volume":"353","author":"GD Rubenfeld","year":"2005","unstructured":"Rubenfeld, G. D. et al. Incidence and outcomes of acute lung injury. N Engl J Med \n                           353, 1685\u20131693 (2005).","journal-title":"N Engl J Med"},{"key":"3852_CR32","doi-asserted-by":"publisher","first-page":"721","DOI":"10.4049\/jimmunol.173.2.721","volume":"173","author":"L Xu","year":"2004","unstructured":"Xu, L. et al. Cutting edge: pulmonary immunopathology mediated by antigen-specific expression of TNF-alpha by antiviral CD8+ T cells. J Immunol. \n                           173, 721\u2013725 (2004).","journal-title":"J Immunol."},{"key":"3852_CR33","doi-asserted-by":"publisher","first-page":"965","DOI":"10.1089\/10430349950018364","volume":"10","author":"DA Muruve","year":"1999","unstructured":"Muruve, D. A., Barnes, M. J., Stillman, I. E. & Libermann, T. A. Adenoviral gene therapy leads to rapid induction of multiple chemokines and acute neutrophil-dependent hepatic injury in vivo. Hum Gene Ther \n                           10, 965\u2013976 (1999).","journal-title":"Hum Gene Ther"},{"key":"3852_CR34","doi-asserted-by":"crossref","first-page":"8798","DOI":"10.1128\/jvi.71.11.8798-8807.1997","volume":"71","author":"A Lieber","year":"1997","unstructured":"Lieber, A. et al. The role of Kupffer cell activation and viral gene expression in early liver toxicity after infusion of recombinant adenovirus vectors. J Virol. \n                           71, 8798\u20138807 (1997).","journal-title":"J Virol."},{"key":"3852_CR35","first-page":"637","volume":"14","author":"R Maier","year":"2008","unstructured":"Maier, R. et al. Multiplex bead analysis of vitreous and serum concentrations of inflammatory and proangiogenic factors in diabetic patients. Mol Vis. \n                           14, 637\u2013643 (2008).","journal-title":"Mol Vis."},{"key":"3852_CR36","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1089\/104303403321618146","volume":"14","author":"Q Liu","year":"2003","unstructured":"Liu, Q. et al. The role of capsid-endothelial interactions in the innate immune response to adenovirus vectors. Hum Gene Ther \n                           14, 627\u2013643 (2003).","journal-title":"Hum Gene Ther"},{"key":"3852_CR37","doi-asserted-by":"publisher","first-page":"732","DOI":"10.1038\/sj.mt.6300102","volume":"15","author":"N Brunetti-Pierri","year":"2007","unstructured":"Brunetti-Pierri, N. et al. Pseudo-hydrodynamic delivery of helper-dependent adenoviral vectors into non-human primates for liver-directed gene therapy. Mol Ther. \n                           15, 732\u2013740 (2007).","journal-title":"Mol Ther."},{"key":"3852_CR38","doi-asserted-by":"publisher","first-page":"2667","DOI":"10.1089\/10430349950016708","volume":"10","author":"P Ng","year":"1999","unstructured":"Ng, P. et al. A high-efficiency Cre\/loxP-based system for construction of adenoviral vectors. Hum Gene Ther \n                           10, 2667\u20132672 (1999).","journal-title":"Hum Gene Ther"},{"key":"3852_CR39","doi-asserted-by":"publisher","first-page":"6124","DOI":"10.1016\/j.vaccine.2008.09.017","volume":"26","author":"S Yu","year":"2008","unstructured":"Yu, S. et al. Potent specific immune responses induced by prime-boost-boost strategies based on DNA, adenovirus, and Sendai virus vectors expressing gag gene of Chinese HIV-1 subtype B. Vaccine. \n                           26, 6124\u20136131 (2008).","journal-title":"Vaccine."},{"key":"3852_CR40","doi-asserted-by":"publisher","first-page":"34","DOI":"10.1016\/j.brainres.2006.01.105","volume":"1081","author":"M Maeda","year":"2006","unstructured":"Maeda, M. et al. Targeted gene therapy toward astrocytoma using a Cre\/loxP-based adenovirus system. Brain Res. \n                           1081, 34\u201343 (2006).","journal-title":"Brain Res."},{"key":"3852_CR41","doi-asserted-by":"crossref","unstructured":"Nicholson, O. et al. Safety and Immunogenicity of the MRKAd5 gag HIV Type 1 Vaccine in a Worldwide Phase 1 Study of Healthy Adults. AIDS Res Hum Retroviruses (2010).","DOI":"10.1089\/aid.2010.0151"},{"key":"3852_CR42","doi-asserted-by":"publisher","first-page":"2508","DOI":"10.1200\/JCO.2003.21.13.2508","volume":"21","author":"FF Lang","year":"2003","unstructured":"Lang, F. F. et al. Phase I trial of adenovirus-mediated p53 gene therapy for recurrent glioma: biological and clinical results. J Clin Oncol \n                           21, 2508\u20132518 (2003).","journal-title":"J Clin Oncol"},{"key":"3852_CR43","doi-asserted-by":"publisher","first-page":"10437","DOI":"10.1128\/JVI.01296-09","volume":"83","author":"M Zaitseva","year":"2009","unstructured":"Zaitseva, M. et al. Application of bioluminescence imaging to the prediction of lethality in vaccinia virus-infected mice. J Virol. \n                           83, 10437\u201310447 (2009).","journal-title":"J Virol."},{"key":"3852_CR44","doi-asserted-by":"publisher","first-page":"6497","DOI":"10.4049\/jimmunol.177.9.6497","volume":"177","author":"P Sun","year":"2006","unstructured":"Sun, P. et al. CD40 ligand enhances dengue viral infection of dendritic cells: a possible mechanism for T cell-mediated immunopathology. J Immunol. \n                           177, 6497\u20136503 (2006).","journal-title":"J Immunol."},{"key":"3852_CR45","doi-asserted-by":"publisher","first-page":"5338","DOI":"10.1128\/JVI.00274-06","volume":"80","author":"B Shrestha","year":"2006","unstructured":"Shrestha, B. et al. Gamma interferon plays a crucial early antiviral role in protection against West Nile virus infection. J Virol. \n                           80, 5338\u20135348 (2006).","journal-title":"J Virol."},{"key":"3852_CR46","doi-asserted-by":"publisher","first-page":"7356","DOI":"10.4049\/jimmunol.181.10.7356","volume":"181","author":"XL Yu","year":"2008","unstructured":"Yu, X. L. et al. Measles virus infection in adults induces production of IL-10 and is associated with increased CD4+ CD25+ regulatory T cells. J Immunol. \n                           181, 7356\u20137366 (2008).","journal-title":"J Immunol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03852-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03852-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03852-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,23]],"date-time":"2022-12-23T05:28:23Z","timestamp":1671773303000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-017-03852-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,6,15]]},"references-count":46,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["3852"],"URL":"https:\/\/doi.org\/10.1038\/s41598-017-03852-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,6,15]]},"assertion":[{"value":"26 August 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 May 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 June 2017","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing Interests"}}],"article-number":"3597"}}