{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,6]],"date-time":"2026-03-06T06:59:19Z","timestamp":1772780359048,"version":"3.50.1"},"reference-count":45,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2019,10,8]],"date-time":"2019-10-08T00:00:00Z","timestamp":1570492800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2019,10,8]],"date-time":"2019-10-08T00:00:00Z","timestamp":1570492800000},"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>\n                    p21-activated kinases (PAKs) are serine\/threonine kinases functioning as downstream effectors of the small GTPases Rac1 and Cdc42. Members of the PAK family are overexpressed in human breast cancer, but their role in mammary gland development is not fully explored. Here we examined the functional role of PAK4 in mammary gland development by creating a mouse model of MMTV-Cre driven conditional PAK4 gene depletion in the mammary gland. The PAK4 conditional knock-out mice were born healthy, with no observed developmental deficits. Mammary gland whole-mounts revealed no defects in ductal formation or elongation of the mammary tree through the fat pad. PAK4 gene depletion also did not alter proliferation and invasion of the mammary epithelium in young virgin mice. Moreover, adult mice gave birth to healthy pups with normal body weight upon weaning. This implies that MMTV-Cre induced gene depletion of PAK4 in mice does not impair normal mammary gland development and thereby provides an\n                    <jats:italic>in vivo<\/jats:italic>\n                    model that can be explored for examination of the potential function of PAK4 in breast cancer.\n                  <\/jats:p>","DOI":"10.1038\/s41598-019-50819-4","type":"journal-article","created":{"date-parts":[[2019,10,8]],"date-time":"2019-10-08T06:25:35Z","timestamp":1570515935000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Normal mammary gland development after MMTV-Cre mediated conditional PAK4 gene depletion"],"prefix":"10.1038","volume":"9","author":[{"given":"Parisa","family":"Rabieifar","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ting","family":"Zhuang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6296-5225","authenticated-orcid":false,"given":"T\u00e2nia D. F.","family":"Costa","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Miao","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1236-6339","authenticated-orcid":false,"given":"Staffan","family":"Str\u00f6mblad","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,10,8]]},"reference":[{"key":"50819_CR1","doi-asserted-by":"publisher","first-page":"274","DOI":"10.1016\/0012-1606(83)90086-6","volume":"97","author":"JMDC Williams","year":"1983","unstructured":"Williams, J. M. D. C. Mammary ductal elongation: differentiation of myoepithelium and basal lamina during branching morphogenesis. Dev Biol 97, 274\u2013290 (1983).","journal-title":"Dev Biol"},{"key":"50819_CR2","doi-asserted-by":"crossref","unstructured":"Cheryll Tickle, H.-S. J. Embryonic Mammary Gland Development. eLS (2016).","DOI":"10.1002\/9780470015902.a0026057"},{"key":"50819_CR3","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1002\/wdev.35","volume":"1","author":"H Macias","year":"2012","unstructured":"Macias, H. & Hinck, L. Mammary gland development. Wiley Interdiscip Rev Dev Biol 1, 533\u2013557, https:\/\/doi.org\/10.1002\/wdev.35 (2012).","journal-title":"Wiley Interdiscip Rev Dev Biol"},{"key":"50819_CR4","doi-asserted-by":"publisher","first-page":"1028","DOI":"10.1242\/dev.087643","volume":"142","author":"JL Inman","year":"2015","unstructured":"Inman, J. L., Robertson, C., Mott, J. D. & Bissell, M. J. Mammary gland development: cell fate specification, stem cells and the microenvironment. Development 142, 1028\u20131042, https:\/\/doi.org\/10.1242\/dev.087643 (2015).","journal-title":"Development"},{"key":"50819_CR5","doi-asserted-by":"publisher","first-page":"1041","DOI":"10.1016\/j.cell.2006.09.048","volume":"127","author":"H Kouros-Mehr","year":"2006","unstructured":"Kouros-Mehr, H., Slorach, E. M., Sternlicht, M. D. & Werb, Z. GATA-3 maintains the differentiation of the luminal cell fate in the mammary gland. Cell 127, 1041\u20131055, https:\/\/doi.org\/10.1016\/j.cell.2006.09.048 (2006).","journal-title":"Cell"},{"key":"50819_CR6","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1002\/iub.1365","volume":"67","author":"R Zaragoza","year":"2015","unstructured":"Zaragoza, R., Garcia-Trevijano, E. R., Lluch, A., Ribas, G. & Vina, J. R. Involvement of Different networks in mammary gland involution after the pregnancy\/lactation cycle: Implications in breast cancer. IUBMB Life 67, 227\u2013238, https:\/\/doi.org\/10.1002\/iub.1365 (2015).","journal-title":"IUBMB Life"},{"key":"50819_CR7","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1016\/j.biocel.2006.11.004","volume":"39","author":"E Katz","year":"2007","unstructured":"Katz, E. & Streuli, C. H. The extracellular matrix as an adhesion checkpoint for mammary epithelial function. Int J Biochem Cell Biol 39, 715\u2013726, https:\/\/doi.org\/10.1016\/j.biocel.2006.11.004 (2007).","journal-title":"Int J Biochem Cell Biol"},{"key":"50819_CR8","doi-asserted-by":"publisher","first-page":"1948","DOI":"10.1210\/me.2014-1128","volume":"28","author":"Y Zuo","year":"2014","unstructured":"Zuo, Y., Berdeaux, R. & Frost, J. A. The RhoGEF Net1 is required for normal mammary gland development. Mol Endocrinol 28, 1948\u20131960, https:\/\/doi.org\/10.1210\/me.2014-1128 (2014).","journal-title":"Mol Endocrinol"},{"key":"50819_CR9","doi-asserted-by":"publisher","first-page":"13","DOI":"10.1038\/nrc3645","volume":"14","author":"M Radu","year":"2014","unstructured":"Radu, M., Semenova, G., Kosoff, R. & Chernoff, J. PAK signalling during the development and progression of cancer. Nat Rev Cancer 14, 13\u201325 (2014).","journal-title":"Nat Rev Cancer"},{"key":"50819_CR10","doi-asserted-by":"publisher","first-page":"659","DOI":"10.1038\/nrc1892","volume":"6","author":"R Kumar","year":"2006","unstructured":"Kumar, R., Gururaj, A. E. & Barnes, C. J. p21-activated kinases in cancer. Nature Reviews Cancer 6, 659\u2013471 (2006).","journal-title":"Nature Reviews Cancer"},{"key":"50819_CR11","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcancer.2018.01.006","author":"CK Rane","year":"2018","unstructured":"Rane, C. K. & Minden, A. P21 activated kinase signaling in cancer. Semin Cancer Biol. https:\/\/doi.org\/10.1016\/j.semcancer.2018.01.006 (2018).","journal-title":"Semin Cancer Biol"},{"key":"50819_CR12","doi-asserted-by":"crossref","unstructured":"Poonam R., Molli, D.-Q. L., Murray Brion, Suresh K. Rayala, Rakesh Kumar. PAK Signaling in Oncogenesis. 28 28, 2545\u20132555 (2010).","DOI":"10.1038\/onc.2009.119"},{"key":"50819_CR13","doi-asserted-by":"publisher","first-page":"129","DOI":"10.1016\/j.ejcb.2013.03.002","volume":"92","author":"AE Dart","year":"2013","unstructured":"Dart, A. E. & Wells, C. M. P21-activated kinase 4\u2013not just one of the PAK. Eur J Cell Biol 92, 129\u2013138, https:\/\/doi.org\/10.1016\/j.ejcb.2013.03.002 (2013).","journal-title":"Eur J Cell Biol"},{"key":"50819_CR14","doi-asserted-by":"publisher","first-page":"6527","DOI":"10.1093\/emboj\/17.22.6527","volume":"17","author":"A Abo","year":"1998","unstructured":"Abo, A. et al. PAK4, a novel effector for Cdc42Hs, is implicated in the reorganization of the actin cytoskeleton and in the formation of filopodia. Embo J 17, 6527\u20136540, https:\/\/doi.org\/10.1093\/emboj\/17.22.6527 (1998).","journal-title":"Embo J"},{"key":"50819_CR15","doi-asserted-by":"crossref","unstructured":"Li, Z. et al.\u00a0 Integrin-mediated Cell Attachment Induces a PAK4-dependent Feedback Loop Regulating Cell Adhesion through Modified Integrin \u03b1v\u03b25 Clustering and Turnover. Molecular Biology of the Cell 21, 3317\u20133329 (2010).","DOI":"10.1091\/mbc.e10-03-0245"},{"key":"50819_CR16","doi-asserted-by":"publisher","first-page":"550","DOI":"10.1074\/jbc.M105732200","volume":"277","author":"MG Callow","year":"2002","unstructured":"Callow, M. G. et al. Requirement for PAK4 in the anchorage-independent growth of human cancer cell lines. J Biol Chem 277, 550\u2013558, https:\/\/doi.org\/10.1074\/jbc.M105732200 (2002).","journal-title":"J Biol Chem"},{"key":"50819_CR17","doi-asserted-by":"crossref","unstructured":"Li Z, et al. p21-activated kinase 4 phosphorylation of integrin beta5 Ser-759 and Ser-762 regulates cell migration. J Biol Chem 285, 23699\u201323710 (2010).\u00a0","DOI":"10.1074\/jbc.M110.123497"},{"key":"50819_CR18","doi-asserted-by":"crossref","unstructured":"Zhang, H., Li, Z. & Viklund, EK. Str\u00f6mblad S. P21-activated kinase 4 interacts with integrin alpha v beta 5 and regulates alpha v beta 5-mediated cell migration. J Cell Biol 158, 1287\u20131297 (2002).\u00a0","DOI":"10.1083\/jcb.200207008"},{"key":"50819_CR19","doi-asserted-by":"publisher","first-page":"7122","DOI":"10.1128\/MCB.23.20.7122-7133.2003","volume":"23","author":"J Qu","year":"2003","unstructured":"Qu, J. et al. PAK4 kinase is essential for embryonic viability and for proper neuronal development. Mol Cell Biol 23, 7122\u20137133 (2003).","journal-title":"Mol Cell Biol"},{"key":"50819_CR20","doi-asserted-by":"publisher","first-page":"710","DOI":"10.1016\/j.mod.2009.05.002","volume":"126","author":"Y Tian","year":"2009","unstructured":"Tian, Y., Lei, L., Cammarano, M., Nekrasova, T. & Minden, A. Essential role for the Pak4 protein kinase in extraembryonic tissue development and vessel formation. Mech Dev 126, 710\u2013720, https:\/\/doi.org\/10.1016\/j.mod.2009.05.002 (2009).","journal-title":"Mech Dev"},{"key":"50819_CR21","doi-asserted-by":"publisher","first-page":"206","DOI":"10.1016\/j.ydbio.2011.02.026","volume":"353","author":"Y Tian","year":"2011","unstructured":"Tian, Y., Lei, L. & Minden, A. A key role for Pak4 in proliferation and differentiation of neural progenitor cells. Dev Biol 353, 206\u2013216, https:\/\/doi.org\/10.1016\/j.ydbio.2011.02.026 (2011).","journal-title":"Dev Biol"},{"key":"50819_CR22","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1007\/s11248-011-9578-7","volume":"21","author":"TMA Nekrasova","year":"2012","unstructured":"Nekrasova, T. M. A. Role for p21-activated kinase PAK4 in development of the mammalian heart. Transgenic Res 21, 797\u2013811 (2012).","journal-title":"Transgenic Res"},{"key":"50819_CR23","doi-asserted-by":"publisher","first-page":"545","DOI":"10.1023\/A:1013063514007","volume":"10","author":"KU Wagner","year":"2001","unstructured":"Wagner, K. U., Ward, M. K., Davis, T., Wiseman, B. & Hennighausen, R. L Spatial and temporal expression of the Cre gene under the control of the MMTV-LTR in different lines of transgenic mice. Transgenic Res 10, 545\u2013553 (2001).","journal-title":"Transgenic Res"},{"key":"50819_CR24","doi-asserted-by":"publisher","first-page":"5080","DOI":"10.1093\/nar\/23.24.5080","volume":"23","author":"F Schwenk","year":"1995","unstructured":"Schwenk, F., Baron, U. & Rajewsky, K. A cre-transgenic mouse strain for the ubiquitous deletion of loxP-flanked gene segments including deletion in germ cells. Nucleic Acids Res 23, 5080\u20135081 (1995).","journal-title":"Nucleic Acids Res"},{"key":"50819_CR25","doi-asserted-by":"publisher","first-page":"4323","DOI":"10.1093\/nar\/25.21.4323","volume":"25","author":"KU Wagner","year":"1997","unstructured":"Wagner, K. U. et al. Cre-mediated gene deletion in the mammary gland. Nucleic Acids Res 25, 4323\u20134330 (1997).","journal-title":"Nucleic Acids Res"},{"key":"50819_CR26","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1172\/JCI37160","volume":"119","author":"Y Pylayeva","year":"2009","unstructured":"Pylayeva, Y. et al. Ras- and PI3K-dependent breast tumorigenesis in mice and humans requires focal adhesion kinase signaling. The Journal of clinical investigation 119, 252\u2013266, https:\/\/doi.org\/10.1172\/JCI37160 (2009).","journal-title":"The Journal of clinical investigation"},{"key":"50819_CR27","doi-asserted-by":"crossref","unstructured":"Laila Elsherif, M. O. et al. Potential Compensation among Group I PAK Members in Hindlimb Ischemia and Wound Healing. PLoS One 10 (2014).","DOI":"10.1371\/journal.pone.0112239"},{"key":"50819_CR28","doi-asserted-by":"publisher","first-page":"857","DOI":"10.1002\/hipo.20451","volume":"18","author":"BJL Boda","year":"2008","unstructured":"Boda, B. J. L. & Muller, D. Distinct, but compensatory roles of PAK1 and PAK3 in spine morphogenesis. Hippocampus 18, 857\u2013861 (2008).","journal-title":"Hippocampus"},{"key":"50819_CR29","doi-asserted-by":"publisher","first-page":"43853","DOI":"10.18632\/oncotarget.6081","volume":"6","author":"T Zhuang","year":"2015","unstructured":"Zhuang, T. et al. p21-activated kinase group II small compound inhibitor GNE-2861 perturbs estrogen receptor alpha signaling and restores tamoxifen-sensitivity in breast cancer cells. Oncotarget 6, 43853\u201343868, https:\/\/doi.org\/10.18632\/oncotarget.6081 (2015).","journal-title":"Oncotarget"},{"key":"50819_CR30","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1038\/cddis.2012.182","volume":"3","author":"D Close","year":"2012","unstructured":"Close, D., Kesanakurti, C. C., Rajasekhar Maddirela, D., Gujrati, M. & Rao, J. S. Functional cooperativity by direct interaction between PAK4 and MMP-2 in the regulation of anoikis resistance, migration and invasion in glioma. Cell death Disease 3, 445 (2012).","journal-title":"Cell death Disease"},{"key":"50819_CR31","doi-asserted-by":"publisher","first-page":"3015","DOI":"10.2353\/ajpath.2010.091263","volume":"176","author":"MK Siu","year":"2010","unstructured":"Siu, M. K. et al. p21-Activated kinase-1 promotes aggressive phenotype, cell proliferation, and invasion in gestational trophoblastic disease. Am J Pathol 176, 3015\u20133022, https:\/\/doi.org\/10.2353\/ajpath.2010.091263 (2010).","journal-title":"Am J Pathol"},{"key":"50819_CR32","doi-asserted-by":"crossref","first-page":"439","DOI":"10.1242\/dev.112.2.439","volume":"112","author":"RS Talhouk","year":"1991","unstructured":"Talhouk, R. S., Chin, J. R., Unemori, E. N., Werb, Z. & Bissell, M. J. Proteinases of the mammary gland: developmental regulation in vivo and vectorial secretion in culture. Development 112, 439\u2013449 (1991).","journal-title":"Development"},{"key":"50819_CR33","doi-asserted-by":"publisher","first-page":"805","DOI":"10.1101\/gad.211383.112","volume":"27","author":"ALMH Correia","year":"2013","unstructured":"Correia, A. L. M. H., Chen, E. I., Schmitt, F. C. & Bissell, M. J. The hemopexin domain of MMP3 is responsible for mammary epithelial invasion and morphogenesis through extracellular interaction with HSP90\u03b2. Genes Dev 27, 805\u2013817 (2013).","journal-title":"Genes Dev"},{"key":"50819_CR34","doi-asserted-by":"publisher","first-page":"84","DOI":"10.4161\/cl.21381","volume":"2","author":"MLKaJ Chernoff","year":"2012","unstructured":"Chernoff, M. L. Ka. J. Mouse models of PAK function. Cell Logist 2, 84\u201388 (2012).","journal-title":"Cell Logist"},{"key":"50819_CR35","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-017-07322-5","volume":"7","author":"M Zhao","year":"2017","unstructured":"Zhao, M. et al. Pdx1-Cre-driven conditional gene depletion suggests PAK4 as dispensable for mouse pancreas development. Sci Rep 7, 7031, https:\/\/doi.org\/10.1038\/s41598-017-07322-5 (2017).","journal-title":"Sci Rep"},{"key":"50819_CR36","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1083\/jcb.200212066","volume":"161","author":"RKV Rui-An Wang","year":"2003","unstructured":"Rui-An Wang, R. K. V. et al. Essential functions of p21-activated kinase 1 in morphogenesis and differentiation of mammary glands. J Cell Biol 161, 583\u2013592 (2003).","journal-title":"J Cell Biol"},{"key":"50819_CR37","doi-asserted-by":"publisher","first-page":"7134","DOI":"10.1128\/MCB.23.20.7134-7142.2003","volume":"23","author":"XMA Li","year":"2003","unstructured":"Li, X. M. A. Targeted disruption of the gene for the PAK5 kinase in mice. Mol Cell Bio 23, 7134\u20137142 (2003).","journal-title":"Mol Cell Bio"},{"key":"50819_CR38","doi-asserted-by":"publisher","first-page":"109","DOI":"10.1179\/1476830513Y.0000000072","volume":"17","author":"MA Furnari","year":"2014","unstructured":"Furnari, M. A., Jobes, M. L., Nekrasova, T., Minden, A. & Wagner, G. C. Differential sensitivity of Pak5, Pak6, and Pak5\/Pak6 double-knockout mice to the stimulant effects of amphetamine and exercise-induced alterations in body weight. Nutritional neuroscience 17, 109\u2013115 (2014).","journal-title":"Nutritional neuroscience"},{"key":"50819_CR39","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-11510-4","volume":"10","author":"TDF Costa","year":"2019","unstructured":"Costa, T. D. F. et al. PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer. Nat Commun 10, 3589, https:\/\/doi.org\/10.1038\/s41467-019-11510-4 (2019).","journal-title":"Nat Commun"},{"key":"50819_CR40","doi-asserted-by":"publisher","first-page":"954","DOI":"10.1128\/MCB.12.3.954","volume":"12","author":"CT Guy","year":"1992","unstructured":"Guy, C. T., Cardiff, R. D. & Muller, W. J. Induction of mammary tumors by expression of polyomavirus middle T oncogene: a transgenic mouse model for metastatic disease. Mol Cell Biol 12, 954\u2013961 (1992).","journal-title":"Mol Cell Biol"},{"key":"50819_CR41","doi-asserted-by":"publisher","first-page":"2113","DOI":"10.1016\/s0002-9440(10)63568-7","volume":"163","author":"EY Lin","year":"2003","unstructured":"Lin, E. Y. et al. Progression to malignancy in the polyoma middle T oncoprotein mouse breast cancer model provides a reliable model for human diseases. Am J Pathol 163, 2113\u20132126, https:\/\/doi.org\/10.1016\/s0002-9440(10)63568-7 (2003).","journal-title":"Am J Pathol"},{"key":"50819_CR42","doi-asserted-by":"crossref","unstructured":"Rennhack J, To B, Wermuth H, Andrechek ER. Mouse Models of Breast Cancer Share Amplification and Deletion Events with Human Breast Cancer. J Mammary Gland Biol Neoplasia 22, 71\u201384 (2017).\u00a0","DOI":"10.1007\/s10911-017-9374-y"},{"key":"50819_CR43","doi-asserted-by":"publisher","first-page":"92","DOI":"10.1016\/j.ab.2011.01.020","volume":"412","author":"GW Robinson","year":"2011","unstructured":"Robinson, G. W. & Hennighausen, L. MMTV-Cre transgenes can adversely affect lactation: considerations for conditional gene deletion in mammary tissue. Anal Biochem 412, 92\u201395, https:\/\/doi.org\/10.1016\/j.ab.2011.01.020 (2011).","journal-title":"Anal Biochem"},{"key":"50819_CR44","doi-asserted-by":"publisher","first-page":"e43778","DOI":"10.1371\/journal.pone.0043778","volume":"7","author":"KSJ Sakamoto","year":"2012","unstructured":"Sakamoto, K. S. J. & Wagner, K.-U. Generation of a Novel MMTV-tTA Transgenic Mouse Strain for the Targeted Expression of Genes in the Embryonic and Postnatal Mammary Gland. PLoS One 7, e43778 (2012).","journal-title":"PLoS One"},{"key":"50819_CR45","doi-asserted-by":"publisher","first-page":"655","DOI":"10.1101\/pdb.prot073411","volume":"2014","author":"RD Cardiff","year":"2014","unstructured":"Cardiff, R. D., Miller, C. H. & Munn, R. J. Manual hematoxylin and eosin staining of mouse tissue sections. Cold Spring Harb Protoc 2014, 655\u2013658, https:\/\/doi.org\/10.1101\/pdb.prot073411 (2014).","journal-title":"Cold Spring Harb Protoc"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50819-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50819-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50819-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,17]],"date-time":"2022-12-17T09:19:20Z","timestamp":1671268760000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-019-50819-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,10,8]]},"references-count":45,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["50819"],"URL":"https:\/\/doi.org\/10.1038\/s41598-019-50819-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/658583","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,10,8]]},"assertion":[{"value":"15 March 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 September 2019","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 October 2019","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":"14436"}}