{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T02:50:50Z","timestamp":1790736650660,"version":"4.1.0"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,12,9]],"date-time":"2016-12-09T00:00:00Z","timestamp":1481241600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,12,9]],"date-time":"2016-12-09T00:00:00Z","timestamp":1481241600000},"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>Psoriasis vulgaris is a chronic inflammatory skin disease affecting millions of people. Its pathophysiology is complex and involves a skin compartment with epidermal and immune cells which produce cytokines, e.g. belonging to the IL-23\u2013Th17-cell axis. Glucocorticoids (GCs) are the most common therapeutics used in cutaneous inflammatory disorders and GC-induced leucine zipper (GILZ) has emerged as a mediator of GCs due to its anti-inflammatory actions, theoretically lacking GC side-effects. We evaluated whether GILZ may provide a better therapeutic index in comparison to GCs during the onset and progression of psoriasis by generating and characterizing a mouse model with generalized overexpression of this protein (GILZ-Tg mice) and the imiquimod (IMQ) psoriasis model. Unexpectedly, in GILZ-Tg mice, the severity of IMQ-induced psoriasis-like skin lesions as well as induction of cytokines commonly up-regulated in human psoriasis (<jats:italic>Il-17, Il-22, Il-23, Il-6, S100a8\/a9<\/jats:italic>, and <jats:italic>Stat3<\/jats:italic>) was significantly more pronounced relative to GILZ-Wt mice. The increased susceptibility to IMQ-induced psoriasis of GILZ-Tg mice was significantly associated with skin-specific over-activation of TGF-\u03b21-mediated signaling via SMAD2\/3. Our findings demonstrate that GILZ may behave as pro-inflammatory protein in certain tissues and that, similar to prolonged GC therapy, GILZ as an alternative treatment for psoriasis may also have adverse effects.<\/jats:p>","DOI":"10.1038\/srep38825","type":"journal-article","created":{"date-parts":[[2016,12,9]],"date-time":"2016-12-09T13:03:13Z","timestamp":1481288593000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Overexpression of Glucocorticoid-induced Leucine Zipper (GILZ) increases susceptibility to Imiquimod-induced psoriasis and involves cutaneous activation of TGF-\u03b21"],"prefix":"10.1038","volume":"6","author":[{"given":"Elena","family":"Carceller","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marlies","family":"Ballegeer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Deckers","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carlo","family":"Riccardi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefano","family":"Bruscoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tino","family":"Hochepied","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claude","family":"Libert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paloma","family":"P\u00e9rez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,12,9]]},"reference":[{"key":"BFsrep38825_CR1","doi-asserted-by":"crossref","first-page":"423","DOI":"10.1242\/dmm.009092","volume":"5","author":"LM Johnson-Huang","year":"2012","unstructured":"Johnson-Huang, L. M., Lowes, M. A. & Krueger, J. G. Putting together the psoriasis puzzle: an update on developing targeted therapies. Dis. Model Mech. 5, 423\u2013433 (2012).","journal-title":"Dis. Model Mech"},{"key":"BFsrep38825_CR2","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1189\/jlb.0212101","volume":"92","author":"MM Elloso","year":"2012","unstructured":"Elloso, M. M., Gomez-Angelats, M. & Fourie, A. M. Targeting the Th17 pathway in psoriasis. J. Leukoc. Biol. 92, 1187\u20131197 (2012).","journal-title":"J. Leukoc. Biol."},{"key":"BFsrep38825_CR3","doi-asserted-by":"crossref","first-page":"10723","DOI":"10.1073\/pnas.1307569110","volume":"110","author":"C Wohn","year":"2013","unstructured":"Wohn, C. et al. Langerin(neg) conventional dendritic cells produce IL-23 to drive psoriatic plaque formation in mice. Proc. Natl. Acad. Sci. USA 110, 10723\u201310728 (2013).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"BFsrep38825_CR4","doi-asserted-by":"crossref","first-page":"1912","DOI":"10.1038\/jid.2014.98","volume":"134","author":"R Yoshiki","year":"2014","unstructured":"Yoshiki, R. et al. IL-23 from Langerhans cells is required for the development of imiquimod-induced psoriasis-like dermatitis by induction of IL-17A-producing \u03b3\u03b4 T cells. J. Invest. Dermatol. 134, 1912\u20131921 (2014).","journal-title":"J. Invest. Dermatol."},{"key":"BFsrep38825_CR5","doi-asserted-by":"crossref","first-page":"1292","DOI":"10.1038\/sj.jid.5700807","volume":"127","author":"JE Gudjonsson","year":"2007","unstructured":"Gudjonsson, J. E., Johnston, A., Dyson, M., Valdimarsson, H. & Elder, J. T. Mouse models of psoriasis. J. Invest. Dermatol. 127, 1292\u20131308 (2007).","journal-title":"J. Invest. Dermatol."},{"key":"BFsrep38825_CR6","doi-asserted-by":"crossref","first-page":"704","DOI":"10.1038\/nrrheum.2010.157","volume":"6","author":"EF Wagner","year":"2010","unstructured":"Wagner, E. F., Schonthaler, H. B., Guinea-Viniegra, J. & Tschachler, E. Psoriasis: what we have learned from mouse models. Nat. Rev. Rheumatol. 6, 704\u2013714 (2010).","journal-title":"Nat. Rev. Rheumatol"},{"key":"BFsrep38825_CR7","doi-asserted-by":"crossref","first-page":"1770","DOI":"10.1038\/sj.emboj.7600183","volume":"23","author":"AG Li","year":"2004","unstructured":"Li, A. G., Wang, D., Feng, X. H. & Wang, X. J. Latent TGFbeta1 overexpression in keratinocytes results in a severe psoriasis-like skin disorder. EMBO J. 23, 1770\u20131781 (2004).","journal-title":"EMBO J."},{"key":"BFsrep38825_CR8","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1038\/nm1162","volume":"11","author":"S Sano","year":"2005","unstructured":"Sano, S. et al. Stat3 links activated keratinocytes and immunocytes required for development of psoriasis in a novel transgenic mouse model. Nat. Med. 11, 43\u201349 (2005).","journal-title":"Nat. Med."},{"key":"BFsrep38825_CR9","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1038\/nature03963","volume":"437","author":"R Zenz","year":"2005","unstructured":"Zenz, R. et al. Psoriasis-like skin disease and arthritis caused by inducible epidermal deletion of Jun proteins. Nature 437, 369\u2013375 (2005).","journal-title":"Nature"},{"key":"BFsrep38825_CR10","doi-asserted-by":"crossref","first-page":"287","DOI":"10.2174\/187153012802002901","volume":"12","author":"M Rahman","year":"2012","unstructured":"Rahman, M. et al. Classical to current approach for treatment of psoriasis: a review. Endocr Metab Immune Disord. Drug Targets 12, 287\u2013302 (2012).","journal-title":"Endocr Metab Immune Disord. Drug Targets"},{"key":"BFsrep38825_CR11","first-page":"561018","volume":"2012","author":"L Uva","year":"2012","unstructured":"Uva, L. et al. Mechanisms of action of topical corticosteroids in psoriasis. Int. J. Endocrinol. 2012, 561018 (2012).","journal-title":"Int. J. Endocrinol."},{"key":"BFsrep38825_CR12","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1016\/j.tips.2013.07.003","volume":"34","author":"M Kadmiel","year":"2013","unstructured":"Kadmiel, M. & Cidlowski, J. A. Glucocorticoid receptor signaling in health and disease. Trends Pharm. Sci. 34, 518\u2013530 (2013).","journal-title":"Trends Pharm. Sci"},{"key":"BFsrep38825_CR13","doi-asserted-by":"crossref","first-page":"993","DOI":"10.1210\/en.2012-2045","volume":"154","author":"S Vandevyver","year":"2013","unstructured":"Vandevyver, S., Dejager, L., Tuckermann, J. & Libert, C. New insights into the anti-inflammatory mechanisms of glucocorticoids: an emerging role for glucocorticoid-receptor-mediated transactivation. Endocrinology 154, 993\u20131007 (2013).","journal-title":"Endocrinology"},{"key":"BFsrep38825_CR14","doi-asserted-by":"crossref","first-page":"3649","DOI":"10.1096\/fj.09-134684","volume":"23","author":"E Ayroldi","year":"2009","unstructured":"Ayroldi, E. & Riccardi, C. Glucocorticoid-induced leucine zipper (GILZ): a new important mediator of glucocorticoid action. FASEB J. 23, 3649\u20133658 (2009).","journal-title":"FASEB J."},{"key":"BFsrep38825_CR15","doi-asserted-by":"crossref","first-page":"169","DOI":"10.3389\/fphar.2014.00169","volume":"5","author":"Q Cheng","year":"2014","unstructured":"Cheng, Q. & Yang, Y. H. Development of novel treatment strategies for inflammatory diseases-similarities and divergence between glucocorticoids and GILZ. Front. Pharmacol. 5, 169 (2014).","journal-title":"Front. Pharmacol"},{"key":"BFsrep38825_CR16","doi-asserted-by":"crossref","first-page":"803","DOI":"10.1016\/S1074-7613(00)80398-2","volume":"7","author":"F D\u2019Adamio","year":"1997","unstructured":"D\u2019Adamio, F. et al. A new dexamethasone-induced gene of the leucine zipper family protects T lymphocytes from TCR\/CD3-activated cell death. Immunity 7, 803\u2013812 (1997).","journal-title":"Immunity"},{"key":"BFsrep38825_CR17","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1182\/blood.V98.3.743","volume":"98","author":"E Ayroldi","year":"2001","unstructured":"Ayroldi, E. et al. Modulation of T-cell activation by the glucocorticoid-induced leucine zipper factor via inhibition of nuclear factor kappaB. Blood 98, 743\u2013753 (2001).","journal-title":"Blood"},{"key":"BFsrep38825_CR18","doi-asserted-by":"crossref","first-page":"44799","DOI":"10.1074\/jbc.M111.279257","volume":"286","author":"M Srinivasan","year":"2011","unstructured":"Srinivasan, M. & Janardhanam, S. Novel p65 binding glucocorticoid-induced leucine zipper peptide suppresses experimental autoimmune encephalomyelitis. J. Biol. Chem. 286, 44799\u201344810 (2011).","journal-title":"J. Biol. Chem."},{"key":"BFsrep38825_CR19","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1038\/nrrheum.2011.59","volume":"7","author":"E Beaulieu","year":"2011","unstructured":"Beaulieu, E. & Morand, E. F. Role of GILZ in immune regulation, glucocorticoid actions and rheumatoid arthritis. Nat. Rev. Rheumatol. 7, 340\u2013348 (2011).","journal-title":"Nat. Rev. Rheumatol"},{"key":"BFsrep38825_CR20","doi-asserted-by":"crossref","first-page":"424","DOI":"10.4049\/jimmunol.1202662","volume":"191","author":"Q Cheng","year":"2013","unstructured":"Cheng, Q. et al. GILZ overexpression inhibits endothelial cell adhesive function through regulation of NF-\u03baB and MAPK activity. J. Immunol. 191, 424\u2013433 (2013).","journal-title":"J. Immunol."},{"key":"BFsrep38825_CR21","doi-asserted-by":"crossref","first-page":"38446","DOI":"10.18632\/oncotarget.6197","volume":"6","author":"J Hoppst\u00e4dter","year":"2015","unstructured":"Hoppst\u00e4dter, J. & Kiemer, A. K. Glucocorticoid-induced leucine zipper (GILZ) in immuno suppression: master regulator or bystander? Oncotarget 6, 38446\u20133857 (2015).","journal-title":"Oncotarget"},{"key":"BFsrep38825_CR22","doi-asserted-by":"crossref","first-page":"170","DOI":"10.3389\/fendo.2015.00170","volume":"6","author":"S Ronchetti","year":"2015","unstructured":"Ronchetti, S., Migliorati, G. & Riccardi, C. GILZ as a Mediator of the Anti-Inflammatory Effects of Glucocorticoids. Front. Endocrinol. (Lausanne) 6, 170 (2015).","journal-title":"Front. Endocrinol. (Lausanne)"},{"key":"BFsrep38825_CR23","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1053\/j.gastro.2008.09.024","volume":"136","author":"L Cannarile","year":"2009","unstructured":"Cannarile, L. et al. Glucocorticoid-induced leucine zipper is protective in Th1-mediated models of colitis. Gastroenterology 136, 530\u2013541 (2009).","journal-title":"Gastroenterology"},{"key":"BFsrep38825_CR24","doi-asserted-by":"crossref","first-page":"456","DOI":"10.1002\/emmm.201201683","volume":"5","author":"I Pinheiro","year":"2013","unstructured":"Pinheiro, I. et al. LPS resistance of SPRET\/Ei mice is mediated by Gilz, encoded by the Tsc22d3 gene on the X chromosome. EMBO Mol. Med. 5, 456\u2013470 (2013).","journal-title":"EMBO Mol. Med."},{"key":"BFsrep38825_CR25","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1016\/j.jaut.2015.05.010","volume":"61","author":"SA Jones","year":"2015","unstructured":"Jones, S. A. et al. GILZ regulates Th17 responses and restrains IL-17-mediated skin inflammation. J. Autoimmunity 61, 73\u201380 (2015).","journal-title":"J. Autoimmunity"},{"key":"BFsrep38825_CR26","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1016\/j.celrep.2014.03.004","volume":"7","author":"O Bereshchenko","year":"2014","unstructured":"Bereshchenko, O. et al. GILZ promotes production of peripherally induced Treg cells and mediates the crosstalk between glucocorticoids and TGF-\u03b2 signaling. Cell Rep. 7, 464\u2013475 (2014).","journal-title":"Cell Rep"},{"key":"BFsrep38825_CR27","doi-asserted-by":"crossref","first-page":"1514","DOI":"10.1002\/art.39069","volume":"67","author":"P Luz-Crawford","year":"2015","unstructured":"Luz-Crawford, P. et al. Glucocorticoid-induced leucine zipper governs the therapeutic potential of mesenchymal stem cells by inducing a switch from pathogenic to regulatory Th17 cells in a mouse model of collagen-induced arthritis. Arthritis Rheumatol. 67, 1514\u20131524 (2015).","journal-title":"Arthritis Rheumatol"},{"key":"BFsrep38825_CR28","doi-asserted-by":"crossref","first-page":"281","DOI":"10.1016\/j.mce.2015.05.015","volume":"412","author":"LM Sevilla","year":"2015","unstructured":"Sevilla, L. M. et al. Glucocorticoid receptor and Klf4 co-regulate anti-inflammatory genes in keratinocytes. Mol. Cell Endocrinol. 412, 281\u2013289 (2015).","journal-title":"Mol. Cell Endocrinol."},{"key":"BFsrep38825_CR29","doi-asserted-by":"crossref","first-page":"5836","DOI":"10.4049\/jimmunol.0802999","volume":"182","author":"L Van der Fits","year":"2009","unstructured":"Van der Fits, L. et al. Imiquimod-induced psoriasis-like skin inflammation in mice is mediated via the IL-23\/IL-17 axis. J. Immunol. 182, 5836\u20135845 (2009).","journal-title":"J. Immunol."},{"key":"BFsrep38825_CR30","doi-asserted-by":"crossref","first-page":"3138","DOI":"10.1002\/eji.201343801","volume":"43","author":"B Flutter","year":"2013","unstructured":"Flutter, B. & Nestle, F. O. TLRs to cytokines: mechanistic insights from the imiquimod mouse model of psoriasis. Eur. J. Immunol. 43, 3138\u20133146 (2013).","journal-title":"Eur. J. Immunol."},{"key":"BFsrep38825_CR31","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1016\/j.cytogfr.2014.10.009","volume":"26","author":"L Grine","year":"2015","unstructured":"Grine, L., Dejager, L., Libert, C. & Vandenbroucke, R. E. An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17. Cytokine Growth Factor Rev. 26, 25\u201333 (2015).","journal-title":"Cytokine Growth Factor Rev"},{"key":"BFsrep38825_CR32","doi-asserted-by":"crossref","first-page":"20134","DOI":"10.1038\/srep20134","volume":"6","author":"L Grine","year":"2016","unstructured":"Grine, L. et al. Topical imiquimod yields systemic effects due to unintended oral uptake. Sci. Rep. 6, 20134 (2016).","journal-title":"Sci. Rep"},{"key":"BFsrep38825_CR33","doi-asserted-by":"crossref","first-page":"55","DOI":"10.1093\/nar\/gkp112","volume":"37","author":"O Nyabi","year":"2009","unstructured":"Nyabi, O. et al. Efficient mouse transgenesis using Gateway-compatible ROSA26 locus targeting vectors and F1 hybrid ES cells. Nucleic Acids Res. 37, 55 (2009).","journal-title":"Nucleic Acids Res"},{"key":"BFsrep38825_CR34","doi-asserted-by":"crossref","first-page":"1307","DOI":"10.1016\/S0960-9822(02)70717-3","volume":"6","author":"UA Betz","year":"1996","unstructured":"Betz, U. A., Vosshenrich, C. A., Rajewsky, K. & M\u00fcller, W. Bypass of lethality with mosaic mice generated by Cre-loxP-mediated recombination. Curr. Biol. 6, 1307\u20131316 (1996).","journal-title":"Curr. Biol."},{"key":"BFsrep38825_CR35","doi-asserted-by":"crossref","first-page":"3923","DOI":"10.1242\/jcs.099655","volume":"125","author":"RL Haines","year":"2012","unstructured":"Haines, R. L. & Lane, E. B. Keratins and disease at a glance. J. Cell Sci. 125, 3923\u20133928 (2012).","journal-title":"J. Cell Sci."},{"key":"BFsrep38825_CR36","doi-asserted-by":"crossref","first-page":"328","DOI":"10.1038\/nrm1619","volume":"6","author":"E Candi","year":"2005","unstructured":"Candi, E., Schmidt, R. & Melino, G. The cornified envelope: a model of cell death in the skin. Nat. Rev. Mol. Cell Biol. 6, 328\u2013340 (2005).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"BFsrep38825_CR37","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1083\/jcb.200709098","volume":"180","author":"G Denecker","year":"2008","unstructured":"Denecker, G., Ovaere, P., Vandenabeele, P. & Declercq, W. Caspase-14 reveals its secrets. J. Cell Biol. 180, 451\u2013458 (2008).","journal-title":"J. Cell Biol."},{"key":"BFsrep38825_CR38","doi-asserted-by":"crossref","first-page":"2233","DOI":"10.1038\/jid.2011.153","volume":"131","author":"E Hoste","year":"2011","unstructured":"Hoste, E. et al. Caspase-14 is required for filaggrin degradation to natural moisturizing factors in the skin. J. Invest. Dermatol. 131, 2233\u20132241 (2011).","journal-title":"J. Invest. Dermatol."},{"key":"BFsrep38825_CR39","doi-asserted-by":"crossref","first-page":"647","DOI":"10.1016\/j.bbrc.2012.05.162","volume":"423","author":"Y Lee","year":"2012","unstructured":"Lee, Y. et al. S100A8 and S100A9 are messengers in the crosstalk between epidermis and dermis modulating a psoriatic milieu in human skin. Biochem. Biophys. Res. Commun. 423, 647\u2013653 (2012).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"BFsrep38825_CR40","doi-asserted-by":"crossref","first-page":"921","DOI":"10.1111\/1440-1681.12294","volume":"41","author":"Y Zhang","year":"2014","unstructured":"Zhang, Y. et al. Transforming growth factor-b1 mediates psoriasis-like lesions via a Smad3-dependent mechanism in mice. Clin. Exp. Pharmacol. Physiol. 41, 921\u2013932 (2014).","journal-title":"Clin. Exp. Pharmacol. Physiol."},{"key":"BFsrep38825_CR41","doi-asserted-by":"crossref","first-page":"742","DOI":"10.1038\/jid.2012.350","volume":"133","author":"E Hoste","year":"2013","unstructured":"Hoste, E. et al. Caspase-14-deficient mice are more prone to the development of parakeratosis. J. Invest. Dermatol. 133, 742\u2013750 (2013).","journal-title":"J. Invest. Dermatol."},{"key":"BFsrep38825_CR42","doi-asserted-by":"crossref","first-page":"633","DOI":"10.1111\/j.1600-0625.2011.01280.x","volume":"20","author":"M Hvid","year":"2011","unstructured":"Hvid, M. et al. Regulation of caspase 14 expression in keratinocytes by inflammatory cytokines\u2013a possible link between reduced skin barrier function and inflammation? Exp. Dermatol. 20, 633\u2013636 (2011).","journal-title":"Exp. Dermatol"},{"key":"BFsrep38825_CR43","doi-asserted-by":"crossref","first-page":"2552","DOI":"10.1038\/jid.2012.184","volume":"132","author":"M Su\u00e1rez-Fari\u00f1as","year":"2012","unstructured":"Su\u00e1rez-Fari\u00f1as, M. et al. Expanding the psoriasis disease profile: interrogation of the skin and serum of patients with moderate-to-severe psoriasis. J. Invest. Dermatol. 132, 2552\u20132564 (2012).","journal-title":"J. Invest. Dermatol."},{"key":"BFsrep38825_CR44","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1038\/jid.2012.281","volume":"133","author":"LM Sevilla","year":"2013","unstructured":"Sevilla, L. M., Latorre, V., Sanchis, A. & P\u00e9rez, P. Epidermal inactivation of the glucocorticoid receptor triggers skin barrier defects and cutaneous inflammation. J. Invest. Dermatol. 133, 361\u2013370 (2013).","journal-title":"J. Invest. Dermatol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep38825.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep38825","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep38825.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,5]],"date-time":"2023-01-05T03:14:57Z","timestamp":1672888497000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep38825"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,12,9]]},"references-count":44,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,23]]}},"alternative-id":["BFsrep38825"],"URL":"https:\/\/doi.org\/10.1038\/srep38825","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,12,9]]},"assertion":[{"value":"1 July 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"15 November 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 December 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"38825"}}