{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,19]],"date-time":"2025-10-19T20:50:18Z","timestamp":1760907018373},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2017,2,24]],"date-time":"2017-02-24T00:00:00Z","timestamp":1487894400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2017,2,24]],"date-time":"2017-02-24T00:00:00Z","timestamp":1487894400000},"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>Estrogen receptor alpha (ER\u03b1) is a major regulator of metabolic processes in obesity. In this study we aimed to define the relevance of adipose tissue ER\u03b1 during high-fat diet (HFD)-induced obesity using female aP2-Cre<jats:sup>\u2212\/+<\/jats:sup>\/ER\u03b1<jats:sup>fl\/fl<\/jats:sup> mice (atER\u03b1KO). HFD did not affect body weight or glucose metabolism in atER\u03b1KO- compared to control mice. Surprisingly, HFD feeding markedly increased mortality in atER\u03b1KO mice associated with a destructive bacterial infection of the uterus driven by commensal microbes, an alteration likely explaining the absence of a metabolic phenotype in HFD-fed atER\u03b1KO mice. In order to identify a mechanism of the exaggerated uterine infection in HFD-fed atER\u03b1KO mice, a marked reduction of uterine M2-macrophages was detected, a cell type relevant for anti-microbial defence. In parallel, atER\u03b1KO mice exhibited elevated circulating estradiol (E2) acting on E2-responsive tissue\/cells such as macrophages. Accompanying cell culture experiments showed that despite E2 co-administration stearic acid (C18:0), a fatty acid elevated in plasma from HFD-fed atER\u03b1KO mice, blocks M2-polarization, a process known to be enhanced by E2. In this study we demonstrate an unexpected phenotype in HFD-fed atER\u03b1KO involving severe uterine bacterial infections likely resulting from a previously unknown negative interference between dietary FAs and ER\u03b1-signaling during anti-microbial defence.<\/jats:p>","DOI":"10.1038\/srep43269","type":"journal-article","created":{"date-parts":[[2017,2,24]],"date-time":"2017-02-24T11:28:56Z","timestamp":1487935736000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["High-Fat Diet Induces Unexpected Fatal Uterine Infections in Mice with aP2-Cre-mediated Deletion of Estrogen Receptor Alpha"],"prefix":"10.1038","volume":"7","author":[{"given":"Zsofia","family":"Ban","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paul","family":"Maurischat","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Verena","family":"Benz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sarah","family":"Brix","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Sonnenburg","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gerhard","family":"Schuler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Robert","family":"Klopfleisch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michael","family":"Rothe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jan-\u00c5ke","family":"Gustafsson","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Anna","family":"Foryst-Ludwig","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ulrich","family":"Kintscher","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2017,2,24]]},"reference":[{"key":"BFsrep43269_CR1","doi-asserted-by":"publisher","first-page":"113","DOI":"10.1016\/j.mce.2014.11.029","volume":"402","author":"BF Palmer","year":"2015","unstructured":"Palmer, B. F. & Clegg, D. J. The sexual dimorphism of obesity. Mol Cell Endocrinol 402, 113\u2013119, doi: 10.1016\/j.mce.2014.11.029 (2015).","journal-title":"Mol Cell Endocrinol"},{"key":"BFsrep43269_CR2","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1111\/j.1749-6632.2000.tb06506.x","volume":"904","author":"MJ Toth","year":"2000","unstructured":"Toth, M. J., Tchernof, A., Sites, C. K. & Poehlman, E. T. Menopause-related changes in body fat distribution. Ann N Y Acad Sci 904, 502\u2013506 (2000).","journal-title":"Ann N Y Acad Sci"},{"key":"BFsrep43269_CR3","doi-asserted-by":"publisher","first-page":"561","DOI":"10.1172\/JCI27987","volume":"116","author":"BJ Deroo","year":"2006","unstructured":"Deroo, B. J. & Korach, K. S. Estrogen receptors and human disease. J Clin Invest. 116, 561\u2013570. (2006).","journal-title":"J Clin Invest"},{"key":"BFsrep43269_CR4","doi-asserted-by":"crossref","unstructured":"Stubbins, R. E., Holcomb, V. B., Hong, J. & Nunez, N. P. Estrogen modulates abdominal adiposity and protects female mice from obesity and impaired glucose tolerance. Eur J Nutr, doi: 10.1007\/s00394-011-0266-4 [doi] (2011).","DOI":"10.1007\/s00394-011-0266-4"},{"key":"BFsrep43269_CR5","doi-asserted-by":"publisher","first-page":"12729","DOI":"10.1073\/pnas.97.23.12729","volume":"97","author":"PA Heine","year":"2000","unstructured":"Heine, P. A., Taylor, J. A., Iwamoto, G. A., Lubahn, D. B. & Cooke, P. S. Increased adipose tissue in male and female estrogen receptor-alpha knockout mice. Proc Natl Acad Sci USA 97, 12729\u201312734 (2000).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep43269_CR6","doi-asserted-by":"publisher","first-page":"e1000108","DOI":"10.1371\/journal.pgen.1000108","volume":"4","author":"A Foryst-Ludwig","year":"2008","unstructured":"Foryst-Ludwig, A. et al. Metabolic actions of estrogen receptor beta (ERbeta) are mediated by a negative cross-talk with PPARgamma. PLoS Genet 4, e1000108, doi: 10.1371\/journal.pgen.1000108 (2008).","journal-title":"PLoS Genet"},{"key":"BFsrep43269_CR7","doi-asserted-by":"crossref","unstructured":"Hevener, A. L., Clegg, D. J. & Mauvais-Jarvis, F. Impaired estrogen receptor action in the pathogenesis of the metabolic syndrome. Mol Cell Endocrinol, doi: 10.1016\/j.mce.2015.05.020 (2015).","DOI":"10.1016\/j.mce.2015.05.020"},{"key":"BFsrep43269_CR8","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1016\/j.molmet.2013.05.006","volume":"2","author":"KE Davis","year":"2013","unstructured":"Davis, K. E. et al. The sexually dimorphic role of adipose and adipocyte estrogen receptors in modulating adipose tissue expansion, inflammation, and fibrosis. Molecular metabolism 2, 227\u2013242, doi: 10.1016\/j.molmet.2013.05.006 (2013).","journal-title":"Molecular metabolism"},{"key":"BFsrep43269_CR9","doi-asserted-by":"publisher","first-page":"16457","DOI":"10.1073\/pnas.1104533108","volume":"108","author":"V Ribas","year":"2011","unstructured":"Ribas, V. et al. Myeloid-specific estrogen receptor alpha deficiency impairs metabolic homeostasis and accelerates atherosclerotic lesion development. Proc Natl Acad Sci USA 108, 16457\u201316462, doi: 10.1073\/pnas.1104533108 (2011).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep43269_CR10","doi-asserted-by":"publisher","first-page":"453","DOI":"10.1016\/j.cmet.2011.08.009","volume":"14","author":"Y Xu","year":"2011","unstructured":"Xu, Y. et al. Distinct hypothalamic neurons mediate estrogenic effects on energy homeostasis and reproduction. Cell Metab 14, 453\u2013465, doi: 10.1016\/j.cmet.2011.08.009 (2011).","journal-title":"Cell Metab"},{"key":"BFsrep43269_CR11","first-page":"11404","volume":"275","author":"H Homma","year":"2000","unstructured":"Homma, H. et al. Estrogen suppresses transcription of lipoprotein lipase gene. Existence of a unique estrogen response element on the lipoprotein lipase promoter. J Biol Chem 275, 11404\u201311411 (2000).","journal-title":"Existence of a unique estrogen response element on the lipoprotein lipase promoter. J Biol Chem"},{"key":"BFsrep43269_CR12","doi-asserted-by":"publisher","first-page":"e37794","DOI":"10.1371\/journal.pone.0037794","volume":"7","author":"V Benz","year":"2012","unstructured":"Benz, V. et al. Sexual dimorphic regulation of body weight dynamics and adipose tissue lipolysis. PLoS One 7, e37794, doi: 10.1371\/journal.pone.0037794 (2012).","journal-title":"PLoS One"},{"key":"BFsrep43269_CR13","doi-asserted-by":"publisher","first-page":"e85581","DOI":"10.1371\/journal.pone.0085581","volume":"9","author":"P Antonson","year":"2014","unstructured":"Antonson, P. et al. aP2-Cre-mediated inactivation of estrogen receptor alpha causes hydrometra. PLoS One 9, e85581, doi: 10.1371\/journal.pone.0085581 (2014).","journal-title":"PLoS One"},{"key":"BFsrep43269_CR14","doi-asserted-by":"publisher","first-page":"350","DOI":"10.1016\/j.it.2011.04.009","volume":"32","author":"DL Bratton","year":"2011","unstructured":"Bratton, D. L. & Henson, P. M. Neutrophil clearance: when the party is over, clean-up begins. Trends in immunology 32, 350\u2013357, doi: 10.1016\/j.it.2011.04.009 (2011).","journal-title":"Trends in immunology"},{"key":"BFsrep43269_CR15","doi-asserted-by":"publisher","first-page":"162","DOI":"10.1016\/j.ajpath.2014.09.005","volume":"185","author":"K Kambara","year":"2015","unstructured":"Kambara, K. et al. In vivo depletion of CD206+ M2 macrophages exaggerates lung injury in endotoxemic mice. Am J Pathol 185, 162\u2013171, doi: 10.1016\/j.ajpath.2014.09.005 (2015).","journal-title":"Am J Pathol"},{"key":"BFsrep43269_CR16","doi-asserted-by":"publisher","first-page":"1687","DOI":"10.1161\/atvbaha.112.250142","volume":"32","author":"EK Anderson","year":"2012","unstructured":"Anderson, E. K., Hill, A. A. & Hasty, A. H. Stearic acid accumulation in macrophages induces toll-like receptor 4\/2-independent inflammation leading to endoplasmic reticulum stress-mediated apoptosis. Arterioscler Thromb Vasc Biol 32, 1687\u20131695, doi: 10.1161\/atvbaha.112.250142 (2012).","journal-title":"Arterioscler Thromb Vasc Biol"},{"key":"BFsrep43269_CR17","doi-asserted-by":"publisher","first-page":"E50","DOI":"10.1210\/jc.2014-2751","volume":"100","author":"A Toniolo","year":"2015","unstructured":"Toniolo, A. et al. Alternative activation of human macrophages is rescued by estrogen treatment in vitro and impaired by menopausal status. J Clin Endocrinol Metab 100, E50\u201358, doi: 10.1210\/jc.2014-2751 (2015).","journal-title":"J Clin Endocrinol Metab"},{"key":"BFsrep43269_CR18","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1111\/imm.12126","volume":"140","author":"A Mercalli","year":"2013","unstructured":"Mercalli, A. et al. Rapamycin unbalances the polarization of human macrophages to M1. Immunology 140, 179\u2013190, doi: 10.1111\/imm.12126 (2013).","journal-title":"Immunology"},{"key":"BFsrep43269_CR19","doi-asserted-by":"publisher","first-page":"241","DOI":"10.1089\/AID.2013.0145","volume":"30","author":"GC Preza","year":"2014","unstructured":"Preza, G. C. et al. Antigen-presenting cell candidates for HIV-1 transmission in human distal colonic mucosa defined by CD207 dendritic cells and CD209 macrophages. AIDS Res Hum Retroviruses 30, 241\u2013249, doi: 10.1089\/AID.2013.0145 (2014).","journal-title":"AIDS Res Hum Retroviruses"},{"key":"BFsrep43269_CR20","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1016\/j.immuni.2010.05.007","volume":"32","author":"S Gordon","year":"2010","unstructured":"Gordon, S. & Martinez, F. O. Alternative activation of macrophages: mechanism and functions. Immunity 32, 593\u2013604, doi: 10.1016\/j.immuni.2010.05.007 (2010).","journal-title":"Immunity"},{"key":"BFsrep43269_CR21","doi-asserted-by":"publisher","first-page":"762","DOI":"10.1210\/me.2011-1208","volume":"26","author":"P La Rosa","year":"2012","unstructured":"La Rosa, P., Pesiri, V., Leclercq, G., Marino, M. & Acconcia, F. Palmitoylation regulates 17beta-estradiol-induced estrogen receptor-alpha degradation and transcriptional activity. Mol Endocrinol 26, 762\u2013774, doi: 10.1210\/me.2011-1208 (2012).","journal-title":"Mol Endocrinol"},{"key":"BFsrep43269_CR22","doi-asserted-by":"publisher","first-page":"127","DOI":"10.1210\/me.2012-1267","volume":"27","author":"SE Mullican","year":"2013","unstructured":"Mullican, S. E. et al. A novel adipose-specific gene deletion model demonstrates potential pitfalls of existing methods. Mol Endocrinol 27, 127\u2013134, doi: 10.1210\/me.2012-1267 (2013).","journal-title":"Mol Endocrinol"},{"key":"BFsrep43269_CR23","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1016\/j.neuron.2006.07.023","volume":"52","author":"TM Wintermantel","year":"2006","unstructured":"Wintermantel, T. M. et al. Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility. Neuron 52, 271\u2013280, doi: 10.1016\/j.neuron.2006.07.023 (2006).","journal-title":"Neuron"},{"key":"BFsrep43269_CR24","doi-asserted-by":"publisher","first-page":"923","DOI":"10.1038\/nri2449","volume":"8","author":"GS Hotamisligil","year":"2008","unstructured":"Hotamisligil, G. S. & Erbay, E. Nutrient sensing and inflammation in metabolic diseases. Nat Rev Immunol 8, 923\u2013934, doi: 10.1038\/nri2449 (2008).","journal-title":"Nat Rev Immunol"},{"key":"BFsrep43269_CR25","doi-asserted-by":"publisher","first-page":"153","DOI":"10.1172\/jci59660","volume":"122","author":"JP Thaler","year":"2012","unstructured":"Thaler, J. P. et al. Obesity is associated with hypothalamic injury in rodents and humans. J Clin Invest 122, 153\u2013162, doi: 10.1172\/jci59660 (2012).","journal-title":"J Clin Invest"},{"key":"BFsrep43269_CR26","doi-asserted-by":"publisher","first-page":"15","DOI":"10.4137\/JCD.S11038","volume":"7","author":"JM McCracken","year":"2014","unstructured":"McCracken, J. M. & Allen, L. A. Regulation of human neutrophil apoptosis and lifespan in health and disease. J Cell Death 7, 15\u201323, doi: 10.4137\/JCD.S11038 (2014).","journal-title":"J Cell Death"},{"key":"BFsrep43269_CR27","doi-asserted-by":"publisher","first-page":"456","DOI":"10.1016\/j.cell.2014.01.006","volume":"156","author":"M Schiwon","year":"2014","unstructured":"Schiwon, M. et al. Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium. Cell 156, 456\u2013468, doi: 10.1016\/j.cell.2014.01.006 (2014).","journal-title":"Cell"},{"key":"BFsrep43269_CR28","doi-asserted-by":"publisher","first-page":"2447","DOI":"10.1038\/jid.2014.175","volume":"134","author":"L Campbell","year":"2014","unstructured":"Campbell, L. et al. Estrogen receptor-alpha promotes alternative macrophage activation during cutaneous repair. J Invest Dermatol 134, 2447\u20132457, doi: 10.1038\/jid.2014.175 (2014).","journal-title":"J Invest Dermatol"},{"key":"BFsrep43269_CR29","doi-asserted-by":"publisher","first-page":"647","DOI":"10.1007\/s11248-006-9000-z","volume":"15","author":"S Urs","year":"2006","unstructured":"Urs, S., Harrington, A., Liaw, L. & Small, D. Selective expression of an aP2\/Fatty Acid Binding Protein 4-Cre transgene in non-adipogenic tissues during embryonic development. Transgenic research 15, 647\u2013653, doi: 10.1007\/s11248-006-9000-z (2006).","journal-title":"Transgenic research"},{"key":"BFsrep43269_CR30","doi-asserted-by":"publisher","first-page":"17576","DOI":"10.1073\/pnas.0909055106","volume":"106","author":"J Mao","year":"2009","unstructured":"Mao, J. et al. aP2-Cre-mediated inactivation of acetyl-CoA carboxylase 1 causes growth retardation and reduced lipid accumulation in adipose tissues. Proc Natl Acad Sci USA 106, 17576\u201317581, doi: 10.1073\/pnas.0909055106 (2009).","journal-title":"Proc Natl Acad Sci USA"},{"key":"BFsrep43269_CR31","doi-asserted-by":"publisher","first-page":"378","DOI":"10.1016\/j.molmet.2015.02.007","volume":"4","author":"R Mayoral","year":"2015","unstructured":"Mayoral, R. et al. Adipocyte SIRT1 knockout promotes PPARgamma activity, adipogenesis and insulin sensitivity in chronic-HFD and obesity. Mol Metab 4, 378\u2013391, doi: 10.1016\/j.molmet.2015.02.007 (2015).","journal-title":"Mol Metab"},{"key":"BFsrep43269_CR32","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1038\/nature14601","volume":"525","author":"D Senyilmaz","year":"2015","unstructured":"Senyilmaz, D. et al. Regulation of mitochondrial morphology and function by stearoylation of TFR1. Nature 525, 124\u2013128, doi: 10.1038\/nature14601 (2015).","journal-title":"Nature"},{"key":"BFsrep43269_CR33","doi-asserted-by":"publisher","first-page":"633","DOI":"10.1016\/j.celrep.2014.09.025","volume":"9","author":"E Morselli","year":"2014","unstructured":"Morselli, E. et al. Hypothalamic PGC-1alpha protects against high-fat diet exposure by regulating ERalpha. Cell reports 9, 633\u2013645, doi: 10.1016\/j.celrep.2014.09.025 (2014).","journal-title":"Cell reports"},{"key":"BFsrep43269_CR34","doi-asserted-by":"publisher","first-page":"1187","DOI":"10.1007\/s11745-005-1484-z","volume":"40","author":"H Sampath","year":"2005","unstructured":"Sampath, H. & Ntambi, J. M. The fate and intermediary metabolism of stearic acid. Lipids 40, 1187\u20131191 (2005).","journal-title":"Lipids"},{"key":"BFsrep43269_CR35","doi-asserted-by":"publisher","first-page":"847","DOI":"10.1042\/bj3160847","volume":"316","author":"JS Bruce","year":"1996","unstructured":"Bruce, J. S. & Salter, A. M. Metabolic fate of oleic acid, palmitic acid and stearic acid in cultured hamster hepatocytes. The Biochemical journal 316(Pt 3), 847\u2013852 (1996).","journal-title":"The Biochemical journal"},{"key":"BFsrep43269_CR36","doi-asserted-by":"publisher","first-page":"610","DOI":"10.1016\/j.theriogenology.2006.04.023","volume":"66","author":"FO Smith","year":"2006","unstructured":"Smith, F. O. Canine pyometra. Theriogenology 66, 610\u2013612, doi: 10.1016\/j.theriogenology.2006.04.023 (2006).","journal-title":"Theriogenology"},{"key":"BFsrep43269_CR37","doi-asserted-by":"crossref","unstructured":"Weischenfeldt, J. & Porse, B. Bone Marrow-Derived Macrophages (BMM): Isolation and Applications. CSH Protoc 2008, pdb prot5080, doi: 10.1101\/pdb.prot5080 (2008).","DOI":"10.1101\/pdb.prot5080"},{"key":"BFsrep43269_CR38","doi-asserted-by":"publisher","first-page":"837","DOI":"10.1530\/jrf.0.0960837","volume":"96","author":"B Hoffmann","year":"1992","unstructured":"Hoffmann, B., Hoveler, R., Hasan, S. H. & Failing, K. Ovarian and pituitary function in dogs after hysterectomy. J Reprod Fertil 96, 837\u2013845 (1992).","journal-title":"J Reprod Fertil"},{"key":"BFsrep43269_CR39","doi-asserted-by":"publisher","first-page":"23603","DOI":"10.1074\/jbc.M115.645341","volume":"290","author":"A Foryst-Ludwig","year":"2015","unstructured":"Foryst-Ludwig, A. et al. Adipose Tissue Lipolysis Promotes Exercise-induced Cardiac Hypertrophy Involving the Lipokine C16:1n7-Palmitoleate. J Biol Chem 290, 23603\u201323615, doi: 10.1074\/jbc.M115.645341 (2015).","journal-title":"J Biol Chem"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/srep43269.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep43269","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/srep43269.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,24]],"date-time":"2022-12-24T01:15:10Z","timestamp":1671844510000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/srep43269"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,2,24]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2017,4,10]]}},"alternative-id":["BFsrep43269"],"URL":"https:\/\/doi.org\/10.1038\/srep43269","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,2,24]]},"assertion":[{"value":"5 October 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"23 January 2017","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 February 2017","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":"43269"}}