{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,10]],"date-time":"2026-11-10T03:05:49Z","timestamp":1794279949463,"version":"4.9.0"},"reference-count":37,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2020,1,7]],"date-time":"2020-01-07T00:00:00Z","timestamp":1578355200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,1,7]],"date-time":"2020-01-07T00:00:00Z","timestamp":1578355200000},"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":["Int J Obes"],"published-print":{"date-parts":[[2020,5]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec>\n<jats:title>Background\/objectives<\/jats:title>\n<jats:p>Based on the recent identification of <jats:italic>E.coli<\/jats:italic> heat shock protein ClpB as a mimetic of the anorexigenic \u03b1-melanocyte stimulating hormone (\u03b1-MSH), the objective of this study was to preclinically validate <jats:italic>Hafnia alvei<\/jats:italic>, a ClpB-producing commensal bacterium as a potential probiotic for appetite and body weight management in overweight and obesity.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Methods<\/jats:title>\n<jats:p>The involvement of enterobacterial ClpB in the putative anti-obesity effects was studied using ClpB-deficient <jats:italic>E.coli<\/jats:italic>. A food-grade <jats:italic>H. alvei<\/jats:italic> HA4597 strain synthetizing the ClpB protein with an \u03b1-MSH-like motif was selected as a candidate probiotic to be tested in <jats:italic>ob\/ob<\/jats:italic> and high-fat diet (HFD)-fed obese and overweight mice. The relevance of the enterobacterial ClpB gene to human obesity was studied by in silico analysis of fecal metagenomes of 569 healthy individuals from the \u201cMetaHIT\u201d database.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Results<\/jats:title>\n<jats:p>Chronic per os administration of native but not ClpB-deficient <jats:italic>E.coli<\/jats:italic> strain reduced body weight gain (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and daily meal frequency (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001) in <jats:italic>ob\/ob<\/jats:italic> mice. Oral gavage of <jats:italic>H.alvei<\/jats:italic> for 18 and 46 days in <jats:italic>ob\/ob<\/jats:italic> and HFD-fed obese mice, respectively, was well tolerated, reduced body weight gain and fat mass in both obesity models (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.05) and decreased food intake in hyperphagic <jats:italic>ob\/ob<\/jats:italic> mice (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.001). Elevated fat tissue levels of phosphorylated hormone-sensitive lipase were detected in <jats:italic>H.alvei<\/jats:italic> -treated <jats:italic>ob\/ob<\/jats:italic> mice (<jats:italic>p<\/jats:italic>\u2009&lt;\u20090.01). Enterobacterial ClpB gene richness was lower in obese vs. non-obese humans (p\u2009&lt;\u20090.0001) and correlated negatively with BMI in genera of <jats:italic>Enterobacter, Klebsiella<\/jats:italic> and <jats:italic>Hafnia<\/jats:italic>.<\/jats:p>\n<\/jats:sec><jats:sec>\n<jats:title>Conclusions<\/jats:title>\n<jats:p><jats:italic>H.alvei<\/jats:italic> HA4597 strain reduces food intake, body weight and fat mass gain in hyperphagic and obese mice. These data combined with low enterobacterial ClpB gene abundance in the microbiota of obese humans provide the rationale for using <jats:italic>H.alvei<\/jats:italic> as a probiotic for appetite and body weight management in overweight and obesity.<\/jats:p>\n<\/jats:sec>","DOI":"10.1038\/s41366-019-0515-9","type":"journal-article","created":{"date-parts":[[2020,1,7]],"date-time":"2020-01-07T12:02:56Z","timestamp":1578398576000},"page":"1041-1051","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":96,"title":["Commensal Hafnia alvei strain reduces food intake and fat mass in obese mice\u2014a new potential probiotic for appetite and body weight management"],"prefix":"10.1038","volume":"44","author":[{"given":"Romain","family":"Legrand","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Lucas","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Manon","family":"Dominique","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Saida","family":"Azhar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Camille","family":"Deroissart","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marie-Anne","family":"Le Solliec","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julie","family":"Rondeaux","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9verine","family":"Nobis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charl\u00e8ne","family":"Gu\u00e9rin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatima","family":"L\u00e9on","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jean-Claude","family":"do Rego","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicolas","family":"Pons","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emmanuelle","family":"Le Chatelier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7563-4046","authenticated-orcid":false,"given":"S. Dusko","family":"Ehrlich","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory","family":"Lambert","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5224-6166","authenticated-orcid":false,"given":"Pierre","family":"D\u00e9chelotte","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sergue\u00ef O.","family":"Fetissov","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,1,7]]},"reference":[{"key":"515_CR1","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.tem.2015.07.002","volume":"26","author":"M Rosenbaum","year":"2015","unstructured":"Rosenbaum M, Knight R, Leibel RL. The gut microbiota in human energy homeostasis and obesity. Trends Endocrinol Metab. 2015;26:493\u2013501.","journal-title":"Trends Endocrinol Metab."},{"key":"515_CR2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.1002533","volume":"14","author":"R Sender","year":"2016","unstructured":"Sender R, Fuchs S, Milo R. Revised estimates for the number of human and bacteria cells in the body. PLoS Biol. 2016;14:e1002533.","journal-title":"PLoS Biol"},{"key":"515_CR3","doi-asserted-by":"publisher","first-page":"222","DOI":"10.1038\/nature11053","volume":"486","author":"T Yatsunenko","year":"2012","unstructured":"Yatsunenko T, Rey FE, Manary MJ, Trehan I, Dominguez-Bello MG, Contreras M, et al. Human gut microbiome viewed across age and geography. Nature. 2012;486:222\u20137.","journal-title":"Nature"},{"key":"515_CR4","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms5500","volume":"5","author":"DI Bolnick","year":"2014","unstructured":"Bolnick DI, Snowberg LK, Hirsch PE, Lauber CL, Org E, Parks B, et al. Individual diet has sex-dependent effects on vertebrate gut microbiota. Nat Commun. 2014;5:4500.","journal-title":"Nat Commun"},{"key":"515_CR5","doi-asserted-by":"publisher","first-page":"585","DOI":"10.1038\/nature12480","volume":"500","author":"A Cotillard","year":"2013","unstructured":"Cotillard A, Kennedy SP, Kong LC, Prifti E, Pons N, Le Chatelier E, et al. Dietary intervention impact on gut microbial gene richness. Nature. 2013;500:585\u20138.","journal-title":"Nature"},{"key":"515_CR6","doi-asserted-by":"publisher","first-page":"1027","DOI":"10.1038\/nature05414","volume":"444","author":"PJ Turnbaugh","year":"2006","unstructured":"Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature. 2006;444:1027\u2013131.","journal-title":"Nature"},{"key":"515_CR7","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1038\/nrendo.2016.150","volume":"13","author":"SO Fetissov","year":"2017","unstructured":"Fetissov SO. Role of the gut microbiota in host appetite control: bacterial growth to animal feeding behaviour. Nat Rev Endocrinol. 2017;13:11\u201325.","journal-title":"Nat Rev Endocrinol"},{"key":"515_CR8","doi-asserted-by":"publisher","unstructured":"Muscogiuri G, Cantone E, Cassarano S, Tuccinardi D, Barrea L, Savastano S, et al. Gut microbiota: a new path to treat obesity. Int J Obes Suppl. 2019. https:\/\/doi.org\/10.1038\/s41367-019-0011-7.","DOI":"10.1038\/s41367-019-0011-7"},{"key":"515_CR9","doi-asserted-by":"publisher","first-page":"14","DOI":"10.1186\/s12986-016-0067-0","volume":"13","author":"N Kobyliak","year":"2016","unstructured":"Kobyliak N, Conte C, Cammarota G, Haley AP, Styriak I, Gaspar L, et al. Probiotics in prevention and treatment of obesity: a critical view. Nutr Metab (Lond). 2016;13:14.","journal-title":"Nutr Metab (Lond)"},{"key":"515_CR10","doi-asserted-by":"publisher","first-page":"1607","DOI":"10.1038\/ijo.2017.161","volume":"41","author":"L Crovesy","year":"2017","unstructured":"Crovesy L, Ostrowski M, Ferreira DMTP, Rosado EL, Soares-Mota M. Effect of Lactobacillus on body weight and body fat in overweight subjects: a systematic review of randomized controlled clinical trials. Int J Obes. 2017;41:1607.","journal-title":"Int J Obes"},{"key":"515_CR11","doi-asserted-by":"crossref","unstructured":"Cani PD, de Vos WM. Next-generation beneficial microbes: the case of akkermansia muciniphila. Front Microbiol. 2017;8:1765.","DOI":"10.3389\/fmicb.2017.01765"},{"key":"515_CR12","doi-asserted-by":"publisher","DOI":"10.1038\/tp.2014.98","volume":"4","author":"N Tennoune","year":"2014","unstructured":"Tennoune N, Chan P, Breton J, Legrand R, Chabane YN, Akkermann K, et al. Bacterial ClpB heat-shock protein, an antigen-mimetic of the anorexigenic peptide [alpha]-MSH, at the origin of eating disorders. Transl Psychiatry. 2014;4:e458.","journal-title":"Transl Psychiatry"},{"key":"515_CR13","doi-asserted-by":"publisher","first-page":"1066","DOI":"10.1038\/12506","volume":"5","author":"L Yaswen","year":"1999","unstructured":"Yaswen L, Diehl N, Brennan MB, Hochgeschwender U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat Med. 1999;5:1066\u201370.","journal-title":"Nat Med"},{"key":"515_CR14","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/509","volume":"19","author":"H Krude","year":"1998","unstructured":"Krude H, Biebermann H, Luck W, Horn R, Brabant G, Gruters A. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat Genet. 1998;19:155\u20137.","journal-title":"Nat Genet"},{"key":"515_CR15","doi-asserted-by":"publisher","first-page":"1085","DOI":"10.1056\/NEJMoa022050","volume":"348","author":"IS Farooqi","year":"2003","unstructured":"Farooqi IS, Keogh JM, Yeo GSH, Lank EJ, Cheetham T, O'Rahilly S. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N Engl J Med. 2003;348:1085\u201395.","journal-title":"N Engl J Med"},{"key":"515_CR16","doi-asserted-by":"publisher","first-page":"5575","DOI":"10.1099\/ijsem.0.001485","volume":"66","author":"M Adeolu","year":"2016","unstructured":"Adeolu M, Alnajar S, Naushad S, S. Gupta R. Genome-based phylogeny and taxonomy of the \u2018Enterobacteriales\u2019: proposal for Enterobacterales ord. nov. divided into the families Enterobacteriaceae, Erwiniaceae fam. nov., Pectobacteriaceae fam. nov., Yersiniaceae fam. nov., Hafniaceae fam. nov., Morganellaceae fam. nov., and Budviciaceae fam. nov. Int J Syst Evol Microbiol. 2016;66:5575\u201399.","journal-title":"Int J Syst Evol Microbiol"},{"key":"515_CR17","doi-asserted-by":"publisher","first-page":"834","DOI":"10.1038\/nbt.2942","volume":"32","author":"J Li","year":"2014","unstructured":"Li J, Jia H, Cai X, Zhong H, Feng Q, Sunagawa S, et al. An integrated catalog of reference genes in the human gut microbiome. Nat Biotechnol. 2014;32:834.","journal-title":"Nat Biotechnol"},{"key":"515_CR18","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.cmet.2015.10.017","volume":"23","author":"J Breton","year":"2016","unstructured":"Breton J, Tennoune N, Lucas N, Fran\u00e7ois M, Legrand R, Jacquemot J, et al. Gut commensal E.coli proteins activate host satiety pathways following nutrient-induced bacterial growth. Cell Metab. 2016;23:1\u201311.","journal-title":"Cell Metab"},{"key":"515_CR19","doi-asserted-by":"publisher","first-page":"327","DOI":"10.1111\/j.1550-7408.1999.tb04612.x","volume":"46","author":"S Turner","year":"1999","unstructured":"Turner S, Pryer KM, Miao VPW, Palmer JD. Investigating deep phylogenetic relationships among cyanobacteria and plastids by small subunit rRNA sequence analysis1. J Eukaryotic Microbiol. 1999;46:327\u201338.","journal-title":"J Eukaryotic Microbiol"},{"key":"515_CR20","doi-asserted-by":"publisher","first-page":"140","DOI":"10.1016\/j.psyneuen.2008.08.021","volume":"34","author":"M Hamze Sinno","year":"2009","unstructured":"Hamze Sinno M, Do Rego JC, Co\u00ebffier M, Bole-Feysot C, Ducrotte P, Gilbert D, et al. Regulation of feeding and anxiety by \u03b1-MSH reactive autoantibodies. Psychoneuroendocrinology. 2009;34:140\u20139.","journal-title":"Psychoneuroendocrinology"},{"key":"515_CR21","doi-asserted-by":"publisher","first-page":"259","DOI":"10.1111\/j.1699-0463.1954.tb00869.x","volume":"35","author":"V Moller","year":"1954","unstructured":"Moller V. Distribution of amino acid decarboxylases in Enterobacteriaceae. Acta Pathol Microbiol Scand. 1954;35:259\u201377.","journal-title":"Acta Pathol Microbiol Scand"},{"key":"515_CR22","doi-asserted-by":"publisher","first-page":"321","DOI":"10.1111\/j.1365-2672.1987.tb04927.x","volume":"62","author":"P Gaya","year":"1987","unstructured":"Gaya P, Medina M, Nuntez M. Enterobacteriaceae, coliforms, faecal coliforms and salmonellas in raw ewes'milk. J Appl Bacteriol. 1987;62:321\u20136.","journal-title":"J Appl Bacteriol"},{"key":"515_CR23","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1111\/j.1365-2672.1993.tb02772.x","volume":"75","author":"E Tornadijo","year":"1993","unstructured":"Tornadijo E, Fresno JM, Carballo J, Mart\u00edn-Sarmiento R. Study of Enterobacteriaceae throughout the manufacturing and ripening of hard goats' cheese. J Appl Bacteriol. 1993;75:240\u20136.","journal-title":"J Appl Bacteriol"},{"key":"515_CR24","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1051\/lait:1983623-6243","volume":"63","author":"J Richard","year":"1983","unstructured":"Richard J, Zadi H. Inventaire de la flore bact\u00e9rienne dominante des Camemberts fabriqu\u00e9s avec lait cru. Le Lait, INRA Ed. 1983;63:25\u201342.","journal-title":"Le Lait, INRA Ed"},{"key":"515_CR25","first-page":"68","volume":"455","author":"ID Federation","year":"2012","unstructured":"Federation ID. Safety demonstration of microbial food cultures (MFC) in fermented food products (Annex 4). Bull Int Dairy Fed. 2012;455:68.","journal-title":"Bull Int Dairy Fed"},{"key":"515_CR26","doi-asserted-by":"crossref","unstructured":"Mogren L, Windstam S, Boqvist S, V\u00e5gsholm I, S\u00f6derqvist K, Rosberg AK, et al. The hurdle approach\u2014a holistic concept for controlling food safety risks associated with pathogenic bacterial contamination of leafy green vegetables. A Review. Front Microbiol. 2018;9:1965.","DOI":"10.3389\/fmicb.2018.01965"},{"key":"515_CR27","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1038\/nrendo.2015.103","volume":"11","author":"D Richard","year":"2015","unstructured":"Richard D. Cognitive and autonomic determinants of energy homeostasis in obesity. Nat Rev Endocrinol. 2015;11:489.","journal-title":"Nat Rev Endocrinol"},{"key":"515_CR28","doi-asserted-by":"publisher","first-page":"T157","DOI":"10.1530\/JME-16-0014","volume":"56","author":"EJP Anderson","year":"2016","unstructured":"Anderson EJP, \u00c7akir I, Carrington SJ, Cone RD, Ghamari-Langroudi M, Gillyard T, et al. 60 YEARS OF POMC: regulation of feeding and energy homeostasis by \u03b1-MSH. J Mol Endocrinol. 2016;56:T157\u2013T74.","journal-title":"J Mol Endocrinol"},{"key":"515_CR29","doi-asserted-by":"publisher","first-page":"240","DOI":"10.1056\/NEJMoa1512693","volume":"375","author":"P K\u00fchnen","year":"2016","unstructured":"K\u00fchnen P, Cl\u00e9ment K, Wiegand S, Blankenstein O, Gottesdiener K, Martini LL, et al. Proopiomelanocortin deficiency treated with a melanocortin-4 receptor agonist. N Engl J Med. 2016;375:240\u20136.","journal-title":"N Engl J Med"},{"key":"515_CR30","doi-asserted-by":"publisher","DOI":"10.1038\/s41522-017-0039-9","volume":"3","author":"X Qiang","year":"2017","unstructured":"Qiang X, Liotta AS, Shiloach J, Gutierrez JC, Wang H, Ochani M, et al. New melanocortin-like peptide of E. coli can suppress inflammation via the mammalian melanocortin-1 receptor (MC1R): possible endocrine-like function for microbes of the gut. NPJ Biofilms Microb. 2017;3:31.","journal-title":"NPJ Biofilms Microb"},{"key":"515_CR31","doi-asserted-by":"publisher","first-page":"546","DOI":"10.2174\/0929867324666171005110620","volume":"26","author":"SO Fetissov","year":"2019","unstructured":"Fetissov SO, Legrand R, Lucas N. Bacterial protein mimetic of peptide hormone as a new class of protein-based drugs. Curr Med Chem. 2019;26:546\u201353.","journal-title":"Curr Med Chem"},{"key":"515_CR32","doi-asserted-by":"publisher","first-page":"2115","DOI":"10.3390\/nu11092115","volume":"11","author":"M Dominique","year":"2019","unstructured":"Dominique M, Breton J, Gu\u00e9rin C, Bole-Feysot C, Lambert G, D\u00e9chelotte P, et al. Effects of macronutrients on the in vitro production of ClpB, a bacterial mimetic protein of \u03b1-MSH and its possible role in the satiety signaling. Nutrients. 2019;11:2115.","journal-title":"Nutrients"},{"key":"515_CR33","doi-asserted-by":"publisher","first-page":"532","DOI":"10.1016\/j.cmet.2010.04.014","volume":"11","author":"HM Cox","year":"2010","unstructured":"Cox HM, Tough IR, Woolston A-M, Zhang L, Nguyen AD, Sainsbury A, et al. Peptide YY is critical for acylethanolamine receptor Gpr119-induced activation of gastrointestinal mucosal responses. Cell Metab. 2010;11:532\u201342.","journal-title":"Cell Metab"},{"key":"515_CR34","doi-asserted-by":"publisher","first-page":"5306","DOI":"10.1016\/j.bmcl.2015.09.046","volume":"25","author":"MD Ericson","year":"2015","unstructured":"Ericson MD, Schnell SM, Freeman KT, Haskell-Luevano C. A fragment of the Escherichia coli ClpB heat-shock protein is a micromolar melanocortin 1 receptor agonist. Bioorg Med Chem Lett. 2015;25:5306\u20138.","journal-title":"Bioorg Med Chem Lett"},{"key":"515_CR35","doi-asserted-by":"publisher","first-page":"650","DOI":"10.1038\/nature00887","volume":"418","author":"RL Batterham","year":"2002","unstructured":"Batterham RL, Cowley MA, Small CJ, Herzog H, Cohen MA, Dakin CL, et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature. 2002;418:650\u20134.","journal-title":"Nature"},{"key":"515_CR36","doi-asserted-by":"publisher","first-page":"1018","DOI":"10.1016\/j.cmet.2014.10.004","volume":"20","author":"L Panaro Brandon","year":"2014","unstructured":"Panaro Brandon L, Tough Iain R, Engelstoft Maja S, Matthews Robert T, Digby Gregory J, M\u00f8ller Cathrine L, et al. The melanocortin-4 receptor is expressed in enteroendocrine L cells and regulates the release of peptide YY and glucagon-like peptide 1 in vivo. Cell Metab. 2014;20:1018\u201329.","journal-title":"Cell Metab"},{"key":"515_CR37","doi-asserted-by":"publisher","first-page":"1460","DOI":"10.1038\/ijo.2013.20","volume":"37","author":"M Million","year":"2013","unstructured":"Million M, Angelakis E, Maraninchi M, Henry M, Giorgi R, Valero R, et al. Correlation between body mass index and gut concentrations of Lactobacillus reuteri, Bifidobacterium animalis, Methanobrevibacter smithii and Escherichia coli. Int J Obes. 2013;37:1460\u20136.","journal-title":"Int J Obes"}],"container-title":["International Journal of Obesity"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/www.nature.com\/articles\/s41366-019-0515-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41366-019-0515-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"http:\/\/www.nature.com\/articles\/s41366-019-0515-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,5,20]],"date-time":"2023-05-20T21:17:01Z","timestamp":1684617421000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41366-019-0515-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,1,7]]},"references-count":37,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2020,5]]}},"alternative-id":["515"],"URL":"https:\/\/doi.org\/10.1038\/s41366-019-0515-9","relation":{},"ISSN":["0307-0565","1476-5497"],"issn-type":[{"value":"0307-0565","type":"print"},{"value":"1476-5497","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,1,7]]},"assertion":[{"value":"27 April 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"2 December 2019","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 December 2019","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 January 2020","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Compliance with ethical standards"}},{"value":"NL, RL, SA, CD, and MALS were full-time employees of TargEDys SA. SOF and PD are co-founders and consultants of TargEDys SA. GL is the CEO of TargEDys SA. Other co-authors declare no conflict of interest.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}