{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T16:07:37Z","timestamp":1790611657651,"version":"4.1.0"},"reference-count":57,"publisher":"eLife Sciences Publications, Ltd","license":[{"start":{"date-parts":[[2016,4,26]],"date-time":"2016-04-26T00:00:00Z","timestamp":1461628800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,4,26]],"date-time":"2016-04-26T00:00:00Z","timestamp":1461628800000},"content-version":"am","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"},{"start":{"date-parts":[[2016,4,26]],"date-time":"2016-04-26T00:00:00Z","timestamp":1461628800000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["RO1 CA163566"],"award-info":[{"award-number":["RO1 CA163566"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["P50CA174523"],"award-info":[{"award-number":["P50CA174523"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["T32 AR0007465-32"],"award-info":[{"award-number":["T32 AR0007465-32"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000069","name":"National Institute of Arthritis and Musculoskeletal and Skin Diseases","doi-asserted-by":"publisher","award":["T32 AR0007465-30"],"award-info":[{"award-number":["T32 AR0007465-30"]}],"id":[{"id":"10.13039\/100000069","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000054","name":"National Cancer Institute","doi-asserted-by":"publisher","award":["F31 CA186446"],"award-info":[{"award-number":["F31 CA186446"]}],"id":[{"id":"10.13039\/100000054","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["elifesciences.org"],"crossmark-restriction":false},"short-container-title":[],"abstract":"<jats:p>The association between pregnancy and altered cutaneous pigmentation has been documented for over two millennia, suggesting that sex hormones play a role in regulating epidermal melanocyte (MC) homeostasis. Here we show that physiologic estrogen (17\u03b2-estradiol) and progesterone reciprocally regulate melanin synthesis. This is intriguing given that we also show that normal primary human MCs lack classical estrogen or progesterone receptors (ER or PR). Utilizing both genetic and pharmacologic approaches, we establish that sex steroid effects on human pigment synthesis are mediated by the membrane-bound, steroid hormone receptors G protein-coupled estrogen receptor (GPER), and progestin and adipoQ receptor 7 (PAQR7). Activity of these receptors was activated or inhibited by synthetic estrogen or progesterone analogs that do not bind to ER or PR. As safe and effective treatment options for skin pigmentation disorders are limited, these specific GPER and PAQR7 ligands may represent a novel class of therapeutics.<\/jats:p>","DOI":"10.7554\/elife.15104","type":"journal-article","created":{"date-parts":[[2016,4,12]],"date-time":"2016-04-12T07:31:16Z","timestamp":1460446276000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.15104","source":"Crossref","is-referenced-by-count":120,"title":["Sex steroids regulate skin pigmentation through nonclassical membrane-bound receptors"],"prefix":"10.7554","volume":"5","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4949-3849","authenticated-orcid":true,"given":"Christopher A","family":"Natale","sequence":"first","affiliation":[{"name":"Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1640-4205","authenticated-orcid":true,"given":"Elizabeth K","family":"Duperret","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junqian","family":"Zhang","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rochelle","family":"Sadeghi","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ankit","family":"Dahal","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9584-9589","authenticated-orcid":true,"given":"Kevin Tyler","family":"O'Brien","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rosa","family":"Cookson","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey D","family":"Winkler","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8482-1284","authenticated-orcid":true,"given":"Todd W","family":"Ridky","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, United States"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"4374","published-online":{"date-parts":[[2016,4,26]]},"reference":[{"key":"bib1","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.1097\/AOG.0b013e3181c2bde8","article-title":"Pregnancy and laboratory studies: A reference table for clinicians","volume":"114","author":"Abbassi-Ghanavati","year":"2009","journal-title":"Obstetrics and Gynecology"},{"key":"bib2","doi-asserted-by":"publisher","first-page":"1459","DOI":"10.1111\/bph.12445","article-title":"The concise guide to PHARMACOLOGY 2013\/14: G protein-coupled receptors","volume":"170","author":"Alexander","year":"2013","journal-title":"British Journal of Pharmacology"},{"key":"bib3","doi-asserted-by":"publisher","first-page":"6337","DOI":"10.1074\/jbc.M109.083477","article-title":"Leukotriene BLT2 receptor monomers activate the g(i2) gtp-binding protein more efficiently than dimers","volume":"285","author":"Arcemisb\u00e9h\u00e8re","year":"2010","journal-title":"Journal of Biological Chemistry"},{"key":"bib4","doi-asserted-by":"publisher","first-page":"4125","DOI":"10.1016\/S0040-4020(98)00140-9","article-title":"Parallel synthesis of polysubstituted tetrahydroquinolines","volume":"54","author":"Baudelle","year":"1998","journal-title":"Tetrahedron"},{"key":"bib5","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1111\/exd.12594","article-title":"Comparative analysis of colorimetric staining in skin using open-source software","volume":"24","author":"Billings","year":"2015","journal-title":"Experimental Dermatology"},{"key":"bib6","doi-asserted-by":"publisher","first-page":"207","DOI":"10.1038\/nchembio775","article-title":"Virtual and biomolecular screening converge on a selective agonist for GPR30","volume":"2","author":"Bologa","year":"2006","journal-title":"Nature Chemical Biology"},{"key":"bib7","doi-asserted-by":"publisher","first-page":"2252","DOI":"10.1039\/c001307b","article-title":"Highly efficient synthesis and characterization of the gpr30-selective agonist G-1 and related tetrahydroquinoline analogs","volume":"8","author":"Burai","year":"2010","journal-title":"Organic & Biomolecular Chemistry"},{"key":"bib8","doi-asserted-by":"publisher","first-page":"4628","DOI":"10.4049\/jimmunol.1301613","article-title":"Estrogen signaling through the G protein-coupled estrogen receptor regulates granulocyte activation in fish","volume":"191","author":"Cabas","year":"2013","journal-title":"Journal of Immunology"},{"key":"bib9","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1038\/ng1586","article-title":"Use of human tissue to assess the oncogenic activity of melanoma-associated mutations","volume":"37","author":"Chudnovsky","year":"2005","journal-title":"Nature Genetics"},{"key":"bib10","doi-asserted-by":"publisher","first-page":"853","DOI":"10.1016\/j.cell.2006.12.045","article-title":"Central role of p53 in the suntan response and pathologic hyperpigmentation","volume":"128","author":"Cui","year":"2007","journal-title":"Cell"},{"key":"bib11","doi-asserted-by":"publisher","first-page":"340","DOI":"10.1038\/nature05098","article-title":"Topical drug rescue strategy and skin protection based on the role of mc1r in uv-induced tanning","volume":"443","author":"D'Orazio","year":"2006","journal-title":"Nature"},{"key":"bib12","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1038\/nchembio.168","article-title":"In vivo effects of a GPR30 antagonist","volume":"5","author":"Dennis","year":"2009","journal-title":"Nature Chemical Biology"},{"key":"bib13","doi-asserted-by":"publisher","first-page":"358","DOI":"10.1016\/j.jsbmb.2011.07.002","article-title":"Identification of a GPER\/GPR30 antagonist with improved estrogen receptor counterselectivity","volume":"127","author":"Dennis","year":"2011","journal-title":"Journal of Steroid Biochemistry and Molecular Biology"},{"key":"bib14","doi-asserted-by":"publisher","first-page":"67","DOI":"10.1677\/JOE-07-0317","article-title":"Expression of membrane progesterone receptors on human T lymphocytes and jurkat cells and activation of g-proteins by progesterone","volume":"196","author":"Dosiou","year":"2008","journal-title":"Journal of Endocrinology"},{"key":"bib15","doi-asserted-by":"publisher","first-page":"1551","DOI":"10.4161\/cc.28492","article-title":"Activating FGFR3 mutations cause mild hyperplasia in human skin, but are insufficient to drive benign or malignant skin tumors","volume":"13","author":"Duperret","year":"2014","journal-title":"Cell Cycle"},{"key":"bib16","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1210\/mend.16.1.0758","article-title":"Estrogen action via the G protein-coupled receptor, GPR30: Stimulation of adenylyl cyclase and camp-mediated attenuation of the epidermal growth factor receptor-to-mapk signaling axis","volume":"16","author":"Filardo","year":"2002","journal-title":"Molecular Endocrinology"},{"key":"bib17","doi-asserted-by":"publisher","first-page":"1006","DOI":"10.1101\/gr.140061.112","article-title":"Brafv600e remodels the melanocyte transcriptome and induces BANCR to regulate melanoma cell migration","volume":"22","author":"Flockhart","year":"2012","journal-title":"Genome Research"},{"key":"bib18","doi-asserted-by":"publisher","first-page":"1976","DOI":"10.1002\/ijc.22074","article-title":"Melanocortin 1 receptor variants and skin cancer risk","volume":"119","author":"Han","year":"2006","journal-title":"International Journal of Cancer"},{"key":"bib19","doi-asserted-by":"publisher","first-page":"827","DOI":"10.1038\/nbt.2647","article-title":"Dna targeting specificity of rna-guided cas9 nucleases","volume":"31","author":"Hsu","year":"2013","journal-title":"Nature Biotechnology"},{"key":"bib20","doi-asserted-by":"publisher","first-page":"58","DOI":"10.3346\/jkms.2002.17.1.58","article-title":"Donor specific response of estrogen and progesterone on cultured human melanocytes","volume":"17","author":"Im","year":"2002","journal-title":"Journal of Korean Medical Science"},{"key":"bib21","doi-asserted-by":"publisher","DOI":"10.1002\/mrd.22496","article-title":"Estrogen and progesterone differentially regulate the levels of cystic fibrosis transmembrane regulator (CFTR), adenylate cyclase (AC), and cyclic adenosine mono-phosphate (camp) in the rat cervix","volume":"82","author":"Ismail","year":"2015","journal-title":"Molecular Reproduction and Development"},{"key":"bib22","first-page":"959","volume-title":"Andrews' Diseases of the Skin: Clinical Dermatology","author":"James","year":"2011"},{"key":"bib23","doi-asserted-by":"publisher","first-page":"1407","DOI":"10.1006\/bbrc.1994.1387","article-title":"Effects of estrogen and estrogen receptor in normal human melanocytes","volume":"199","author":"Jee","year":"1994","journal-title":"Biochemical and Biophysical Research Communications"},{"key":"bib24","doi-asserted-by":"publisher","first-page":"663","DOI":"10.1083\/jcb.66.3.663","article-title":"Mitotic activity in non-neoplastic melanocytes in vivo as determined by histochemical, autoradiographic, and electron microscope studies","volume":"66","author":"Jimbow","year":"1975","journal-title":"Journal of Cell Biology"},{"key":"bib25","doi-asserted-by":"publisher","first-page":"314","DOI":"10.1016\/j.steroids.2010.01.010","article-title":"Comparison between steroid binding to membrane progesterone receptor alpha (mpralpha) and to nuclear progesterone receptor: Correlation with physicochemical properties assessed by comparative molecular field analysis and identification of mpralpha-specific agonists","volume":"75","author":"Kelder","year":"2010","journal-title":"Steroids"},{"key":"bib26","doi-asserted-by":"publisher","first-page":"1199","DOI":"10.1111\/j.1468-3083.2009.03113.x","article-title":"Tamoxifen-induced melasma in a postmenopausal woman","volume":"23","author":"Kim","year":"2009","journal-title":"Journal of the European Academy of Dermatology and Venereology"},{"key":"bib27","doi-asserted-by":"publisher","first-page":"81","DOI":"10.1034\/j.1600-0749.2003.00004.x","article-title":"Effects of melanogenesis-inducing nitric oxide and histamine on the production of eumelanin and pheomelanin in cultured human melanocytes","volume":"16","author":"Lassalle","year":"2003","journal-title":"Pigment Cell Research"},{"key":"bib28","doi-asserted-by":"publisher","first-page":"969","DOI":"10.1210\/me.2009-0148","article-title":"Regulation of erralpha gene expression by estrogen receptor agonists and antagonists in SKBR3 breast cancer cells: Differential molecular mechanisms mediated by g protein-coupled receptor GPR30\/GPER-1","volume":"24","author":"Li","year":"2010","journal-title":"Molecular Endocrinology"},{"key":"bib29","doi-asserted-by":"publisher","first-page":"183","DOI":"10.1530\/JOE-14-0470","article-title":"Progesterone-induced activation of membrane-bound progesterone receptors in murine macrophage cells","volume":"224","author":"Lu","year":"2015","journal-title":"Journal of Endocrinology"},{"key":"bib30","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.ygcen.2014.11.011","article-title":"G-protein coupled estrogen receptor (GPER) inhibits final oocyte maturation in common carp, cyprinus carpio","volume":"211","author":"Majumder","year":"2015","journal-title":"General and Comparative Endocrinology"},{"key":"bib31","first-page":"181","article-title":"Carcinoids (argentaffin-cell tumors) and nerve hyperplasia of the appendicular mucosa","volume":"4","author":"Masson","year":"1928","journal-title":"American Journal of Pathology"},{"key":"bib32","doi-asserted-by":"publisher","first-page":"887","DOI":"10.1080\/10408440701638970","article-title":"Hydroquinone: An evaluation of the human risks from its carcinogenic and mutagenic properties","volume":"37","author":"McGregor","year":"2007","journal-title":"Critical Reviews in Toxicology"},{"key":"bib33","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1016\/0960-0760(94)90295-x","article-title":"Effects of estrogens on human melanocytes in vitro","volume":"49","author":"McLeod","year":"1994","journal-title":"Journal of Steroid Biochemistry and Molecular Biology"},{"key":"bib34","doi-asserted-by":"publisher","DOI":"10.1158\/2159-8290.CD-15-0196","article-title":"Cdkn2b loss promotes progression from benign melanocytic nevus to melanoma","volume":"5","author":"McNeal","year":"2015","journal-title":"Cancer Discovery"},{"key":"bib35","doi-asserted-by":"publisher","first-page":"899","DOI":"10.1095\/biolreprod.105.041285","article-title":"Dual role of histamine in modulation of leydig cell steroidogenesis via HRH1 and HRH2 receptor subtypes","volume":"73","author":"Mondillo","year":"2005","journal-title":"Biology of Reproduction"},{"key":"bib36","doi-asserted-by":"publisher","DOI":"10.1038\/jid.2015.140","article-title":"Iqgap1 and IQGAP3 serve individually essential roles in normal epidermal homeostasis and tumor progression","volume":"135","author":"Monteleon","year":"2015","journal-title":"Journal of Investigative Dermatology"},{"key":"bib37","doi-asserted-by":"publisher","first-page":"66","DOI":"10.1016\/j.clindermatol.2013.05.026","article-title":"Pigmentation disorders: Hyperpigmentation and hypopigmentation","volume":"32","author":"Nicolaidou","year":"2014","journal-title":"Clinics in Dermatology"},{"key":"bib38","doi-asserted-by":"publisher","first-page":"316","DOI":"10.1101\/gad.12.3.316","article-title":"Interaction of agouti protein with the melanocortin 1 receptor in vitro and in vivo","volume":"12","author":"Ollmann","year":"1998","journal-title":"Genes & Development"},{"key":"bib39","doi-asserted-by":"publisher","first-page":"194","DOI":"10.1016\/j.ydbio.2010.03.027","article-title":"Role of G protein-coupled estrogen receptor 1, GPER, in inhibition of oocyte maturation by endogenous estrogens in zebrafish","volume":"342","author":"Pang","year":"2010","journal-title":"Developmental Biology"},{"key":"bib40","doi-asserted-by":"publisher","first-page":"715","DOI":"10.1038\/nrendo.2011.122","article-title":"The g-protein-coupled estrogen receptor GPER in health and disease","volume":"7","author":"Prossnitz","year":"2011","journal-title":"Nature Reviews. Endocrinology"},{"key":"bib41","doi-asserted-by":"publisher","first-page":"593","DOI":"10.1111\/1523-1747.ep12477126","article-title":"Human melanocytes as a target tissue for hormones: In vitro studies with 1 alpha-25, dihydroxyvitamin D3, alpha-melanocyte stimulating hormone, and beta-estradiol","volume":"91","author":"Ranson","year":"1988","journal-title":"Journal of Investigative Dermatology"},{"key":"bib42","first-page":"101","article-title":"Melasma and other skin manifestations or oral contraceptives","volume":"21","author":"Resnik","year":"1967","journal-title":"Transactions of the New England Obstetrical and Gynecological Society"},{"key":"bib43","doi-asserted-by":"publisher","first-page":"601","DOI":"10.1001\/jama.199.9.601","article-title":"Melasma induced by oral contraceptive drugs","volume":"199","author":"Resnik","year":"1967","journal-title":"JAMA"},{"key":"bib44","doi-asserted-by":"publisher","first-page":"1450","DOI":"10.1038\/nm.2265","article-title":"Invasive three-dimensional organotypic neoplasia from multiple normal human epithelia","volume":"16","author":"Ridky","year":"2010","journal-title":"Nature Medicine"},{"key":"bib45","doi-asserted-by":"publisher","first-page":"22","DOI":"10.1016\/j.abb.2014.07.003","article-title":"Cyclic AMP (camp) signaling in melanocytes and melanoma","volume":"563","author":"Rodr\u00edguez","year":"2014","journal-title":"Archives of Biochemistry and Biophysics"},{"key":"bib46","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1038\/jid.1957.4","article-title":"Quantitative and qualitative data on the pigment cells of adult human epidermis","volume":"28","author":"Staricco","year":"1957","journal-title":"Journal of Investigative Dermatology"},{"key":"bib47","doi-asserted-by":"publisher","first-page":"1016","DOI":"10.1136\/bmj.1.4869.1016","article-title":"The number of melanocytes in human epidermis","volume":"1","author":"Szabo","year":"1954","journal-title":"British Medical Journal"},{"key":"bib48","doi-asserted-by":"publisher","first-page":"783","DOI":"10.1038\/nmeth.3047","article-title":"Improved vectors and genome-wide libraries for CRISPR screening","volume":"11","author":"Sanjana","year":"2014","journal-title":"Nature Methods"},{"key":"bib49","doi-asserted-by":"publisher","first-page":"689","DOI":"10.1016\/j.jaad.2010.12.046","article-title":"Melasma: A comprehensive update: Part I","volume":"65","author":"Sheth","year":"2011","journal-title":"Journal of the American Academy of Dermatology"},{"key":"bib50","doi-asserted-by":"publisher","first-page":"372","DOI":"10.1007\/s00239-004-0375-2","article-title":"Paqr proteins: A novel membrane receptor family defined by an ancient 7-transmembrane pass motif","volume":"61","author":"Tang","year":"2005","journal-title":"Journal of Molecular Evolution"},{"key":"bib51","doi-asserted-by":"publisher","first-page":"624","DOI":"10.1210\/en.2004-1064","article-title":"Identity of an estrogen membrane receptor coupled to a G protein in human breast cancer cells","volume":"146","author":"Thomas","year":"2005","journal-title":"Endocrinology"},{"key":"bib52","doi-asserted-by":"publisher","first-page":"168","DOI":"10.1016\/j.ygcen.2012.03.005","article-title":"Characterization of multiple membrane progestin receptor (mpr) subtypes from the goldfish ovary and their roles in the induction of oocyte maturation","volume":"177","author":"Tokumoto","year":"2012","journal-title":"General and Comparative Endocrinology"},{"key":"bib53","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2016.02.015","article-title":"Establishment of procedures for studying mpr-interacting agents and physiological roles of mpr","author":"Tokumoto","year":"2016","journal-title":"Steroids"},{"key":"bib54","volume-title":"De morbis cutaneis : a treatise of diseases incident to the skin","author":"Turner","year":"1726"},{"key":"bib55","doi-asserted-by":"publisher","first-page":"328","DOI":"10.1038\/ng1195-328","article-title":"Variants of the melanocyte-stimulating hormone receptor gene are associated with red hair and fair skin in humans","volume":"11","author":"Valverde","year":"1995","journal-title":"Nature Genetics"},{"key":"bib56","doi-asserted-by":"publisher","first-page":"334","DOI":"10.1046\/j.1523-1747.2000.00874.x","article-title":"Histamine induces melanogenesis and morphologic changes by protein kinase A activation via H2 receptors in human normal melanocytes","volume":"114","author":"Yoshida","year":"2000","journal-title":"Journal of Investigative Dermatology"},{"key":"bib57","doi-asserted-by":"publisher","first-page":"2231","DOI":"10.1073\/pnas.0336132100","article-title":"Cloning, expression, and characterization of a membrane progestin receptor and evidence it is an intermediary in meiotic maturation of fish oocytes","volume":"100","author":"Zhu","year":"2003","journal-title":"Proceedings of the National Academy of Sciences of the United States of America"}],"container-title":["eLife"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/cdn.elifesciences.org\/articles\/15104\/elife-15104-v2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/cdn.elifesciences.org\/articles\/15104\/elife-15104-v2.xml","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/elifesciences.org\/articles\/15104","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,11]],"date-time":"2023-10-11T20:50:52Z","timestamp":1697057452000},"score":1,"resource":{"primary":{"URL":"https:\/\/elifesciences.org\/articles\/15104"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,4,26]]},"references-count":57,"alternative-id":["10.7554\/eLife.15104"],"URL":"https:\/\/doi.org\/10.7554\/elife.15104","archive":["CLOCKSS"],"relation":{"references":[{"id-type":"uri","id":"http:\/\/www.ncbi.nlm.nih.gov\/geo\/query\/acc.cgi?acc=GSE33092","asserted-by":"subject"}],"has-review":[{"id-type":"doi","id":"10.7554\/eLife.15104.019","asserted-by":"object"},{"id-type":"doi","id":"10.7554\/eLife.15104.018","asserted-by":"object"}]},"ISSN":["2050-084X"],"issn-type":[{"value":"2050-084X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,4,26]]},"article-number":"e15104"}}