{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T20:00:00Z","timestamp":1790107200927,"version":"4.0.1"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2018,4,18]],"date-time":"2018-04-18T00:00:00Z","timestamp":1524009600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2018,4,18]],"date-time":"2018-04-18T00:00:00Z","timestamp":1524009600000},"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":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Seipin gene is originally found in type 2 congenital generalized lipodystrophy (CGL2) to involve lipid droplet formation. Recently, decrease of seipin expression is reported in substantia nigra of Parkinson\u2019s disease patients. Dopaminergic neurons in substantia nigra pars compacta expressed the seipin protein. The objective of this study is to investigate influence of the seipin deficiency on dopaminergic neurons and motor behaviors. Neuronal <jats:italic>seipin<\/jats:italic> knockout (<jats:italic>seipin<\/jats:italic>-nKO) mice (3\u201312 months of age) displayed an age-related deficit in motor coordination. The number of dopaminergic neurons in <jats:italic>seipin<\/jats:italic>-nKO mice was age dependently reduced with increase in cleaved caspase-3. The levels of \u03b1Syn oligomers and oligomer phosphorylation (S129), but not \u03b1Syn monomers, were elevated in dopaminergic neurons and substantia nigra of <jats:italic>seipin<\/jats:italic>-nKO mice. The PPAR\u03b3 expression in <jats:italic>seipin<\/jats:italic>-nKO mice was reduced. In <jats:italic>seipin<\/jats:italic>-nKO mice, the phosphorylation of GSK3\u03b2 was increased at Tyr216 and was reduced at Ser9, which was corrected by the PPAR\u03b3 agonist rosiglitazone. The increased IL-6 level in <jats:italic>seipin<\/jats:italic>-nKO mice was sensitive to rosiglitazone and GSK3\u03b2 inhibitor AR-A014418. The enhanced phosphorylation of \u03b1Syn was prevented by rosiglitazone and AR-A014418, while the increase in \u03b1Syn oligomers was corrected only by rosiglitazone. The treatment of <jats:italic>seipin<\/jats:italic>-nKO mice with rosiglitazone and AR-A014418 rescued the death of dopaminergic neurons, which was accompanied by the improvement of motor coordination. Therefore, the results indicate that seipin deficiency causes an age-related loss of dopaminergic neurons and impairment of motor coordination through reducing PPAR\u03b3 to enhance aggregation and phosphorylation of \u03b1Syn and neuroinflammation.<\/jats:p>","DOI":"10.1038\/s41419-018-0471-7","type":"journal-article","created":{"date-parts":[[2018,4,18]],"date-time":"2018-04-18T09:45:43Z","timestamp":1524044743000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":30,"title":["Seipin deficiency in mice causes loss of dopaminergic neurons via aggregation and phosphorylation of \u03b1-synuclein and neuroinflammation"],"prefix":"10.1038","volume":"9","author":[{"given":"Ling","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juan","family":"Hong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yajuan","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenfeng","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ling","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2018,4,18]]},"reference":[{"key":"471_CR1","doi-asserted-by":"publisher","first-page":"4840","DOI":"10.1210\/jc.2003-030855","volume":"88","author":"AK Agarwal","year":"2003","unstructured":"Agarwal, A. K. et al. Phenotypic and genetic heterogeneity in congenital generalized lipodystrophy. J. Clin. Endocrinol. Metab. 88, 4840\u20134847 (2003).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"471_CR2","doi-asserted-by":"publisher","first-page":"20890","DOI":"10.1073\/pnas.0704154104","volume":"104","author":"KM Szymanski","year":"2007","unstructured":"Szymanski, K. M. et al. The lipodystrophy protein seipin is found at endoplasmic reticulum lipid droplet junctions and is important for droplet morphology. Proc. Natl Acad. Sci. USA 104, 20890\u201320895 (2007).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"471_CR3","doi-asserted-by":"publisher","first-page":"271","DOI":"10.1002\/ajmg.a.20245","volume":"121A","author":"A Rajab","year":"2003","unstructured":"Rajab, A., Khaburi, M., Spranger, S., Kunze, J. & Spranger, J. Congenital generalized lipodystrophy, mental retardation, deafness, short stature, and slender bones: a newly recognized syndrome? Am. J. Med. Genet. A 121A, 271\u2013276 (2003).","journal-title":"Am. J. Med. Genet. A"},{"key":"471_CR4","doi-asserted-by":"publisher","first-page":"2360","DOI":"10.1210\/jc.2003-031211","volume":"89","author":"K Ebihara","year":"2004","unstructured":"Ebihara, K. et al. Gene and phenotype analysis of congenital generalized lipodystrophy in Japanese: a novel homozygous nonsense mutation in seipin gene. J. Clin. Endocrinol. Metab. 89, 2360\u20132364 (2004).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"471_CR5","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1038\/ng585","volume":"28","author":"J Magre","year":"2001","unstructured":"Magre, J. et al. Identification of the gene altered in Berardinelli-Seip congenital lipodystrophy on chromosome 11q13. Nat. Genet. 28, 365\u2013370 (2001).","journal-title":"Nat. Genet."},{"key":"471_CR6","doi-asserted-by":"publisher","first-page":"8","DOI":"10.1093\/brain\/awn216","volume":"132","author":"D Ito","year":"2009","unstructured":"Ito, D. & Suzuki, N. Seipinopathy: a novel endoplasmic reticulum stress-associated disease. Brain 132, 8\u201315 (2009).","journal-title":"Brain"},{"key":"471_CR7","doi-asserted-by":"publisher","first-page":"266","DOI":"10.1016\/j.nbd.2008.05.004","volume":"31","author":"D Ito","year":"2008","unstructured":"Ito, D., Fujisawa, T., Iida, H. & Suzuki, N. Characterization of seipin\/BSCL2, a protein associated with spastic paraplegia 17. Neurobiol. Dis. 31, 266\u2013277 (2008).","journal-title":"Neurobiol. Dis."},{"key":"471_CR8","doi-asserted-by":"publisher","first-page":"415","DOI":"10.1002\/ana.20410","volume":"57","author":"M Auer-Grumbach","year":"2005","unstructured":"Auer-Grumbach, M. et al. Phenotypes of the N88S Berardinelli-Seip congenital lipodystrophy 2 mutation. Ann. Neurol. 57, 415\u2013424 (2005).","journal-title":"Ann. Neurol."},{"key":"471_CR9","doi-asserted-by":"publisher","first-page":"2124","DOI":"10.1093\/brain\/awh232","volume":"127","author":"J Irobi","year":"2004","unstructured":"Irobi, J. The phenotype of motor neuropathies associated with BSCL2 mutations is broader than Silver syndrome and distal HMN type V. Brain 127, 2124\u20132130 (2004).","journal-title":"Brain"},{"key":"471_CR10","doi-asserted-by":"publisher","first-page":"3831","DOI":"10.1093\/hmg\/ddr304","volume":"20","author":"T Yagi","year":"2011","unstructured":"Yagi, T., Ito, D., Nihei, Y., Ishihara, T. & Suzuki, N. N88S seipin mutant transgenic mice develop features of seipinopathy\/BSCL2-related motor neuron disease via endoplasmic reticulum stress. Hum. Mol. Genet. 20, 3831\u20133840 (2011).","journal-title":"Hum. Mol. Genet."},{"key":"471_CR11","doi-asserted-by":"publisher","first-page":"4094","DOI":"10.1093\/hmg\/ddu126","volume":"23","author":"L Zhou","year":"2014","unstructured":"Zhou, L. et al. Lack of seipin in neurons results in anxiety- and depression-like behaviors via down regulation of PPARgamma. Hum. Mol. Genet. 23, 4094\u20134102 (2014).","journal-title":"Hum. Mol. Genet."},{"key":"471_CR12","doi-asserted-by":"publisher","first-page":"784","DOI":"10.1002\/pmic.201300342","volume":"14","author":"V Licker","year":"2014","unstructured":"Licker, V. et al. Proteomic analysis of human substantia nigra identifies novel candidates involved in Parkinson\u2019s disease pathogenesis. Proteomics 14, 784\u2013794 (2014).","journal-title":"Proteomics"},{"key":"471_CR13","doi-asserted-by":"publisher","first-page":"485","DOI":"10.1111\/j.1750-3639.2011.00540.x","volume":"22","author":"KD van Dijk","year":"2012","unstructured":"van Dijk, K. D. et al. The proteome of the locus ceruleus in Parkinson\u2019s disease: relevance to pathogenesis. Brain Pathol. 22, 485\u2013498 (2012).","journal-title":"Brain Pathol."},{"key":"471_CR14","doi-asserted-by":"publisher","first-page":"3301","DOI":"10.1523\/JNEUROSCI.5368-11.2012","volume":"32","author":"E Colla","year":"2012","unstructured":"Colla, E. et al. Accumulation of toxic \u03b1-synuclein oligomer within endoplasmic reticulum occurs in \u03b1-synucleinopathy in vivo. J. Neurosci. 32, 3301\u20133305 (2012).","journal-title":"J. Neurosci."},{"key":"471_CR15","doi-asserted-by":"publisher","DOI":"10.1186\/s12974-016-0598-3","volume":"13","author":"Y Qian","year":"2016","unstructured":"Qian, Y. et al. Neuronal seipin knockout facilitates Abeta-induced neuroinflammation and neurotoxicity via reduction of PPARgamma in hippocampus of mouse. J. Neuroinflamm. 13, 145 (2016).","journal-title":"J. Neuroinflamm."},{"key":"471_CR16","doi-asserted-by":"publisher","first-page":"e275","DOI":"10.1111\/j.1365-2567.2008.02959.x","volume":"128","author":"WC Huang","year":"2009","unstructured":"Huang, W. C. et al. Glycogen synthase kinase-3 negatively regulates anti-inflammatory interleukin-10 for lipopolysaccharide-induced iNOS\/NO biosynthesis and RANTES production in microglial cells. Immunology 128, e275\u2013e286 (2009).","journal-title":"Immunology"},{"key":"471_CR17","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1002\/ana.24294","volume":"77","author":"J Eschbach","year":"2015","unstructured":"Eschbach, J. et al. Mutual exacerbation of peroxisome proliferator-activated receptor gamma coactivator 1alpha deregulation and alpha-synuclein oligomerization. Ann. Neurol. 77, 15\u201332 (2015).","journal-title":"Ann. Neurol."},{"key":"471_CR18","doi-asserted-by":"publisher","first-page":"256","DOI":"10.1002\/cmdc.200500039","volume":"1","author":"AP Kozikowski","year":"2006","unstructured":"Kozikowski, A. P. et al. Highly potent and specific GSK-3beta inhibitors that block tau phosphorylation and decrease alpha-synuclein protein expression in a cellular model of Parkinson\u2019s disease. ChemMedChem 1, 256\u2013266 (2006).","journal-title":"ChemMedChem"},{"key":"471_CR19","doi-asserted-by":"publisher","first-page":"2320","DOI":"10.2337\/db13-0729","volume":"63","author":"L Liu","year":"2014","unstructured":"Liu, L. et al. Adipose-specific knockout of SEIPIN\/BSCL2 results in progressive lipodystrophy. Diabetes 63, 2320\u20132331 (2014).","journal-title":"Diabetes"},{"key":"471_CR20","doi-asserted-by":"publisher","first-page":"1615","DOI":"10.1242\/dmm.021550","volume":"8","author":"G Li","year":"2015","unstructured":"Li, G. et al. Seipin knockout in mice impairs stem cell proliferation and progenitor cell differentiation in the adult hippocampal dentate gyrus via reduced levels of PPARgamma. Dis. Model Mech. 8, 1615\u20131624 (2015).","journal-title":"Dis. Model Mech."},{"key":"471_CR21","doi-asserted-by":"publisher","first-page":"2000","DOI":"10.2353\/ajpath.2007.070373","volume":"171","author":"K Assayag","year":"2007","unstructured":"Assayag, K., Yakunin, E., Loeb, V., Selkoe, D. J. & Sharon, R. Polyunsaturated fatty acids induce \u03b1-synuclein-related pathogenic changes in neuronal cells. Am. J. Pathol. 171, 2000\u20132011 (2007).","journal-title":"Am. J. Pathol."},{"key":"471_CR22","doi-asserted-by":"publisher","first-page":"1641","DOI":"10.1074\/jbc.C100560200","volume":"277","author":"AB Manning-Bog","year":"2002","unstructured":"Manning-Bog, A. B. et al. The herbicide paraquat causes up-regulation and aggregation of alpha-synuclein in mice: paraquat and alpha-synuclein. J. Biol. Chem. 277, 1641\u20131644 (2002).","journal-title":"J. Biol. Chem."},{"key":"471_CR23","doi-asserted-by":"publisher","first-page":"4238","DOI":"10.1093\/hmg\/ddv156","volume":"24","author":"C Ebihara","year":"2015","unstructured":"Ebihara, C. et al. Seipin is necessary for normal brain development and spermatogenesis in addition to adipogenesis. Hum. Mol. Genet. 24, 4238\u20134249 (2015).","journal-title":"Hum. Mol. Genet."},{"key":"471_CR24","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1111\/j.1750-3639.2011.00530.x","volume":"22","author":"E Yakunin","year":"2012","unstructured":"Yakunin, E. et al. Alpha-synuclein neuropathology is controlled by nuclear hormone receptors and enhanced by docosahexaenoic acid in a mouse model for Parkinson\u2019s disease. Brain Pathol. 22, 280\u2013294 (2012).","journal-title":"Brain Pathol."},{"key":"471_CR25","doi-asserted-by":"publisher","first-page":"41958","DOI":"10.1074\/jbc.M105022200","volume":"276","author":"RJ Perrin","year":"2001","unstructured":"Perrin, R. J. Exposure to long chain polyunsaturated fatty acids triggers rapid multimerization of synucleins. J. Biol. Chem. 276, 41958\u201341962 (2001).","journal-title":"J. Biol. Chem."},{"key":"471_CR26","doi-asserted-by":"publisher","first-page":"583","DOI":"10.1016\/S0896-6273(03)00024-2","volume":"37","author":"R Sharon","year":"2003","unstructured":"Sharon, R. et al. The formation of highly soluble oligomers of alpha-synuclein is regulated by fatty acids and enhanced in Parkinson\u2019s disease. Neuron 37, 583\u2013595 (2003).","journal-title":"Neuron"},{"key":"471_CR27","doi-asserted-by":"publisher","first-page":"10211","DOI":"10.1074\/jbc.M809671200","volume":"284","author":"CL Kragh","year":"2009","unstructured":"Kragh, C. L. et al. Alpha-synuclein aggregation and Ser-129 phosphorylation-dependent cell death in oligodendroglial cells. J. Biol. Chem. 284, 10211\u201310222 (2009).","journal-title":"J. Biol. Chem."},{"key":"471_CR28","doi-asserted-by":"publisher","first-page":"2820","DOI":"10.1096\/fj.08-120410","volume":"23","author":"T Duka","year":"2009","unstructured":"Duka, T., Duka, V., Joyce, J. N. & Sidhu, A. Alpha-synuclein contributes to GSK-3beta-catalyzed Tau phosphorylation in Parkinson\u2019s disease models. FASEB J. 23, 2820\u20132830 (2009).","journal-title":"FASEB J."},{"key":"471_CR29","doi-asserted-by":"publisher","first-page":"838","DOI":"10.1038\/cdd.2014.179","volume":"22","author":"JJ Credle","year":"2015","unstructured":"Credle, J. J. et al. GSK-3beta dysregulation contributes to parkinson\u2019s-like pathophysiology with associated region-specific phosphorylation and accumulation of tau and alpha-synuclein. Cell Death Differ. 22, 838\u2013851 (2015).","journal-title":"Cell Death Differ."},{"key":"471_CR30","doi-asserted-by":"publisher","first-page":"1525","DOI":"10.1038\/aps.2016.75","volume":"37","author":"Z Mou","year":"2016","unstructured":"Mou, Z. et al. Bibenzyl compound 20c protects against endoplasmic reticulum stress in tunicamycin-treated PC12 cells in vitro. Acta Pharmacol. Sin. 37, 1525\u20131533 (2016).","journal-title":"Acta Pharmacol. Sin."},{"key":"471_CR31","doi-asserted-by":"publisher","first-page":"23179","DOI":"10.1074\/jbc.M802223200","volume":"283","author":"N Sugeno","year":"2008","unstructured":"Sugeno, N. et al. Serine 129 phosphorylation of alpha-synuclein induces unfolded protein response-mediated cell death. J. Biol. Chem. 283, 23179\u201323188 (2008).","journal-title":"J. Biol. Chem."},{"key":"471_CR32","doi-asserted-by":"publisher","first-page":"383","DOI":"10.1016\/j.neuroscience.2014.12.003","volume":"286","author":"M Chen","year":"2015","unstructured":"Chen, M. et al. Tea polyphenols alleviate motor impairments, dopaminergic neuronal injury, and cerebral \u03b1-synuclein aggregation in MPTP-intoxicated parkinsonian monkeys. Neuroscience 286, 383\u2013392 (2015).","journal-title":"Neuroscience"},{"key":"471_CR33","doi-asserted-by":"publisher","DOI":"10.1186\/s13041-016-0191-9","volume":"9","author":"H Shoji","year":"2016","unstructured":"Shoji, H., Takao, K., Hattori, S. & Miyakawa, T. Age-related changes in behavior in C57BL\/6J mice from young adulthood to middle age. Mol. Brain 9, 11 (2016).","journal-title":"Mol. Brain"},{"key":"471_CR34","doi-asserted-by":"publisher","first-page":"382","DOI":"10.1016\/S1474-4422(09)70062-6","volume":"8","author":"EC Hirsch","year":"2009","unstructured":"Hirsch, E. C. & Hunot, S. Neuroinflammation in Parkinson\u2019s disease: a target for neuroprotection? Lancet Neurol. 8, 382\u2013397 (2009).","journal-title":"Lancet Neurol."},{"key":"471_CR35","doi-asserted-by":"publisher","first-page":"6186","DOI":"10.1523\/JNEUROSCI.5857-08.2009","volume":"29","author":"X Zhao","year":"2009","unstructured":"Zhao, X. et al. Neuronal PPARgamma deficiency increases susceptibility to brain damage after cerebral ischemia. J. Neurosci. 29, 6186\u20136195 (2009).","journal-title":"J. Neurosci."},{"key":"471_CR36","doi-asserted-by":"publisher","first-page":"7871","DOI":"10.1021\/bi030086j","volume":"42","author":"MJ Volles","year":"2003","unstructured":"Volles, M. J. & Lansbury, P. T. Jr. Zeroing in on the pathogenic form of alpha-synuclein and its mechanism of neurotoxicity in Parkinson\u2019s disease. Biochemistry 42, 7871\u20137878 (2003).","journal-title":"Biochemistry"},{"key":"471_CR37","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1002\/1097-4547(20000715)61:2<121::AID-JNR1>3.0.CO;2-4","volume":"61","author":"JE Duda","year":"2000","unstructured":"Duda, J. E., Lee, V. M. & Trojanowski, J. Q. Neuropathology of synuclein aggregates. J. Neurosci. Res. 61, 121\u2013127 (2000).","journal-title":"J. Neurosci. Res."},{"key":"471_CR38","doi-asserted-by":"publisher","first-page":"7687","DOI":"10.1523\/JNEUROSCI.0143-07.2008","volume":"28","author":"HM Gao","year":"2008","unstructured":"Gao, H. M. et al. M. Neuroinflammation and oxidation\/nitration of alpha-synuclein linked to dopaminergic neurodegeneration. J. Neurosci. 28, 7687\u20137698 (2008).","journal-title":"J. Neurosci."},{"key":"471_CR39","doi-asserted-by":"publisher","first-page":"704","DOI":"10.1016\/j.pbb.2011.06.026","volume":"99","author":"G Patki","year":"2011","unstructured":"Patki, G. & Lau, Y.-S. Melatonin protects against neurobehavioral and mitochondrial deficits in a chronic mouse model of Parkinson\u2019s disease. Pharmacol. Biochem. Behav. 99, 704\u2013711 (2011).","journal-title":"Pharmacol. Biochem. Behav."},{"key":"471_CR40","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1016\/0197-4580(93)90112-O","volume":"14","author":"MJ West","year":"1993","unstructured":"West, M. J. New stereological methods for counting neurons. Neurobiol. Aging 14, 275\u2013285 (1993).","journal-title":"Neurobiol. Aging"},{"key":"471_CR41","doi-asserted-by":"publisher","first-page":"7054","DOI":"10.1073\/pnas.1324025111","volume":"111","author":"M Jiang","year":"2014","unstructured":"Jiang, M. et al. Lack of testicular seipin causes teratozoospermia syndrome in men. Proc. Natl Acad. Sci. USA 111, 7054\u20137059 (2014).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"471_CR42","doi-asserted-by":"publisher","first-page":"418","DOI":"10.1038\/nprot.2006.62","volume":"1","author":"I Wittig","year":"2006","unstructured":"Wittig, I., Braun, H. P. & Schagger, H. Blue native PAGE. Nat. Protoc. 1, 418\u2013428 (2006).","journal-title":"Nat. Protoc."},{"key":"471_CR43","doi-asserted-by":"publisher","first-page":"345","DOI":"10.1007\/s00213-012-2722-0","volume":"223","author":"M Salehi-Sadaghiani","year":"2012","unstructured":"Salehi-Sadaghiani, M. et al. NMDA receptor involvement in antidepressant-like effect of pioglitazone in the forced swimming test in mice. Psychopharmacology 223, 345\u2013355 (2012).","journal-title":"Psychopharmacology"},{"key":"471_CR44","doi-asserted-by":"publisher","first-page":"315","DOI":"10.1016\/j.jpain.2010.06.007","volume":"12","author":"DF Martins","year":"2011","unstructured":"Martins, D. F. et al. The antinociceptive effects of AR-A014418, a selective inhibitor of glycogen synthase kinase-3 beta, in mice. J. Pain 12, 315\u2013322 (2011).","journal-title":"J. Pain"}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-018-0471-7","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-018-0471-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-018-0471-7.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,20]],"date-time":"2022-12-20T11:52:57Z","timestamp":1671537177000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-018-0471-7"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,4,18]]},"references-count":44,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2018,5]]}},"alternative-id":["471"],"URL":"https:\/\/doi.org\/10.1038\/s41419-018-0471-7","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,4,18]]},"assertion":[{"value":"31 August 2017","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 February 2018","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"9 March 2018","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 April 2018","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare that they have no conflict of interest.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"440"}}