{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T14:37:21Z","timestamp":1787063841982,"version":"build-2736575974"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","issue":"12","license":[{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"},{"start":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T00:00:00Z","timestamp":1631750400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.springer.com\/tdm"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Acta Pharmacol Sin"],"published-print":{"date-parts":[[2021,12]]},"DOI":"10.1038\/s41401-021-00768-4","type":"journal-article","created":{"date-parts":[[2021,9,16]],"date-time":"2021-09-16T05:02:47Z","timestamp":1631768567000},"page":"1991-2003","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":23,"title":["Roflupram protects against rotenone-induced neurotoxicity and facilitates \u03b1-synuclein degradation in Parkinson\u2019s disease models"],"prefix":"10.1038","volume":"42","author":[{"given":"Wen-li","family":"Dong","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jia-hong","family":"Zhong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-qing","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jin-feng","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yun-yun","family":"Qin","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiang-ping","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ning-bo","family":"Cai","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meng-fan","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hai-tao","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,9,16]]},"reference":[{"key":"768_CR1","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1002\/mds.28412","volume":"36","author":"M Elfil","year":"2021","unstructured":"Elfil M, Bahbah EI, Attia MM, Eldokmak M, Koo BB. Impact of obstructive sleep apnea on cognitive and motor functions in Parkinson\u2019s disease. Mov Disord. 2021;36:570\u201380.","journal-title":"Mov Disord"},{"key":"768_CR2","doi-asserted-by":"crossref","first-page":"2573","DOI":"10.2174\/1381612824666180820150150","volume":"24","author":"A Kabra","year":"2018","unstructured":"Kabra A, Sharma R, Kabra R, Baghel US. Emerging and alternative therapies for Parkinson disease: an updated review. Curr Pharm Des. 2018;24:2573\u201382.","journal-title":"Curr Pharm Des"},{"key":"768_CR3","doi-asserted-by":"crossref","first-page":"75","DOI":"10.1038\/s41582-020-00426-z","volume":"17","author":"JK Krauss","year":"2021","unstructured":"Krauss JK, Lipsman N, Aziz T, Boutet A, Brown P, Chang JW, et al. Technology of deep brain stimulation: current status and future directions. Nat Rev Neurol. 2021;17:75\u201387.","journal-title":"Nat Rev Neurol"},{"key":"768_CR4","doi-asserted-by":"crossref","first-page":"1248","DOI":"10.1002\/mds.27372","volume":"33","author":"SH Fox","year":"2018","unstructured":"Fox SH, Katzenschlager R, Lim SY, Barton B, de Bie RMA, Seppi K, et al. International Parkinson and movement disorder society evidence-based medicine review: Update on treatments for the motor symptoms of Parkinson\u2019s disease. Mov Disord. 2018;33:1248\u201366.","journal-title":"Mov Disord"},{"key":"768_CR5","doi-asserted-by":"crossref","first-page":"455","DOI":"10.3233\/JPD-202481","volume":"11","author":"P Borghammer","year":"2021","unstructured":"Borghammer P. The alpha-synuclein origin and connectome model (SOC Model) of Parkinson\u2019s disease: explaining motor asymmetry, non-motor phenotypes, and cognitive decline. J Parkinsons Dis. 2021;11:455\u201374.","journal-title":"J Parkinsons Dis."},{"key":"768_CR6","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1038\/s41583-020-00416-6","volume":"22","author":"MB Fares","year":"2021","unstructured":"Fares MB, Jagannath S, Lashuel HA. Reverse engineering Lewy bodies: how far have we come and how far can we go? Nat Rev Neurosci. 2021;22:111\u201331.","journal-title":"Nat Rev Neurosci"},{"key":"768_CR7","doi-asserted-by":"crossref","first-page":"649","DOI":"10.1007\/s12264-012-1263-1","volume":"28","author":"TF Jiang","year":"2012","unstructured":"Jiang TF, Chen SD. Dysfunction of two lysosome degradation pathways of alpha-synuclein in Parkinson\u2019s disease: potential therapeutic targets? Neurosci Bull. 2012;28:649\u201357.","journal-title":"Neurosci Bull"},{"key":"768_CR8","doi-asserted-by":"crossref","first-page":"537","DOI":"10.1007\/s12035-012-8341-2","volume":"47","author":"M Xilouri","year":"2013","unstructured":"Xilouri M, Brekk OR, Stefanis L. alpha-Synuclein and protein degradation systems: a reciprocal relationship. Mol Neurobiol. 2013;47:537\u201351.","journal-title":"Mol Neurobiol"},{"key":"768_CR9","doi-asserted-by":"crossref","first-page":"eaal4161","DOI":"10.1126\/scisignal.aal4161","volume":"10","author":"N Abuarab","year":"2017","unstructured":"Abuarab N, Munsey TS, Jiang LH, Li J, Sivaprasadarao A. High glucose-induced ROS activates TRPM2 to trigger lysosomal membrane permeabilization and Zn2+-mediated mitochondrial fission. Sci Signal. 2017;10:eaal4161.","journal-title":"Sci Signal"},{"key":"768_CR10","doi-asserted-by":"crossref","first-page":"1745","DOI":"10.7150\/ijbs.26230","volume":"14","author":"H Wang","year":"2018","unstructured":"Wang H, Gaur U, Xiao J, Xu B, Xu J, Zheng W. Targeting phosphodiesterase 4 as a potential therapeutic strategy for enhancing neuroplasticity following ischemic stroke. Int J Biol Sci. 2018;14:1745\u201354.","journal-title":"Int J Biol Sci"},{"key":"768_CR11","doi-asserted-by":"crossref","first-page":"269","DOI":"10.3233\/JAD-122236","volume":"38","author":"C Zhang","year":"2014","unstructured":"Zhang C, Cheng Y, Wang H, Wang C, Wilson SP, Xu J, et al. RNA interference-mediated knockdown of long-form phosphodiesterase-4D (PDE4D) enzyme reverses amyloid-beta42-induced memory deficits in mice. J Alzheimers Dis. 2014;38:269\u201380.","journal-title":"J Alzheimers Dis"},{"key":"768_CR12","doi-asserted-by":"crossref","first-page":"105078","DOI":"10.1016\/j.phrs.2020.105078","volume":"160","author":"A Bhat","year":"2020","unstructured":"Bhat A, Ray B, Mahalakshmi AM, Tuladhar S, Nandakumar DN, Srinivasan M, et al. Phosphodiesterase-4 enzyme as a therapeutic target in neurological disorders. Pharmacol Res. 2020;160:105078.","journal-title":"Pharmacol Res"},{"key":"768_CR13","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/S0021-5198(19)31327-7","volume":"75","author":"N Yamashita","year":"1997","unstructured":"Yamashita N, Hayashi A, Baba J, Sawa A. Rolipram, a phosphodiesterase-4-selective inhibitor, promotes the survival of cultured rat dopaminergic neurons. Jpn J Pharmacol. 1997;75:155\u20139.","journal-title":"Jpn J Pharmacol"},{"key":"768_CR14","doi-asserted-by":"crossref","first-page":"2431","DOI":"10.1111\/j.1460-9568.1995.tb01041.x","volume":"7","author":"P Hulley","year":"1995","unstructured":"Hulley P, Hartikka J, Abdel\u2019Al S, Engels P, Buerki HR, Wiederhold KH, et al. Inhibitors of type IV phosphodiesterases reduce the toxicity of MPTP in substantia nigra neurons in vivo. Eur J Neurosci. 1995;7:2431\u201340.","journal-title":"Eur J Neurosci"},{"key":"768_CR15","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1016\/j.freeradbiomed.2019.02.027","volume":"135","author":"J Zhong","year":"2019","unstructured":"Zhong J, Xie J, Xiao J, Li D, Xu B, Wang X, et al. Inhibition of PDE4 by FCPR16 induces AMPK-dependent autophagy and confers neuroprotection in SH-SY5Y cells and neurons exposed to MPP+-induced oxidative insult. Free Radic Biol Med. 2019;135:87\u20131.","journal-title":"Free Radic Biol Med"},{"key":"768_CR16","doi-asserted-by":"crossref","first-page":"2333","DOI":"10.1111\/bph.14983","volume":"177","author":"J Zhong","year":"2020","unstructured":"Zhong J, Dong W, Qin Y, Xie J, Xiao J, Xu J, et al. Roflupram exerts neuroprotection via activation of CREB\/PGC-1alpha signalling in experimental models of Parkinson\u2019s disease. Br J Pharmacol. 2020;177:2333\u201350.","journal-title":"Br J Pharmacol"},{"key":"768_CR17","doi-asserted-by":"crossref","first-page":"7673","DOI":"10.1021\/jm701635j","volume":"51","author":"S Zheng","year":"2008","unstructured":"Zheng S, Kaur G, Wang H, Li M, Macnaughtan M, Yang X, et al. Design, synthesis, and structure-activity relationship, molecular modeling, and NMR studies of a series of phenyl alkyl ketones as highly potent and selective phosphodiesterase-4 inhibitors. J Med Chem. 2008;51:7673\u201388.","journal-title":"J Med Chem"},{"key":"768_CR18","doi-asserted-by":"crossref","first-page":"260","DOI":"10.1016\/j.neuropharm.2017.01.004","volume":"116","author":"H Guo","year":"2017","unstructured":"Guo H, Cheng Y, Wang C, Wu J, Zou Z, Niu B, et al. FFPM, a PDE4 inhibitor, reverses learning and memory deficits in APP\/PS1 transgenic mice via cAMP\/PKA\/CREB signaling and anti-inflammatory effects. Neuropharmacology. 2017;116:260\u20139.","journal-title":"Neuropharmacology"},{"key":"768_CR19","doi-asserted-by":"crossref","first-page":"2381","DOI":"10.1021\/acschemneuro.7b00065","volume":"8","author":"T You","year":"2017","unstructured":"You T, Cheng Y, Zhong J, Bi B, Zeng B, Zheng W, et al. Roflupram, a phosphodiesterase 4 inhibitior, suppresses inflammasome activation through autophagy in microglial cells. ACS Chem Neurosci. 2017;8:2381\u201392.","journal-title":"ACS Chem Neurosci"},{"key":"768_CR20","doi-asserted-by":"crossref","first-page":"107176","DOI":"10.1016\/j.intimp.2020.107176","volume":"90","author":"D Li","year":"2021","unstructured":"Li D, Xu J, Qin Y, Cai N, Cheng Y, Wang H. Roflupram, a novel phosphodiesterase 4 inhibitor, inhibits lipopolysaccharide-induced neuroinflammatory responses through activation of the AMPK\/Sirt1 pathway. Int Immunopharmacol. 2021;90:107176.","journal-title":"Int Immunopharmacol"},{"key":"768_CR21","doi-asserted-by":"crossref","first-page":"249","DOI":"10.1007\/s00401-017-1786-7","volume":"135","author":"I St-Amour","year":"2018","unstructured":"St-Amour I, Turgeon A, Goupil C, Planel E, Hebert SS. Co-occurrence of mixed proteinopathies in late-stage Huntington\u2019s disease. Acta Neuropathol. 2018;135:249\u201365.","journal-title":"Acta Neuropathol"},{"key":"768_CR22","doi-asserted-by":"crossref","first-page":"222","DOI":"10.1111\/bph.13360","volume":"173","author":"M Kurano","year":"2016","unstructured":"Kurano M, Hara M, Nojiri T, Ikeda H, Tsukamoto K, Yatomi Y. Resveratrol exerts a biphasic effect on apolipoprotein M. Br J Pharmacol. 2016;173:222\u201333.","journal-title":"Br J Pharmacol"},{"key":"768_CR23","doi-asserted-by":"crossref","first-page":"518","DOI":"10.1038\/s41401-020-0454-y","volume":"42","author":"YL Guo","year":"2021","unstructured":"Guo YL, Duan WJ, Lu DH, Ma XH, Li XX, Li Z, et al. Autophagy-dependent removal of alpha-synuclein: a novel mechanism of GM1 ganglioside neuroprotection against Parkinson\u2019s disease. Acta Pharmacol Sin. 2021;42:518\u201328.","journal-title":"Acta Pharmacol Sin"},{"key":"768_CR24","doi-asserted-by":"crossref","first-page":"845","DOI":"10.1080\/15548627.2017.1390636","volume":"14","author":"J Liu","year":"2018","unstructured":"Liu J, Liu W, Lu Y, Tian H, Duan C, Lu L, et al. Piperlongumine restores the balance of autophagy and apoptosis by increasing BCL2 phosphorylation in rotenone-induced Parkinson disease models. Autophagy. 2018;14:845\u201361.","journal-title":"Autophagy"},{"key":"768_CR25","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1038\/s41401-018-0077-8","volume":"40","author":"ZL Ren","year":"2019","unstructured":"Ren ZL, Wang CD, Wang T, Ding H, Zhou M, Yang N, et al. Ganoderma lucidum extract ameliorates MPTP-induced parkinsonism and protects dopaminergic neurons from oxidative stress via regulating mitochondrial function, autophagy, and apoptosis. Acta Pharmacol Sin. 2019;40:441\u201350.","journal-title":"Acta Pharmacol Sin"},{"key":"768_CR26","doi-asserted-by":"crossref","first-page":"1028","DOI":"10.3389\/fnins.2019.01028","volume":"13","author":"M Ramalingam","year":"2019","unstructured":"Ramalingam M, Huh YJ, Lee YI. The impairments of alpha-synuclein and mechanistic target of rapamycin in rotenone-induced SH-SY5Y cells and mice model of Parkinson\u2019s disease. Front Neurosci. 2019;13:1028.","journal-title":"Front Neurosci"},{"key":"768_CR27","doi-asserted-by":"crossref","first-page":"668","DOI":"10.1111\/jnc.13172","volume":"134","author":"Y Feng","year":"2015","unstructured":"Feng Y, Liu T, Dong SY, Guo YJ, Jankovic J, Xu H, et al. Rotenone affects p53 transcriptional activity and apoptosis via targeting SIRT1 and H3K9 acetylation in SH-SY5Y cells. J Neurochem. 2015;134:668\u201376.","journal-title":"J Neurochem"},{"key":"768_CR28","doi-asserted-by":"crossref","first-page":"67","DOI":"10.1016\/j.bbi.2020.11.029","volume":"92","author":"J Xie","year":"2021","unstructured":"Xie J, Bi B, Qin Y, Dong W, Zhong J, Li M, et al. Inhibition of phosphodiesterase-4 suppresses HMGB1\/RAGE signaling pathway and NLRP3 inflammasome activation in mice exposed to chronic unpredictable mild stress. Brain Behav Immun. 2021;92:67\u201377.","journal-title":"Brain Behav Immun"},{"key":"768_CR29","doi-asserted-by":"crossref","first-page":"483","DOI":"10.1038\/s41401-019-0304-y","volume":"41","author":"MM Xu","year":"2020","unstructured":"Xu MM, Ryan P, Rudrawar S, Quinn RJ, Zhang HY, Mellick GD. Advances in the development of imaging probes and aggregation inhibitors for alpha-synuclein. Acta Pharmacol Sin. 2020;41:483\u201398.","journal-title":"Acta Pharmacol Sin"},{"key":"768_CR30","doi-asserted-by":"crossref","first-page":"570","DOI":"10.1038\/s41418-020-00706-7","volume":"28","author":"MF Schmidt","year":"2021","unstructured":"Schmidt MF, Gan ZY, Komander D, Dewson G. Ubiquitin signalling in neurodegeneration: mechanisms and therapeutic opportunities. Cell Death Differ. 2021;28:570\u201390.","journal-title":"Cell Death Differ"},{"key":"768_CR31","doi-asserted-by":"crossref","first-page":"560891","DOI":"10.3389\/fnmol.2020.560891","volume":"13","author":"M Li","year":"2020","unstructured":"Li M, Hu J, Yuan X, Shen L, Zhu L, Luo Q. Hepcidin decreases rotenone-induced alpha-Synuclein accumulation via autophagy in SH-SY5Y cells. Front Mol Neurosci. 2020;13:560891.","journal-title":"Front Mol Neurosci"},{"key":"768_CR32","doi-asserted-by":"crossref","first-page":"152842","DOI":"10.1016\/j.phymed.2019.152842","volume":"61","author":"CZ Cai","year":"2019","unstructured":"Cai CZ, Zhou HF, Yuan NN, Wu MY, Lee SM, Ren JY, et al. Natural alkaloid harmine promotes degradation of alpha-synuclein via PKA-mediated ubiquitin-proteasome system activation. Phytomedicine. 2019;61:152842.","journal-title":"Phytomedicine"},{"key":"768_CR33","doi-asserted-by":"crossref","first-page":"8516","DOI":"10.1074\/jbc.M210432200","volume":"278","author":"N Li","year":"2003","unstructured":"Li N, Ragheb K, Lawler G, Sturgis J, Rajwa B, Melendez JA, et al. Mitochondrial complex I inhibitor rotenone induces apoptosis through enhancing mitochondrial reactive oxygen species production. J Biol Chem. 2003;278:8516\u201325.","journal-title":"J Biol Chem"},{"key":"768_CR34","doi-asserted-by":"crossref","first-page":"101164","DOI":"10.1016\/j.redox.2019.101164","volume":"24","author":"V Tapias","year":"2019","unstructured":"Tapias V, McCoy JL, Greenamyre JT. Phenothiazine normalizes the NADH\/NAD+ ratio, maintains mitochondrial integrity and protects the nigrostriatal dopamine system in a chronic rotenone model of Parkinson\u2019s disease. Redox Biol. 2019;24:101164.","journal-title":"Redox Biol"},{"key":"768_CR35","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1007\/s00213-020-05605-w","volume":"237","author":"EO Farombi","year":"2020","unstructured":"Farombi EO, Awogbindin IO, Olorunkalu PD, Ogbuewu E, Oyetunde BF, Agedah AE, et al. Kolaviron protects against nigrostriatal degeneration and gut oxidative damage in a stereotaxic rotenone model of Parkinson\u2019s disease. Psychopharmacol (Berl). 2020;237:3225\u201336.","journal-title":"Psychopharmacol (Berl)"},{"key":"768_CR36","doi-asserted-by":"crossref","first-page":"104626","DOI":"10.1016\/j.nbd.2019.104626","volume":"134","author":"EM Rocha","year":"2020","unstructured":"Rocha EM, De Miranda BR, Castro S, Drolet R, Hatcher NG, Yao L, et al. LRRK2 inhibition prevents endolysosomal deficits seen in human Parkinson\u2019s disease. Neurobiol Dis. 2020;134:104626.","journal-title":"Neurobiol Dis"},{"key":"768_CR37","doi-asserted-by":"crossref","first-page":"712","DOI":"10.1038\/nature06261","volume":"450","author":"JC Milne","year":"2007","unstructured":"Milne JC, Lambert PD, Schenk S, Carney DP, Smith JJ, Gagne DJ, et al. Small molecule activators of SIRT1 as therapeutics for the treatment of type 2 diabetes. Nature. 2007;450:712\u20136.","journal-title":"Nature"},{"key":"768_CR38","doi-asserted-by":"crossref","first-page":"1608","DOI":"10.14336\/AD.2020.0216","volume":"11","author":"X Li","year":"2020","unstructured":"Li X, Feng Y, Wang XX, Truong D, Wu YC. The critical role of SIRT1 in Parkinson\u2019s disease: mechanism and therapeutic considerations. Aging Dis. 2020;11:1608\u201322.","journal-title":"Aging Dis"},{"key":"768_CR39","doi-asserted-by":"crossref","first-page":"1388","DOI":"10.1016\/j.neuroscience.2008.04.065","volume":"154","author":"M Pallas","year":"2008","unstructured":"Pallas M, Pizarro JG, Gutierrez-Cuesta J, Crespo-Biel N, Alvira D, Tajes M, et al. Modulation of SIRT1 expression in different neurodegenerative models and human pathologies. Neuroscience. 2008;154:1388\u201397.","journal-title":"Neuroscience"},{"key":"768_CR40","doi-asserted-by":"crossref","DOI":"10.1186\/s12868-017-0364-1","volume":"18","author":"P Singh","year":"2017","unstructured":"Singh P, Hanson PS, Morris CM. SIRT1 ameliorates oxidative stress induced neural cell death and is down-regulated in Parkinson\u2019s disease. BMC Neurosci. 2017;18:46.","journal-title":"BMC Neurosci"},{"key":"768_CR41","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1111\/j.1471-4159.2009.06228.x","volume":"110","author":"D Albani","year":"2009","unstructured":"Albani D, Polito L, Batelli S, De Mauro S, Fracasso C, Martelli G, et al. The SIRT1 activator resveratrol protects SK-N-BE cells from oxidative stress and against toxicity caused by alpha-synuclein or amyloid-beta (1-42) peptide. J Neurochem. 2009;110:1445\u201356.","journal-title":"J Neurochem"},{"key":"768_CR42","doi-asserted-by":"crossref","first-page":"188","DOI":"10.2174\/1570159X17666191010103044","volume":"18","author":"R Schreiber","year":"2020","unstructured":"Schreiber R, Hollands R, Blokland A. A mechanistic rationale for PDE-4 inhibitors to treat residual cognitive deficits in acquired brain injury. Curr Neuropharmacol. 2020;18:188\u2013201.","journal-title":"Curr Neuropharmacol"},{"key":"768_CR43","doi-asserted-by":"crossref","first-page":"101747","DOI":"10.1016\/j.redox.2020.101747","volume":"37","author":"C Hu","year":"2020","unstructured":"Hu C, Zhang X, Song P, Yuan YP, Kong CY, Wu HM, et al. Meteorin-like protein attenuates doxorubicin-induced cardiotoxicity via activating cAMP\/PKA\/SIRT1 pathway. Redox Biol. 2020;37:101747.","journal-title":"Redox Biol"},{"key":"768_CR44","doi-asserted-by":"crossref","first-page":"2929","DOI":"10.1016\/j.bbamcr.2015.09.003","volume":"1853","author":"J Li","year":"2015","unstructured":"Li J, Dou X, Li S, Zhang X, Zeng Y, Song Z. Nicotinamide ameliorates palmitate-induced ER stress in hepatocytes via cAMP\/PKA\/CREB pathway-dependent Sirt1 upregulation. Biochim Biophys Acta. 2015;1853:2929\u201336.","journal-title":"Biochim Biophys Acta"}],"container-title":["Acta Pharmacologica Sinica"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41401-021-00768-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41401-021-00768-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41401-021-00768-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,11,30]],"date-time":"2021-11-30T12:31:53Z","timestamp":1638275513000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41401-021-00768-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,16]]},"references-count":44,"journal-issue":{"issue":"12","published-print":{"date-parts":[[2021,12]]}},"alternative-id":["768"],"URL":"https:\/\/doi.org\/10.1038\/s41401-021-00768-4","relation":{},"ISSN":["1671-4083","1745-7254"],"issn-type":[{"value":"1671-4083","type":"print"},{"value":"1745-7254","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,16]]},"assertion":[{"value":"20 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 August 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"16 September 2021","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}]}}