{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,21]],"date-time":"2026-08-21T13:26:13Z","timestamp":1787318773492,"version":"build-2736575974"},"reference-count":47,"publisher":"Springer Science and Business Media LLC","issue":"5","license":[{"start":{"date-parts":[[2021,5,8]],"date-time":"2021-05-08T00:00:00Z","timestamp":1620432000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,5,8]],"date-time":"2021-05-08T00:00:00Z","timestamp":1620432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81672643"],"award-info":[{"award-number":["81672643"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Cell Death Dis"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>The sonic hedgehog (Shh) pathway is highly activated in a variety of malignancies and plays important roles in tumorigenesis, tumor growth, drug resistance, and metastasis. Our recent study showed that the inhibitors of the Shh pathway such as cyclopamine (CP), a Smothened (SMO) inhibitor, and GANT61, a Gli1 inhibitor, have modest inhibitory effects on thyroid tumor cell proliferation and tumor growth. The objective of this study was to determine whether autophagy was induced by inhibition of the Shh pathway and could negatively regulate GANT61-induced apoptosis. Here we report that inhibition of the Shh pathway by Gli1 siRNA or by cyclopamine and GANT61 induced autophagy in SW1736 and KAT-18 cells, two anaplastic thyroid cancer cell lines; whereas Gli1 overexpression suppressed autophagy. Mechanistic investigation revealed that inhibition of the Shh pathway activated TAK1 and its two downstream kinases, the c-Jun-terminal kinase (JNK) and AMP-activated protein kinase (AMPK). GANT61-induced autophagy was blocked by TAK1 siRNA and the inhibitors of TAK1 (5Z-7-oxozeaenol, 5Z), JNK (SP600125), and AMPK (Compound C, CC). Inhibition of autophagy by chloroquine and 5Z and by TAK1 and Beclin-1 siRNA enhanced GANT61-induced apoptosis and its antiproliferative activity. Our study has shown that inhibition of the Shh pathway induces autophagy by activating TAK1, whereas autophagy in turn suppresses GANT61-induced apoptosis. We have uncovered a previously unrecognized role of TAK1 in Shh pathway inhibition-induced autophagy and apoptosis.<\/jats:p>","DOI":"10.1038\/s41419-021-03744-2","type":"journal-article","created":{"date-parts":[[2021,5,8]],"date-time":"2021-05-08T02:06:20Z","timestamp":1620439580000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Inhibition of the sonic hedgehog pathway activates TGF-\u03b2-activated kinase (TAK1) to induce autophagy and suppress apoptosis in thyroid tumor cells"],"prefix":"10.1038","volume":"12","author":[{"given":"Sumei","family":"Li","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingxiang","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yurong","family":"Lu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuqing","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard A.","family":"Prinz","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6140-5173","authenticated-orcid":false,"given":"Xiulong","family":"Xu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,5,8]]},"reference":[{"key":"3744_CR1","doi-asserted-by":"publisher","first-page":"1054","DOI":"10.1056\/NEJMra1501993","volume":"375","author":"JA Fagin","year":"2016","unstructured":"Fagin, J. A. & Wells, S. A. Jr. Biologic and clinical perspectives on thyroid cancer. N. Engl. J. Med. 375, 1054\u20131067 (2016).","journal-title":"N. Engl. J. Med."},{"key":"3744_CR2","doi-asserted-by":"publisher","first-page":"311","DOI":"10.1089\/thy.2018.0509","volume":"29","author":"T Ibrahimpasic","year":"2019","unstructured":"Ibrahimpasic, T., Ghossein, R., Shah, J. P. & Ganly, I. Poorly differentiated carcinoma of the thyroid gland: current status and future prospects. Thyroid 29, 311\u2013321 (2019).","journal-title":"Thyroid"},{"key":"3744_CR3","doi-asserted-by":"publisher","first-page":"884","DOI":"10.3389\/fendo.2019.00884","volume":"10","author":"A Matrone","year":"2019","unstructured":"Matrone, A. et al. Differentiated thyroid cancer, from active surveillance to advanced therapy: toward a personalized medicine. Front. Endocrinol. 10, 884 (2019).","journal-title":"Front. Endocrinol."},{"key":"3744_CR4","doi-asserted-by":"publisher","first-page":"2783","DOI":"10.1016\/S0140-6736(16)30172-6","volume":"388","author":"ME Cabanillas","year":"2016","unstructured":"Cabanillas, M. E., McFadden, D. G. & Durante, C. Thyroid cancer. Lancet 388, 2783\u20132795 (2016).","journal-title":"Lancet"},{"key":"3744_CR5","doi-asserted-by":"publisher","first-page":"758","DOI":"10.3390\/ijms21030758","volume":"21","author":"KS Jeng","year":"2020","unstructured":"Jeng, K. S., Chang, C. F. & Lin, S. S. Sonic hedgehog signaling in organogenesis, tumors, and tumor microenvironments. Int. J. Mol. Sci. 21, 758 (2020).","journal-title":"Int. J. Mol. Sci."},{"key":"3744_CR6","doi-asserted-by":"publisher","first-page":"22","DOI":"10.3390\/cancers8020022","volume":"8","author":"TK Rimkus","year":"2016","unstructured":"Rimkus, T. K., Carpenter, R. L., Qasem, S., Chan, M. & Lo, H. W. Targeting the sonic hedgehog signaling pathway: review of smoothened and GLI inhibitors. Cancers 8, 22 (2016).","journal-title":"Cancers"},{"key":"3744_CR7","doi-asserted-by":"publisher","first-page":"284","DOI":"10.3389\/fendo.2017.00284","volume":"8","author":"X Xu","year":"2017","unstructured":"Xu, X., Lu, Y., Li, Y. & Prinz, R. A. Sonic hedgehog signaling in thyroid. Cancer Front. Endocrinol. 8, 284 (2017).","journal-title":"Cancer Front. Endocrinol."},{"key":"3744_CR8","doi-asserted-by":"publisher","first-page":"2316","DOI":"10.3390\/cells9102316","volume":"9","author":"LJ Larsen","year":"2020","unstructured":"Larsen, L. J. & Moller, L. B. Crosstalk of hedgehog and mTORC1 pathways. Cells 9, 2316 (2020).","journal-title":"Cells"},{"key":"3744_CR9","doi-asserted-by":"publisher","first-page":"418","DOI":"10.3390\/cancers13030418","volume":"13","author":"Y Lu","year":"2021","unstructured":"Lu, Y. et al. Targeting the sonic hedgehog pathway to suppress the expression of the cancer stem cell (CSC)-related transcription factors and CSC-driven thyroid tumor growth. Cancers 13, 418 (2021).","journal-title":"Cancers"},{"key":"3744_CR10","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1080\/15548627.2020.1797280","volume":"17","author":"DJ Klionsky","year":"2021","unstructured":"Klionsky, D. J. et al. Guidelines for the use and interpretation of assays for monitoring autophagy (4th edition) (1). Autophagy 17, 1\u2013382 (2021).","journal-title":"Autophagy"},{"key":"3744_CR11","doi-asserted-by":"publisher","first-page":"995","DOI":"10.1002\/hep.26394","volume":"58","author":"Y Wang","year":"2013","unstructured":"Wang, Y., Han, C., Lu, L., Magliato, S. & Wu, T. Hedgehog signaling pathway regulates autophagy in human hepatocellular carcinoma cells. Hepatology 58, 995\u20131010 (2013).","journal-title":"Hepatology"},{"key":"3744_CR12","doi-asserted-by":"publisher","unstructured":"Carballo, G. B. et al. GANT-61 induces autophagy and apoptosis in glioblastoma cells despite their heterogeneity. Cell. Mol. Neurobiol. (2020). https:\/\/doi.org\/10.1007\/s10571-020-00891-6.","DOI":"10.1007\/s10571-020-00891-6"},{"key":"3744_CR13","doi-asserted-by":"publisher","DOI":"10.1186\/1471-2407-14-768","volume":"14","author":"J Wang","year":"2014","unstructured":"Wang, J. et al. Inhibition of autophagy potentiates the efficacy of Gli inhibitor GANT-61 in MYCN-amplified neuroblastoma cells. BMC Cancer 14, 768 (2014).","journal-title":"BMC Cancer"},{"key":"3744_CR14","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-019-1840-6","volume":"10","author":"J Fan","year":"2019","unstructured":"Fan, J. et al. Regulating autophagy facilitated therapeutic efficacy of the sonic Hedgehog pathway inhibition on lung adenocarcinoma through GLI2 suppression and ROS production. Cell Death Dis. 10, 626 (2019).","journal-title":"Cell Death Dis."},{"key":"3744_CR15","doi-asserted-by":"publisher","first-page":"724","DOI":"10.1016\/j.cell.2011.10.021","volume":"147","author":"J Moscat","year":"2011","unstructured":"Moscat, J. & Diaz-Meco, M. T. Feedback on fat: p62-mTORC1-autophagy connections. Cell 147, 724\u2013727 (2011).","journal-title":"Cell"},{"key":"3744_CR16","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1007\/s10495-018-1490-7","volume":"24","author":"S Aashaq","year":"2019","unstructured":"Aashaq, S., Batool, A. & Andrabi, K. I. TAK1 mediates convergence of cellular signals for death and survival. Apoptosis 24, 3\u201320 (2019).","journal-title":"Apoptosis"},{"key":"3744_CR17","doi-asserted-by":"publisher","first-page":"2412","DOI":"10.3390\/ijms19082412","volume":"19","author":"D Neumann","year":"2018","unstructured":"Neumann, D. Is TAK1 a direct upstream kinase of AMPK? Int. J. Mol. Sci. 19, 2412 (2018).","journal-title":"Int. J. Mol. Sci."},{"key":"3744_CR18","doi-asserted-by":"publisher","first-page":"1402","DOI":"10.1038\/s41388-019-1088-8","volume":"39","author":"H Mukhopadhyay","year":"2020","unstructured":"Mukhopadhyay, H. & Lee, N. Y. Multifaceted roles of TAK1 signaling in cancer. Oncogene 39, 1402\u20131413 (2020).","journal-title":"Oncogene"},{"key":"3744_CR19","doi-asserted-by":"publisher","first-page":"1263","DOI":"10.1016\/j.cell.2014.11.006","volume":"159","author":"L Galluzzi","year":"2014","unstructured":"Galluzzi, L., Pietrocola, F., Levine, B. & Kroemer, G. Metabolic control of autophagy. Cell 159, 1263\u20131276 (2014).","journal-title":"Cell"},{"key":"3744_CR20","doi-asserted-by":"publisher","first-page":"42","DOI":"10.1038\/cr.2013.166","volume":"24","author":"RC Russell","year":"2014","unstructured":"Russell, R. C., Yuan, H. X. & Guan, K. L. Autophagy regulation by nutrient signaling. Cell Res. 24, 42\u201357 (2014).","journal-title":"Cell Res."},{"key":"3744_CR21","doi-asserted-by":"publisher","first-page":"3461","DOI":"10.3390\/cancers12113461","volume":"12","author":"VR Silva","year":"2020","unstructured":"Silva, V. R., Neves, S. P., Santos, L., Dias, R. B. & Bezerra, D. P. Challlenges and therapeutic opportunities of autophagy in cancer therapy. Cancers 12, 3461 (2020).","journal-title":"Cancers"},{"key":"3744_CR22","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1016\/j.canlet.2016.10.034","volume":"385","author":"X Wang","year":"2017","unstructured":"Wang, X. et al. Anti-proliferation of breast cancer cells with itraconazole: Hedgehog pathway inhibition induces apoptosis and autophagic cell death. Cancer Lett. 385, 128\u2013136 (2017).","journal-title":"Cancer Lett."},{"key":"3744_CR23","doi-asserted-by":"publisher","first-page":"608976","DOI":"10.3389\/fimmu.2020.608976","volume":"11","author":"YR Xu","year":"2020","unstructured":"Xu, Y. R. & Lei, C. Q. TAK1-TABs complex: a central signalosome in inflammatory responses. Front. Immunol. 11, 608976 (2020).","journal-title":"Front. Immunol."},{"key":"3744_CR24","doi-asserted-by":"publisher","first-page":"1667","DOI":"10.1038\/cdd.2014.123","volume":"21","author":"SR Mihaly","year":"2014","unstructured":"Mihaly, S. R., Ninomiya-Tsuji, J. & Morioka, S. TAK1 control of cell death. Cell Death Differ. 21, 1667\u20131676 (2014).","journal-title":"Cell Death Differ."},{"key":"3744_CR25","doi-asserted-by":"publisher","first-page":"11677","DOI":"10.1074\/jbc.M111.308460","volume":"287","author":"SI Kim","year":"2012","unstructured":"Kim, S. I. et al. Autophagy promotes intracellular degradation of type I collagen induced by transforming growth factor (TGF)-beta1. J. Biol. Chem. 287, 11677\u201311688 (2012).","journal-title":"J. Biol. Chem."},{"key":"3744_CR26","doi-asserted-by":"publisher","first-page":"677","DOI":"10.1038\/emboj.2009.8","volume":"28","author":"G Herrero-Martin","year":"2009","unstructured":"Herrero-Martin, G. et al. TAK1 activates AMPK-dependent cytoprotective autophagy in TRAIL-treated epithelial cells. EMBO J. 28, 677\u2013685 (2009).","journal-title":"EMBO J."},{"key":"3744_CR27","doi-asserted-by":"publisher","first-page":"30438","DOI":"10.18632\/oncotarget.16737","volume":"8","author":"X Xu","year":"2017","unstructured":"Xu, X. et al. Inhibition of p70 S6 kinase (S6K1) activity by A77 1726, the active metabolite of leflunomide, induces autophagy through TAK1-mediated AMPK and JNK activation. Oncotarget 8, 30438\u201330454 (2017).","journal-title":"Oncotarget"},{"key":"3744_CR28","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0441-0","volume":"9","author":"J Sun","year":"2018","unstructured":"Sun, J. et al. Inhibition of p70 S6 kinase activity by A77 1726 induces autophagy and enhances the degradation of superoxide dismutase 1 (SOD1) protein aggregates. Cell Death Dis. 9, 407 (2018).","journal-title":"Cell Death Dis."},{"key":"3744_CR29","doi-asserted-by":"publisher","DOI":"10.1038\/s41419-018-0612-z","volume":"9","author":"W Liu","year":"2018","unstructured":"Liu, W. et al. Activation of TGF-beta-activated kinase 1 (TAK1) restricts Salmonella Typhimurium growth by inducing AMPK activation and autophagy. Cell Death Dis. 9, 570 (2018).","journal-title":"Cell Death Dis."},{"key":"3744_CR30","doi-asserted-by":"publisher","first-page":"e13095","DOI":"10.1111\/cmi.13095","volume":"21","author":"W Liu","year":"2019","unstructured":"Liu, W. et al. Toll-like receptor signalling cross-activates the autophagic pathway to restrict Salmonella Typhimurium growth in macrophages. Cell. Microbiol. 21, e13095 (2019).","journal-title":"Cell. Microbiol."},{"key":"3744_CR31","doi-asserted-by":"publisher","first-page":"399","DOI":"10.3390\/ijms18020399","volume":"18","author":"A Gonnissen","year":"2017","unstructured":"Gonnissen, A., Isebaert, S., McKee, C. M., Muschel, R. J. & Haustermans, K. The effect of metformin and GANT61 combinations on the radiosensitivity of prostate cancer cells. Int. J. Mol. Sci. 18, 399 (2017).","journal-title":"Int. J. Mol. Sci."},{"key":"3744_CR32","doi-asserted-by":"publisher","first-page":"599","DOI":"10.1016\/j.celrep.2015.06.054","volume":"12","author":"YH Li","year":"2015","unstructured":"Li, Y. H. et al. AMP-activated protein kinase directly phosphorylates and destabilizes hedgehog pathway transcription factor GLI1 in medulloblastoma. Cell Rep. 12, 599\u2013609 (2015).","journal-title":"Cell Rep."},{"key":"3744_CR33","doi-asserted-by":"publisher","first-page":"204","DOI":"10.3892\/ijmm.2015.2217","volume":"36","author":"C Fan","year":"2015","unstructured":"Fan, C. et al. Metformin exerts anticancer effects through the inhibition of the Sonic hedgehog signaling pathway in breast cancer. Int. J. Mol. Med. 36, 204\u2013214 (2015).","journal-title":"Int. J. Mol. Med."},{"key":"3744_CR34","doi-asserted-by":"publisher","first-page":"263","DOI":"10.1016\/j.virol.2019.09.004","volume":"537","author":"T Sheng","year":"2019","unstructured":"Sheng, T. et al. Role of TGF-beta-activated kinase 1 (TAK1) activation in H5N1 influenza A virus-induced c-Jun terminal kinase activation and virus replication. Virology 537, 263\u2013271 (2019).","journal-title":"Virology"},{"key":"3744_CR35","doi-asserted-by":"publisher","first-page":"753","DOI":"10.1158\/1541-7786.MCR-16-0035","volume":"14","author":"IA Vasilevskaya","year":"2016","unstructured":"Vasilevskaya, I. A., Selvakumaran, M., Roberts, D. & O\u2019Dwyer, P. J. JNK1 inhibition attenuates hypoxia-induced autophagy and sensitizes to chemotherapy. Mol. Cancer Res. 14, 753\u2013763 (2016).","journal-title":"Mol. Cancer Res."},{"key":"3744_CR36","doi-asserted-by":"publisher","first-page":"341","DOI":"10.1016\/j.canlet.2018.11.005","volume":"442","author":"A Azatyan","year":"2019","unstructured":"Azatyan, A. et al. RITA downregulates Hedgehog-GLI in medulloblastoma and rhabdomyosarcoma via JNK-dependent but p53-independent mechanism. Cancer Lett. 442, 341\u2013350 (2019).","journal-title":"Cancer Lett."},{"key":"3744_CR37","doi-asserted-by":"publisher","first-page":"1374","DOI":"10.3390\/cancers11091374","volume":"11","author":"Y Kwon","year":"2019","unstructured":"Kwon, Y., Kim, M., Jung, H. S., Kim, Y. & Jeoung, D. Targeting autophagy for overcoming resistance to anti-EGFR treatments. Cancers 11, 1374 (2019).","journal-title":"Cancers"},{"key":"3744_CR38","doi-asserted-by":"publisher","first-page":"R181","DOI":"10.1530\/ERC-18-0502","volume":"26","author":"W Wei","year":"2019","unstructured":"Wei, W., Hardin, H. & Luo, Q. Y. Targeting autophagy in thyroid cancers. Endocr. Relat. Cancer 26, R181\u2013R194 (2019).","journal-title":"Endocr. Relat. Cancer"},{"key":"3744_CR39","doi-asserted-by":"publisher","first-page":"1599","DOI":"10.3390\/cancers11101599","volume":"11","author":"M Perez-Hernandez","year":"2019","unstructured":"Perez-Hernandez, M. et al. Targeting autophagy for cancer treatment and tumor chemosensitization. Cancers 11, 1599 (2019).","journal-title":"Cancers"},{"key":"3744_CR40","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04010-4","volume":"9","author":"B Zhang","year":"2018","unstructured":"Zhang, B. et al. The senescence-associated secretory phenotype is potentiated by feedforward regulatory mechanisms involving Zscan4 and TAK1. Nat. Commun. 9, 1723 (2018).","journal-title":"Nat. Commun."},{"key":"3744_CR41","doi-asserted-by":"publisher","first-page":"pe2","DOI":"10.1126\/scisignal.2001712","volume":"4","author":"K Hadian","year":"2011","unstructured":"Hadian, K. & Krappmann, D. Signals from the nucleus: activation of NF-kappaB by cytosolic ATM in the DNA damage response. Sci. Signal 4, pe2 (2011).","journal-title":"Sci. Signal"},{"key":"3744_CR42","doi-asserted-by":"publisher","first-page":"63","DOI":"10.1016\/j.molcel.2010.09.008","volume":"40","author":"M Hinz","year":"2010","unstructured":"Hinz, M. et al. A cytoplasmic ATM-TRAF6-cIAP1 module links nuclear DNA damage signaling to ubiquitin-mediated NF-kappaB activation. Mol. Cell 40, 63\u201374 (2010).","journal-title":"Mol. Cell"},{"key":"3744_CR43","doi-asserted-by":"publisher","first-page":"1042","DOI":"10.1158\/0008-5472.CAN-09-3537","volume":"70","author":"A Puissant","year":"2010","unstructured":"Puissant, A. et al. Resveratrol promotes autophagic cell death in chronic myelogenous leukemia cells via JNK-mediated p62\/SQSTM1 expression and AMPK activation. Cancer Res. 70, 1042\u20131052 (2010).","journal-title":"Cancer Res."},{"key":"3744_CR44","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1093\/carcin\/bgw003","volume":"37","author":"R Vegliante","year":"2016","unstructured":"Vegliante, R., Desideri, E., Di Leo, L. & Ciriolo, M. R. Dehydroepiandrosterone triggers autophagic cell death in human hepatoma cell line HepG2 via JNK-mediated p62\/SQSTM1 expression. Carcinogenesis 37, 233\u2013244 (2016).","journal-title":"Carcinogenesis"},{"key":"3744_CR45","doi-asserted-by":"publisher","first-page":"e46238","DOI":"10.15252\/embr.201846238","volume":"20","author":"SR Kehl","year":"2019","unstructured":"Kehl, S. R. et al. TAK1 converts Sequestosome 1\/p62 from an autophagy receptor to a signaling platform. EMBO Rep. 20, e46238 (2019).","journal-title":"EMBO Rep."},{"key":"3744_CR46","doi-asserted-by":"publisher","first-page":"1172","DOI":"10.1038\/cdd.2017.46","volume":"24","author":"M Lork","year":"2017","unstructured":"Lork, M., Verhelst, K. & Beyaert, R. CYLD, A20 and OTULIN deubiquitinases in NF-kappaB signaling and cell death: so similar, yet so different. Cell Death Differ. 24, 1172\u20131183 (2017).","journal-title":"Cell Death Differ."},{"key":"3744_CR47","doi-asserted-by":"publisher","first-page":"2178","DOI":"10.1210\/jc.2014-1844","volume":"99","author":"KB Heiden","year":"2014","unstructured":"Heiden, K. B. et al. The sonic hedgehog signaling pathway maintains the cancer stem cell self-renewal of anaplastic thyroid cancer by inducing snail expression. J. Clin. Endocrinol. Metab. 99, 2178\u20132187 (2014).","journal-title":"J. Clin. Endocrinol. Metab."}],"container-title":["Cell Death &amp; Disease"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03744-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03744-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03744-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,2,1]],"date-time":"2023-02-01T17:04:19Z","timestamp":1675271059000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41419-021-03744-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,5,8]]},"references-count":47,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2021,5]]}},"alternative-id":["3744"],"URL":"https:\/\/doi.org\/10.1038\/s41419-021-03744-2","relation":{},"ISSN":["2041-4889"],"issn-type":[{"value":"2041-4889","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,5,8]]},"assertion":[{"value":"25 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 April 2021","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"21 April 2021","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 May 2021","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Not applicable.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical statement"}},{"value":"The authors declare no competing interests.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}],"article-number":"459"}}