{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,14]],"date-time":"2026-11-14T03:12:51Z","timestamp":1794625971474,"version":"4.9.1"},"reference-count":42,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T00:00:00Z","timestamp":1616976000000},"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":["81602042"],"award-info":[{"award-number":["81602042"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81874055"],"award-info":[{"award-number":["81874055"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Metabolic enzymes and metabolites display non-metabolic functions in immune cell signalling that modulate immune attack ability. However, whether and how a tumour\u2019s metabolic remodelling contributes to its immune resistance remain to be clarified. Here we perform a functional screen of metabolic genes that rescue tumour cells from effector T cell cytotoxicity, and identify the embryo- and tumour-specific folate cycle enzyme methylenetetrahydrofolate dehydrogenase 2 (MTHFD2). Mechanistically, MTHFD2 promotes basal and IFN-\u03b3-stimulated PD-L1 expression, which is necessary for tumourigenesis in vivo. Moreover, IFN-\u03b3 stimulates MTHFD2 through the AKT\u2013mTORC1 pathway. Meanwhile, MTHFD2 drives the folate cycle to sustain sufficient uridine-related metabolites including UDP-GlcNAc, which promotes the global O-GlcNAcylation of proteins including cMYC, resulting in increased cMYC stability and PD-L1 transcription. Consistently, the O-GlcNAcylation level positively correlates with MTHFD2 and PD-L1 in pancreatic cancer patients. These findings uncover a non-metabolic role for MTHFD2 in cell signalling and cancer biology.<\/jats:p>","DOI":"10.1038\/s41467-021-22173-5","type":"journal-article","created":{"date-parts":[[2021,3,29]],"date-time":"2021-03-29T10:04:22Z","timestamp":1617012262000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":165,"title":["The folate cycle enzyme MTHFD2 induces cancer immune evasion through PD-L1 up-regulation"],"prefix":"10.1038","volume":"12","author":[{"given":"Man","family":"Shang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huijie","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ran","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tao","family":"Chen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuan","family":"Fu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yeyi","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xianlong","family":"Fang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kangjian","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianju","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hui","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xueping","family":"Cao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinfa","family":"Gu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianwen","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qi","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xinyuan","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3978-643X","authenticated-orcid":false,"given":"Qiujing","family":"Yu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2257-0699","authenticated-orcid":false,"given":"Ting","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,3,29]]},"reference":[{"key":"22173_CR1","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1038\/s42255-018-0014-7","volume":"1","author":"DG Ryan","year":"2019","unstructured":"Ryan, D. G. et al. Coupling Krebs cycle metabolites to signalling in immunity and cancer. Nat. Metab. 1, 16\u201333 (2019).","journal-title":"Nat. Metab."},{"key":"22173_CR2","doi-asserted-by":"publisher","first-page":"237","DOI":"10.3389\/fonc.2018.00237","volume":"8","author":"T Le Bourgeois","year":"2018","unstructured":"Le Bourgeois, T. et al. Targeting T cell metabolism for improvement of cancer immunotherapy. Front. Oncol. 8, 237 (2018).","journal-title":"Front. Oncol."},{"key":"22173_CR3","doi-asserted-by":"publisher","first-page":"27","DOI":"10.1016\/j.cmet.2016.08.009","volume":"25","author":"GS Ducker","year":"2017","unstructured":"Ducker, G. S. & Rabinowitz, J. D. One-carbon metabolism in health and disease. Cell Metab. 25, 27\u201342 (2017).","journal-title":"Cell Metab."},{"key":"22173_CR4","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1146\/annurev.nutr.012809.104810","volume":"30","author":"AS Tibbetts","year":"2010","unstructured":"Tibbetts, A. S. & Appling, D. R. Compartmentalization of mammalian folate-mediated one-carbon metabolism. Annu. Rev. Nutr. 30, 57\u201381 (2010).","journal-title":"Annu. Rev. Nutr."},{"key":"22173_CR5","doi-asserted-by":"publisher","first-page":"4158","DOI":"10.1128\/MCB.22.12.4158-4166.2002","volume":"22","author":"E Di Pietro","year":"2002","unstructured":"Di Pietro, E., Sirois, J., Tremblay, M. L. & MacKenzie, R. E. Mitochondrial NAD-dependent methylenetetrahydrofolate dehydrogenase-methenyltetrahydrofolate cyclohydrolase is essential for embryonic development. Mol. Cell. Biol. 22, 4158\u20134166 (2002).","journal-title":"Mol. Cell. Biol."},{"key":"22173_CR6","doi-asserted-by":"publisher","DOI":"10.1038\/ncomms4128","volume":"5","author":"R Nilsson","year":"2014","unstructured":"Nilsson, R. et al. Metabolic enzyme expression highlights a key role for MTHFD2 and the mitochondrial folate pathway in cancer. Nat. Commun. 5, 3128 (2014).","journal-title":"Nat. Commun."},{"key":"22173_CR7","doi-asserted-by":"publisher","first-page":"192","DOI":"10.1111\/j.1600-065X.2008.00606.x","volume":"222","author":"AB Frey","year":"2008","unstructured":"Frey, A. B. & Monu, N. Signaling defects in anti-tumor T cells. Immunological Rev. 222, 192\u2013205 (2008).","journal-title":"Immunological Rev."},{"key":"22173_CR8","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1016\/j.immuni.2019.12.010","volume":"52","author":"JG Egen","year":"2020","unstructured":"Egen, J. G., Ouyang, W. & Wu, L. C. Human anti-tumor immunity: insights from immunotherapy clinical trials. Immunity 52, 36\u201354 (2020).","journal-title":"Immunity"},{"key":"22173_CR9","doi-asserted-by":"publisher","first-page":"336","DOI":"10.1038\/nri1349","volume":"4","author":"L Chen","year":"2004","unstructured":"Chen, L. Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat. Rev. Immunol. 4, 336\u2013347 (2004).","journal-title":"Nat. Rev. Immunol."},{"key":"22173_CR10","doi-asserted-by":"publisher","first-page":"2108","DOI":"10.1056\/NEJMoa1809615","volume":"379","author":"P Schmid","year":"2018","unstructured":"Schmid, P. et al. Atezolizumab and Nab-paclitaxel in advanced triple-negative breast cancer. N. Engl. J. Med. 379, 2108\u20132121 (2018).","journal-title":"N. Engl. J. Med."},{"key":"22173_CR11","doi-asserted-by":"publisher","first-page":"2288","DOI":"10.1056\/NEJMoa1716948","volume":"378","author":"MA Socinski","year":"2018","unstructured":"Socinski, M. A. et al. Atezolizumab for first-line treatment of metastatic nonsquamous NSCLC. N. Engl. J. Med. 378, 2288\u20132301 (2018).","journal-title":"N. Engl. J. Med."},{"key":"22173_CR12","doi-asserted-by":"publisher","first-page":"627","DOI":"10.1080\/17476348.2018.1494575","volume":"12","author":"L Mezquita","year":"2018","unstructured":"Mezquita, L. & Planchard, D. Durvalumab for the treatment of non-small cell lung cancer. Expert Rev. Respiratory Med. 12, 627\u2013639 (2018).","journal-title":"Expert Rev. Respiratory Med."},{"key":"22173_CR13","first-page":"5713","volume":"37","author":"N Haratake","year":"2017","unstructured":"Haratake, N. et al. Positive conversion of PD-L1 expression after treatments with chemotherapy and nivolumab. Anticancer Res. 37, 5713\u20135717 (2017).","journal-title":"Anticancer Res."},{"key":"22173_CR14","doi-asserted-by":"publisher","first-page":"2305","DOI":"10.1007\/s00726-014-1827-7","volume":"46","author":"AK Nagel","year":"2014","unstructured":"Nagel, A. K. & Ball, L. E. O-GlcNAc transferase and O-GlcNAcase: achieving target substrate specificity. Amino Acids 46, 2305\u20132316 (2014).","journal-title":"Amino Acids"},{"key":"22173_CR15","doi-asserted-by":"publisher","first-page":"88","DOI":"10.1016\/j.cbpa.2016.06.005","volume":"33","author":"S Hardiville","year":"2016","unstructured":"Hardiville, S. & Hart, G. W. Nutrient regulation of gene expression by O-GlcNAcylation of chromatin. Curr. Opin. Chem. Biol. 33, 88\u201394 (2016).","journal-title":"Curr. Opin. Chem. Biol."},{"key":"22173_CR16","doi-asserted-by":"crossref","unstructured":"Ferrer, C. M., Sodi, V. L. & Reginato, M. J. O-GlcNAcylation in cancer biology: linking metabolism and signaling. J. Mol. Biol. 428, 3282\u20133294 (2016).","DOI":"10.1016\/j.jmb.2016.05.028"},{"key":"22173_CR17","doi-asserted-by":"publisher","first-page":"6","DOI":"10.3389\/fonc.2016.00006","volume":"6","author":"SF Baldini","year":"2016","unstructured":"Baldini, S. F. & Lefebvre, T. O-GlcNAcylation and the metabolic shift in high-proliferating cells: all the evidence suggests that sugars dictate the flux of lipid biogenesis in tumor processes. Front. Oncol. 6, 6 (2016).","journal-title":"Front. Oncol."},{"key":"22173_CR18","doi-asserted-by":"publisher","first-page":"e961809","DOI":"10.4161\/23723548.2014.961809","volume":"2","author":"CM Ferrer","year":"2015","unstructured":"Ferrer, C. M. & Reginato, M. J. Sweet connections: O-GlcNAcylation links cancer cell metabolism and survival. Mol. Cell. Oncol. 2, e961809 (2015).","journal-title":"Mol. Cell. Oncol."},{"key":"22173_CR19","doi-asserted-by":"crossref","unstructured":"Birsoy, K. et al. An essential role of the mitochondrial electron transport chain in cell proliferation is to enable aspartate synthesis. Cell 162, 540\u2013551 (2015)..","DOI":"10.1016\/j.cell.2015.07.016"},{"key":"22173_CR20","doi-asserted-by":"publisher","first-page":"6361","DOI":"10.2147\/OTT.S210800","volume":"12","author":"Y Wei","year":"2019","unstructured":"Wei, Y. et al. The effect of MTHFD2 on the proliferation and migration of colorectal cancer cell lines. OncoTargets Ther. 12, 6361\u20136370 (2019).","journal-title":"OncoTargets Ther."},{"key":"22173_CR21","doi-asserted-by":"publisher","first-page":"15545","DOI":"10.1073\/pnas.0506580102","volume":"102","author":"A Subramanian","year":"2005","unstructured":"Subramanian, A. et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc. Natl Acad. Sci. USA 102, 15545\u201315550 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"22173_CR22","doi-asserted-by":"publisher","first-page":"252","DOI":"10.1038\/nrc3239","volume":"12","author":"DM Pardoll","year":"2012","unstructured":"Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252\u2013264 (2012).","journal-title":"Nat. Rev. Cancer"},{"key":"22173_CR23","doi-asserted-by":"publisher","first-page":"728","DOI":"10.1126\/science.aad0489","volume":"351","author":"I Ben-Sahra","year":"2016","unstructured":"Ben-Sahra, I., Hoxhaj, G., Ricoult, S. J. H., Asara, J. M. & Manning, B. D. mTORC1 induces purine synthesis through control of the mitochondrial tetrahydrofolate cycle. Science 351, 728\u2013733 (2016).","journal-title":"Science"},{"key":"22173_CR24","doi-asserted-by":"publisher","first-page":"227","DOI":"10.1126\/science.aac9935","volume":"352","author":"SC Casey","year":"2016","unstructured":"Casey, S. C. et al. MYC regulates the antitumor immune response through CD47 and PD-L1. Science 352, 227\u2013231 (2016).","journal-title":"Science"},{"key":"22173_CR25","doi-asserted-by":"publisher","first-page":"18961","DOI":"10.1074\/jbc.270.32.18961","volume":"270","author":"TY Chou","year":"1995","unstructured":"Chou, T. Y., Hart, G. W. & Dang, C. V. c-Myc is glycosylated at threonine 58, a known phosphorylation site and a mutational hot spot in lymphomas. J. Biol. Chem. 270, 18961\u201318965 (1995).","journal-title":"J. Biol. Chem."},{"key":"22173_CR26","first-page":"3199","volume":"8","author":"M Henriksson","year":"1993","unstructured":"Henriksson, M., Bakardjiev, A., Klein, G. & Luscher, B. Phosphorylation sites mapping in the N-terminal domain of c-myc modulate its transforming potential. Oncogene 8, 3199\u20133209 (1993).","journal-title":"Oncogene"},{"key":"22173_CR27","doi-asserted-by":"publisher","first-page":"2423","DOI":"10.1128\/MCB.20.7.2423-2435.2000","volume":"20","author":"MA Gregory","year":"2000","unstructured":"Gregory, M. A. & Hann, S. R. c-Myc proteolysis by the ubiquitin-proteasome pathway: stabilization of c-Myc in Burkitt\u2019s lymphoma cells. Mol. Cell. Biol. 20, 2423\u20132435 (2000).","journal-title":"Mol. Cell. Biol."},{"key":"22173_CR28","doi-asserted-by":"publisher","first-page":"e1600200","DOI":"10.1126\/sciadv.1600200","volume":"2","author":"RJ DeBerardinis","year":"2016","unstructured":"DeBerardinis, R. J. & Chandel, N. S. Fundamentals of cancer metabolism. Sci. Adv. 2, e1600200 (2016).","journal-title":"Sci. Adv."},{"key":"22173_CR29","doi-asserted-by":"crossref","unstructured":"Singer, K., Cheng, W. C., Kreutz, M., Ho, P. C. & Siska, P. J. Immunometabolism in cancer at a glance. Disease models & mechanisms 11, dmm034272 (2018).","DOI":"10.1242\/dmm.034272"},{"key":"22173_CR30","doi-asserted-by":"publisher","first-page":"822","DOI":"10.1016\/j.trecan.2019.10.007","volume":"5","author":"K Mehla","year":"2019","unstructured":"Mehla, K. & Singh, P. K. Metabolic regulation of macrophage polarization in cancer. Trends Cancer 5, 822\u2013834 (2019).","journal-title":"Trends Cancer"},{"key":"22173_CR31","doi-asserted-by":"publisher","first-page":"570","DOI":"10.1016\/j.cell.2017.04.004","volume":"169","author":"MD Buck","year":"2017","unstructured":"Buck, M. D., Sowell, R. T., Kaech, S. M. & Pearce, E. L. Metabolic instruction of immunity. Cell 169, 570\u2013586 (2017).","journal-title":"Cell"},{"key":"22173_CR32","doi-asserted-by":"publisher","first-page":"95","DOI":"10.1016\/S1359-6101(01)00038-7","volume":"13","author":"H Ikeda","year":"2002","unstructured":"Ikeda, H., Old, L. J. & Schreiber, R. D. The roles of IFN gamma in protection against tumor development and cancer immunoediting. Cytokine Growth Factor Rev. 13, 95\u2013109 (2002).","journal-title":"Cytokine Growth Factor Rev."},{"key":"22173_CR33","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.imbio.2015.07.012","volume":"222","author":"J Pahl","year":"2017","unstructured":"Pahl, J. & Cerwenka, A. Tricking the balance: NK cells in anti-cancer immunity. Immunobiology 222, 11\u201320 (2017).","journal-title":"Immunobiology"},{"key":"22173_CR34","doi-asserted-by":"publisher","first-page":"2329","DOI":"10.1158\/1078-0432.CCR-16-0224","volume":"22","author":"M Mandai","year":"2016","unstructured":"Mandai, M. et al. Dual faces of IFN-gamma in cancer progression: a role of pd-l1 induction in the determination of pro- and antitumor immunity. Clin. Cancer Res. 22, 2329\u20132334 (2016).","journal-title":"Clin. Cancer Res."},{"key":"22173_CR35","doi-asserted-by":"crossref","unstructured":"Mojic, M., Takeda, K. & Hayakawa, Y. The dark side of IFN-gamma: its role in promoting cancer immunoevasion. Int. J. Mol. Sci. 19, 89 (2017).","DOI":"10.3390\/ijms19010089"},{"key":"22173_CR36","doi-asserted-by":"publisher","first-page":"L376","DOI":"10.1152\/ajplung.00447.2002","volume":"285","author":"R Schafer","year":"2003","unstructured":"Schafer, R., Sedehizade, F., Welte, T. & Reiser, G. ATP- and UTP-activated P2Y receptors differently regulate proliferation of human lung epithelial tumor cells. Am. J. Physiol. Lung Cell. Mol. Physiol. 285, L376\u2013L385 (2003).","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"22173_CR37","doi-asserted-by":"publisher","first-page":"680","DOI":"10.1097\/MPA.0b013e318271bb4b","volume":"42","author":"JH Choi","year":"2013","unstructured":"Choi, J. H., Ji, Y. G. & Lee, D. H. Uridine triphosphate increases proliferation of human cancerous pancreatic duct epithelial cells by activating P2Y2 receptor. Pancreas 42, 680\u2013686 (2013).","journal-title":"Pancreas"},{"key":"22173_CR38","doi-asserted-by":"publisher","first-page":"1455","DOI":"10.1111\/j.1476-5381.1994.tb17160.x","volume":"113","author":"A Huwiler","year":"1994","unstructured":"Huwiler, A. & Pfeilschifter, J. Stimulation by extracellular ATP and UTP of the mitogen-activated protein kinase cascade and proliferation of rat renal mesangial cells. Br. J. Pharmacol. 113, 1455\u20131463 (1994).","journal-title":"Br. J. Pharmacol."},{"key":"22173_CR39","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1038\/nature13557","volume":"513","author":"B Li","year":"2014","unstructured":"Li, B. et al. Fructose-1,6-bisphosphatase opposes renal carcinoma progression. Nature 513, 251\u2013255 (2014).","journal-title":"Nature"},{"key":"22173_CR40","doi-asserted-by":"publisher","first-page":"1655","DOI":"10.1242\/jcs.166629","volume":"128","author":"W Yang","year":"2015","unstructured":"Yang, W. & Lu, Z. Pyruvate kinase M2 at a glance. J. Cell Sci. 128, 1655\u20131660 (2015).","journal-title":"J. Cell Sci."},{"key":"22173_CR41","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1038\/ncb3562","volume":"19","author":"T Wang","year":"2017","unstructured":"Wang, T. et al. O-GlcNAcylation of fumarase maintains tumour growth under glucose deficiency. Nat. Cell Biol. 19, 833\u2013843 (2017).","journal-title":"Nat. Cell Biol."},{"key":"22173_CR42","doi-asserted-by":"crossref","unstructured":"Menyhart, O., Nagy, A. & Gyorffy, B. Determining consistent prognostic biomarkers of overall survival and vascular invasion in hepatocellular carcinoma. R. Soc. Open Sci. 5, 181006 (2018).","DOI":"10.1098\/rsos.181006"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-22173-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-22173-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-22173-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,2]],"date-time":"2022-12-02T11:31:38Z","timestamp":1669980698000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41467-021-22173-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,29]]},"references-count":42,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["22173"],"URL":"https:\/\/doi.org\/10.1038\/s41467-021-22173-5","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,3,29]]},"assertion":[{"value":"21 September 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"3 March 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"29 March 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"}}],"article-number":"1940"}}