{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,18]],"date-time":"2026-10-18T01:23:37Z","timestamp":1792286617551,"version":"4.4.0"},"reference-count":40,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T00:00:00Z","timestamp":1633651200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,10,8]],"date-time":"2021-10-08T00:00:00Z","timestamp":1633651200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000060","name":"National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","award":["AI46709"],"award-info":[{"award-number":["AI46709"]}],"id":[{"id":"10.13039\/100000060","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Due to redundancy with other tyrosine phosphatases, the ubiquitously expressed tyrosine phosphatase SHP-2 (encoded by <jats:italic>Ptpn11<\/jats:italic>) is not required for T cell development. However, <jats:italic>Ptpn11<\/jats:italic> gene deletion driven by CD4 Cre recombinase leads to cartilage tumors in the wrist. Using a fate mapping system, we demonstrate that wrist tumor development correlates with increased frequency and numbers of non-hematopoietic lineage negative CD45 negative cells with a bone chondrocyte stromal cell precursor cell (BCSP) phenotype. Importantly, the BCSP subset has a history of CD4 expression and a marked wrist location tropism, explaining why the wrist is the main site of tumor development. Mechanistically, we found that in SHP-2 absence, SOX-9 is no longer regulated, leading to an uncontrolled proliferation of the BCSP subset. Altogether, these results identify a unique subset of chondrocyte precursors tightly regulated by SHP-2. These findings underscore the need for the development of methods to therapeutically target this subset of cells, which could potentially have an impact on treatment of SHP-2 dysfunction linked debilitating diseases.<\/jats:p>","DOI":"10.1038\/s41598-021-99339-0","type":"journal-article","created":{"date-parts":[[2021,10,9]],"date-time":"2021-10-09T07:03:53Z","timestamp":1633763033000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["SHP-2 deletion in CD4Cre expressing chondrocyte precursors leads to tumor development with wrist tropism"],"prefix":"10.1038","volume":"11","author":[{"given":"Jeffrey T.","family":"McNamara","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kelsey E.","family":"Huntington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4960-131X","authenticated-orcid":false,"given":"Samantha","family":"Borys","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chathuraka T.","family":"Jayasuriya","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7497-8488","authenticated-orcid":false,"given":"Laurent","family":"Brossay","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2021,10,8]]},"reference":[{"key":"99339_CR1","doi-asserted-by":"publisher","first-page":"2352","DOI":"10.1093\/emboj\/16.9.2352","volume":"16","author":"TM Saxton","year":"1997","unstructured":"Saxton, T. M. et al. Abnormal mesoderm patterning in mouse embryos mutant for the SH2 tyrosine phosphatase Shp-2. EMBO J. 16, 2352\u20132364. https:\/\/doi.org\/10.1093\/emboj\/16.9.2352 (1997).","journal-title":"EMBO J."},{"key":"99339_CR2","doi-asserted-by":"publisher","first-page":"2468","DOI":"10.3389\/fimmu.2019.02468","volume":"10","author":"C Niogret","year":"2019","unstructured":"Niogret, C., Birchmeier, W. & Guarda, G. SHP-2 in lymphocytes\u2019 cytokine and inhibitory receptor signaling. Front. Immunol. 10, 2468. https:\/\/doi.org\/10.3389\/fimmu.2019.02468 (2019).","journal-title":"Front. Immunol."},{"key":"99339_CR3","doi-asserted-by":"publisher","first-page":"1201","DOI":"10.1084\/jem.20112741","volume":"209","author":"T Yokosuka","year":"2012","unstructured":"Yokosuka, T. et al. Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J. Exp. Med. 209, 1201\u20131217. https:\/\/doi.org\/10.1084\/jem.20112741 (2012).","journal-title":"J. Exp. Med."},{"key":"99339_CR4","doi-asserted-by":"publisher","first-page":"8351374","DOI":"10.1155\/2018\/8351374","volume":"2018","author":"C Kan","year":"2018","unstructured":"Kan, C., Yang, F. & Wang, S. SHP2-mediated signal networks in stem cell homeostasis and dysfunction. Stem Cells Int. 2018, 8351374. https:\/\/doi.org\/10.1155\/2018\/8351374 (2018).","journal-title":"Stem Cells Int."},{"key":"99339_CR5","doi-asserted-by":"publisher","first-page":"2075","DOI":"10.1111\/jcmm.12618","volume":"19","author":"J Zhang","year":"2015","unstructured":"Zhang, J., Zhang, F. & Niu, R. Functions of Shp2 in cancer. J. Cell Mol. Med. 19, 2075\u20132083. https:\/\/doi.org\/10.1111\/jcmm.12618 (2015).","journal-title":"J. Cell Mol. Med."},{"key":"99339_CR6","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1038\/ng772","volume":"29","author":"M Tartaglia","year":"2001","unstructured":"Tartaglia, M. et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat. Genet. 29, 465\u2013468 (2001).","journal-title":"Nat. Genet."},{"key":"99339_CR7","doi-asserted-by":"publisher","first-page":"e1002050","DOI":"10.1371\/journal.pgen.1002050","volume":"7","author":"ME Bowen","year":"2011","unstructured":"Bowen, M. E. et al. Loss-of-function mutations in PTPN11 cause metachondromatosis, but not Ollier disease or Maffucci syndrome. PLoS\u00a0Genet 7, e1002050. https:\/\/doi.org\/10.1371\/journal.pgen.1002050 (2011).","journal-title":"PLoS\u00a0Genet"},{"key":"99339_CR8","doi-asserted-by":"publisher","first-page":"491","DOI":"10.1038\/nature12396","volume":"499","author":"W Yang","year":"2013","unstructured":"Yang, W. et al. Ptpn11 deletion in a novel progenitor causes metachondromatosis by inducing hedgehog signalling. Nature 499, 491\u2013495. https:\/\/doi.org\/10.1038\/nature12396 (2013).","journal-title":"Nature"},{"key":"99339_CR9","doi-asserted-by":"publisher","first-page":"275","DOI":"10.1007\/978-3-540-40035-6_14","volume":"2","author":"L Lai","year":"2004","unstructured":"Lai, L., Zhao, C., Zhang, E. & Feng, G. S. The Shp-2 tyrosine phosphatase. Prot. Phosphatases 2, 275\u2013299 (2004).","journal-title":"Prot. Phosphatases"},{"key":"99339_CR10","doi-asserted-by":"publisher","first-page":"e1004364","DOI":"10.1371\/journal.pgen.1004364","volume":"10","author":"ME Bowen","year":"2014","unstructured":"Bowen, M. E., Ayturk, U. M., Kurek, K. C., Yang, W. & Warman, M. L. SHP2 regulates chondrocyte terminal differentiation, growth plate architecture and skeletal cell fates. PLoS\u00a0Genet. 10, e1004364. https:\/\/doi.org\/10.1371\/journal.pgen.1004364 (2014).","journal-title":"PLoS\u00a0Genet."},{"key":"99339_CR11","doi-asserted-by":"publisher","first-page":"12699","DOI":"10.1038\/s41598-017-12767-9","volume":"7","author":"L Wang","year":"2017","unstructured":"Wang, L. et al. SHP2 regulates the osteogenic fate of growth plate hypertrophic chondrocytes. Sci. Rep. 7, 12699. https:\/\/doi.org\/10.1038\/s41598-017-12767-9 (2017).","journal-title":"Sci. Rep."},{"key":"99339_CR12","doi-asserted-by":"publisher","first-page":"12","DOI":"10.1038\/s41413-018-0013-z","volume":"6","author":"C Zuo","year":"2018","unstructured":"Zuo, C. et al. SHP2 regulates skeletal cell fate by modifying SOX9 expression and transcriptional activity. Bone Res. 6, 12. https:\/\/doi.org\/10.1038\/s41413-018-0013-z (2018).","journal-title":"Bone Res."},{"key":"99339_CR13","doi-asserted-by":"publisher","first-page":"1326","DOI":"10.3389\/fimmu.2017.01326","volume":"8","author":"SMS Miah","year":"2017","unstructured":"Miah, S. M. S. et al. Ptpn11 deletion in CD4(+) cells does not affect T cell development and functions but causes cartilage tumors in a T cell-independent manner. Front. Immunol. 8, 1326. https:\/\/doi.org\/10.3389\/fimmu.2017.01326 (2017).","journal-title":"Front. Immunol."},{"key":"99339_CR14","doi-asserted-by":"publisher","first-page":"343","DOI":"10.3389\/fimmu.2017.00343","volume":"8","author":"G Guittard","year":"2017","unstructured":"Guittard, G. et al. Unexpected cartilage phenotype in CD4-Cre-conditional SOS-deficient mice. Front. Immunol. 8, 343. https:\/\/doi.org\/10.3389\/fimmu.2017.00343 (2017).","journal-title":"Front. Immunol."},{"key":"99339_CR15","doi-asserted-by":"publisher","first-page":"482","DOI":"10.3389\/fimmu.2017.00482","volume":"8","author":"M Wehenkel","year":"2017","unstructured":"Wehenkel, M. et al. Extracellular signal-regulated kinase signaling in CD4-expressing cells inhibits osteochondromas. Front. Immunol. 8, 482. https:\/\/doi.org\/10.3389\/fimmu.2017.00482 (2017).","journal-title":"Front. Immunol."},{"key":"99339_CR16","doi-asserted-by":"publisher","first-page":"a008334","DOI":"10.1101\/cshperspect.a008334","volume":"5","author":"F Long","year":"2013","unstructured":"Long, F. & Ornitz, D. M. Development of the endochondral skeleton. Cold Spring Harb. Perspect. Biol. 5, a008334. https:\/\/doi.org\/10.1101\/cshperspect.a008334 (2013).","journal-title":"Cold Spring Harb. Perspect. Biol."},{"key":"99339_CR17","doi-asserted-by":"publisher","first-page":"696","DOI":"10.1038\/s41580-020-00279-w","volume":"21","author":"A Salhotra","year":"2020","unstructured":"Salhotra, A., Shah, H. N., Levi, B. & Longaker, M. T. Mechanisms of bone development and repair. Nat. Rev. Mol. Cell Biol. 21, 696\u2013711. https:\/\/doi.org\/10.1038\/s41580-020-00279-w (2020).","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"99339_CR18","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20236009","author":"SA Hallett","year":"2019","unstructured":"Hallett, S. A., Ono, W. & Ono, N. Growth plate chondrocytes: Skeletal development, growth and beyond. Int. J. Mol. Sci. https:\/\/doi.org\/10.3390\/ijms20236009 (2019).","journal-title":"Int. J. Mol. Sci."},{"key":"99339_CR19","doi-asserted-by":"publisher","first-page":"285","DOI":"10.1016\/j.cell.2014.12.002","volume":"160","author":"CK Chan","year":"2015","unstructured":"Chan, C. K. et al. Identification and specification of the mouse skeletal stem cell. Cell 160, 285\u2013298. https:\/\/doi.org\/10.1016\/j.cell.2014.12.002 (2015).","journal-title":"Cell"},{"key":"99339_CR20","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1080\/03008207.2016.1183667","volume":"58","author":"V Lefebvre","year":"2017","unstructured":"Lefebvre, V. & Dvir-Ginzberg, M. SOX9 and the many facets of its regulation in the chondrocyte lineage. Connect. Tissue Res. 58, 2\u201314. https:\/\/doi.org\/10.1080\/03008207.2016.1183667 (2017).","journal-title":"Connect. Tissue Res."},{"key":"99339_CR21","doi-asserted-by":"publisher","first-page":"3088","DOI":"10.1210\/jc.2007-2397","volume":"93","author":"EP Smith","year":"2008","unstructured":"Smith, E. P. et al. Impact on bone of an estrogen receptor-alpha gene loss of function mutation. J. Clin. Endocrinol. Metab. 93, 3088\u20133096. https:\/\/doi.org\/10.1210\/jc.2007-2397 (2008).","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"99339_CR22","doi-asserted-by":"publisher","first-page":"E1381","DOI":"10.1152\/ajpendo.00646.2011","volume":"302","author":"AE Borjesson","year":"2012","unstructured":"Borjesson, A. E. et al. The role of estrogen receptor-alpha and its activation function-1 for growth plate closure in female mice. Am. J. Physiol. Endocrinol. Metab. 302, E1381-1389. https:\/\/doi.org\/10.1152\/ajpendo.00646.2011 (2012).","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"99339_CR23","doi-asserted-by":"publisher","first-page":"317","DOI":"10.1016\/j.devcel.2006.01.002","volume":"10","author":"W Yang","year":"2006","unstructured":"Yang, W. et al. An Shp2\/SFK\/Ras\/Erk signaling pathway controls trophoblast stem cell survival. Dev. Cell 10, 317\u2013327. https:\/\/doi.org\/10.1016\/j.devcel.2006.01.002 (2006).","journal-title":"Dev. Cell"},{"key":"99339_CR24","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1016\/j.jim.2016.06.005","volume":"436","author":"K Westendorf","year":"2016","unstructured":"Westendorf, K., Durek, P., Ayew, S., Mashreghi, M. F. & Radbruch, A. Chromosomal localisation of the CD4cre transgene in B6.Cg-Tg(Cd4-cre)1Cwi mice. J. Immunol. Methods 436, 54\u201357. https:\/\/doi.org\/10.1016\/j.jim.2016.06.005 (2016).","journal-title":"J. Immunol. Methods"},{"key":"99339_CR25","doi-asserted-by":"publisher","first-page":"1267","DOI":"10.1002\/jbmr.30","volume":"25","author":"D Belluoccio","year":"2010","unstructured":"Belluoccio, D. et al. Sorting of growth plate chondrocytes allows the isolation and characterization of cells of a defined differentiation status. J. Bone Miner. Res. 25, 1267\u20131281. https:\/\/doi.org\/10.1002\/jbmr.30 (2010).","journal-title":"J. Bone Miner. Res."},{"key":"99339_CR26","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1007\/978-1-4939-3584-0_11","volume":"1416","author":"SV Boregowda","year":"2016","unstructured":"Boregowda, S. V., Krishnappa, V. & Phinney, D. G. Isolation of mouse bone marrow mesenchymal stem cells. Methods Mol. Biol. 1416, 205\u2013223. https:\/\/doi.org\/10.1007\/978-1-4939-3584-0_11 (2016).","journal-title":"Methods Mol. Biol."},{"key":"99339_CR27","doi-asserted-by":"publisher","first-page":"1253","DOI":"10.1038\/nprot.2008.95","volume":"3","author":"M Gosset","year":"2008","unstructured":"Gosset, M., Berenbaum, F., Thirion, S. & Jacques, C. Primary culture and phenotyping of murine chondrocytes. Nat. Protoc. 3, 1253\u20131260. https:\/\/doi.org\/10.1038\/nprot.2008.95 (2008).","journal-title":"Nat. Protoc."},{"key":"99339_CR28","doi-asserted-by":"publisher","first-page":"132","DOI":"10.4049\/jimmunol.2000870","volume":"206","author":"CK Anderson","year":"2021","unstructured":"Anderson, C. K., Reilly, S. P. & Brossay, L. The invariant NKT cell response has differential signaling requirements during antigen-dependent and antigen-independent activation. J. Immunol. 206, 132\u2013140. https:\/\/doi.org\/10.4049\/jimmunol.2000870 (2021).","journal-title":"J. Immunol."},{"key":"99339_CR29","doi-asserted-by":"publisher","first-page":"1904","DOI":"10.1038\/nprot.2015.125","volume":"10","author":"AP Kusumbe","year":"2015","unstructured":"Kusumbe, A. P., Ramasamy, S. K., Starsichova, A. & Adams, R. H. Sample preparation for high-resolution 3D confocal imaging of mouse skeletal tissue. Nat. Protoc. 10, 1904\u20131914. https:\/\/doi.org\/10.1038\/nprot.2015.125 (2015).","journal-title":"Nat. Protoc."},{"key":"99339_CR30","doi-asserted-by":"publisher","first-page":"191","DOI":"10.2144\/btn-2018-0021","volume":"65","author":"MA Serowoky","year":"2018","unstructured":"Serowoky, M. A., Patel, D. D., Hsieh, J. W. & Mariani, F. V. The use of commercially available adhesive tapes to preserve cartilage and bone tissue integrity during cryosectioning. Biotechniques 65, 191\u2013196. https:\/\/doi.org\/10.2144\/btn-2018-0021 (2018).","journal-title":"Biotechniques"},{"key":"99339_CR31","doi-asserted-by":"publisher","first-page":"676","DOI":"10.1038\/nmeth.2019","volume":"9","author":"J Schindelin","year":"2012","unstructured":"Schindelin, J. et al. Fiji: An open-source platform for biological-image analysis. Nat. Methods 9, 676\u2013682. https:\/\/doi.org\/10.1038\/nmeth.2019 (2012).","journal-title":"Nat. Methods"},{"key":"99339_CR32","doi-asserted-by":"publisher","first-page":"4","DOI":"10.1186\/1471-213X-1-4","volume":"1","author":"S Srinivas","year":"2001","unstructured":"Srinivas, S. et al. Cre reporter strains produced by targeted insertion of EYFP and ECFP into the ROSA26 locus. BMC Dev. Biol. 1, 4 (2001).","journal-title":"BMC Dev. Biol."},{"key":"99339_CR33","doi-asserted-by":"publisher","first-page":"39","DOI":"10.1002\/jbmr.5650090106","volume":"9","author":"DE Hughes","year":"1994","unstructured":"Hughes, D. E., Salter, D. M. & Simpson, R. CD44 expression in human bone: A novel marker of osteocytic differentiation. J. Bone Miner. Res. 9, 39\u201344. https:\/\/doi.org\/10.1002\/jbmr.5650090106 (1994).","journal-title":"J. Bone Miner. Res."},{"key":"99339_CR34","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1038\/8792","volume":"22","author":"W Bi","year":"1999","unstructured":"Bi, W., Deng, J. M., Zhang, Z., Behringer, R. R. & de Crombrugghe, B. Sox9 is required for cartilage formation. Nat. Genet. 22, 85\u201389. https:\/\/doi.org\/10.1038\/8792 (1999).","journal-title":"Nat. Genet."},{"key":"99339_CR35","doi-asserted-by":"publisher","first-page":"55","DOI":"10.1016\/j.bone.2014.08.015","volume":"69","author":"N Kamiya","year":"2014","unstructured":"Kamiya, N., Kim, H. K. & King, P. D. Regulation of bone and skeletal development by the SHP-2 protein tyrosine phosphatase. Bone 69, 55\u201360. https:\/\/doi.org\/10.1016\/j.bone.2014.08.015 (2014).","journal-title":"Bone"},{"key":"99339_CR36","doi-asserted-by":"publisher","first-page":"11","DOI":"10.1016\/j.matbio.2014.08.007","volume":"39","author":"RF Loeser","year":"2014","unstructured":"Loeser, R. F. Integrins and chondrocyte-matrix interactions in articular cartilage. Matrix Biol. 39, 11\u201316. https:\/\/doi.org\/10.1016\/j.matbio.2014.08.007 (2014).","journal-title":"Matrix Biol."},{"key":"99339_CR37","doi-asserted-by":"publisher","first-page":"9920","DOI":"10.1073\/pnas.1513066112","volume":"112","author":"O Marecic","year":"2015","unstructured":"Marecic, O. et al. Identification and characterization of an injury-induced skeletal progenitor. Proc. Natl. Acad. Sci. USA 112, 9920\u20139925. https:\/\/doi.org\/10.1073\/pnas.1513066112 (2015).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"99339_CR38","doi-asserted-by":"publisher","first-page":"e1005214","DOI":"10.1371\/journal.pgen.1005214","volume":"11","author":"S Zhou","year":"2015","unstructured":"Zhou, S. et al. FGFR3 deficiency causes multiple chondroma-like lesions by upregulating hedgehog signaling. PLoS\u00a0Genet. 11, e1005214. https:\/\/doi.org\/10.1371\/journal.pgen.1005214 (2015).","journal-title":"PLoS\u00a0Genet."},{"key":"99339_CR39","doi-asserted-by":"publisher","first-page":"577","DOI":"10.1016\/j.bone.2006.10.013","volume":"40","author":"JE Lazarus","year":"2007","unstructured":"Lazarus, J. E., Hegde, A., Andrade, A. C., Nilsson, O. & Baron, J. Fibroblast growth factor expression in the postnatal growth plate. Bone 40, 577\u2013586. https:\/\/doi.org\/10.1016\/j.bone.2006.10.013 (2007).","journal-title":"Bone"},{"key":"99339_CR40","doi-asserted-by":"publisher","first-page":"80","DOI":"10.1016\/j.ydbio.2006.08.071","volume":"302","author":"Z Liu","year":"2007","unstructured":"Liu, Z., Lavine, K. J., Hung, I. H. & Ornitz, D. M. FGF18 is required for early chondrocyte proliferation, hypertrophy and vascular invasion of the growth plate. Dev. Biol. 302, 80\u201391. https:\/\/doi.org\/10.1016\/j.ydbio.2006.08.071 (2007).","journal-title":"Dev. Biol."}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-99339-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-99339-0","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-99339-0.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,3]],"date-time":"2022-12-03T16:31:50Z","timestamp":1670085110000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-99339-0"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,10,8]]},"references-count":40,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["99339"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-99339-0","relation":{},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10,8]]},"assertion":[{"value":"16 April 2021","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"20 September 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"8 October 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":"20006"}}