{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,27]],"date-time":"2025-09-27T03:34:39Z","timestamp":1758944079906},"reference-count":41,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:00:00Z","timestamp":1614816000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T00:00:00Z","timestamp":1614816000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Grant-in-Aid for Young Scientists from the Japanese Ministry of Education, Culture, Sports, Science, and Technology","award":["20K16795"],"award-info":[{"award-number":["20K16795"]}]},{"name":"Network-type Joint Usage\/Research Center for Radiation Disaster Medical Science"},{"name":"Grant-in-Aid for Scientific Research (C) from the Japanese Ministry of Education, Culture, Sports, Science, and Technology","award":["20K08738"],"award-info":[{"award-number":["20K08738"]}]},{"name":"The Japanese Society of Hematology Research Grant"},{"name":"Japan Leukemia Research Fund"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Multiple myeloma (MM) cells are derived from mature B cells based on immunoglobulin heavy chain (<jats:italic>IgH<\/jats:italic>) gene analysis. The onset of MM is often caused by a reciprocal chromosomal translocation (cTr) between chr 14 with<jats:italic>IgH<\/jats:italic>and chr 11 with<jats:italic>CCND1<\/jats:italic>. We propose that mature B cells gain potential to transform by reprograming, and then chromosomal aberrations cause the development of abnormal B cells as a myeloma-initiating cell during B cell redifferentiation. To study myeloma-initiating cells, we have already established normal B cell-derived induced pluripotent stem cells (BiPSCs). Here we established two BiPSCs with reciprocal cTr t(11;14) using the CRISPR\/Cas9 system; the cleavage site were located in the<jats:italic>IgH<\/jats:italic>E\u03bc region of either the VDJ rearranged allele or non-rearranged allele of<jats:italic>IgH<\/jats:italic>and the 5\u2032-upsteam region of the<jats:italic>CCND1<\/jats:italic>(two types of BiPSC13 with t(11;14) and MIB2-6 with t(11;14)). Furthermore,<jats:italic>p53<\/jats:italic>was deleted using the CRISPR\/Cas9 system in BiPSC13 with t(11;14). These BiPSCs differentiated into hematopoietic progenitor cells (HPCs). However, unlike cord blood, those HPCs did not differentiated into B lymphocytes by co-culture with BM stromal cell. Therefore, further ingenuity is required to differentiate those BiPSCs-derived HPCs into B lymphocytes.<\/jats:p>","DOI":"10.1038\/s41598-021-84628-5","type":"journal-article","created":{"date-parts":[[2021,3,4]],"date-time":"2021-03-04T11:04:29Z","timestamp":1614855869000},"update-policy":"http:\/\/dx.doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Chromosomal translocation t(11;14) and p53 deletion induced by the CRISPR\/Cas9 system in normal B cell-derived iPS cells"],"prefix":"10.1038","volume":"11","author":[{"given":"Yusuke","family":"Azami","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Naohiro","family":"Tsuyama","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Abe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Misaki","family":"Sugai-Takahashi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ken-ichi","family":"Kudo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akinobu","family":"Ota","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karnan","family":"Sivasundaram","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Moe","family":"Muramatsu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tomonari","family":"Shigemura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megumi","family":"Sasatani","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuko","family":"Hashimoto","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Shigehira","family":"Saji","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kenji","family":"Kamiya","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ichiro","family":"Hanamura","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Takayuki","family":"Ikezoe","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Masafumi","family":"Onodera","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Akira","family":"Sakai","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2021,3,4]]},"reference":[{"key":"84628_CR1","doi-asserted-by":"publisher","first-page":"2135","DOI":"10.1038\/leu.2012.80","volume":"26","author":"N Hosen","year":"2012","unstructured":"Hosen, N. et al. CD138-negative clonogenic cells are plasma cells but not B cells in some multiple myeloma patients. Leukemia 26, 2135\u20132141 (2012).","journal-title":"Leukemia"},{"key":"84628_CR2","doi-asserted-by":"publisher","first-page":"2530","DOI":"10.1038\/leu.2012.140","volume":"26","author":"D Kim","year":"2012","unstructured":"Kim, D., Park, C. Y., Medeiros, B. C. & Weissman, I. L. CD19- CD45low\/- CD38high\/CD138+ plasma cells enrich for human tumorigenic myeloma cells. Leukemia 26, 2530\u20132537 (2012).","journal-title":"Leukemia"},{"key":"84628_CR3","doi-asserted-by":"publisher","first-page":"3112","DOI":"10.1182\/blood-2007-02-069625","volume":"110","author":"D Gonz\u00e1lez","year":"2007","unstructured":"Gonz\u00e1lez, D. et al. Immunoglobulin gene rearrangements and the pathogenesis of multiple myeloma. Blood 110, 3112\u20133121 (2007).","journal-title":"Blood"},{"key":"84628_CR4","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1038\/nrc3257","volume":"12","author":"GJ Morgan","year":"2012","unstructured":"Morgan, G. J., Walker, B. A. & Davies, F. E. The genetic architecture of multiple myeloma. Nat. Rev. Cancer 12, 335\u2013348 (2012).","journal-title":"Nat. Rev. Cancer"},{"key":"84628_CR5","first-page":"1","volume":"3","author":"SK Kumar","year":"2017","unstructured":"Kumar, S. K. et al. Multiple myeloma . Nat. Rev. Dis. Prim. 3, 1\u201320 (2017).","journal-title":"Nat. Rev. Dis. Prim."},{"key":"84628_CR6","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-017-01627-1","volume":"7","author":"F Kawamura","year":"2017","unstructured":"Kawamura, F. et al. Establishment of induced pluripotent stem cells from normal B cells and inducing AID expression in their differentiation into hematopoietic progenitor cells. Sci. Rep. 7, 1\u201311 (2017).","journal-title":"Sci. Rep."},{"key":"84628_CR7","first-page":"275","volume":"18","author":"N Tsuyama","year":"2019","unstructured":"Tsuyama, N. et al. Induction of t(11;14) igh enhancer\/promoter-cyclin d1 gene translocation using crispr\/cas9. Oncol. Lett. 18, 275\u2013282 (2019).","journal-title":"Oncol. Lett."},{"key":"84628_CR8","doi-asserted-by":"publisher","first-page":"1330","DOI":"10.1182\/blood.V93.4.1330","volume":"93","author":"D Ronchetti","year":"1999","unstructured":"Ronchetti, D. et al. Molecular analysis of 11q13 breakpoints in multiple myeloma. Blood 93, 1330\u20131337 (1999).","journal-title":"Blood"},{"key":"84628_CR9","first-page":"151","volume":"39","author":"JAL Fenton","year":"2004","unstructured":"Fenton, J. A. L., Pratt, G., Rothwell, D. G., Rawstron, A. C. & Morgan, G. J. Translocation t(11;14) in multiple myeloma: analysis of translocation breakpoints on der(11) and der(14) chromosomes suggests complex molecular mechanisms of recombination. Genes chromosom. . Cancer 39, 151\u2013155 (2004).","journal-title":"Cancer"},{"key":"84628_CR10","doi-asserted-by":"publisher","first-page":"2032","DOI":"10.1182\/blood.V92.6.2032","volume":"92","author":"MJ Xu","year":"1998","unstructured":"Xu, M. J. et al. Stimulation of mouse and human primitive hematopoiesis by murine embryonic aorta-gonad-mesonephros-derived stromal cell lines. Blood 92, 2032\u20132040 (1998).","journal-title":"Blood"},{"key":"84628_CR11","doi-asserted-by":"publisher","first-page":"2095","DOI":"10.1182\/blood-2006-02-003327","volume":"108","author":"MA Vodyanik","year":"2006","unstructured":"Vodyanik, M. A., Thomson, J. A. & Slukvin, I. I. Leukosialin (CD43) defines hematopoietic progenitors in human embryonic stem cell differentiation cultures. Blood 108, 2095\u20132105 (2006).","journal-title":"Blood"},{"key":"84628_CR12","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41598-018-26123-y","volume":"8","author":"GA MacLean","year":"2018","unstructured":"MacLean, G. A. et al. Downregulation of endothelin receptor B contributes to defective B cell lymphopoiesis in trisomy 21 pluripotent stem cells. Sci. Rep. 8, 1\u201310 (2018).","journal-title":"Sci. Rep."},{"key":"84628_CR13","doi-asserted-by":"publisher","first-page":"855","DOI":"10.1002\/(SICI)1521-4141(199803)28:03<855::AID-IMMU855>3.0.CO;2-X","volume":"28","author":"M Nishihara","year":"1998","unstructured":"Nishihara, M. et al. A combination of stem cell factor and granulocyte colony-stimulating factor enhances the growth of human progenitor B cells supported by murine stromal cell line MS-5. Eur. J. Immunol. 28, 855\u2013864 (1998).","journal-title":"Eur. J. Immunol."},{"key":"84628_CR14","doi-asserted-by":"publisher","first-page":"410","DOI":"10.1046\/j.1365-2567.2001.01336.x","volume":"104","author":"Y Hirose","year":"2001","unstructured":"Hirose, Y. et al. B-cell precursors differentiated from cord blood CD34+ cells are more immature than those derived from granulocyte colony-stimulating factor-mobilized peripheral blood CD34+ cells. Immunology 104, 410\u2013417 (2001).","journal-title":"Immunology"},{"key":"84628_CR15","doi-asserted-by":"publisher","first-page":"758","DOI":"10.1073\/pnas.1614197114","volume":"114","author":"K Hashimoto","year":"2017","unstructured":"Hashimoto, K. et al. Cellular context-dependent consequences of Apc mutations on gene regulation and cellular behavior. Proc. Natl. Acad. Sci. USA 114, 758\u2013763 (2017).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"84628_CR16","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1038\/s41467-018-04449-5","volume":"9","author":"H Shibata","year":"2018","unstructured":"Shibata, H. et al. In vivo reprogramming drives Kras-induced cancer development. Nat. Commun. 9, 1\u20137 (2018).","journal-title":"Nat. Commun."},{"key":"84628_CR17","doi-asserted-by":"publisher","first-page":"293","DOI":"10.1016\/j.stem.2017.02.001","volume":"20","author":"J Taguchi","year":"2017","unstructured":"Taguchi, J. & Yamada, Y. Unveiling the role of senescence-induced cellular plasticity. Cell Stem Cell 20, 293\u2013294 (2017).","journal-title":"Cell Stem Cell"},{"key":"84628_CR18","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/nrc.2016.40","volume":"16","author":"MR Lieber","year":"2016","unstructured":"Lieber, M. R. Mechanisms of human lymphoid chromosomal translocations. Nat. Rev. Cancer 16, 387\u2013398 (2016).","journal-title":"Nat. Rev. Cancer"},{"key":"84628_CR19","doi-asserted-by":"publisher","first-page":"296","DOI":"10.1182\/blood-2005-01-0034","volume":"106","author":"PL Bergsagel","year":"2005","unstructured":"Bergsagel, P. L. et al. Cyclin D dysregulation: an early and unifying pathogenic event in multiple myeloma. Blood 106, 296\u2013303 (2005).","journal-title":"Blood"},{"key":"84628_CR20","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1016\/j.ccr.2008.01.007","volume":"13","author":"M Chesi","year":"2008","unstructured":"Chesi, M. et al. AID-dependent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. Cancer Cell 13, 167\u2013180 (2008).","journal-title":"Cancer Cell"},{"key":"84628_CR21","doi-asserted-by":"publisher","first-page":"2487","DOI":"10.4049\/jimmunol.155.5.2487","volume":"155","author":"RA Vescio","year":"1995","unstructured":"Vescio, R. A. et al. Myeloma Ig heavy chain V region sequences reveal prior antigenic selection and marked somatic mutation but no intraclonal diversity. J. Immunol. 155, 2487\u20132497 (1995).","journal-title":"J. Immunol."},{"key":"84628_CR22","doi-asserted-by":"publisher","first-page":"219","DOI":"10.1182\/blood.V89.1.219","volume":"89","author":"BSS Sahota","year":"1997","unstructured":"Sahota, B. S. S. et al. Myeloma VL and VH gene sequences reveal a complementary imprint of antigen selection in tumor cells. Blood 89, 219\u2013226 (1997).","journal-title":"Blood"},{"key":"84628_CR23","doi-asserted-by":"publisher","first-page":"1718","DOI":"10.1038\/sj.leu.2401908","volume":"14","author":"C Kosmas","year":"2000","unstructured":"Kosmas, C. et al. Origin and diversification of the clonogenic cell in multiple myeloma: lessons from the immunoglobulin repertoire. Leukemia 14, 1718\u20131726 (2000).","journal-title":"Leukemia"},{"key":"84628_CR24","doi-asserted-by":"publisher","first-page":"1295","DOI":"10.1084\/jem.189.8.1295","volume":"189","author":"Y Chang","year":"1999","unstructured":"Chang, Y., Bosma, M. J. & Bosma, G. C. Extended duration of DH-JH rearrangement in immunoglobulin heavy chain transgenic mice: Implications for regulation of allelic exclusion. J. Exp. Med. 189, 1295\u20131305 (1999).","journal-title":"J. Exp. Med."},{"key":"84628_CR25","doi-asserted-by":"publisher","first-page":"541","DOI":"10.1146\/annurev.immunol.23.021704.115830","volume":"1","author":"D Jung","year":"2006","unstructured":"Jung, D., Giallourakis, C., Mostoslavsky, R. & Alt, F. W. (2006) Mechanism and control of V(D)J recombination at the immunoglobulin heavy chain locus. Annu. Rev. Immunol. 1, 541\u2013570 (2006).","journal-title":"Annu. Rev. Immunol."},{"key":"84628_CR26","doi-asserted-by":"publisher","first-page":"3413","DOI":"10.1182\/blood-2012-12-471888","volume":"121","author":"G Morgan","year":"2013","unstructured":"Morgan, G. et al. Characterization of IgH breakpoints in multiple myeloma indicates a subset of translocations appear to occur in pre-germinal center B cells. Blood 121, 3413\u20133420 (2013).","journal-title":"Blood"},{"key":"84628_CR27","doi-asserted-by":"publisher","first-page":"486","DOI":"10.1182\/blood.V98.2.486","volume":"98","author":"M Yasukawa","year":"2001","unstructured":"Yasukawa, M. et al. Low frequency of BCL-2\/JH translocation in peripheral blood lymphocytes of healthy Japanese individuals. Blood 98, 486\u2013488 (2001).","journal-title":"Blood"},{"key":"84628_CR28","doi-asserted-by":"publisher","first-page":"2425","DOI":"10.1084\/jem.20061292","volume":"203","author":"S Roulland","year":"2006","unstructured":"Roulland, S. et al. Follicular lymphoma-like B cells in healthy individuals: A novel intermediate step in early lymphomagenesis. J. Exp. Med. 203, 2425\u20132431 (2006).","journal-title":"J. Exp. Med."},{"key":"84628_CR29","doi-asserted-by":"publisher","first-page":"1190","DOI":"10.1038\/leu.2009.31","volume":"23","author":"Y Lecluse","year":"2009","unstructured":"Lecluse, Y. et al. T(11;14)-positive clones can persist over a long period of time in the peripheral blood of healthy individuals. Leukemia 23, 1190\u20131193 (2009).","journal-title":"Leukemia"},{"key":"84628_CR30","doi-asserted-by":"publisher","first-page":"4311","DOI":"10.1182\/blood.V87.10.4311.bloodjournal87104311","volume":"87","author":"MS Mahmoud","year":"1996","unstructured":"Mahmoud, M. S. et al. Altered expression of Pax-5 gene in human myeloma cells. Blood 87, 4311\u20134315 (1996).","journal-title":"Blood"},{"key":"84628_CR31","first-page":"310","volume":"6","author":"Y Matsuo","year":"1993","unstructured":"Matsuo, Y. et al. Establishment and characterization of new IgD lambda type myeloma cell lines, MOLP-2 and MOLP-3, expressing CD28, CD33 antigens and the IL-6 receptor. Hum. Cell 6, 310\u2013313 (1993).","journal-title":"Hum. Cell"},{"key":"84628_CR32","doi-asserted-by":"publisher","first-page":"978","DOI":"10.1182\/blood.V72.3.978.bloodjournal723978","volume":"72","author":"H Matsuzaki","year":"1988","unstructured":"Matsuzaki, H., Hata, H., Takeya, M. & Takatsuki, K. Establishment and characterization of an amylase-producing human myeloma cell line. Blood 72, 978\u2013982 (1988).","journal-title":"Blood"},{"key":"84628_CR33","doi-asserted-by":"publisher","first-page":"199","DOI":"10.1111\/j.1365-2141.1989.tb00252.x","volume":"73","author":"T Ohtsuki","year":"1989","unstructured":"Ohtsuki, T. et al. Two human myeloma cell lines, amylase-producing KMS-12-PE and amylase-non-producing KMS-12-BM, were established from a patient, having the same chromosome marker, t(11;14)(q13;q32). Br. J. Haematol. 73, 199\u2013204 (1989).","journal-title":"Br. J. Haematol."},{"key":"84628_CR34","doi-asserted-by":"publisher","first-page":"339","DOI":"10.2169\/internalmedicine.31.339","volume":"31","author":"H Matsuzaki","year":"1992","unstructured":"Matsuzaki, H. et al. Human Myeloma Cell Line (KHM-4) Established from a Patient with Multiple Myeloma Associated with Hyperammonemia. Intern. Med. 31, 339\u2013343 (1992).","journal-title":"Intern. Med."},{"key":"84628_CR35","doi-asserted-by":"publisher","first-page":"356","DOI":"10.1038\/nature09650","volume":"469","author":"K Anderson","year":"2011","unstructured":"Anderson, K. et al. Genetic variegation of clonal architecture and propagating cells in leukaemia. Nature 469, 356\u2013361 (2011).","journal-title":"Nature"},{"key":"84628_CR36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1371\/journal.pone.0126007","volume":"10","author":"M Schneider","year":"2015","unstructured":"Schneider, M. et al. CD38 is expressed on inflammatory cells of the intestine and promotes intestinal inflammation. PLoS ONE 10, 1\u201316 (2015).","journal-title":"PLoS ONE"},{"key":"84628_CR37","doi-asserted-by":"publisher","first-page":"228","DOI":"10.3390\/cells9010228","volume":"9","author":"E Glar\u00eda","year":"2020","unstructured":"Glar\u00eda, E. & Valledor, A. F. Roles of CD38 in the Immune Response to Infection. Cells 9, 228 (2020).","journal-title":"Cells"},{"key":"84628_CR38","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1038\/nbt.3437","volume":"34","author":"JG Doench","year":"2016","unstructured":"Doench, J. G. et al. Optimized sgRNA design to maximize activity and minimize off-target effects of CRISPR-Cas9. Nat. Biotechnol. 34, 184\u2013191 (2016).","journal-title":"Nat. Biotechnol."},{"key":"84628_CR39","doi-asserted-by":"publisher","first-page":"2257","DOI":"10.1038\/sj.leu.2403202","volume":"17","author":"JJM van Dongen","year":"2003","unstructured":"van Dongen, J. J. M. et al. Design and standardization of PCR primers and protocols for detection of clonal immunoglobulin and T-cell receptor gene recombinations in suspect lymphoproliferations: Report of the BIOMED-2 concerted action BMH4-CT98-3936. Leukemia 17, 2257\u20132317 (2003).","journal-title":"Leukemia"},{"key":"84628_CR40","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1242\/jcs.190736","volume":"130","author":"A Ota","year":"2017","unstructured":"Ota, A. et al. \u039440P53\u0391 Suppresses Tumor Cell Proliferation and Induces Cellular Senescence in Hepatocellular Carcinoma Cells. J. Cell Sci. 130, 614\u2013625 (2017).","journal-title":"J. Cell Sci."},{"key":"84628_CR41","doi-asserted-by":"publisher","first-page":"3218","DOI":"10.1182\/blood.V87.8.3218.bloodjournal8783218","volume":"87","author":"K Itoh","year":"1996","unstructured":"Itoh, K. et al. A novel hematopoietic multilineage clone, Myl-D-7, is stromal cell-dependent and supported by an alternative mechanism(s) independent of stem cell factor\/c-kit interaction. Blood 87, 3218\u20133228 (1996).","journal-title":"Blood"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-84628-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-84628-5","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-84628-5.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,8,25]],"date-time":"2024-08-25T10:18:17Z","timestamp":1724581097000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-021-84628-5"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,3,4]]},"references-count":41,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["84628"],"URL":"https:\/\/doi.org\/10.1038\/s41598-021-84628-5","relation":{},"ISSN":["2045-2322"],"issn-type":[{"type":"electronic","value":"2045-2322"}],"subject":[],"published":{"date-parts":[[2021,3,4]]},"assertion":[{"value":"3 November 2020","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"18 February 2021","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"4 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":"5216"}}