{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:15:46Z","timestamp":1789168546429,"version":"build-2803163510"},"reference-count":44,"publisher":"Springer Science and Business Media LLC","license":[{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T00:00:00Z","timestamp":1788739200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Qatar Research Development and Innovation (QRDI) NPRP-BSRA grant","award":["NPRP-BSRA01-0504-210082"],"award-info":[{"award-number":["NPRP-BSRA01-0504-210082"]}]},{"DOI":"10.13039\/501100004252","name":"Qatar University","doi-asserted-by":"crossref","id":[{"id":"10.13039\/501100004252","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["J Assist Reprod Genet"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Purpose<\/jats:title>\n                    <jats:p>The PLC\u03b6 p.Arg385Gln (R385Q) variant was recently identified in infertile patients with recurrent fertilization failure and markedly reduced sperm PLC\u03b6 levels. However, whether this variant causes infertility through loss of catalytic function or protein insufficiency remains unknown.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The structural and functional consequences of the R385Q variant were investigated using structural modelling, protein stability prediction, recombinant PLC\u03b6 enzymatic assays, and mouse oocyte microinjection followed by Ca\n                      <jats:sup>2+<\/jats:sup>\n                      oscillation analysis.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Structural modelling predicted that the R385Q substitution destabilizes the catalytic domain without disrupting the active site. Consistent with this prediction, recombinant PLC\u03b6\n                      <jats:sup>R385Q<\/jats:sup>\n                      exhibited phosphatidylinositol 4,5-bisphosphate (PIP\n                      <jats:sub>2<\/jats:sub>\n                      ) hydrolytic activity comparable to wild-type PLC\u03b6. Likewise, microinjection of PLC\u03b6\n                      <jats:sup>R385Q<\/jats:sup>\n                      cRNA into mouse oocytes induced Ca\n                      <jats:sup>2+<\/jats:sup>\n                      oscillations with frequencies and patterns indistinguishable from those elicited by wild-type PLC\u03b6, demonstrating preserved catalytic and oocyte activation activity.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>These findings indicate that the R385Q variant is catalytically competent and does not cause infertility through loss of enzymatic function. Instead, together with our previous demonstration of markedly reduced PLC\u03b6 protein levels in patient sperm, the results support a protein insufficiency mechanism in which fertilization failure arises when PLC\u03b6 levels fall below the threshold required for physiological oocyte activation. This study expands the spectrum of pathogenic mechanisms underlying PLC\u03b6-associated male infertility.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10815-026-04023-9","type":"journal-article","created":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T21:44:58Z","timestamp":1788817498000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["A catalytically competent sperm PLCzeta variant causes fertilization failure through protein insufficiency"],"prefix":"10.1007","author":[{"given":"Alaaeldin","family":"Saleh","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zizhen","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5444-3910","authenticated-orcid":false,"given":"Zeyaul","family":"Islam","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karl","family":"Swann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michail","family":"Nomikos","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,9,7]]},"reference":[{"issue":"2","key":"4023_CR1","doi-asserted-by":"publisher","first-page":"157","DOI":"10.1006\/dbio.1999.9340","volume":"211","author":"SA Stricker","year":"1999","unstructured":"Stricker SA. Comparative biology of calcium signaling during fertilization and egg activation in animals. Dev Biol. 1999;211(2):157\u201376.","journal-title":"Dev Biol"},{"issue":"2","key":"4023_CR2","doi-asserted-by":"publisher","first-page":"280","DOI":"10.1006\/dbio.2002.0788","volume":"250","author":"T Ducibella","year":"2002","unstructured":"Ducibella T, et al. Egg-to-embryo transition is driven by differential responses to Ca(2+) oscillation number. Dev Biol. 2002;250(2):280\u201391.","journal-title":"Dev Biol"},{"key":"4023_CR3","doi-asserted-by":"publisher","first-page":"28","DOI":"10.3389\/fcell.2020.00028","volume":"8","author":"A Saleh","year":"2020","unstructured":"Saleh A, et al. Essential role of sperm-specific PLC-zeta in egg activation and male factor infertility: an update. Front Cell Dev Biol. 2020;8:28.","journal-title":"Front Cell Dev Biol"},{"issue":"4","key":"4023_CR4","doi-asserted-by":"publisher","first-page":"369","DOI":"10.1093\/humupd\/dmad007","volume":"29","author":"G Campos","year":"2023","unstructured":"Campos G, Sciorio R, Esteves SC. Total fertilization failure after ICSI: insights into pathophysiology, diagnosis, and management through artificial oocyte activation. Hum Reprod Update. 2023;29(4):369\u201394.","journal-title":"Hum Reprod Update"},{"issue":"15","key":"4023_CR5","doi-asserted-by":"publisher","first-page":"3533","DOI":"10.1242\/dev.129.15.3533","volume":"129","author":"CM Saunders","year":"2002","unstructured":"Saunders CM, et al. PLC zeta: a sperm-specific trigger of Ca(2+) oscillations in eggs and embryo development. Development. 2002;129(15):3533\u201344.","journal-title":"Development"},{"issue":"5","key":"4023_CR6","doi-asserted-by":"publisher","first-page":"611","DOI":"10.1530\/rep.0.1240611","volume":"124","author":"LJ Cox","year":"2002","unstructured":"Cox LJ, et al. Sperm phospholipase Czeta from humans and cynomolgus monkeys triggers Ca2+ oscillations, activation and development of mouse oocytes. Reproduction. 2002;124(5):611\u201323.","journal-title":"Reproduction"},{"issue":"1","key":"4023_CR7","doi-asserted-by":"publisher","first-page":"F1","DOI":"10.1530\/REP-21-0477","volume":"164","author":"A Thanassoulas","year":"2022","unstructured":"Thanassoulas A, et al. Sperm factors and egg activation: the structure and function relationship of sperm PLCZ1. Reprod. 2022;164(1):F1\u20138.","journal-title":"Reprod"},{"issue":"16","key":"4023_CR8","doi-asserted-by":"publisher","first-page":"2914","DOI":"10.1242\/dev.150227","volume":"144","author":"A Hachem","year":"2017","unstructured":"Hachem A, et al. PLCzeta is the physiological trigger of the Ca(2+) oscillations that induce embryogenesis in mammals but conception can occur in its absence. Development. 2017;144(16):2914\u201324.","journal-title":"Development"},{"issue":"1","key":"4023_CR9","doi-asserted-by":"publisher","first-page":"76","DOI":"10.1016\/j.fertnstert.2012.08.035","volume":"99","author":"M Nomikos","year":"2013","unstructured":"Nomikos M, et al. Phospholipase Czeta rescues failed oocyte activation in a prototype of male factor infertility. Fertil Steril. 2013;99(1):76\u201385.","journal-title":"Fertil Steril"},{"issue":"3","key":"4023_CR10","doi-asserted-by":"publisher","first-page":"371","DOI":"10.1042\/BST20140291","volume":"43","author":"M Nomikos","year":"2015","unstructured":"Nomikos M. Novel signalling mechanism and clinical applications of sperm-specific PLCzeta. Biochem Soc Trans. 2015;43(3):371\u20136.","journal-title":"Biochem Soc Trans"},{"issue":"11","key":"4023_CR11","doi-asserted-by":"publisher","first-page":"10408","DOI":"10.1074\/jbc.M313801200","volume":"279","author":"Z Kouchi","year":"2004","unstructured":"Kouchi Z, et al. Recombinant phospholipase Czeta has high Ca2+ sensitivity and induces Ca2+ oscillations in mouse eggs. J Biol Chem. 2004;279(11):10408\u201312.","journal-title":"J Biol Chem"},{"issue":"35","key":"4023_CR12","doi-asserted-by":"publisher","first-page":"31011","DOI":"10.1074\/jbc.M500629200","volume":"280","author":"M Nomikos","year":"2005","unstructured":"Nomikos M, et al. Role of phospholipase C-zeta domains in Ca2+-dependent phosphatidylinositol 4,5-bisphosphate hydrolysis and cytoplasmic Ca2+ oscillations. J Biol Chem. 2005;280(35):31011\u20138.","journal-title":"J Biol Chem"},{"issue":"Pt 15","key":"4023_CR13","doi-asserted-by":"publisher","first-page":"2582","DOI":"10.1242\/jcs.083485","volume":"124","author":"M Nomikos","year":"2011","unstructured":"Nomikos M, et al. Phospholipase Czeta binding to PtdIns(4,5)P2 requires the XY-linker region. J Cell Sci. 2011;124(Pt 15):2582\u201390.","journal-title":"J Cell Sci"},{"issue":"6","key":"4023_CR14","doi-asserted-by":"publisher","first-page":"1003","DOI":"10.1042\/BCJ20161057","volume":"474","author":"M Nomikos","year":"2017","unstructured":"Nomikos M, et al. Male infertility-linked point mutation reveals a vital binding role for the C2 domain of sperm PLCzeta. Biochem J. 2017;474(6):1003\u201316.","journal-title":"Biochem J"},{"issue":"49","key":"4023_CR15","doi-asserted-by":"publisher","first-page":"29519","DOI":"10.1074\/jbc.M115.658443","volume":"290","author":"M Nomikos","year":"2015","unstructured":"Nomikos M, et al. Essential role of the EF-hand domain in targeting sperm phospholipase Czeta to membrane phosphatidylinositol 4,5-bisphosphate (PIP2). J Biol Chem. 2015;290(49):29519\u201330.","journal-title":"J Biol Chem"},{"issue":"11","key":"4023_CR16","doi-asserted-by":"publisher","first-page":"3671","DOI":"10.1172\/JCI36942","volume":"118","author":"SY Yoon","year":"2008","unstructured":"Yoon SY, et al. Human sperm devoid of PLC, zeta 1 fail to induce Ca2+ release and are unable to initiate the first step of embryo development. J Clin Invest. 2008;118(11):3671\u201381.","journal-title":"J Clin Invest"},{"issue":"10","key":"4023_CR17","doi-asserted-by":"publisher","first-page":"2417","DOI":"10.1093\/humrep\/dep207","volume":"24","author":"E Heytens","year":"2009","unstructured":"Heytens E, et al. Reduced amounts and abnormal forms of phospholipase C zeta (PLCzeta) in spermatozoa from infertile men. Hum Reprod. 2009;24(10):2417\u201328.","journal-title":"Hum Reprod"},{"issue":"8","key":"4023_CR18","doi-asserted-by":"publisher","first-page":"1494","DOI":"10.1093\/humrep\/dez094","volume":"34","author":"M Torra-Massana","year":"2019","unstructured":"Torra-Massana M, et al. Novel phospholipase C zeta 1 mutations associated with fertilization failures after ICSI. Hum Reprod. 2019;34(8):1494\u2013504.","journal-title":"Hum Reprod"},{"issue":"5","key":"4023_CR19","doi-asserted-by":"publisher","first-page":"878","DOI":"10.1093\/hmg\/ddv617","volume":"25","author":"J Escoffier","year":"2016","unstructured":"Escoffier J, et al. Homozygous mutation of PLCZ1 leads to defective human oocyte activation and infertility that is not rescued by the WW-binding protein PAWP. Hum Mol Genet. 2016;25(5):878\u201391.","journal-title":"Hum Mol Genet"},{"issue":"2","key":"4023_CR20","doi-asserted-by":"publisher","first-page":"347","DOI":"10.1111\/cge.13636","volume":"97","author":"J Dai","year":"2020","unstructured":"Dai J, et al. Novel homozygous variations in PLCZ1 lead to poor or failed fertilization characterized by abnormal localization patterns of PLCzeta in sperm. Clin Genet. 2020;97(2):347\u201351.","journal-title":"Clin Genet"},{"issue":"2","key":"4023_CR21","doi-asserted-by":"publisher","first-page":"472","DOI":"10.1093\/humrep\/dez282","volume":"35","author":"Z Yan","year":"2020","unstructured":"Yan Z, et al. Novel mutations in PLCZ1 cause male infertility due to fertilization failure or poor fertilization. Hum Reprod. 2020;35(2):472\u201381.","journal-title":"Hum Reprod"},{"key":"4023_CR22","doi-asserted-by":"publisher","DOI":"10.1530\/REP-23-0466","author":"Q Li","year":"2024","unstructured":"Li Q, et al. Novel PLCZ1 compound heterozygous mutations indicate gene dosage effect involved in total fertilisation failure after ICSI. Reproduction. 2024. https:\/\/doi.org\/10.1530\/REP-23-0466.","journal-title":"Reproduction"},{"issue":"1","key":"4023_CR23","doi-asserted-by":"publisher","first-page":"F53","DOI":"10.1530\/REP-21-0458","volume":"164","author":"C Jones","year":"2022","unstructured":"Jones C, Meng X, Coward K. Sperm factors and egg activation: phospholipase C zeta (PLCZ1) and the clinical diagnosis of oocyte activation deficiency. Reprod. 2022;164(1):F53-66.","journal-title":"Reprod"},{"key":"4023_CR24","doi-asserted-by":"publisher","DOI":"10.1093\/hropen\/hoac003","author":"J Kashir","year":"2022","unstructured":"Kashir J, et al. Oocyte activation deficiency and assisted oocyte activation: mechanisms, obstacles and prospects for clinical application. Hum Reprod Open. 2022. https:\/\/doi.org\/10.1093\/hropen\/hoac003.","journal-title":"Hum Reprod Open"},{"key":"4023_CR25","doi-asserted-by":"publisher","DOI":"10.1530\/RAF-25-0085","author":"J Kashir","year":"2026","unstructured":"Kashir J, et al. Pathogenic homozygous PLCZ1 mutation reduces sperm protein levels with a simulated reduction of PIP2 binding: a case report. Reprod Fertil. 2026. https:\/\/doi.org\/10.1530\/RAF-25-0085.","journal-title":"Reprod Fertil"},{"issue":"4","key":"4023_CR26","doi-asserted-by":"publisher","first-page":"389","DOI":"10.4103\/aja202376","volume":"26","author":"KY Tong","year":"2024","unstructured":"Tong KY, et al. Novel PLCZ1 mutation caused polyspermy during in vitro fertilization. Asian J Androl. 2024;26(4):389\u201395.","journal-title":"Asian J Androl"},{"issue":"W1","key":"4023_CR27","doi-asserted-by":"publisher","first-page":"W296","DOI":"10.1093\/nar\/gky427","volume":"46","author":"A Waterhouse","year":"2018","unstructured":"Waterhouse A, et al. SWISS-MODEL: homology modelling of protein structures and complexes. Nucleic Acids Res. 2018;46(W1):W296-303.","journal-title":"Nucleic Acids Res"},{"issue":"3","key":"4023_CR28","doi-asserted-by":"publisher","first-page":"335","DOI":"10.1093\/bioinformatics\/btt691","volume":"30","author":"DE Pires","year":"2014","unstructured":"Pires DE, Ascher DB, Blundell TL. mCSM: predicting the effects of mutations in proteins using graph-based signatures. Bioinformatics. 2014;30(3):335\u201342.","journal-title":"Bioinformatics"},{"issue":"W1","key":"4023_CR29","doi-asserted-by":"publisher","first-page":"W229","DOI":"10.1093\/nar\/gkx439","volume":"45","author":"AP Pandurangan","year":"2017","unstructured":"Pandurangan AP, et al. SDM: a server for predicting effects of mutations on protein stability. Nucleic Acids Res. 2017;45(W1):W229-35.","journal-title":"Nucleic Acids Res"},{"issue":"Web Server issu","key":"4023_CR30","doi-asserted-by":"publisher","first-page":"W239","DOI":"10.1093\/nar\/gkl190","volume":"34","author":"V Parthiban","year":"2006","unstructured":"Parthiban V, Gromiha MM, Schomburg D. CUPSAT: prediction of protein stability upon point mutations. Nucleic Acids Res. 2006;34(Web Server issue):W239\u201342.","journal-title":"Nucleic Acids Res"},{"issue":"1","key":"4023_CR31","doi-asserted-by":"publisher","first-page":"70","DOI":"10.1002\/pro.3943","volume":"30","author":"EF Pettersen","year":"2021","unstructured":"Pettersen EF, et al. UCSF ChimeraX: structure visualization for researchers, educators, and developers. Protein Sci. 2021;30(1):70\u201382.","journal-title":"Protein Sci"},{"issue":"3","key":"4023_CR32","doi-asserted-by":"publisher","first-page":"365","DOI":"10.1016\/j.jmb.2016.12.004","volume":"429","author":"HC Jubb","year":"2017","unstructured":"Jubb HC, et al. Arpeggio: a web server for calculating and visualising interatomic interactions in protein structures. J Mol Biol. 2017;429(3):365\u201371.","journal-title":"J Mol Biol"},{"issue":"13","key":"4023_CR33","doi-asserted-by":"publisher","DOI":"10.3390\/ijms26136241","volume":"26","author":"A Saleh","year":"2025","unstructured":"Saleh A, Huang Z, Al Shaikh M, Jurkowski TP, Islam Z, Swann K, et al. A novel PLC\u03b6 mutation linked to male factor infertility induces a gain-of-function effect on Ca2+ oscillations in eggs. Int J Mol Sci. 2025;26(13):6241.","journal-title":"Int J Mol Sci"},{"key":"4023_CR34","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines12061183","author":"A Saleh","year":"2024","unstructured":"Saleh A, et al. Development of recombinant PLC-zeta protein as a therapeutic intervention for the clinical treatment of oocyte activation failure. Biomedicines. 2024. https:\/\/doi.org\/10.3390\/biomedicines12061183.","journal-title":"Biomedicines"},{"issue":"3","key":"4023_CR35","doi-asserted-by":"publisher","first-page":"516","DOI":"10.1038\/s41590-023-01419-y","volume":"24","author":"J Edwards-Hicks","year":"2023","unstructured":"Edwards-Hicks J, et al. Phosphoinositide acyl chain saturation drives CD8(+) effector T cell signaling and function. Nat Immunol. 2023;24(3):516\u201330.","journal-title":"Nat Immunol"},{"issue":"24","key":"4023_CR36","doi-asserted-by":"publisher","first-page":"2023","DOI":"10.1042\/BCJ20230065","volume":"480","author":"C Ikie-Eshalomi","year":"2023","unstructured":"Ikie-Eshalomi C, et al. Sperm induce a secondary increase in ATP levels in mouse eggs that is independent of Ca2+ oscillations. Biochem J. 2023;480(24):2023\u201335.","journal-title":"Biochem J"},{"key":"4023_CR37","doi-asserted-by":"publisher","first-page":"431","DOI":"10.1016\/bs.mcb.2018.03.036","volume":"144","author":"G FitzHarris","year":"2018","unstructured":"FitzHarris G, Carroll J, Swann K. Electrical-assisted microinjection for analysis of fertilization and cell division in mammalian oocytes and early embryos. Methods Cell Biol. 2018;144:431\u201340.","journal-title":"Methods Cell Biol"},{"issue":"3","key":"4023_CR38","doi-asserted-by":"publisher","first-page":"427","DOI":"10.1042\/BJ20110953","volume":"438","author":"M Nomikos","year":"2011","unstructured":"Nomikos M, et al. Novel regulation of PLCzeta activity via its XY-linker. Biochem J. 2011;438(3):427\u201332.","journal-title":"Biochem J"},{"issue":"12","key":"4023_CR39","doi-asserted-by":"publisher","first-page":"2062","DOI":"10.1016\/j.str.2012.09.005","volume":"20","author":"TD Bunney","year":"2012","unstructured":"Bunney TD, et al. Structural and functional integration of the PLCgamma interaction domains critical for regulatory mechanisms and signaling deregulation. Structure. 2012;20(12):2062\u201375.","journal-title":"Structure"},{"key":"4023_CR40","doi-asserted-by":"publisher","DOI":"10.1016\/j.cellsig.2019.109349","volume":"62","author":"CM Esquina","year":"2019","unstructured":"Esquina CM, et al. Intramolecular electrostatic interactions contribute to phospholipase Cbeta3 autoinhibition. Cell Signal. 2019;62.","journal-title":"Cell Signal"},{"issue":"22","key":"4023_CR41","doi-asserted-by":"publisher","first-page":"21015","DOI":"10.1074\/jbc.M412123200","volume":"280","author":"Z Kouchi","year":"2005","unstructured":"Kouchi Z, et al. The role of EF-hand domains and C2 domain in regulation of enzymatic activity of phospholipase Czeta. J Biol Chem. 2005;280(22):21015\u201321.","journal-title":"J Biol Chem"},{"issue":"1","key":"4023_CR42","doi-asserted-by":"publisher","DOI":"10.3390\/jmp7010008","volume":"7","author":"M-H Godin Pag\u00e9","year":"2026","unstructured":"Godin Pag\u00e9 M-H, et al. Validated approach for flow cytometric quantification of phospholipase C zeta (PLC\u03b6, PLCZ1) protein levels in sperm. J Mol Pathol. 2026;7(1).","journal-title":"J Mol Pathol"},{"key":"4023_CR43","doi-asserted-by":"publisher","DOI":"10.3390\/ph16030441","author":"HMR Abdulsamad","year":"2023","unstructured":"Abdulsamad HMR, et al. The therapeutic and diagnostic potential of phospholipase C zeta, oocyte activation, and calcium in treating human infertility. Pharmaceuticals (Basel). 2023. https:\/\/doi.org\/10.3390\/ph16030441.","journal-title":"Pharmaceuticals (Basel)"},{"issue":"6","key":"4023_CR44","doi-asserted-by":"publisher","first-page":"963","DOI":"10.3390\/medicina61060963","volume":"61","author":"A Kaltsas","year":"2025","unstructured":"Kaltsas A, Kyrgiafini MA, Mamuris Z, Dimitriadis F, Zachariou A, Chrisofos M, Sofikitis N. Phospholipase C\u03b6, the molecular spark of fertilization and male infertility: insights from bench to bedside. Medicina. 2025;61(6):963.","journal-title":"Medicina"}],"container-title":["Journal of Assisted Reproduction and Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10815-026-04023-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/article\/10.1007\/s10815-026-04023-9","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/link.springer.com\/content\/pdf\/10.1007\/s10815-026-04023-9.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T23:02:25Z","timestamp":1789167745000},"score":1,"resource":{"primary":{"URL":"https:\/\/link.springer.com\/10.1007\/s10815-026-04023-9"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,9,7]]},"references-count":44,"alternative-id":["4023"],"URL":"https:\/\/doi.org\/10.1007\/s10815-026-04023-9","relation":{},"ISSN":["1058-0468","1573-7330"],"issn-type":[{"value":"1058-0468","type":"print"},{"value":"1573-7330","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,9,7]]},"assertion":[{"value":"6 May 2026","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"27 August 2026","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"7 September 2026","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"12 September 2026","order":5,"name":"change_date","label":"Change Date","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Update","order":6,"name":"change_type","label":"Change Type","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The original online version of this article has been revised. The funding statement has been changed from \"Open Access funding provided by the Qatar National Library\" to \"This work was funded by a Qatar Research Development and Innovation (QRDI) NPRP-BSRA grant (NPRP-BSRA01-0504-210082) to MN\".","order":7,"name":"change_details","label":"Change Details","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"Procedures on mice were reviewed and approved by the Animal Welfare and Review Body at Cardiff University and carried out in the Biological Services Unit in the School of Biosciences at Cardiff University. They were in compliance with, and under the authority, of a UK Home Office Licence held by K.S. at Cardiff University.Procedures on mice were reviewed and approved by the Animal Welfare and Review Body at Cardiff University and carried out in the Biological Services Unit in the School of Biosciences at Cardiff University. They were in compliance with, and under the authority, of a UK Home Office Licence held by K.S. at Cardiff University.","order":1,"name":"Ethics","label":"Ethics approval and consent to participate","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"Not applicable.","order":2,"name":"Ethics","label":"Consent for publication","group":{"name":"EthicsHeading","label":"Declarations"}},{"value":"The authors declare no competing interests.","order":3,"name":"Ethics","label":"Competing interests","group":{"name":"EthicsHeading","label":"Declarations"}}]}}