{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T00:05:47Z","timestamp":1790121947651,"version":"4.0.1"},"reference-count":55,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T00:00:00Z","timestamp":1728432000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000038","name":"Natural Sciences and Engineering Research Council of Canada","doi-asserted-by":"publisher","award":["RGPIN\u20102019\u2010 06980"],"award-info":[{"award-number":["RGPIN\u20102019\u2010 06980"]}],"id":[{"id":"10.13039\/501100000038","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003151","name":"Fonds de recherche du Qu\u00e9bec \u2013 Nature et technologies","doi-asserted-by":"publisher","award":["2023-2024 - B2X \u2013 334802"],"award-info":[{"award-number":["2023-2024 - B2X \u2013 334802"]}],"id":[{"id":"10.13039\/501100003151","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec>\n                    <jats:title>Introduction<\/jats:title>\n                    <jats:p>\n                      Adrenergic receptors regulate metabolic, cardiovascular, and immunological functions in response to the sympathetic nervous system. The effect of \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      -adrenergic receptor (AR) as a high expression receptor on different subpopulations of T cells is complex and varies depending on the type of ligand and context. While traditional \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      -AR agonists generally suppress T cells, they potentially enhance IL-17A production by Th17 cells. The effects of pharmacological drugs that count as biased agonists of AR like nebivolol are not completely understood. We investigated the impact of nebivolol on human memory CD4\n                      <jats:sup>+<\/jats:sup>\n                      T (Th1, Th2, Th17) cells and polarized naive Th17 cells, highlighting its potential for IL-17A suppression via a non-canonical \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      -AR cell signaling pathway.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The effects of nebivolol were tested on healthy human peripheral blood mononuclear cells, purified memory Th cells, and polarized naive Th17 cells activated with anti-CD3\/anti-CD28\/anti-CD2 ImmunoCult reagent. IFN-\u03b3, IL-4, and IL-17A, which are primarily derived from Th1, Th2, and Th17 cells, respectively, were quantified by ELISA and flow cytometry. IL-10 was measured by ELISA. Gene expression of RORC, ADRB1, ADRB2, and ADRB3 was evaluated by qPCR. The ADRB2 gene was knocked out in memory Th cells using CRISPR\/Cas9. Protein expression of phosphorylated serine133-CREB and phosphorylated NF-\u03baB p65 was assessed by Western blot. Proliferation was assessed by fluorescent dye loading and flow cytometry.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      Nebivolol treatment decreased IL-17A and IFN-\u03b3 secretion by activated memory Th cells and elevated IL-4 levels. Nebivolol reduced the proportion of IL-17A\n                      <jats:sup>+<\/jats:sup>\n                      Th cells and downregulated RORC expression. Unlike the \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      -AR agonist terbutaline, nebivolol inhibited the shift of naive CD4\n                      <jats:sup>+<\/jats:sup>\n                      T cells toward the Th17 phenotype. IL-10 and the proliferation index remained unchanged. Nebivolol-treated \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      -knockout memory Th cells showed significant inhibition of \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      -AR-mediated signaling, evidenced by the absence of IL-17A suppression compared to controls. Phosphorylation of the NF-\u03baB p65 subunit was inhibited by nebivolol, but CREB phosphorylation was not changed, suggesting a selective transcriptional control.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>\n                      The findings demonstrate that nebivolol acts through a \u03b2\n                      <jats:sub>2<\/jats:sub>\n                      -AR-mediated signaling pathway, as a distinctive anti-inflammatory agent capable of selectively shifting Th17 cells and suppressing the phosphorylation of NF-\u03baB. This highlights nebivolol\u2019s potential for therapeutic interventions in chronic autoimmune conditions with elevated IL-17A levels.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.3389\/fimmu.2024.1446424","type":"journal-article","created":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T00:57:03Z","timestamp":1728435423000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":9,"title":["The \u03b22-adrenergic biased agonist nebivolol inhibits the development of Th17 and the response of memory Th17 cells in an NF-\u03baB-dependent manner"],"prefix":"10.3389","volume":"15","author":[{"given":"Mehri","family":"Hajiaghayi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Gholizadeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Han","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel R.","family":"Little","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Niloufar","family":"Rahbari","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Isabella","family":"Ardila","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Lopez Naranjo","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kasra","family":"Tehranimeh","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steve C. C.","family":"Shih","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter J.","family":"Darlington","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2024,10,9]]},"reference":[{"key":"B1","article-title":"The role of the sympathetic nervous system in cardiovascular disease","volume":"4","author":"Borchard","year":"2001","journal-title":"J Clin Basic Cardiol"},{"key":"B2","doi-asserted-by":"publisher","first-page":"R89","DOI":"10.1088\/1361-6579\/aa6782","article-title":"An introduction into autonomic nervous function","volume":"38","author":"Karemaker","year":"2017","journal-title":"Physiol measurement"},{"key":"B3","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/S0889-1591(02)00059-4","article-title":"Catecholamines, sympathetic innervation, and immunity","volume":"17","author":"Madden","year":"2003","journal-title":"Brain behavior immunity"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1159\/000535467.","article-title":"Sympathetic-immune interactions during different types of immune challenge","volume":"31","author":"Del Rey","year":"2023","journal-title":"Neuroimmunomodulation"},{"key":"B5","first-page":"595","article-title":"The sympathetic nerve\u2014an integrative interface between two supersystems: the brain and the immune system","volume":"52","author":"Elenkov","year":"2000","journal-title":"Pharmacol Rev"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1016\/0192-0561(92)90162-E","article-title":"Innervation of lymphoid organs and implications in development, aging, and autoimmunity","volume":"14","author":"Bellinger","year":"1992","journal-title":"Int J immunopharmacology"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2007.03.008","article-title":"Autonomic innervation and regulation of the immune system (1987\u20132007)","volume":"21","author":"Nance","year":"2007","journal-title":"Brain behavior immunity"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3390\/ijms16035635","article-title":"Molecular mechanisms underlying \u03b2-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells","volume":"16","author":"Lorton","year":"2015","journal-title":"Int J Mol Sci"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20131115","article-title":"CREB phosphorylation at Ser133 regulates transcription via distinct mechanisms downstream of cAMP and MAPK signalling","volume":"458","author":"Naqvi","year":"2014","journal-title":"Biochem J"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1002\/eji.201243005","article-title":"Beta2-adrenergic receptor signaling in CD 4+ F oxp3+ regulatory T cells enhances their suppressive function in a PKA-dependent manner","volume":"43","author":"Guereschi","year":"2013","journal-title":"Eur J Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.158.9.4200","article-title":"Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help","volume":"158","author":"Sanders","year":"1997","journal-title":"J Immunol"},{"key":"B12","doi-asserted-by":"publisher","first-page":"499","DOI":"10.1038\/gene.2015.37","article-title":"Multifaceted role of \u03b2-arrestins in inflammation and disease","volume":"16","author":"Sharma","year":"2015","journal-title":"Genes Immunity"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M506576200","article-title":"[amp]]beta;-Arrestin-dependent, G protein-independent ERK1\/2 activation by the \u03b22 adrenergic receptor","volume":"281","author":"Shenoy","year":"2006","journal-title":"J Biol Chem"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/S1097-2765(04)00216-3","article-title":"Identification of \u03b2-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-\u03baB pathways","volume":"14","author":"Gao","year":"2004","journal-title":"Mol Cell"},{"key":"B15","doi-asserted-by":"publisher","first-page":"35","DOI":"10.1016\/j.immuni.2010.07.004","article-title":"Modular utilization of distal cis-regulatory elements controls Ifng gene expression in T cells activated by distinct stimuli","volume":"33","author":"Balasubramani","year":"2010","journal-title":"Immunity"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20110462","article-title":"The Th17 immune response is controlled by the Rel\u2013ROR\u03b3\u2013ROR\u03b3T transcriptional axis","volume":"208","author":"Ruan","year":"2011","journal-title":"J Exp Med"},{"key":"B17","article-title":"Neurotransmitter receptors on lymphocytes and other lymphoid cells","volume":"1","author":"Sanders","year":"2001","journal-title":"Psychoneuroimmunology"},{"key":"B18","doi-asserted-by":"publisher","first-page":"531","DOI":"10.3390\/cells9030531","article-title":"Memory CD4+ T cells in immunity and autoimmune diseases","volume":"9","author":"Raphael","year":"2020","journal-title":"Cells"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbi.2015.01.015","article-title":"Norepinephrine preferentially modulates memory CD8 T cell function inducing inflammatory cytokine production and reducing proliferation in response to activation","volume":"46","author":"Slota","year":"2015","journal-title":"Brain behavior immunity"},{"key":"B20","doi-asserted-by":"publisher","first-page":"57","DOI":"10.1016\/j.coi.2020.09.001","article-title":"Cytokines and transcription factors in the differentiation of CD4+ T helper cell subsets and induction of tissue inflammation and autoimmunity","volume":"67","author":"Pawlak","year":"2020","journal-title":"Curr Opin Immunol"},{"key":"B21","doi-asserted-by":"crossref","DOI":"10.4049\/jimmunol.166.1.232","article-title":"IFN-\u03b3 production by Th1 cells generated from naive CD4+ T cells exposed to norepinephrine","volume":"166","author":"Swanson","year":"2001","journal-title":"J Immunol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1501206","article-title":"Norepinephrine controls effector T cell differentiation through \u03b22-adrenergic receptor\u2013mediated inhibition of NF-\u03baB and AP-1 in dendritic cells","volume":"196","author":"Takenaka","year":"2016","journal-title":"J Immunol"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2011.05.013","article-title":"[amp]]beta;2-Adrenergic agonists bias TLR-2 and NOD2 activated dendritic cells towards inducing an IL-17 immune response","volume":"55","author":"Manni","year":"2011","journal-title":"Cytokine"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1159\/000531956","article-title":"Regulation of T helper cell type 2 immune response by controlling beta-2 adrenergic receptor in dendritic cells of patients with allergic rhinitis","volume":"184","author":"Kima","year":"2023","journal-title":"Int Arch Allergy Immunol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1111\/febs.2017.284.issue-18","article-title":"Reciprocal modulation of helper Th1 and Th17 cells by the \u03b22-adrenergic receptor agonist drug terbutaline","volume":"284","author":"Carvajal Gonczi","year":"2017","journal-title":"FEBS J"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1016\/j.humimm.2023.06.007","article-title":"The \u03b22-adrenergic receptor agonist terbutaline upregulates T helper-17 cells in a protein kinase A-dependent manner","volume":"84","author":"Gonczi","year":"2023","journal-title":"Hum Immunol"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.3934\/Allergy.2021017","article-title":"Modulation of IL-17A and IFN\u03b3 by \u03b22-adrenergic agonist terbutaline and inverse-agonist nebivolol, influence of ADRB2 polymorphisms","volume":"5","author":"Gonczi","year":"2021","journal-title":"AIMS Allergy Immunol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1002\/prp2.v12.2","article-title":"Modulation of TNF-\u03b1, interleukin-6, and interleukin-10 by nebivolol\u2013valsartan and nebivolol\u2013lisinopril polytherapy in SHR rats","volume":"12","author":"Diego","year":"2024","journal-title":"Pharmacol Res Perspectives"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1016\/S0008-6363(03)00459-0","article-title":"Carvedilol, a new antioxidative \u03b2-blocker, blocks in vitro human peripheral blood T cell activation by downregulating NF-\u03baB activity","volume":"59","author":"Yang","year":"2003","journal-title":"Cardiovasc Res"},{"key":"B30","article-title":"Nebivolol in the treatment of chronic heart failure","volume":"3","author":"Veverka","year":"2007","journal-title":"Vasc Health Risk management"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0098179","article-title":"Nebivolol protects against myocardial infarction injury via stimulation of beta 3-adrenergic receptors and nitric oxide signaling","volume":"9","author":"Zhang","year":"2014","journal-title":"PloS One"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0071980","article-title":"The \u03b2-blocker nebivolol is a GRK\/\u03b2-arrestin biased agonist","volume":"8","author":"Erickson","year":"2013","journal-title":"PloS One"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1097\/00005344-198805000-00007","article-title":"Pharmacological and hemodynamic profile of nebivolol, a chemically novel, potent, and selective beta 1-adrenergic antagonist","volume":"11","author":"Van de Water","year":"1988","journal-title":"J Cardiovasc Pharmacol"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1038\/sj.bjp.0704188","article-title":"Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium","volume":"133","author":"Brixius","year":"2001","journal-title":"Br J Pharmacol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1002\/ana.23784","article-title":"Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation","volume":"73","author":"Darlington","year":"2013","journal-title":"Ann neurology"},{"key":"B36","doi-asserted-by":"publisher","first-page":"2300719","DOI":"10.1002\/admt.202300719","article-title":"A tri-droplet liquid structure for highly efficient intracellular delivery in primary mammalian cells using digital microfluidics","volume":"8","author":"Little","year":"2023","journal-title":"Advanced Materials Technologies"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1512503112","article-title":"Generation of knock-in primary human T cells using Cas9 ribonucleoproteins","volume":"112","author":"Schumann","year":"2015","journal-title":"Proc Natl Acad Sci"},{"key":"B38","first-page":"199","article-title":"Regulation of transcription and gene expression in eukaryotes","volume":"1","author":"Phillips","year":"2008","journal-title":"Nat Education"},{"key":"B39","doi-asserted-by":"publisher","first-page":"195","DOI":"10.1016\/j.bbi.2011.08.001","article-title":"The beta2-adrenergic receptor on T and B lymphocytes: do we understand it yet","volume":"26","author":"Sanders","year":"2012","journal-title":"Brain behavior Immun"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1097\/01.fjc.0000238593.67191.e2","article-title":"Effect of nebivolol on endothelial nitric oxide and peroxynitrite release in hypertensive animals: role of antioxidant activity","volume":"48","author":"Mason","year":"2006","journal-title":"J Cardiovasc Pharmacol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0326-5","article-title":"Reprogramming human T cell function and specificity with non-viral genome targeting","volume":"559","author":"Roth","year":"2018","journal-title":"Nature"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.6.3223","article-title":"Agonist regulation of human \u03b22-adrenergic receptor mRNA stability occurs via a specific AU-rich element","volume":"273","author":"Danner","year":"1998","journal-title":"J Biol Chem"},{"key":"B43","doi-asserted-by":"publisher","first-page":"3262","DOI":"10.1038\/s41598-017-03646-4","article-title":"Benzo (a) pyrene triggers desensitization of \u03b22-adrenergic pathway","volume":"7","author":"Mayati","year":"2017","journal-title":"Sci Rep"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1016\/S0898-6568(03)00099-8","article-title":"Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases","volume":"15","author":"Penela","year":"2003","journal-title":"Cell signalling"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001829","article-title":"The role of the transcription factor CREB in immune function","volume":"185","author":"Wen","year":"2010","journal-title":"J Immunol"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1523\/JNEUROSCI.2985-10.2010","article-title":"Norepinephrine promotes microglia to uptake and degrade amyloid \u03b2 peptide through upregulation of mouse formyl peptide receptor 2 and induction of insulin-degrading enzyme","volume":"30","author":"Kong","year":"2010","journal-title":"J Neurosci"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.168.12.6314","article-title":"B cell receptor-and \u03b22-adrenergic receptor-induced regulation of B7-2 (CD86) expression in B cells","volume":"168","author":"Kohm","year":"2002","journal-title":"J Immunol"},{"key":"B48","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1141712","article-title":"Adrenergic receptor signaling regulates the CD40-receptor mediated anti-tumor immunity","volume":"14","author":"Singh","year":"2023","journal-title":"Front Immunol"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1936664100","article-title":"[amp]]beta;-Arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors","volume":"100","author":"Azzi","year":"2003","journal-title":"Proc Natl Acad Sci"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1124\/mol.117.110890","article-title":"Biased agonism in drug discovery\u2014is it too soon to choose a path","volume":"93","author":"Michel","year":"2018","journal-title":"Mol Pharmacol"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.2174\/13816128113199990550","article-title":"Action and disposition of the \u03b23-agonist nebivolol in the presence of inflammation; an alternative to conventional \u03b21-blockers","volume":"20","author":"Sanaee","year":"2014","journal-title":"Curr Pharm Design"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.54133\/ajms.v6i1.527","article-title":"Histopathological and immunological effects of nebivolol 5% Topical cream in mice model of imiquimod-induced psoriasis","volume":"6","author":"Mahdi","year":"2024","journal-title":"Al-Rafidain J Med Sci (ISSN 2789-3219)"},{"key":"B53","doi-asserted-by":"publisher","first-page":"892","DOI":"10.1016\/j.immuni.2019.03.021","article-title":"The IL-17 family of cytokines in health and disease","volume":"50","author":"McGeachy","year":"2019","journal-title":"Immunity"},{"key":"B54","doi-asserted-by":"publisher","first-page":"5","DOI":"10.1016\/j.cyto.2014.09.011","article-title":"T cell subsets and their signature cytokines in autoimmune and inflammatory diseases","volume":"74","author":"Raphael","year":"2015","journal-title":"Cytokine"},{"key":"B55","doi-asserted-by":"publisher","first-page":"797","DOI":"10.1016\/j.jaci.2016.11.045","article-title":"Recognition of viral and self-antigens by TH1 and TH1\/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses","volume":"140","author":"Paroni","year":"2017","journal-title":"J Allergy Clin Immunol"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1446424\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,10,9]],"date-time":"2024-10-09T00:57:06Z","timestamp":1728435426000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2024.1446424\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,10,9]]},"references-count":55,"alternative-id":["10.3389\/fimmu.2024.1446424"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2024.1446424","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/2024.09.08.611829","asserted-by":"object"}]},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,10,9]]},"article-number":"1446424"}}