{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T21:02:18Z","timestamp":1792789338157,"version":"4.5.0"},"reference-count":56,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T00:00:00Z","timestamp":1651622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"the Target2B consortium"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Animal models of autoimmunity and human genetic association studies indicate that the dysregulation of B-cell receptor (BCR) signaling is an important driver of autoimmunity. We previously showed that in circulating B cells from primary Sj\u00f6gren\u2019s syndrome (pSS) patients with high systemic disease activity, protein expression of the BCR signaling molecule Bruton\u2019s tyrosine kinase (BTK) was increased and correlated with T-cell infiltration in the target organ. We hypothesized that these alterations could be driven by increased B-cell activating factor (BAFF) levels in pSS. Here, we investigated whether altered BCR signaling was already present at diagnosis and distinguished pSS from non-SS sicca patients. Using (phospho-)flow cytometry, we quantified the phosphorylation of BCR signaling molecules, and investigated BTK and BAFF receptor (BAFFR) expression in circulating B cell subsets in an inception cohort of non-SS sicca and pSS patients, as well as healthy controls (HCs). We found that both BTK protein levels and BCR signaling activity were comparable among groups. Interestingly, BAFFR expression was significantly downregulated in pSS, but not in non-SS sicca patients, compared with HCs, and correlated with pSS-associated alterations in B cell subsets. These data indicate reduced BAFFR expression as a possible sign of early B cell involvement and a diagnostic marker for pSS.<\/jats:p>","DOI":"10.3390\/ijms23095101","type":"journal-article","created":{"date-parts":[[2022,5,4]],"date-time":"2022-05-04T08:21:25Z","timestamp":1651652485000},"page":"5101","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Decreased BAFF Receptor Expression and Unaltered B Cell Receptor Signaling in Circulating B Cells from Primary Sj\u00f6gren\u2019s Syndrome Patients at Diagnosis"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2083-6820","authenticated-orcid":false,"given":"Stefan F. H.","family":"Neys","sequence":"first","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gwenny M.","family":"Verstappen","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hendrika","family":"Bootsma","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3660-0617","authenticated-orcid":false,"given":"Frans G. M.","family":"Kroese","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rudi W.","family":"Hendriks","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Odilia B. J.","family":"Corneth","sequence":"additional","affiliation":[{"name":"Department of Pulmonary Medicine, Erasmus MC University Medical Center, 3015 GD Rotterdam, The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,5,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"668131","DOI":"10.3389\/fcell.2021.668131","article-title":"Targeting Bruton\u2019s Tyrosine Kinase in Inflammatory and Autoimmune Pathologies","volume":"9","author":"Neys","year":"2021","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"3744","DOI":"10.1182\/blood-2011-12-397919","article-title":"Btk levels set the threshold for B-cell activation and negative selection of autoreactive B cells in mice","volume":"119","author":"Kil","year":"2012","journal-title":"Blood"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1038\/gene.2009.19","article-title":"Genetic associations of LYN with systemic lupus erythematosus","volume":"10","author":"Lu","year":"2009","journal-title":"Genes Immun."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1038\/gene.2012.46","article-title":"Meta-analysis reveals an association of PTPN22 C1858T with autoimmune diseases, which depends on the localization of the affected tissue","volume":"13","author":"Zheng","year":"2012","journal-title":"Genes Immun."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"4021","DOI":"10.1093\/hmg\/ddt248","article-title":"A systemic sclerosis and systemic lupus erythematosus pan-meta-GWAS reveals new shared susceptibility loci","volume":"22","author":"Martin","year":"2013","journal-title":"Hum. Mol. Genet."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"756","DOI":"10.1016\/j.autrev.2014.02.002","article-title":"Genome-wide association studies in Sj\u00f6gren\u2019s syndrome: What do the genes tell us about disease pathogenesis?","volume":"13","author":"Burbelo","year":"2014","journal-title":"Autoimmun. Rev."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2201","DOI":"10.1038\/s41467-019-10242-9","article-title":"Functional rare and low frequency variants in BLK and BANK1 contribute to human lupus","volume":"10","author":"Jiang","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/art.40059","article-title":"Enhanced Bruton\u2019s Tyrosine Kinase Activity in Peripheral Blood B Lymphocytes From Patients With Autoimmune Disease","volume":"69","author":"Corneth","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2230","DOI":"10.1093\/rheumatology\/kez205","article-title":"Evidence for enhanced Bruton\u2019s tyrosine kinase activity in transitional and na\u00efve B cells of patients with granulomatosis with polyangiitis","volume":"58","author":"Abdulahad","year":"2019","journal-title":"Rheumatology (Oxford)"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1038\/s41584-021-00605-2","article-title":"Epithelial\u2013immune cell interplay in primary Sj\u00f6gren syndrome salivary gland pathogenesis","volume":"17","author":"Verstappen","year":"2021","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nrrheum.2018.1","article-title":"B cells in the pathogenesis of primary Sj\u00f6gren syndrome","volume":"14","author":"Nocturne","year":"2018","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1172\/JCI0214121","article-title":"Association of BAFF\/BLyS overexpression and altered B cell differentiation with Sj\u00f6gren\u2019s syndrome","volume":"109","author":"Groom","year":"2002","journal-title":"J. Clin. Investig."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"600","DOI":"10.1007\/s10875-004-6240-7","article-title":"Programmed cell death of peripheral blood B cells determined by laser scanning cytometry in Sj\u00f6gren\u2019s syndrome with a special emphasis on BAFF","volume":"24","author":"Szodoray","year":"2004","journal-title":"J. Clin. Immunol."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"34","DOI":"10.1196\/annals.1313.004","article-title":"BAFF overexpression is associated with autoantibody production in autoimmune diseases","volume":"1050","author":"Pers","year":"2005","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1136\/ard.62.2.168","article-title":"The level of BLyS (BAFF) correlates with the titre of autoantibodies in human Sj\u00f6gren\u2019s syndrome","volume":"62","author":"Mariette","year":"2003","journal-title":"Ann. Rheum. Dis."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"496","DOI":"10.1002\/path.1533","article-title":"Expression of BAFF (BLyS) in T cells infiltrating labial salivary glands from patients with Sj\u00f6gren\u2019s syndrome","volume":"202","author":"Lavie","year":"2004","journal-title":"J. Pathol."},{"key":"ref_17","first-page":"259","article-title":"BAFF\/APRIL pathway in Sj\u00f6gren syndrome and systemic lupus erythematosus: Relationship with chronic inflammation and disease activity","volume":"62","author":"Vadacca","year":"2010","journal-title":"Reumatismo"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"131","DOI":"10.55563\/clinexprheumatol\/fp741f","article-title":"Serum CXCL13, BAFF, IL-21 and IL-22 levels are related to disease activity and lymphocyte profile in primary Sj\u00f6gren\u2019s syndrome","volume":"39","author":"Palacio","year":"2021","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"785","DOI":"10.1016\/j.immuni.2004.05.010","article-title":"Excess BAFF Rescues Self-Reactive B Cells from Peripheral Deletion and Allows Them to Enter Forbidden Follicular and Marginal Zone Niches","volume":"20","author":"Thien","year":"2004","journal-title":"Immunity"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"5820","DOI":"10.4049\/jimmunol.170.12.5820","article-title":"Cutting edge: B cell receptor signals regulate BLyS receptor levels in mature B cells and their immediate progenitors","volume":"170","author":"Smith","year":"2003","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1379","DOI":"10.1038\/ni.1666","article-title":"Tonic B cell antigen receptor signals supply an NF-kappaB substrate for prosurvival BLyS signaling","volume":"9","author":"Stadanlick","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"3872","DOI":"10.4049\/jimmunol.179.6.3872","article-title":"Bruton\u2019s tyrosine kinase mediates NF-kappa B activation and B cell survival by B cell-activating factor receptor of the TNF-R family","volume":"179","author":"Shinners","year":"2007","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"475","DOI":"10.1016\/j.immuni.2012.11.015","article-title":"The BAFF Receptor Transduces Survival Signals by Co-opting the B Cell Receptor Signaling Pathway","volume":"38","author":"Schweighoffer","year":"2013","journal-title":"Immunity"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1103","DOI":"10.1136\/ard.2009.110619","article-title":"EULAR Sj\u00f6gren\u2019s syndrome disease activity index: Development of a consensus systemic disease activity index for primary Sj\u00f6gren\u2019s syndrome","volume":"69","author":"Seror","year":"2010","journal-title":"Ann. Rheum. Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"822","DOI":"10.1126\/science.271.5250.822","article-title":"Activation of BTK by a phosphorylation mechanism initiated by SRC family kinases","volume":"271","author":"Rawlings","year":"1996","journal-title":"Science"},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"2203","DOI":"10.1002\/art.40215","article-title":"Defective Early B Cell Tolerance Checkpoints in Sjogren\u2019s Syndrome Patients","volume":"69","author":"Glauzy","year":"2017","journal-title":"Arthritis Rheumatol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"90","DOI":"10.1111\/imr.12821","article-title":"Impaired B-cell tolerance checkpoints promote the development of autoimmune diseases and pathogenic autoantibodies","volume":"292","author":"Meffre","year":"2019","journal-title":"Immunol. Rev."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2160","DOI":"10.1002\/art.10445","article-title":"Diminished peripheral blood memory B cells and accumulation of memory B cells in the salivary glands of patients with Sj\u00f6gren\u2019s syndrome","volume":"46","author":"Hansen","year":"2002","journal-title":"Arthritis Rheum."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"3610","DOI":"10.4049\/jimmunol.167.7.3610","article-title":"Bm1-Bm5 classification of peripheral blood B cells reveals circulating germinal center founder cells in healthy individuals and disturbance in the B cell subpopulations in patients with primary Sj\u00f6gren\u2019s syndrome","volume":"167","author":"Bohnhorst","year":"2001","journal-title":"J. Immunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2558","DOI":"10.1002\/art.38734","article-title":"Primary Sj\u00f6gren\u2019s syndrome is characterized by distinct phenotypic and transcriptional profiles of IgD+ unswitched memory B cells","volume":"66","author":"Roberts","year":"2014","journal-title":"Arthritis Rheumatol. (Hoboken NJ)"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1897","DOI":"10.1002\/art.20276","article-title":"Abnormalities in peripheral B cell memory of patients with primary Sj\u00f6gren\u2019s syndrome","volume":"50","author":"Hansen","year":"2004","journal-title":"Arthritis Rheum."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1809","DOI":"10.1016\/j.jaci.2016.01.024","article-title":"Cytometry by time-of-flight immunophenotyping identifies a blood Sj\u00f6gren\u2019s signature correlating with disease activity and glandular inflammation","volume":"137","author":"Mingueneau","year":"2016","journal-title":"J. Allergy Clin. Immunol."},{"key":"ref_33","first-page":"76","article-title":"A comprehensive investigation on the distribution of circulating follicular T helper cells and B cell subsets in primary Sj\u00f6gren\u2019s syndrome and systemic lupus erythematosus","volume":"183","author":"Papp","year":"2016","journal-title":"Clin. Exp. Immunol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Corsiero, E., Sutcliffe, N., Pitzalis, C., and Bombardieri, M. (2014). Accumulation of Self-Reactive Na\u00efve and Memory B Cell Reveals Sequential Defects in B Cell Tolerance Checkpoints in Sj\u00f6gren\u2019s Syndrome. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0114575"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1007\/s00296-018-4018-0","article-title":"Association between memory B-cells and clinical and immunological features of primary Sj\u00f6gren\u2019s syndrome and Sicca patients","volume":"38","author":"Barcelos","year":"2018","journal-title":"Rheumatol. Int."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1488","DOI":"10.1093\/rheumatology\/keu532","article-title":"Amplification of IL-21 signalling pathway through Bruton\u2019s tyrosine kinase in human B cell activation","volume":"54","author":"Wang","year":"2015","journal-title":"Rheumatology (Oxford)."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2136","DOI":"10.3389\/fimmu.2019.02136","article-title":"Identification and Characterization of Post-activated B Cells in Systemic Autoimmune Diseases","volume":"10","author":"Szelinski","year":"2019","journal-title":"Front. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1313","DOI":"10.1002\/1529-0131(200106)44:6<1313::AID-ART223>3.0.CO;2-S","article-title":"Elevated serum B lymphocyte stimulator levels in patients with systemic immune-based rheumatic diseases","volume":"44","author":"Cheema","year":"2001","journal-title":"Arthritis Rheum."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1136\/ard.2006.065656","article-title":"Decreased B cell activating factor receptor expression on peripheral lymphocytes associated with increased disease activity in primary Sj\u00f6gren\u2019s syndrome and systemic lupus erythematosus","volume":"66","author":"Sellam","year":"2007","journal-title":"Ann. Rheum. Dis."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1078","DOI":"10.1002\/art.40016","article-title":"Scleroderma Peripheral B Lymphocytes Secrete Interleukin-6 and Transforming Growth Factor \u03b2 and Activate Fibroblasts","volume":"69","author":"Dumoitier","year":"2017","journal-title":"Arthritis Rheumatol. (Hoboken NJ)"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3943","DOI":"10.1002\/art.21489","article-title":"Expression and occupancy of BAFF-R on B cells in systemic lupus erythematosus","volume":"52","author":"Carter","year":"2005","journal-title":"Arthritis Rheum."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"441","DOI":"10.1016\/S1074-7613(04)00079-2","article-title":"Reduced Competitiveness of Autoantigen-Engaged B Cells due to Increased Dependence on BAFF","volume":"20","author":"Lesley","year":"2004","journal-title":"Immunity"},{"key":"ref_43","first-page":"415","article-title":"Compartmentalization of TNF receptor 1 signaling: Internalized TNF receptosomes as death signaling vesicles","volume":"21","author":"Tchikov","year":"2004","journal-title":"Immunity"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"2189","DOI":"10.1016\/j.celrep.2017.02.005","article-title":"BAFF- and TACI-Dependent Processing of BAFFR by ADAM Proteases Regulates the Survival of B Cells","volume":"18","author":"Smulski","year":"2017","journal-title":"Cell Rep."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2744","DOI":"10.1182\/blood-2007-03-081232","article-title":"BAFF enhances chemotaxis of primary human B cells: A particular synergy between BAFF and CXCL13 on memory B cells","volume":"111","author":"Badr","year":"2008","journal-title":"Blood"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"18","DOI":"10.1111\/j.1365-3083.2010.02475.x","article-title":"Phenotypic diversity of peripheral blood plasma cells in primary Sj\u00f6gren\u2019s syndrome","volume":"73","author":"Szyszko","year":"2011","journal-title":"Scand. J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"526","DOI":"10.1136\/annrheumdis-2013-203991","article-title":"Efficacy and safety of belimumab in primary Sj\u00f6gren\u2019s syndrome: Results of the BELISS open-label phase II study","volume":"74","author":"Mariette","year":"2015","journal-title":"Ann. Rheum. Dis."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"641","DOI":"10.1136\/annrheumdis-2018-214720","article-title":"Treatment of primary Sjogren\u2019s syndrome with ianalumab (VAY736) targeting B cells by BAFF receptor blockade coupled with enhanced, antibody-dependent cellular cytotoxicity","volume":"78","author":"Dorner","year":"2019","journal-title":"Ann. Rheum. Dis."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"161","DOI":"10.1016\/S0140-6736(21)02251-0","article-title":"Safety and efficacy of subcutaneous ianalumab (VAY736) in patients with primary Sj\u00f6gren\u2019s syndrome: A randomised, double-blind, placebo-controlled, phase 2b dose-finding trial","volume":"399","author":"Bowman","year":"2022","journal-title":"Lancet"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1007\/s40265-021-01592-0","article-title":"Bruton\u2019s Tyrosine Kinase Inhibition as an Emerging Therapy in Systemic Autoimmune Disease","volume":"81","author":"Neys","year":"2021","journal-title":"Drugs"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Price, E., Bombardieri, M., Kivitz, A., Matzkies, F., Gurtovaya, O., Pechonkina, A., Jiang, W., Downie, B., Mathur, A., and Mozaffarian, A. (2022). Safety and efficacy of filgotinib, lanraplenib and tirabrutinib in Sj\u00f6gren\u2019s syndrome: A randomized, phase 2, double-blind, placebo-controlled study. Rheumatology, keac167.","DOI":"10.1093\/rheumatology\/keac167"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"44","DOI":"10.1016\/j.jim.2016.03.001","article-title":"Comparison of antibody assays for detection of autoantibodies to Ro 52, Ro 60 and La associated with primary Sj\u00f6gren\u2019s syndrome","volume":"433","author":"Trier","year":"2016","journal-title":"J. Immunol. Methods"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"102439","DOI":"10.1016\/j.jaut.2020.102439","article-title":"Gene expression profiling of epithelium-associated FcRL4(+) B cells in primary Sj\u00f6gren\u2019s syndrome reveals a pathogenic signature","volume":"109","author":"Verstappen","year":"2020","journal-title":"J. Autoimmun."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1136\/annrheumdis-2016-210571","article-title":"2016 American College of Rheumatology\/European League Against Rheumatism classification criteria for primary Sj\u00f6gren\u2019s syndrome","volume":"76","author":"Shiboski","year":"2017","journal-title":"Ann. Rheum. Dis."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"e3902","DOI":"10.21769\/BioProtoc.3902","article-title":"A Versatile Protocol to Quantify BCR-mediated Phosphorylation in Human and Murine B Cell Subpopulations","volume":"11","author":"Rip","year":"2021","journal-title":"Bio-Protocol"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"2852","DOI":"10.4049\/jimmunol.1901117","article-title":"Phosphoflow Protocol for Signaling Studies in Human and Murine B Cell Subpopulations","volume":"204","author":"Rip","year":"2020","journal-title":"J. Immunol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5101\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T23:05:53Z","timestamp":1760137553000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/9\/5101"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,5,4]]},"references-count":56,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2022,5]]}},"alternative-id":["ijms23095101"],"URL":"https:\/\/doi.org\/10.3390\/ijms23095101","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,5,4]]}}}