{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,24]],"date-time":"2026-07-24T23:42:42Z","timestamp":1784936562199,"version":"3.55.0"},"reference-count":58,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2023,7,14]],"date-time":"2023-07-14T00:00:00Z","timestamp":1689292800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Placental trophoblasts contribute to regulatory T (Treg) function <jats:italic>via<\/jats:italic> the programmed cell death-1 (PD-1)\/PD-1 ligand 1 (PD-L1) pathway during normal pregnancy. Decreased expression of PD-L1 in trophoblasts was closely associated with Treg deficiency in the development of pregnancy failure. Thus, targeting PD-L1 might be a novel therapy to prevent pregnancy loss. However, the mechanisms for modulating the expression of PD-L1 in trophoblasts are an enigma.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>The proportion of decidual Treg cells, and the profile of decidual macrophages (DMs) sampled from women with normal pregnancy (NP) and recurrent miscarriage (RM) were evaluated by flow cytometry. The expression of Yin and Yang 1 protein (YY1) and PD-L1 in human villous were measured by Immunohistochemistry (IHC), qRT-PCR and western blot. The determination of soluble PD-L1 (sPD-L1) in serum from NP and RM, and trophoblast conditioned media (TCM) was performed by the PD-L1 SimpleStep ELISA kit. Knockdown of YY1 was processed in the human trophoblast derived cell lines, HTR-8 and Bewo, with siYY1 transfection. Peripheral na\u00efve CD4<jats:sup>+<\/jats:sup> T cells were isolated from women with NP for the <jats:italic>in vitro<\/jats:italic> culture. The percentages of Treg cells differentiated from peripheral na\u00efve CD4<jats:sup>+<\/jats:sup> T cells were measured by flow cytometry. The interaction between YY1 and <jats:italic>CD274<\/jats:italic> was proved by CHIP. The expression of inducible nitric oxide synthase (iNOS) in decidua was evaluated by IHC. The level of NO in serum from women with NP and RM was determined by the Griess reagent system. The effects of NO on YY1 were determined by the <jats:italic>in vitro<\/jats:italic> culture of HTR-8 cells with the NO donor, SNAP. The <jats:italic>in vivo<\/jats:italic> model comprising twelve pregnant mice and underwent different treatment. The percentages of Treg cells in murine uterus were measured by flow cytometry. Similarly, Western blot and IHC were performed to determine the expression of YY1 and PD-L1 in murine placenta.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Decreased expression of YY1 and PD-L1 in trophoblasts and lower proportion of decidual Treg cells were observed in patients with RM. Knockdown of YY1 contributes to a lower expression of YY1 and PD-L1. Soluble PD-L1 in the supernatant from HTR-8 cells was also decreased with siYY1 administration. Lower Treg differentiation was observed in the presence of supernatant from HTR-8 cells treated with siYY1. CHIP analysis revealed that endogenous YY1 directly occupied the promoter region of the <jats:italic>CD274<\/jats:italic> (PD-L1) gene. Accompanied with increased M1 DMs, higher NO was observed in serum sampled from patients with RM. In the presence of Reduced expression of YY1 and PD-L1 was observed in HTR-8 cells with the treatment of SNAP. Furthermore, less Treg differentiation was observed with SNAP treated TCM. Moreover, our <jats:italic>in vivo<\/jats:italic> data found that YY1 deficiency was associated with decreased PD-L1, which further resulting in less Treg differentiation and Treg deficiency at the maternal-fetal interface and increased embryo loss.<\/jats:p><\/jats:sec><jats:sec><jats:title>Discussion<\/jats:title><jats:p>Our work found the modulatory capacity of YY1 on PD-L1 in trophoblasts during early pregnancy. Furthermore, reduced YY1 was supposed resulting from higher levels of NO produced from the M1 DMs in RM.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2023.1180154","type":"journal-article","created":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T03:04:02Z","timestamp":1689390242000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":20,"title":["Decidual macrophages derived NO downregulates PD-L1 in trophoblasts leading to decreased Treg cells in recurrent miscarriage"],"prefix":"10.3389","volume":"14","author":[{"given":"Yonghong","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Huiyan","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Panpan","family":"Qiu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingwen","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuhong","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jie","family":"Mei","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixiang","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2023,7,14]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1038\/nri.2017.64","article-title":"The unique immunological and microbial aspects of pregnancy","volume":"17","author":"Mor","year":"2017","journal-title":"Nat Rev Immunol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1093\/molehr\/gal032","article-title":"Primary unexplained infertility is associated with reduced expression of the T-regulatory cell transcription factor Foxp3 in endometrial tissue","volume":"12","author":"Jasper","year":"2006","journal-title":"Mol Hum Reprod"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/der301","article-title":"An imbalance in interleukin-17-producing T and Foxp3(+) regulatory T cells in women with idiopathic recurrent pregnancy loss","volume":"26","author":"Lee","year":"2011","journal-title":"Hum Reprod"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1016\/j.placenta.2017.07.012","article-title":"Global pregnancy collaboration symposium: prepregnancy and very early pregnancy antecedents of adverse pregnancy outcomes: overview and recommendations","volume":"60","author":"Roberts","year":"2017","journal-title":"Placenta"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2249.2007.03397.x","article-title":"Proportion of peripheral blood and decidual CD4(+) CD25(bright) regulatory T cells in pre-eclampsia","volume":"149","author":"Sasaki","year":"2007","journal-title":"Clin Exp Immunol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.0901154","article-title":"Systemic increase in the ratio between Foxp3+ and IL-17-producing CD4+ T cells in healthy pregnancy but not in preeclampsia","volume":"183","author":"Santner-Nanan","year":"2009","journal-title":"J Immunol"},{"key":"B7","doi-asserted-by":"publisher","first-page":"185","DOI":"10.1146\/annurev-pathmechdis-012418-012743","article-title":"Immunological basis for recurrent fetal loss and pregnancy complications","volume":"14","author":"Deshmukh","year":"2019","journal-title":"Annu Rev Pathol"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2008.05.009","article-title":"Regulatory T cells and immune tolerance","volume":"133","author":"Sakaguchi","year":"2008","journal-title":"Cell"},{"key":"B9","doi-asserted-by":"publisher","first-page":"44","DOI":"10.1111\/j.1600-0897.2011.01046.x","article-title":"Maternal Foxp3 expressing CD4+ CD25+ and CD4+ CD25- regulatory T-cell populations are enriched in human early normal pregnancy decidua: a phenotypic study of paired decidual and peripheral blood samples","volume":"66","author":"Dimova","year":"2011","journal-title":"Am J Repod Immunol"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1038\/nature04753","article-title":"Reciprocal developmental pathways for the generation of pathogenic effector TH17 and regulatory T cells","volume":"441","author":"Bettelli","year":"2006","journal-title":"Nature"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2020.01898","article-title":"Altered levels of decidual immune cell subsets in fetal growth restriction, stillbirth, and placental pathology","volume":"11","author":"Bezemer","year":"2020","journal-title":"Front Immunol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2020.103105","article-title":"Recurrent miscarriages and the association with regulatory T cells; a systematic review","volume":"139","author":"Keller","year":"2020","journal-title":"J Reprod Immunol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0897.2010.00836.x","article-title":"The immune system in pregnancy: a unique complexity","volume":"63","author":"Mor","year":"2010","journal-title":"Am J Reprod Immunol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1038\/srep27683","article-title":"The PD-1\/PD-L1 inhibitory pathway is altered in pre-eclampsia and regulates T cell responses in pre-eclamptic rats","volume":"6","author":"Tian","year":"2016","journal-title":"Sci Rep"},{"key":"B15","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1093\/humrep\/dey347","article-title":"The role of the PD-1\/PD-L1 axis in macrophage differentiation and function during pregnancy","volume":"34","author":"Zhang","year":"2019","journal-title":"Hum Reprod"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.164.12.6166","article-title":"Hill AM. m-1\/M-2 macrophages and the Th1\/Th2 paradigm","volume":"164","author":"Mills","year":"2000","journal-title":"J Immunol"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1016\/j.it.2004.09.015","article-title":"The chemokine system in diverse forms of macrophage activation and polarization","volume":"25","author":"Mantovani","year":"2004","journal-title":"Trends Immunol"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1530\/REP-12-0036","article-title":"V-ATPase upregulation during early pregnancy: a possible link to establishment of an inflammatory response during preimplantation period of pregnancy","volume":"143","author":"Jaiswal","year":"2012","journal-title":"Reprod"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/sj.cr.7290133","article-title":"The role of nitric oxide in cancer","volume":"12","author":"Xu","year":"2002","journal-title":"Cell Res"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1177\/0300060520905985","article-title":"The regulation of nitric oxide in tumor progression and therapy","volume":"48","author":"Hu","year":"2020","journal-title":"J Int Med Res"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1016\/j.redox.2015.08.013","article-title":"Nitric oxide-mediated sensitization of resistant tumor cells to apoptosis by chemo-immunotherapeutics","volume":"6","author":"Bonavida","year":"2015","journal-title":"Redox Biol"},{"key":"B22","doi-asserted-by":"publisher","first-page":"10","DOI":"10.1016\/j.drup.2019.04.001","article-title":"YY1 regulates cancer cell immune resistance by modulating PD-L1 expression","volume":"43","author":"Hays","year":"2019","journal-title":"Drug Resist Update"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1101\/gad.1559007","article-title":"YY1 helps to bring loose ends together","volume":"21","author":"Calame","year":"2007","journal-title":"Genes Dev"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1209080","article-title":"Transcription factor YY1: structure, function, and therapeutic implications in cancer biology","volume":"25","author":"Gordon","year":"2006","journal-title":"Oncogene"},{"key":"B25","doi-asserted-by":"publisher","first-page":"36","DOI":"10.1002\/path.4694","article-title":"The YY1\/MMP2 axis promotes trophoblast invasion at the maternal-fetal interface","volume":"239","author":"Tian","year":"2016","journal-title":"J Pathol"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1093\/humrep\/dey347","article-title":"The altered PD-1\/PD-L1 pathway delivers the 'one-two punch' effects to promote the Treg\/Th17 imbalance in pre-eclampsia","volume":"15","author":"Zhang","year":"2017","journal-title":"Cell Mol Immunol"},{"key":"B27","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1016\/j.apsb.2021.07.016","article-title":"Abrogation of HnRNP l enhances anti-PD-1 therapy efficacy via diminishing PD-L1 and promoting CD8(+) T cell-mediated ferroptosis in castration-resistant prostate cancer","volume":"12","author":"Zhou","year":"2022","journal-title":"Acta Pharm Sin B"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.154.9.4261","article-title":"IL-10 prevents naturally occurring fetal loss in the CBA x DBA\/2 mating combination, and local defect in IL-10 production in this abortion-prone combination is corrected by in vivo injection of IFN-tau","volume":"154","author":"Chaouat","year":"1995","journal-title":"J Immunol"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-020-03071-0","article-title":"RANK links thymic regulatory T cells to fetal loss and gestational diabetes in pregnancy","volume":"589","author":"Paolino","year":"2021","journal-title":"Nature"},{"key":"B30","doi-asserted-by":"publisher","first-page":"103746","DOI":"10.1016\/j.jri.2022.103746","article-title":"Decidual dendritic cells 10 and CD4+CD25+Foxp3 regulatory T cell in preeclampsia and their colleration with nutritional factors in pathomechanism of immune rejection in pregnancy","volume":"154","author":"Silalahi","year":"2022","journal-title":"J Reprod Immunol"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jri.2018.12.002","article-title":"Effect of adoptive transfer of CD4+CD25+Foxp3+Treg induced by trichostatin a on the prevention of spontaneous abortion","volume":"131","author":"Wang","year":"2019","journal-title":"J Reprod Immunol"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.18502\/ijaai.v17i6.618","article-title":"Altered frequencies of CD4+CD25+Foxp3+ and CD8+CD25+Foxp3+ regulatory T cells in pre-clampsia","volume":"17","author":"Zare","year":"2018","journal-title":"Iran J Allergy Asthma Immunol"},{"key":"B33","doi-asserted-by":"publisher","first-page":"300060520980940","DOI":"10.1177\/0300060520980940","article-title":"CD4+CD25+Foxp3+ regulatory T cells regulate immune balance in unexplained recurrent spontaneous abortion via the toll-like receptor 4\/nuclear factor-\u03baB pathway","volume":"48","author":"Qin","year":"2020","journal-title":"J Int Med Res"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13541","article-title":"Progesterone modulates CD4+CD25+Foxp3+ regulatory T cells and TGF-\u03b21 in the maternal-fetal interface of the late pregnant mouse","volume":"88","author":"Yang","year":"2022","journal-title":"Am J Reprod Immunol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0124747","article-title":"Peripheral dendritic cells and CD4+CD25+Foxp3+ regulatory T cells in the first trimester of normal pregnancy and in women with recurrent miscarriage","volume":"10","author":"Kwiatek","year":"2015","journal-title":"PloS One"},{"key":"B36","doi-asserted-by":"publisher","first-page":"46","DOI":"10.1016\/j.molmed.2016.11.001","article-title":"Co-Signaling molecules in maternal-fetal immunity","volume":"23","author":"Xu","year":"2017","journal-title":"Trends Mol Med"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1203425","article-title":"Embryonic trophoblasts induce decidual regulatory T cell differentiation and maternal-fetal tolerance through thymic stromal lymphopoietin instructing dendritic cells","volume":"192","author":"Du","year":"2014","journal-title":"J Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1590\/1414-431x20187334","article-title":"PD-1\/PD-L1 regulates treg differentiation in pregnancy-induced hypertension","volume":"51","author":"Jiang","year":"2018","journal-title":"Braz J Med Biol Res"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13519","article-title":"Soluble PD-L1 and B7-H4 serum levels during the course of physiological pregnancy","volume":"87","author":"Mach","year":"2022","journal-title":"Am J Reprod Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00086","article-title":"Elevated soluble PD-L1 in pregnant women's serum suppresses the immune reaction","volume":"10","author":"Okuyama","year":"2019","journal-title":"Front Immunol"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12795","article-title":"Immune checkpoint molecules soluble program death ligand 1 and galectin-9 are increased in pregnancy","volume":"79","author":"Enninga","year":"2018","journal-title":"Am J Reprod Immunol"},{"key":"B42","doi-asserted-by":"publisher","first-page":"DMD","DOI":"10.1124\/dmd.123.001345","article-title":"Characterization of xenobiotic and steroid disposition potential of human placental tissue and cell lines (BeWo, JEG-3, JAR, and HTR-8\/SVneo) by quantitative proteomics","volume":"10","author":"Kruger","year":"2023","journal-title":"Drug Metab Dispos"},{"key":"B43","doi-asserted-by":"publisher","first-page":"77","DOI":"10.3181\/00379727-102-25149","article-title":"Choriocarcinoma of women maintained in serial passage in hamster and rat","volume":"102","author":"Hertz","year":"1959","journal-title":"Proc Soc Exp Biol Med"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1210\/jcem-32-5-683","article-title":"Isolation of hormone-producing clonal lines of human choriocarcinoma","volume":"32","author":"Kohler","year":"1971","journal-title":"J Clin Endocrinol Metab"},{"key":"B45","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.placenta.2010.10.010","article-title":"Genome-wide expression profile of first trimester villous and extravillous human trophoblast cells","volume":"32","author":"Apps","year":"2011","journal-title":"Placenta"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1053\/plac.1999.0526","article-title":"Cell culture models of trophoblast II: trophoblast cell lines\u2013a workshop report","author":"King","year":"2000","journal-title":"Placenta"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1006\/excr.1993.1139","article-title":"Establishment and characterization of first trimester human trophoblast cells with extended lifespan","volume":"206","author":"Graham","year":"1993","journal-title":"Exp Cell Res"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1016\/j.placenta.2016.12.007","article-title":"HTR-8\/SVneo cell line contains a mixed population of cells","volume":"50","author":"Abou-Kheir","year":"2017","journal-title":"Placenta"},{"key":"B49","doi-asserted-by":"publisher","first-page":"8977","DOI":"10.1038\/s41598-018-27119-4","article-title":"Human trophoblast stem cell self-renewal and differentiation: role of decorin","volume":"8","author":"Nandi","year":"2018","journal-title":"Sci Rep"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1016\/j.stemcr.2018.07.004","article-title":"Self-renewing trophoblast organoids recapitulate the developmental program of the early human placenta","volume":"11","author":"Haider","year":"2018","journal-title":"Stem Cell Rep"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1038\/s41586-018-0753-3","article-title":"Trophoblast organoids as a model for maternal-fetal interactions during human placentation","volume":"564","author":"Turco","year":"2018","journal-title":"Nature"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1007\/s10815-022-02436-w","article-title":"Derivation of human triploid trophoblast stem cells","volume":"39","author":"Kong","year":"2022","journal-title":"J Assist Reprod Genet"},{"key":"B53","doi-asserted-by":"publisher","first-page":"796","DOI":"10.1016\/j.micinf.2013.06.012","article-title":"Progesterone suppresses Th17 cell responses, and enhances the development of regulatory T cells, through thymic stromal lymphopoietin-dependent mechanisms in experimental gonococcal genital tract infection","volume":"15","author":"Xu","year":"2013","journal-title":"Microbes Infect"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1210\/en.2010-0426","article-title":"Progesterone increases systemic and local uterine proportions of CD4+CD25+ treg cells during midterm pregnancy in mice","volume":"151","author":"Mao","year":"2010","journal-title":"Endocrinology"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.1111\/aji.13259","article-title":"Is there a role for HLA-G in the induction of regulatory T cells during the maintenance of a healthy pregnancy","volume":"84","author":"Al-Khunaizi","year":"2020","journal-title":"Am J Reprod Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1111\/aji.12288","article-title":"Trophoblast induces monocyte differentiation into CD14+\/CD16+ macrophages","volume":"72","author":"Aldo","year":"2014","journal-title":"Am J Reprod Immunol"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1093\/biolre\/ioac030","article-title":"Prostaglandin E2 receptor 3 promotes M1 macrophages polarization in unexplained recurrent pregnancy loss","volume":"106","author":"Ye","year":"2022","journal-title":"Biol Reprod"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0702279104","article-title":"Nitric oxide mediates prostaglandins\u2019 deleterious:effect on lipopolysaccharide-triggered mouse:fetal resorption","volume":"104","author":"Aisemberg","year":"2007","journal-title":"Proc Natl Acad Sci USA"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1180154\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,7,15]],"date-time":"2023-07-15T03:04:06Z","timestamp":1689390246000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2023.1180154\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,7,14]]},"references-count":58,"alternative-id":["10.3389\/fimmu.2023.1180154"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2023.1180154","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,7,14]]},"article-number":"1180154"}}