{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T17:41:43Z","timestamp":1790703703549,"version":"4.1.0"},"reference-count":56,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2023,5,24]],"date-time":"2023-05-24T00:00:00Z","timestamp":1684886400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Health &amp; Welfare of the Republic of Korea","award":["HI18C0378"],"award-info":[{"award-number":["HI18C0378"]}]},{"name":"Ministry of Health &amp; Welfare of the Republic of Korea","award":["2019R1A6A1A03032888"],"award-info":[{"award-number":["2019R1A6A1A03032888"]}]},{"name":"Ministry of Education","award":["HI18C0378"],"award-info":[{"award-number":["HI18C0378"]}]},{"name":"Ministry of Education","award":["2019R1A6A1A03032888"],"award-info":[{"award-number":["2019R1A6A1A03032888"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>The expression of High-temperature requirement factor A4 (HtrA4) mRNA is significantly lower in the chorionic villi of patients with recurrent pregnancy loss (RPL) than in the control group. We conducted an investigation into the cellular functions of HtrA4 using the CRISPR\/Cas9 system and shRNA-HtrA4 to create knockout BeWo cells and HtrA4 knockdown JEG3 cells. Our results indicated that the knockout BeWo cells exhibited reduced capacity for invasion and fusion, but increased levels of proliferation and migration, with a significantly shortened cell cycle compared to wild-type cells. Wild-type BeWo cells highly expressed cell invasion- and fusion-related factors, while knockout BeWo cells highly expressed migration-, proliferation-, and cell cycle-related factors. The shRNA-HtrA4 JEG3 cells showed a decreased capacity for invasion, but an increased capacity for migration, accompanied by a decrease in the expression of cell invasion-related factors and an increase in migration-related factors. Moreover, our ELISA results revealed that the serum HtrA4 level was lower in patients with RPL than in the controls. These findings suggest that HtrA4 depletion may be associated with placental dysfunction.<\/jats:p>","DOI":"10.3390\/cells12111459","type":"journal-article","created":{"date-parts":[[2023,5,25]],"date-time":"2023-05-25T01:36:28Z","timestamp":1684978588000},"page":"1459","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Cellular Functions of High-Temperature Requirement Factor A4 in Placenta"],"prefix":"10.3390","volume":"12","author":[{"given":"Chang-Zhu","family":"Pei","sequence":"first","affiliation":[{"name":"Department of Biomedical Science, Cell and Gene Therapy Research Institute, CHA University, Seongnam 13488, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bum-Chae","family":"Choi","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, CL Women\u2019s Hospital, Gwangju 61917, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun-Hyeok","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Cell and Gene Therapy Research Institute, CHA University, Seongnam 13488, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hyo Young","family":"Park","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, CL Women\u2019s Hospital, Gwangju 61917, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyoung","family":"Paek","sequence":"additional","affiliation":[{"name":"Department of Laboratory Medicine, Gangnam CHA Hospital, College of Medicine, Seoul 06135, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyung-Ju","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Korea University Anam Hospital, Korea University College of Medicine, Seoul 02841, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bo-Seong","family":"Yun","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Ilsan CHA Hospital, College of Medicine, Seoul 06135, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3153-3008","authenticated-orcid":false,"given":"Young Ju","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Ewha Woman\u2019s University College of Medicine, Seoul 07985, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7662-7190","authenticated-orcid":false,"given":"Kwang-Hyun","family":"Baek","sequence":"additional","affiliation":[{"name":"Department of Biomedical Science, Cell and Gene Therapy Research Institute, CHA University, Seongnam 13488, Republic of Korea"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,5,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"116350","DOI":"10.1016\/j.bone.2022.116350","article-title":"The multifaced role of HtrA1 in the development of joint and skeletal disorders","volume":"157","author":"Tossetta","year":"2022","journal-title":"Bone"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"103505","DOI":"10.1016\/j.jprot.2019.103505","article-title":"Cellular substrates and pro-apoptotic function of the human HtrA4 protease","volume":"209","author":"Wenta","year":"2019","journal-title":"J. Proteom."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1445","DOI":"10.1042\/BCJ20190224","article-title":"Discerning the mechanism of action of HtrA4: A serine protease implicated in the cell death pathway","volume":"476","author":"Kummari","year":"2019","journal-title":"Biochem. J."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Wenta, T., Rychlowski, M., Jarzab, M., and Lipinska, B. (2019). HtrA4 Protease Promotes Chemotherapeutic-Dependent Cancer Cell Death. Cells, 8.","DOI":"10.3390\/cells8101112"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"5058","DOI":"10.1096\/fj.201802151RR","article-title":"High levels of HtrA4 detected in preeclamptic circulation may disrupt endothelial cell function by cleaving the main VEGFA receptor KDR","volume":"33","author":"Wang","year":"2019","journal-title":"FASEB J."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1016\/j.placenta.2019.01.001","article-title":"Elevated protease HtrA4 in the maternal circulation of preeclampsia may contribute to endothelial barrier disruption by cleaving key junctional protein VE-cadherin","volume":"76","author":"Tseng","year":"2019","journal-title":"Placenta"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1016\/j.placenta.2016.09.003","article-title":"High levels of HtrA4 observed in preeclamptic circulation drastically alter endothelial gene expression and induce inflammation in human umbilical vein endothelial cells","volume":"47","author":"Wang","year":"2016","journal-title":"Placenta"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Wang, Y., and Nie, G. (2021). Overview of Human HtrA Family Proteases and Their Distinctive Physiological Roles and Unique Involvement in Diseases, Especially Cancer and Pregnancy Complications. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms221910756"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"3707","DOI":"10.1128\/MCB.00223-12","article-title":"High-Temperature Requirement Protein A4 (HtrA4) Suppresses the Fusogenic Activity of Syncytin-1 and Promotes Trophoblast Invasion","volume":"32","author":"Wang","year":"2012","journal-title":"Mol. Cell. Biol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1042\/BJ20130175","article-title":"RACK1 (receptor for activated C-kinase 1) interacts with FBW2 (F-box and WD-repeat domain-containing 2) to up-regulate GCM1 (glial cell missing 1) stability and placental cell migration and invasion","volume":"453","author":"Wang","year":"2013","journal-title":"Biochem. J."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"21630","DOI":"10.1038\/srep21630","article-title":"GATA3 inhibits GCM1 activity and trophoblast cell invasion","volume":"6","author":"Chiu","year":"2016","journal-title":"Sci. Rep."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"E936","DOI":"10.1210\/jc.2014-3969","article-title":"Human HtrA4 Expression Is Restricted to the Placenta, Is Significantly Up-Regulated in Early-Onset Preeclampsia, and High Levels of HtrA4 Cause Endothelial Dysfunction","volume":"100","author":"Singh","year":"2015","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_13","first-page":"2937","article-title":"Elevated HTRA1 and HTRA4 in severe preeclampsia and their roles in trophoblast functions","volume":"18","author":"Liu","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1016\/j.ccr.2006.01.013","article-title":"X chromosomal abnormalities in basal-like human breast cancer","volume":"9","author":"Richardson","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/j.ccr.2006.03.003","article-title":"Neuronal and glioma-derived stem cell factor induces angiogenesis within the brain","volume":"9","author":"Sun","year":"2006","journal-title":"Cancer Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"966","DOI":"10.1038\/nature05886","article-title":"Chromosomally unstable mouse tumours have genomic alterations similar to diverse human cancers","volume":"447","author":"Maser","year":"2007","journal-title":"Nature"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"471","DOI":"10.18388\/abp.2018_2623","article-title":"Immune response against HtrA proteases in children with cutaneous mastocytosis","volume":"65","author":"Renke","year":"2018","journal-title":"Acta Biochim. Pol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"393","DOI":"10.1016\/j.ccr.2005.10.001","article-title":"Integrative genomic and proteomic analysis of prostate cancer reveals signatures of metastatic progression","volume":"8","author":"Varambally","year":"2005","journal-title":"Cancer Cell"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"235","DOI":"10.1071\/RD02008","article-title":"Comparison of gene expression at the feto\u2013maternal interface between normal and recurrent pregnancy loss patients","volume":"14","author":"Baek","year":"2002","journal-title":"Reprod. Fertil. Dev."},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Luo, N., Cheng, W., Zhou, Y., Gu, B., Zhao, Z., and Zhao, Y. (2021). Screening Candidate Genes Regulating Placental Development from Trophoblast Transcriptome at Early Pregnancy in Dazu Black Goats (Capra hircus). Animals, 11.","DOI":"10.3390\/ani11072132"},{"key":"ref_21","first-page":"305","article-title":"The Involvement of Cell Adhesion Molecules, Tight Junctions, and Gap Junctions in Human Placentation","volume":"28","author":"Czika","year":"2020","journal-title":"Reprod. Sci."},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Zhang, Y., Tang, Y., Sun, X., Kang, M., Zhao, M., Wan, J., and Chen, Q. (2022). Exporting Proteins Associated with Senescence Repair via Extracellular Vesicles May Be Associated with Early Pregnancy Loss. Cells, 11.","DOI":"10.3390\/cells11182772"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Manna, C., Lacconi, V., Rizzo, G., De Lorenzo, A., and Massimiani, M. (2022). Placental Dysfunction in Assisted Reproductive Pregnancies: Perinatal, Neonatal and Adult Life Outcomes. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms23020659"},{"key":"ref_24","first-page":"1","article-title":"YOD1 Deubiquitinates NEDD4 Involved in the Hippo Signaling Pathway","volume":"54","author":"Park","year":"2020","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14363","DOI":"10.1038\/s41598-021-93520-1","article-title":"HtrA4 is up-regulated during trophoblast syncytialization and BeWo cells fail to syncytialize without HtrA4","volume":"11","author":"Mansilla","year":"2021","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"501","DOI":"10.1093\/humupd\/dmaa017","article-title":"Investigation of human trophoblast invasion in vitro","volume":"26","author":"Abbas","year":"2020","journal-title":"Hum. Reprod. Updat."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"103657","DOI":"10.1016\/j.jri.2022.103657","article-title":"Decreased expression of SEMA4D in recurrent implantation failure induces reduction of trophoblast invasion and migration via the Met\/PI3K\/Akt pathway","volume":"153","author":"Chen","year":"2022","journal-title":"J. Reprod. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"108","DOI":"10.4082\/kjfm.2018.39.2.108","article-title":"Lower Levels of Serum Adiponectin and the T Allele of rs1501299 of the ADIPOQ Gene Are Protective against Polycystic Ovarian Syndrome in Jordan","volume":"39","author":"Alfaqih","year":"2018","journal-title":"Korean J. Fam. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"117137","DOI":"10.1016\/j.envpol.2021.117137","article-title":"Nitric oxide mediates disruption of human placental trophoblast invasion induced by perfluorobutane sulfonate","volume":"283","author":"Du","year":"2021","journal-title":"Environ. Pollut."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"810633","DOI":"10.3389\/fcell.2022.810633","article-title":"TAGLN2-Regulated Trophoblast Migration, Invasion and Fusion are Impaired in Preeclampsia","volume":"10","author":"Wang","year":"2022","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"905","DOI":"10.1095\/biolreprod53.4.905","article-title":"Monoclonal Antiphosphatidylserine Antibody Inhibits Intercellular Fusion of the Choriocarcinoma Line, JAR1","volume":"53","author":"Adler","year":"1995","journal-title":"Biol. Reprod."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/0014-4827(90)90310-7","article-title":"Modulators of cyclic AMP metabolism induce syncytiotrophoblast formation in vitro","volume":"186","author":"Wice","year":"1990","journal-title":"Exp. Cell Res."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1016\/j.cellsig.2017.03.005","article-title":"Roles for RACK1 in cancer cell migration and invasion","volume":"35","author":"Duff","year":"2017","journal-title":"Cell. Signal."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"667","DOI":"10.1038\/ncomms1675","article-title":"EphB3 suppresses non-small-cell lung cancer metastasis via a PP2A\/RACK1\/Akt signalling complex","volume":"3","author":"Li","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"22958","DOI":"10.1074\/jbc.M114.576744","article-title":"Functional Antagonism between High Temperature Requirement Protein A (HtrA) Family Members Regulates Trophoblast Invasion","volume":"289","author":"Chen","year":"2014","journal-title":"J. Biol. Chem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"155","DOI":"10.1016\/j.scr.2015.01.001","article-title":"Cyclic mechanical stretching promotes migration but inhibits invasion of rat bone marrow stromal cells","volume":"14","author":"Zhang","year":"2015","journal-title":"Stem Cell Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"614","DOI":"10.1016\/j.cardiores.2005.08.002","article-title":"Matrix metalloproteinases regulate migration, proliferation, and death of vascular smooth muscle cells by degrading matrix and non-matrix substrates","volume":"69","author":"Newby","year":"2006","journal-title":"Cardiovasc. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"804400","DOI":"10.3389\/fphar.2022.804400","article-title":"Psoralen Promotes Proliferation, Migration, and Invasion of Human Extravillous Trophoblast Derived HTR-8\/Svneo Cells in vitro by NF-\u03baB Pathway","volume":"13","author":"Qi","year":"2022","journal-title":"Front. Pharmacol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"126","DOI":"10.1097\/00130404-200303000-00008","article-title":"FAK Signaling in Anaplastic Astro cytoma and Glioblastoma Tumors","volume":"9","author":"Natarajan","year":"2003","journal-title":"Cancer J."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/S0959-437X(01)00260-X","article-title":"Anchorage-dependent ERK signaling\u2013mechanisms and consequences","volume":"12","author":"Howe","year":"2002","journal-title":"Curr. Opin. Genet. Dev."},{"key":"ref_41","doi-asserted-by":"crossref","unstructured":"Li, Z., Li, C., Du, L., Zhou, Y., and Wu, W. (2013). Human Chorionic Gonadotropin \u03b2 Induces Migration and Invasion via Activating ERK1\/2 and MMP-2 in Human Prostate Cancer DU145 Cells. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0054592"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1083\/jcb.200212114","article-title":"Differential regulation of cell motility and invasion by FAK","volume":"160","author":"Hsia","year":"2003","journal-title":"J. Cell Biol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1016\/j.jbiomech.2009.09.003","article-title":"Mechanics of the F-actin cytoskeleton","volume":"43","author":"Stricker","year":"2010","journal-title":"J. Biomech."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ma, N., Xu, E., Luo, Q., and Song, G. (2023). Rac1: A Regulator of Cell Migration and a Potential Target for Cancer Therapy. Molecules, 28.","DOI":"10.3390\/molecules28072976"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"430142","DOI":"10.1155\/2010\/430142","article-title":"Mesenchymal Migration as a Therapeutic Target in Glioblastoma","volume":"2010","author":"Zhong","year":"2010","journal-title":"J. Oncol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"190","DOI":"10.1038\/s41419-023-05704-4","article-title":"Protein dynamics at invadopodia control invasion\u2013migration transitions in melanoma cells","volume":"14","author":"Legrand","year":"2023","journal-title":"Cell Death Dis."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"574","DOI":"10.1038\/s41567-022-01924-1","article-title":"Liquid-like VASP condensates drive actin polymerization and dynamic bundling","volume":"19","author":"Graham","year":"2023","journal-title":"Nat. Phys."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"4342","DOI":"10.1021\/acs.jmedchem.2c01753","article-title":"Application and Study of ROCK Inhibitors in Pulmonary Fibrosis: Recent Developments and Future Perspectives","volume":"66","author":"Xie","year":"2023","journal-title":"J. Med. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1074506","DOI":"10.3389\/fphar.2023.1074506","article-title":"Anticancer effects of licochalcones: A review of the mechanisms","volume":"14","author":"Deng","year":"2023","journal-title":"Front. Pharmacol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Schmidt, N., Irle, I., Ripkens, K., Lux, V., Nelles, J., Johannes, C., Parry, L., Greenow, K., Amir, S., and Campioni, M. (2016). Epigenetic silencing of serine protease HTRA1 drives polyploidy. BMC Cancer, 16.","DOI":"10.1186\/s12885-016-2425-8"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"e201906147","DOI":"10.1083\/jcb.201906147","article-title":"CDK1 couples proliferation with protein synthesis","volume":"219","author":"Haneke","year":"2020","journal-title":"J. Cell Biol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"2728","DOI":"10.1038\/s41598-019-39565-9","article-title":"HtrA4 may play a major role in inhibiting endothelial repair in pregnancy complication preeclampsia","volume":"9","author":"Wang","year":"2019","journal-title":"Sci. Rep."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Dong, P., Zhang, C., Parker, B.-T., You, L., and Mathey-Prevot, B. (2018). Cyclin D\/CDK4\/6 activity controls G1 length in mammalian cells. PLoS ONE, 13.","DOI":"10.1371\/journal.pone.0185637"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"452","DOI":"10.1038\/sj.emboj.7600554","article-title":"The structure of cyclin E1\/CDK2: Implications for CDK2 activation and CDK2-independent roles","volume":"24","author":"Honda","year":"2005","journal-title":"EMBO J."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"1317","DOI":"10.1007\/s00018-002-8510-y","article-title":"Cyclin A in cell cycle control and cancer","volume":"59","author":"Yam","year":"2002","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"4261","DOI":"10.1038\/onc.2008.74","article-title":"Cyclin A\/cdk2 coordinates centrosomal and nuclear mitotic events","volume":"27","author":"Oakes","year":"2008","journal-title":"Oncogene"}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/11\/1459\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T19:40:51Z","timestamp":1760125251000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/12\/11\/1459"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2023,5,24]]},"references-count":56,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2023,6]]}},"alternative-id":["cells12111459"],"URL":"https:\/\/doi.org\/10.3390\/cells12111459","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,5,24]]}}}