{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,1]],"date-time":"2026-10-01T02:20:38Z","timestamp":1790821238483,"version":"4.1.0"},"reference-count":59,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T00:00:00Z","timestamp":1639008000000},"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:p>The skin protects the human body against dehydration and harmful challenges. Keratinocytes (KCs) are the most abundant epidermal cells, and it is anticipated that KC-mediated transport of Na<jats:sup>+<\/jats:sup> ions creates a physiological barrier of high osmolality against the external environment. Here, we studied the role of NFAT5, a transcription factor whose activity is controlled by osmotic stress in KCs. Cultured KCs from adult mice were found to secrete more than 300 proteins, and upon NFAT5 ablation, the secretion of several matrix proteinases, including metalloproteinase-3 (Mmp3) and kallikrein-related peptidase 7 (Klk7), was markedly enhanced. An increase in Mmp3 and Klk7 RNA levels was also detected in transcriptomes of <jats:italic>Nfat5<jats:sup>-\/-<\/jats:sup><\/jats:italic> KCs, along with increases of numerous members of the \u2018Epidermal Differentiation Complex\u2019 (EDC), such as small proline-rich (Sprr) and S100 proteins. NFAT5 and Mmp3 as well as NFAT5 and Klk7 are co-expressed in the basal KCs of fetal and adult epidermis but not in basal KCs of newborn (NB) mice. The poor NFAT5 expression in NB KCs is correlated with a strong increase in Mmp3 and Klk7 expression in KCs of NB mice. These data suggests that, along with the fragile epidermis of adult <jats:italic>Nfat5<jats:sup>-\/-<\/jats:sup><\/jats:italic> mice, NFAT5 keeps in check the expression of matrix proteases in epidermis. The NFAT5-mediated control of matrix proteases in epidermis contributes to the manifold changes in skin development in embryos before and during birth, and to the integrity of epidermis in adults.<\/jats:p>","DOI":"10.3389\/fimmu.2021.780727","type":"journal-article","created":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T13:14:27Z","timestamp":1639055667000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":4,"title":["NFAT5 Controls the Integrity of Epidermis"],"prefix":"10.3389","volume":"12","author":[{"given":"Khalid","family":"Muhammad","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delicia","family":"Xavier","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Klein-Hessling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Muhammad","family":"Azeem","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tabea","family":"Rauschenberger","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krisna","family":"Murti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andris","family":"Avots","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Goebeler","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Matthias","family":"Klein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tobias","family":"Bopp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Malte","family":"Sielaff","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stefan","family":"Tenzer","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sigrid","family":"M\u00f6ckel","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9","family":"Aramburu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cristina","family":"L\u00f3pez-Rodr\u00edguez","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andreas","family":"Kerstan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Edgar","family":"Serfling","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,12,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0625.2008.00786.x","article-title":"The Skin: An Indispensable Barrier","volume":"17","author":"Proksch","year":"2008","journal-title":"Exp Dermatol"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1007\/s00424-014-1685-x","article-title":"Tissue Sodium Storage: Evidence for Kidney-Like Extrarenal Countercurrent Systems","volume":"467","author":"Hofmeister","year":"2015","journal-title":"Pflugers Arch"},{"key":"B3","doi-asserted-by":"publisher","first-page":"493","DOI":"10.1016\/j.cmet.2015.02.003","article-title":"Cutaneous Na+ Storage Strengthens the Antimicrobial Barrier Function of the Skin and Boosts Macrophage-Driven Host Defense","volume":"21","author":"Jantsch","year":"2015","journal-title":"Cell Metab"},{"key":"B4","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/scitranslmed.aay3850","article-title":"A High-Salt Diet Compromises Antibacterial Neutrophil Responses Through Hormonal Perturbation","volume":"12","author":"Jobin","year":"2020","journal-title":"Sci Transl Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1002\/path.3027","article-title":"Cell-Cell Connectivity: Desmosomes and Disease","volume":"226","author":"Brooke","year":"2012","journal-title":"J Pathol"},{"key":"B6","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1016\/j.devcel.2017.10.001","article-title":"Skin and Its Regenerative Powers: An Alliance Between Stem Cells and Their Niche","volume":"43","author":"Gonzales","year":"2017","journal-title":"Dev Cell"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1007\/s00441-014-2037-z","article-title":"The Biology and Regulation of Corneodesmosomes","volume":"360","author":"Ishida-Yamamoto","year":"2015","journal-title":"Cell Tissue Res"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1016\/j.tibs.2009.08.001","article-title":"The Emerging Roles of Serine Protease Cascades in the Epidermis","volume":"34","author":"Ovaere","year":"2009","journal-title":"Trends Biochem Sci"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1111\/j.1469-7580.2009.01066.x","article-title":"Structure and Functions of Keratin Proteins in Simple, Stratified, Keratinized and Cornified Epithelia","volume":"214","author":"Bragulla","year":"2009","journal-title":"J Anat"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1083\/jcb.109.3.1207","article-title":"Expression of Murine Epidermal Differentiation Markers is Tightly Regulated by Restricted Extracellular Calcium Concentrations In Vitro","volume":"109","author":"Yuspa","year":"1989","journal-title":"J Cell Biol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1016\/j.matbio.2005.05.006","article-title":"A Simplified Laminin Nomenclature","volume":"24","author":"Aumailley","year":"2005","journal-title":"Matrix Biol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1096\/fj.09-151449","article-title":"Unique and Redundant Functions of Integrins in the Epidermis","volume":"24","author":"Margadant","year":"2010","journal-title":"FASEB J"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1101\/sqb.1999.64.517","article-title":"NF-AT5: The NF-AT Family of Transcription Factors Expands in a New Direction","volume":"64","author":"Lopez-Rodriguez","year":"1999","journal-title":"Cold Spring Harb Symp Quant Biol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1001232","article-title":"NFAT5 Regulates T Lymphocyte Homeostasis and CD24-Dependent T Cell Expansion Under Pathologic Hypernatremia","volume":"185","author":"Berga-Bolanos","year":"2010","journal-title":"J Immunol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0308703100","article-title":"Loss of NFAT5 Results in Renal Atrophy and Lack of Tonicity-Responsive Gene Expression","volume":"101","author":"Lopez-Rodriguez","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"B16","doi-asserted-by":"publisher","first-page":"799","DOI":"10.1038\/nprot.2008.50","article-title":"Isolation and Short-Term Culture of Primary Keratinocytes, Hair Follicle Populations and Dermal Cells from Newborn Mice and Keratinocytes from Adult Mice for In Vitro Analysis and for Grafting to Immunodeficient Mice","volume":"3","author":"Lichti","year":"2008","journal-title":"Nat Protoc"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1038\/sj.gt.3301206","article-title":"Plat-E: An Efficient and Stable System for Transient Packaging of Retroviruses","volume":"7","author":"Morita","year":"2000","journal-title":"Gene Ther"},{"key":"B18","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1016\/S1074-7613(01)00165-0","article-title":"Bridging the NFAT and NF-kappaB Families: NFAT5 Dimerization Regulates Cytokine Gene Transcription in Response to Osmotic Stress","volume":"15","author":"Lopez-Rodriguez","year":"2001","journal-title":"Immunity"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1038\/emboj.2011.140","article-title":"The Transcription Factor Pax5 Regulates its Target Genes by Recruiting Chromatin-Modifying Proteins in Committed B Cells","volume":"30","author":"McManus","year":"2011","journal-title":"EMBO J"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1002\/1521-4141(200009)30:9<2576::AID-IMMU2576>3.0.CO;2-N","article-title":"C\/EBPbeta Enhances IL-4 But Impairs IL-2 and IFN-Gamma Induction in T Cells","volume":"30","author":"Berberich-Siebelt","year":"2000","journal-title":"Eur J Immunol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1038\/nprot.2007.52","article-title":"Labeling, Detection and Identification of Newly Synthesized Proteomes With Bioorthogonal non-Canonical Amino-Acid Tagging","volume":"2","author":"Dieterich","year":"2007","journal-title":"Nat Protoc"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2767","article-title":"Drift Time-Specific Collision Energies Enable Deep-Coverage Data-Independent Acquisition Proteomics","volume":"11","author":"Distler","year":"2014","journal-title":"Nat Methods"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1016\/j.ejpb.2008.08.008","article-title":"The Tape Stripping Procedure\u2013Evaluation of Some Critical Parameters","volume":"72","author":"Lademann","year":"2009","journal-title":"Eur J Pharm Biopharm"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1111\/j.1600-0625.2012.01472.x","article-title":"The Human Epidermal Differentiation Complex: Cornified Envelope Precursors, S100 Proteins and the \u2018Fused Genes\u2019 Family","volume":"21","author":"Kypriotou","year":"2012","journal-title":"Exp Dermatol"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.4161\/cc.10.22.18043","article-title":"Nuclear Import of a Lipid-Modified Transcription Factor: Mobilization of NFAT5 Isoform a by Osmotic Stress","volume":"10","author":"Eisenhaber","year":"2011","journal-title":"Cell Cycle"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0403139101","article-title":"NFAT5\/TonEBP Mutant Mice Define Osmotic Stress as a Critical Feature of the Lymphoid Microenvironment","volume":"101","author":"Go","year":"2004","journal-title":"Proc Natl Acad Sci USA"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.10.015","article-title":"Incomplete KLK7 Secretion and Upregulated LEKTI Expression Underlie Hyperkeratotic Stratum Corneum in Atopic Dermatitis","volume":"137","author":"Igawa","year":"2017","journal-title":"J Invest Dermatol"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.22.13055","article-title":"Progression of Coronary Atherosclerosis is Associated With a Common Genetic Variant of the Human Stromelysin-1 Promoter Which Results in Reduced Gene Expression","volume":"271","author":"Ye","year":"1996","journal-title":"J Biol Chem"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s00018-006-6269-2","article-title":"Chitotriosidase: The Yin and Yang","volume":"63","author":"Malaguarnera","year":"2006","journal-title":"Cell Mol Life Sci"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M205380200","article-title":"Suprabasin, a Novel Epidermal Differentiation Marker and Potential Cornified Envelope Precursor","volume":"277","author":"Park","year":"2002","journal-title":"J Biol Chem"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.144808","article-title":"Mice Deficient for the Epidermal Dermokine Beta and Gamma Isoforms Display Transient Cornification Defects","volume":"127","author":"Leclerc","year":"2014","journal-title":"J Cell Sci"},{"key":"B32","doi-asserted-by":"publisher","first-page":"99","DOI":"10.1016\/j.jdermsci.2014.02.005","article-title":"Genetic Skin Diseases Related to Desmosomes and Corneodesmosomes","volume":"74","author":"Ishida-Yamamoto","year":"2014","journal-title":"J Dermatol Sci"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1038\/bjc.1996.257","article-title":"Expression of Mad, an Antagonist of Myc Oncoprotein Function, in Differentiating Keratinocytes During Tumorigenesis of the Skin","volume":"73","author":"Lymboussaki","year":"1996","journal-title":"Br J Cancer"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jid.2016.01.032","article-title":"HOPX: The Unusual Homeodomain-Containing Protein","volume":"136","author":"Mariotto","year":"2016","journal-title":"J Invest Dermatol"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1172\/JCI77138","article-title":"A GRHL3-Regulated Repair Pathway Suppresses Immune-Mediated Epidermal Hyperplasia","volume":"124","author":"Gordon","year":"2014","journal-title":"J Clin Invest"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2012.02.032","article-title":"KLF10, Transforming Growth Factor-Beta-Inducible Early Gene 1, Acts as a Tumor Suppressor","volume":"419","author":"Song","year":"2012","journal-title":"Biochem Biophys Res Commun"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0500519102","article-title":"Barx2 Functions Through Distinct Corepressor Classes to Regulate Hair Follicle Remodeling","volume":"102","author":"Olson","year":"2005","journal-title":"Proc Natl Acad Sci USA"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1242\/dev.093005","article-title":"Hopx Expression Defines a Subset of Multipotent Hair Follicle Stem Cells and a Progenitor Population Primed to Give Rise to K6+ Niche Cells","volume":"140","author":"Takeda","year":"2013","journal-title":"Development"},{"key":"B39","doi-asserted-by":"publisher","first-page":"5425","DOI":"10.1038\/s41598-018-23794-5","article-title":"Foxn1 Expression in Keratinocytes is Stimulated by Hypoxia: Further Evidence of its Role in Skin Wound Healing","volume":"8","author":"Kur-Piotrowska","year":"2018","journal-title":"Sci Rep"},{"key":"B40","doi-asserted-by":"publisher","first-page":"4042","DOI":"10.1038\/s41467-019-11880-9","article-title":"SOX11 and SOX4 Drive the Reactivation of an Embryonic Gene Program During Murine Wound Repair","volume":"10","author":"Miao","year":"2019","journal-title":"Nat Commun"},{"key":"B41","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1002\/cfg.239","article-title":"Early Gene Expression in Wounded Human Keratinocytes Revealed by DNA Microarray Analysis","volume":"4","author":"Dayem","year":"2003","journal-title":"Comp Funct Genomics"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1111\/exd.12554","article-title":"Egr-1 is a Key Regulator of IL-17A-Induced Psoriasin Upregulation in Psoriasis","volume":"23","author":"Jeong","year":"2014","journal-title":"Exp Dermatol"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.1038\/ng1813","article-title":"Seborrhea-Like Dermatitis With Psoriasiform Elements Caused by a Mutation in ZNF750, Encoding a Putative C2H2 Zinc Finger Protein","volume":"38","author":"Birnbaum","year":"2006","journal-title":"Nat Genet"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-4939-7027-8_14","article-title":"Identification of Transcriptional Regulators of Psoriasis From RNA-Seq Experiments","volume":"1613","author":"Zolotarenko","year":"2017","journal-title":"Methods Mol Biol"},{"key":"B45","doi-asserted-by":"publisher","first-page":"51","DOI":"10.1146\/annurev-biochem-062917-012612","article-title":"Regulation of RNA Polymerase I Transcription in Development, Disease, and Aging","volume":"87","author":"Sharifi","year":"2018","journal-title":"Annu Rev Biochem"},{"key":"B46","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1186\/s12864-015-1508-2","article-title":"Transcriptional Landscape of Psoriasis Identifies the Involvement of IL36 and IL36RN","volume":"16","author":"Keermann","year":"2015","journal-title":"BMC Genomics"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/bs.mie.2015.09.032","article-title":"Skin Keratins","volume":"568","author":"Wang","year":"2016","journal-title":"Methods Enzymol"},{"key":"B48","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1126\/scitranslmed.aau0683","article-title":"Sodium Chloride is an Ionic Checkpoint for Human TH2 Cells and Shapes the Atopic Skin Microenvironment","volume":"11","author":"Matthias","year":"2019","journal-title":"Sci Transl Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20111569","article-title":"Gene Expression Induced by Toll-Like Receptors in Macrophages Requires the Transcription Factor NFAT5","volume":"209","author":"Buxade","year":"2012","journal-title":"J Exp Med"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1038\/372103a0","article-title":"New Member of the Winged-Helix Protein Family Disrupted in Mouse and Rat Nude Mutations","volume":"372","author":"Nehls","year":"1994","journal-title":"Nature"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1242\/jcs.01302","article-title":"Transient Activation of FOXN1 in Keratinocytes Induces a Transcriptional Programme That Promotes Terminal Differentiation: Contrasting Roles of FOXN1 and Akt","volume":"117","author":"Janes","year":"2004","journal-title":"J Cell Sci"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-017-0445-z","article-title":"FOXN1 Deficiency: From the Discovery to Novel Therapeutic Approaches","volume":"37","author":"Gallo","year":"2017","journal-title":"J Clin Immunol"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0707323104","article-title":"Epidermal Terminal Differentiation Depends on B Lymphocyte-Induced Maturation Protein-1","volume":"104","author":"Magnusdottir","year":"2007","journal-title":"Proc Natl Acad Sci USA"},{"key":"B54","doi-asserted-by":"publisher","first-page":"85","DOI":"10.1016\/s0197-0186(01)00064-x","article-title":"Transglutaminases in Disease","volume":"40","author":"Kim","year":"2002","journal-title":"Neurochem Int"},{"key":"B55","doi-asserted-by":"publisher","first-page":"15","DOI":"10.1051\/bmdcn\/2017070315","article-title":"Transglutaminase 2 in Human Diseases","volume":"7","author":"Szondy","year":"2017","journal-title":"Biomed (Taipei)"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1016\/s0378-1119(00)00280-8","article-title":"The KLK7 (PRSS6) Gene, Encoding for the Stratum Corneum Chymotryptic Enzyme is a New Member of the Human Kallikrein Gene Family - Genomic Characterization, Mapping, Tissue Expression and Hormonal Regulation","volume":"254","author":"Yousef","year":"2000","journal-title":"Gene"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20205234","article-title":"Matrix Metalloproteinase-3 is Key Effector of TNF-Alpha-Induced Collagen Degradation in Skin","volume":"20","author":"Mirastschijski","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1023\/a:1026028303196","article-title":"Regulation of Matrix Metalloproteinases: An Overview","volume":"253","author":"Chakraborti","year":"2003","journal-title":"Mol Cell Biochem"},{"key":"B59","doi-asserted-by":"publisher","DOI":"10.1016\/j.bbrc.2020.11.089","article-title":"EGR-1 Acts as a Transcriptional Activator of KLK7 Under IL-13 Stimulation","volume":"534","author":"Yeo","year":"2021","journal-title":"Biochem Biophys Res Commun"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.780727\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,12,9]],"date-time":"2021-12-09T13:14:33Z","timestamp":1639055673000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2021.780727\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,9]]},"references-count":59,"alternative-id":["10.3389\/fimmu.2021.780727"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2021.780727","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,9]]},"article-number":"780727"}}