{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T19:43:24Z","timestamp":1790711004923,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"19","license":[{"start":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T00:00:00Z","timestamp":1632700800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["DOC31"],"award-info":[{"award-number":["DOC31"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["F73"],"award-info":[{"award-number":["F73"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["W1226"],"award-info":[{"award-number":["W1226"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P32400"],"award-info":[{"award-number":["P32400"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002428","name":"Austrian Science Fund","doi-asserted-by":"publisher","award":["P30882"],"award-info":[{"award-number":["P30882"]}],"id":[{"id":"10.13039\/501100002428","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100009818","name":"Province of Styria","doi-asserted-by":"publisher","award":["add-on SFB Lipid Hydrolysis"],"award-info":[{"award-number":["add-on SFB Lipid Hydrolysis"]}],"id":[{"id":"10.13039\/501100009818","id-type":"DOI","asserted-by":"publisher"}]},{"name":"City of Graz","award":["add-on SFB Lipid Hydrolysis"],"award-info":[{"award-number":["add-on SFB Lipid Hydrolysis"]}]},{"DOI":"10.13039\/501100019802","name":"BioTechMed-Graz","doi-asserted-by":"publisher","award":["Lipases and Lipid Signaling"],"award-info":[{"award-number":["Lipases and Lipid Signaling"]}],"id":[{"id":"10.13039\/501100019802","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100010109","name":"Medizinische Universit\u00e4t Graz","doi-asserted-by":"publisher","award":["PhD program Molecular Medicine"],"award-info":[{"award-number":["PhD program Molecular Medicine"]}],"id":[{"id":"10.13039\/501100010109","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Cholesterol and fatty acids are essential lipids that are critical for membrane biosynthesis and fetal organ development. Cholesteryl esters (CE) are degraded by hormone-sensitive lipase (HSL) in the cytosol and by lysosomal acid lipase (LAL) in the lysosome. Impaired LAL or HSL activity causes rare pathologies in humans, with HSL deficiency presenting less severe clinical manifestations. The infantile form of LAL deficiency, a lysosomal lipid storage disorder, leads to premature death. However, the importance of defective lysosomal CE degradation and its consequences during early life are incompletely understood. We therefore investigated how defective CE catabolism affects fetus and infant maturation using Lal and Hsl knockout (-\/-) mouse models. This study demonstrates that defective lysosomal but not neutral lipolysis alters placental and fetal cholesterol homeostasis and exhibits an initial disease pathology already in utero as Lal-\/- fetuses accumulate hepatic lysosomal lipids. Immediately after birth, LAL deficiency exacerbates with massive hepatic lysosomal lipid accumulation, which continues to worsen into young adulthood. Our data highlight the crucial role of LAL during early development, with the first weeks after birth being critical for aggravating LAL deficiency.<\/jats:p>","DOI":"10.3390\/ijms221910416","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T10:39:20Z","timestamp":1632739160000},"page":"10416","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Defective Lysosomal Lipolysis Causes Prenatal Lipid Accumulation and Exacerbates Immediately after Birth"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1445-5466","authenticated-orcid":false,"given":"Katharina B.","family":"Kuentzel","sequence":"first","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivan","family":"Bradi\u0107","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2346-7258","authenticated-orcid":false,"given":"Alena","family":"Akhmetshina","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7609-9436","authenticated-orcid":false,"given":"Melanie","family":"Korbelius","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Rainer","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dagmar","family":"Kolb","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Cell Biology, Histology and Embryology, Medical University of Graz, 8010 Graz, Austria"},{"name":"Core Facility Ultrastructural Analysis, Medical University of Graz, 8010 Graz, Austria"},{"name":"BioTechMed-Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0386-6857","authenticated-orcid":false,"given":"Martin","family":"Gauster","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Cell Biology, Histology and Embryology, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2977-7799","authenticated-orcid":false,"given":"Nemanja","family":"Vuji\u0107","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1357-7573","authenticated-orcid":false,"given":"Dagmar","family":"Kratky","sequence":"additional","affiliation":[{"name":"Gottfried Schatz Research Center, Molecular Biology and Biochemistry, Medical University of Graz, 8010 Graz, Austria"},{"name":"BioTechMed-Graz, 8010 Graz, Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1016\/0014-5793(77)80099-9","article-title":"Hormone-sensitive lipase of rat adipose tissue: Identification and some properties of the enzyme protein","volume":"75","author":"Belfrage","year":"1977","journal-title":"FEBS Lett."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"6311","DOI":"10.1016\/S0021-9258(19)69164-7","article-title":"Hormone-sensitive lipase of rat adipose tissue. Purification and some properties","volume":"256","author":"Fredrikson","year":"1981","journal-title":"J. Biol. Chem."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"2952","DOI":"10.1016\/S0021-9258(19)69707-3","article-title":"Purification of the lysosomal acid lipase from human liver and its role in lysosomal lipid hydrolysis","volume":"256","author":"Warner","year":"1981","journal-title":"J. Biol. Chem."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"17977","DOI":"10.1074\/jbc.M116.724054","article-title":"Lysosomal Acid Lipase Hydrolyzes Retinyl Ester and Affects Retinoid Turnover","volume":"291","author":"Grumet","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"27766","DOI":"10.1074\/jbc.270.46.27766","article-title":"Characterization of Lysosomal Acid Lipase by Site-directed Mutagenesis and Heterologous Expression","volume":"270","author":"Sheriff","year":"1995","journal-title":"J. Biol. Chem."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.cmet.2014.07.018","article-title":"Hormone-Sensitive Lipase Deficiency in Humans","volume":"20","author":"Zechner","year":"2014","journal-title":"Cell Metab."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"2307","DOI":"10.1056\/NEJMoa1315496","article-title":"Null Mutation in Hormone-Sensitive Lipase Gene and Risk of Type 2 Diabetes","volume":"370","author":"Albert","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"4806","DOI":"10.1074\/jbc.M110355200","article-title":"Hormone-sensitive Lipase Deficiency in Mice Causes Diglyceride Accumulation in Adipose Tissue, Muscle, and Testis","volume":"277","author":"Haemmerle","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"12946","DOI":"10.1074\/jbc.M108640200","article-title":"Hormone-sensitive Lipase Deficiency in Mice Changes the Plasma Lipid Profile by Affecting the Tissue-specific Expression Pattern of Lipoprotein Lipase in Adipose Tissue and Muscle","volume":"277","author":"Haemmerle","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"787","DOI":"10.1073\/pnas.97.2.787","article-title":"Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity","volume":"97","author":"Osuga","year":"2000","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.2174\/2213988501711010001","article-title":"Targeting Wolman Disease and Cholesteryl Ester Storage Disease: Disease Pathogenesis and Therapeutic Development","volume":"11","author":"Aguisanda","year":"2017","journal-title":"Curr. Chem. Genom. Transl. Med."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1230","DOI":"10.1016\/j.jhep.2013.02.014","article-title":"Cholesteryl ester storage disease: Review of the findings in 135 reported patients with an underdiagnosed disease","volume":"58","author":"Bernstein","year":"2013","journal-title":"J. Hepatol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.1093\/hmg\/7.9.1347","article-title":"Targeted disruption of the mouse lysosomal acid lipase gene: Long-term survival with massive cholesteryl ester and triglyceride storage","volume":"7","author":"Du","year":"1998","journal-title":"Hum. Mol. Genet."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1016\/S0022-2275(20)31157-3","article-title":"Lysosomal acid lipase-deficient mice: Depletion of white and brown fat, severe hepatosplenomegaly, and shortened life span","volume":"42","author":"Du","year":"2001","journal-title":"J. Lipid Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1639","DOI":"10.1093\/hmg\/10.16.1639","article-title":"Enzyme therapy for lysosomal acid lipase deficiency in the mouse","volume":"10","author":"Du","year":"2001","journal-title":"Hum. Mol. Genet."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"G836","DOI":"10.1152\/ajpgi.00243.2014","article-title":"Hepatic entrapment of esterified cholesterol drives continual expansion of whole body sterol pool in lysosomal acid lipase-deficient mice","volume":"307","author":"Aqul","year":"2014","journal-title":"Am. J. Physiol. Gastrointest. Liver Physiol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1743","DOI":"10.1007\/s00125-016-3968-6","article-title":"Lysosomal acid lipase regulates VLDL synthesis and insulin sensitivity in mice","volume":"59","author":"Vujic","year":"2016","journal-title":"Diabetologia"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"2168","DOI":"10.1194\/jlr.M500096-JLR200","article-title":"Transfer of maternal cholesterol to embryo and fetus in pregnant mice","volume":"46","author":"Yoshida","year":"2005","journal-title":"J. Lipid Res."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1155","DOI":"10.1093\/ajcn\/82.6.1155","article-title":"Maternal cholesterol in fetal development: Transport of cholesterol from the maternal to the fetal circulation","volume":"82","author":"Woollett","year":"2005","journal-title":"Am. J. Clin. Nutr."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"33357","DOI":"10.1074\/jbc.M802686200","article-title":"Identification of Neutral Cholesterol Ester Hydrolase, a Key Enzyme Removing Cholesterol from Macrophages","volume":"283","author":"Okazaki","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1007\/s13238-017-0437-z","article-title":"Carboxylesterases in lipid metabolism: From mouse to human","volume":"9","author":"Lian","year":"2018","journal-title":"Protein Cell"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1016\/B978-0-12-800280-3.00010-4","article-title":"Measurement of Lipolysis","volume":"538","author":"Schweiger","year":"2014","journal-title":"Methods Enzymol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Xia, B., Cai, G.H., Yang, H., Wang, S.P., Mitchell, G.A., and Wu, J.W. (2017). Adipose tissue deficiency of hormone-sensitive lipase causes fatty liver in mice. PLoS Genet., 13.","DOI":"10.1371\/journal.pgen.1007110"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e14","DOI":"10.1056\/NEJMicm1610060","article-title":"Cholesteryl Ester Crystals in Lysosomal Acid Lipase Deficiency","volume":"376","author":"Ivashkin","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"14","DOI":"10.1038\/modpathol.3880251","article-title":"Fetal Brain to Liver Weight Ratio as a Measure of Intrauterine Growth Retardation: Analysis of 182 Stillborn Autopsies","volume":"14","author":"Mitchell","year":"2001","journal-title":"Mod. Pathol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"8487","DOI":"10.1016\/S0021-9258(19)40786-2","article-title":"Role of lysosomal acid lipase in the metabolism of plasma low density lipoprotein. Observations in cultured fibroblasts from a patient with cholesteryl ester storage disease","volume":"250","author":"Goldstein","year":"1975","journal-title":"J. Biol. Chem."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"3","DOI":"10.1194\/jlr.R800031-JLR200","article-title":"Adipose triglyceride lipase and the lipolytic catabolism of cellular fat stores","volume":"50","author":"Zechner","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1126\/science.1100747","article-title":"Fat Mobilization in Adipose Tissue Is Promoted by Adipose Triglyceride Lipase","volume":"306","author":"Zimmermann","year":"2004","journal-title":"Science"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"658","DOI":"10.2214\/ajr.184.2.01840658","article-title":"MRI of Fat Distribution in a Mouse Model of Lysosomal Acid Lipase Deficiency","volume":"184","author":"Du","year":"2005","journal-title":"Am. J. Roentgenol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1959","DOI":"10.1093\/eurheartj\/ehv653","article-title":"Cholesterol crystal induced arterial inflammation and destabilization of atherosclerotic plaque","volume":"37","author":"Janoudi","year":"2016","journal-title":"Eur. Heart J."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1007\/s11926-012-0313-z","article-title":"Cholesterol Crystals and Inflammation","volume":"15","author":"Grebe","year":"2013","journal-title":"Curr. Rheumatol. Rep."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1016\/0021-9150(75)90038-6","article-title":"Crystals in atherosclerosic lesions: Real or artefact?","volume":"22","author":"Adams","year":"1975","journal-title":"Atherosclerosis"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1891","DOI":"10.1161\/01.ATV.19.8.1891","article-title":"Crystallization of Free Cholesterol in Model Macrophage Foam Cells","volume":"19","author":"Yancey","year":"1999","journal-title":"Arter. Thromb. Vasc. Biol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"413","DOI":"10.1002\/clc.4960280906","article-title":"Cholesterol crystals cause mechanical damage to biological membranes: A proposed mechanism of plaque rupture and erosion leading to arterial thrombosis","volume":"28","author":"Abela","year":"2005","journal-title":"Clin. Cardiol."},{"key":"ref_35","first-page":"1304","article-title":"Active autophagy but not lipophagy in macrophages with defective lipolysis","volume":"1851","author":"Goeritzer","year":"2015","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Biol. Lipids"},{"key":"ref_36","first-page":"467","article-title":"Lysosomal acid lipase regulates fatty acid channeling in brown adipose tissue to maintain thermogenesis","volume":"1863","author":"Sachdev","year":"2018","journal-title":"Biochim. Biophys. Acta (BBA) Mol. Cell Biol. Lipids"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"499","DOI":"10.1152\/physrev.1978.58.2.499","article-title":"Principal substrates of fetal metabolism","volume":"58","author":"Battaglia","year":"1978","journal-title":"Physiol. Rev."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/1520-7560(200005\/06)16:3<202::AID-DMRR116>3.0.CO;2-#","article-title":"Lipid metabolism in the fetus and the newborn","volume":"16","author":"Herrera","year":"2000","journal-title":"Diabetes Metab. Res. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"40037","DOI":"10.18632\/oncotarget.16673","article-title":"Lysosomal lipid hydrolysis provides substrates for lipid mediator synthesis in murine macrophages","volume":"8","author":"Schlager","year":"2017","journal-title":"Oncotarget"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/S0022-2275(20)38180-3","article-title":"Recognition and receptor-mediated endocytosis of the lysosomal acid lipase secreted by cultured human fibroblasts","volume":"23","author":"Sando","year":"1982","journal-title":"J. Lipid Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"4932","DOI":"10.1091\/mbc.e09-07-0559","article-title":"Macrophages Create an Acidic Extracellular Hydrolytic Compartment to Digest Aggregated Lipoproteins","volume":"20","author":"Haka","year":"2009","journal-title":"Mol. Biol. Cell"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1002\/ajmg.1320260324","article-title":"Cholesteryl ester storage disease: Pathologic changes in an affected fetus","volume":"26","author":"Desai","year":"1987","journal-title":"Am. J. Med. Genet."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1002\/jcu.22481","article-title":"Prenatal sonographic findings in a case of Wolman\u2019s disease","volume":"46","author":"Blitz","year":"2018","journal-title":"J. Clin. Ultrasound"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1051\/ocl\/2020001","article-title":"Milk lipid composition and structure; The relevance for infant brain development","volume":"27","author":"Schipper","year":"2020","journal-title":"OCL"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"8824","DOI":"10.1038\/s41598-018-27115-8","article-title":"Milk cholesterol concentration in mice is not affected by high cholesterol diet- or genetically-induced hypercholesterolaemia","volume":"8","author":"Dimova","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1042\/bst0080292","article-title":"Milk fat composition and biosynthesis in non-ruminants and ruminants","volume":"8","author":"Dils","year":"1980","journal-title":"Biochem. Soc. Trans."},{"key":"ref_47","first-page":"368","article-title":"A Simple and Reliable Method for Early Pregnancy Detection in Inbred Mice","volume":"54","author":"Heyne","year":"2015","journal-title":"J. Am. Assoc. Lab. Anim. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"497","DOI":"10.1016\/S0021-9258(18)64849-5","article-title":"A Simple Method for the Isolation and Purification of Total Lipides from Animal Tissues","volume":"226","author":"Folch","year":"1957","journal-title":"J. Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10416\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:05:52Z","timestamp":1760166352000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10416"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,27]]},"references-count":48,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms221910416"],"URL":"https:\/\/doi.org\/10.3390\/ijms221910416","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,27]]}}}