{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,29]],"date-time":"2026-05-29T10:05:08Z","timestamp":1780049108128,"version":"3.53.1"},"reference-count":60,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T00:00:00Z","timestamp":1625702400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) is a small vessel disease caused by mutations in NOTCH3 that lead to an odd number of cysteines in the epidermal growth factor (EGF)-like repeat domain, causing protein misfolding and aggregation. The main symptoms are migraines, psychiatric disorders, recurrent strokes, and dementia. Omic technologies allow the massive study of different molecules for understanding diseases in a non-biased manner or even for discovering targets and their possible treatments. We analyzed the progress in understanding CADASIL that has been made possible by omics sciences. For this purpose, we included studies that focused on CADASIL and used omics techniques, searching bibliographic resources, such as PubMed. We excluded studies with other phenotypes, such as migraine or leukodystrophies. A total of 18 articles were reviewed. Due to the high prevalence of NOTCH3 mutations considered pathogenic to date in genomic repositories, one can ask whether all of them produce CADASIL, different degrees of the disease, or whether they are just a risk factor for small vessel disease. Besides, proteomics and transcriptomics studies found that the molecules that are significantly altered in CADASIL are mainly related to cell adhesion, the cytoskeleton or extracellular matrix components, misfolding control, autophagia, angiogenesis, or the transforming growth factor \u03b2 (TGF\u03b2) signaling pathway. The omics studies performed on CADASIL have been useful for understanding the biological mechanisms and could be key factors for finding potential drug targets.<\/jats:p>","DOI":"10.3390\/ijms22147357","type":"journal-article","created":{"date-parts":[[2021,7,8]],"date-time":"2021-07-08T10:42:17Z","timestamp":1625740937000},"page":"7357","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":22,"title":["Contribution of \u201cOmic\u201d Studies to the Understanding of Cadasil. A Systematic Review"],"prefix":"10.3390","volume":"22","author":[{"given":"Elena","family":"Mui\u00f1o","sequence":"first","affiliation":[{"name":"Stroke Pharmacogenomics and Genetics Group, Institut de Recerca de l\u2019Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Israel","family":"Fern\u00e1ndez-Cadenas","sequence":"additional","affiliation":[{"name":"Stroke Pharmacogenomics and Genetics Group, Institut de Recerca de l\u2019Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8512-7881","authenticated-orcid":false,"given":"Adri\u00e0","family":"Arboix","sequence":"additional","affiliation":[{"name":"Cerebrovascular Division, Department of Neurology, Hospital Universitari del Sagrat Cor, Universitat de Barcelona, 08007 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,7,8]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1111\/j.1468-1331.2006.01337.x","article-title":"A new de novo Notch3 mutation causing CADASIL","volume":"13","author":"Coto","year":"2006","journal-title":"Eur. J. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"2761","DOI":"10.1093\/hmg\/ddp211","article-title":"CADASIL mutations enhance spontaneous multimerization of NOTCH3","volume":"18","author":"Opherk","year":"2009","journal-title":"Hum. Mol. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"3256","DOI":"10.1093\/hmg\/ddr237","article-title":"Co-aggregate formation of CADASIL-mutant NOTCH3: A single-particle analysis","volume":"20","author":"Duering","year":"2011","journal-title":"Hum. Mol. Genet."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"934","DOI":"10.1016\/S0140-6736(95)91557-5","article-title":"Clinical spectrum of CADASIL: A study of 7 families. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy","volume":"346","author":"Chabriat","year":"1995","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1212\/WNL.59.8.1134","article-title":"Diagnostic strategies in CADASIL","volume":"59","author":"Markus","year":"2002","journal-title":"Neurology"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"628","DOI":"10.1212\/WNL.56.5.628","article-title":"MRI hyperintensities of the temporal lobe and external capsule in patients with CADASIL","volume":"56","author":"Jarosz","year":"2001","journal-title":"Neurology"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1128","DOI":"10.1067\/mjd.2000.110399.","article-title":"CADASIL: The dermatologic diagnosis of a neurologic disease","volume":"43","author":"Rumbaugh","year":"2000","journal-title":"J. Am. Acad. Dermatol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"2215","DOI":"10.1161\/STROKEAHA.108.528661","article-title":"Different clinical phenotypes in monozygotic CADASIL twins with a novel Notch3 mutation","volume":"40","author":"Junna","year":"2009","journal-title":"Stroke"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Ceroni, M., Poloni, T.E., Tonietti, S., Fabozzi, D., Uggetti, C., Frediani, F., Simonetti, F., Malaspina, A., Alimonti, D., and Celano, M. (2000). Migraine with aura and white matter abnormalities: Notch3 mutation. Neurology, 1869\u20131871.","DOI":"10.1212\/WNL.54.9.1869"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Horgan, R.P., and Kenny, L.C. (2011). \u2018Omic\u2019 technologies: Proteomics and metabolomics learning objectives: Ethical issues. Obstet. Gynaecol., 189\u2013195.","DOI":"10.1576\/toag.13.3.189.27672"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Orset, C., De Grange, P., Rousselet, E., Ramsay, L., and Quill, M. (2019). Blood transcriptomic biomarker as a surrogate of ischemic brain gene expression. Ann. Clin. Transl. Neurol., 1681\u20131695.","DOI":"10.1002\/acn3.50861"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1161\/CIRCULATIONAHA.119.040180","article-title":"Novel drug targets for ischemic stroke identified through Mendelian randomization analysis of the blood proteome","volume":"140","author":"Chong","year":"2019","journal-title":"Circulation"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"739","DOI":"10.1136\/jnnp.2004.051847","article-title":"The prevalence of cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL) in the west of Scotland","volume":"76","author":"Razvi","year":"2005","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_14","first-page":"76","article-title":"The minimum prevalence of CADASIL in northeast England","volume":"32","author":"Narayan","year":"2012","journal-title":"Neurology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1111\/ane.12266","article-title":"Changing clinical patterns and increasing prevalence in CADASIL","volume":"130","author":"Moreton","year":"2014","journal-title":"Acta Neurol. Scand."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1007\/s00415-014-7533-2","article-title":"CADASIL in central Italy: A retrospective clinical and genetic study in 229 patients","volume":"262","author":"Bianchi","year":"2015","journal-title":"J. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"844","DOI":"10.1002\/acn3.344","article-title":"Archetypal NOTCH3 mutations frequent in public exome: Implications for CADASIL","volume":"3","author":"Rutten","year":"2016","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Rutten, J.W., Van Eijsden, B.J., Duering, M., Jouvent, E., Opherk, C., Pantoni, L., Federico, A., Dichgans, M., Markus, H.S., and Chabriat, H. (2018). The effect of NOTCH3 pathogenic variant position on CADASIL disease severity: NOTCH3 EGFr 1\u20136 pathogenic variant are associated with a more severe phenotype and lower survival compared with EGFr 7\u201334 pathogenic variant. Genet. Med., 6\u201311.","DOI":"10.1038\/s41436-018-0306-z"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"e1835","DOI":"10.1212\/WNL.0000000000010525","article-title":"Broad phenotype of cysteine altering NOTCH3 variants in UK Biobank: CADASIL to nonpenetrance","volume":"95","author":"Rutten","year":"2020","journal-title":"Neurology"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Cho, B.P.H., Nannoni, S., Harshfield, E.L., Tozer, D., Gr\u00e4f, S., Bell, S., and Markus, H.S. (2021). NOTCH3 variants are more common than expected in the general population and associated with stroke and vascular dementia: An analysis of 200,000 participants. J. Neurol. Neurosurg. Psychiatry, 1\u20138.","DOI":"10.1101\/2020.12.14.20248151"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Hack, R.J., Rutten, J.W., Person, T.N., Li, J., and Khan, A. (2020). Cysteine-altering NOTCH3 variants are a risk factor for stroke in the elderly population. Stroke, 3562\u20133569.","DOI":"10.1161\/STROKEAHA.120.030343"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Lee, Y., Chung, C., Chang, M., and Wang, S. (2020). NOTCH3 cysteine-altering variant is an important risk factor for stroke in the Taiwanese population. Neurology.","DOI":"10.1212\/WNL.0000000000008700"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0044964","article-title":"Biochemical characterization and cellular effects of CADASIL mutants of NOTCH3","volume":"7","author":"Meng","year":"2012","journal-title":"PLoS ONE"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"73","DOI":"10.1002\/bies.201000093","article-title":"Pathogenesis of CADASIL: Transgenic and knock-out mice to probe function and dysfunction of the mutated gene, Notch3, in the cerebrovasculature","volume":"33","author":"Joutel","year":"2011","journal-title":"BioEssays"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1172\/JCI8047","article-title":"The ectodomain of the Notch3 receptor accumulates within the cerebrovasculature of CADASIL patients","volume":"105","author":"Joutel","year":"2000","journal-title":"J. Clin. Investig."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"333","DOI":"10.1007\/s00401-006-0116-2","article-title":"Notch3 ectodomain is a major component of granular osmiophilic material (GOM) in CADASIL","volume":"112","author":"Ishiko","year":"2006","journal-title":"Acta Neuropathol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1111\/j.1365-2990.2009.01029.x","article-title":"Detection of granular osmiophilic material of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy by light microscopy in frozen sections: Scientific correspondence","volume":"35","author":"Ueda","year":"2009","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1046\/j.1365-2990.1998.00087.x","article-title":"Endothelial changes in muscle and skin biopsies in patients with CADASIL","volume":"24","author":"Ruchoux","year":"1998","journal-title":"Neuropathol. Appl. Neurobiol."},{"key":"ref_29","first-page":"265","article-title":"Ultrastructural picture of blood vessels in muscle and skin biopsy in CADASIL","volume":"44","author":"Lewandowska","year":"2006","journal-title":"Folia Neuropathol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"887","DOI":"10.1002\/ana.24512","article-title":"Pericytes are involved in the pathogenesis of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy","volume":"78","author":"Ghosh","year":"2015","journal-title":"Ann. Neurol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"2565","DOI":"10.1161\/01.STR.0000032620.91848.1C","article-title":"Arterial changes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in relation to pathogenesis of diffuse myelin loss of cerebral white matter: Examination of cerebral medullary arteries by reconstruction of serial sections of an autopsy case","volume":"33","author":"Okeda","year":"2002","journal-title":"Stroke"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"241","DOI":"10.1007\/s00401-002-0530-z","article-title":"Morphometric analysis of ultrastructural vascular changes in CADASIL: Analysis of 50 skin biopsy specimens and pathogenic implications","volume":"104","author":"Brulin","year":"2002","journal-title":"Acta Neuropathol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2291","DOI":"10.1161\/01.STR.25.11.2291","article-title":"Presence of ultrastructural arterial lesions in muscle and skin vessels of patients with CADASIL","volume":"25","author":"Ruchoux","year":"1994","journal-title":"Stroke"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2171","DOI":"10.1038\/jcbfm.2012.123","article-title":"CADASIL mutations and ShRNA silencing of NOTCH3 affect actin organization in cultured vascular smooth muscle cells","volume":"32","author":"Tikka","year":"2012","journal-title":"J. Cereb. Blood Flow Metab."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"329","DOI":"10.1016\/S0002-9440(10)63824-2","article-title":"Transgenic mice expressing mutant Notch3 develop vascular alterations characteristic of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy","volume":"162","author":"Ruchoux","year":"2003","journal-title":"Am. J. Pathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1242","DOI":"10.1136\/jnnp.2004.051854","article-title":"Functional analysis of a recurrent missense mutation in Notch3 in CADASIL","volume":"76","author":"Haritunians","year":"2005","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1161\/HYPERTENSIONAHA.116.08015","article-title":"Increased Notch3 activity mediates pathological changes in structure of cerebral arteries","volume":"69","author":"Ghezali","year":"2017","journal-title":"Hypertension"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"557","DOI":"10.1016\/j.ejcb.2018.10.001","article-title":"Autophagy-lysosomal defect in human CADASIL vascular smooth muscle cells","volume":"97","author":"Hanemaaijer","year":"2018","journal-title":"Eur. J. Cell Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"443","DOI":"10.5114\/fn.2014.47846","article-title":"Blood vessel ultrastructural picture in a CADASIL patient diagnosed at an advanced age","volume":"52","author":"Lewandowska","year":"2014","journal-title":"Folia Neuropathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.yexcr.2012.09.015","article-title":"Experimental studies of mitochondrial function in CADASIL vascular smooth muscle cells","volume":"319","author":"Viitanen","year":"2013","journal-title":"Exp. Cell Res."},{"key":"ref_41","first-page":"302","article-title":"CADASIL patient with extracellular calcium deposits","volume":"51","author":"Lewandowska","year":"2013","journal-title":"Folia Neuropathol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"1235","DOI":"10.1212\/WNL.57.7.1235","article-title":"Mitochondrial dysfunction associated with a mutation in the Notch3 gene in a CADASIL family","volume":"57","author":"Bornstein","year":"2001","journal-title":"Neurology"},{"key":"ref_43","first-page":"E128","article-title":"Hypomorphic Notch 3 alleles link Notch signaling to ischemic cerebral small-vessel disease","volume":"108","author":"Manent","year":"2011","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Monet-Lepr\u00eatre, M., Haddad, I., Baron-Menguy, C., Fouillot-Panchal, M., Riani, M., Domenga-Denier, V., Dussaule, C., Cognat, E., Vinh, J., and Joutel, A. (2013). Abnormal recruitment of extracellular matrix proteins by excess Notch3 ECD: A new pathomechanism in CADASIL. Brain, 1830\u20131845.","DOI":"10.1093\/brain\/awt092"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"1","DOI":"10.7554\/eLife.17536","article-title":"Mechanistic insights into a TIMP3-sensitive pathway constitutively engaged in the regulation of cerebral hemodynamics","volume":"5","author":"Capone","year":"2016","journal-title":"Elife"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1007\/s00401-018-1853-8","article-title":"CADASIL brain vessels show a HTRA1 loss-of-function profile","volume":"136","author":"Zellner","year":"2018","journal-title":"Acta Neuropathol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1016\/j.jns.2017.05.033","article-title":"Serum amyloid P component: A novel potential player in vessel degeneration in CADASIL","volume":"379","author":"Nagatoshi","year":"2017","journal-title":"J. Neurol. Sci."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"118","DOI":"10.1016\/j.brainres.2016.05.008","article-title":"Blood biomarkers in a mouse model of CADASIL","volume":"1644","author":"Primo","year":"2016","journal-title":"Brain Res."},{"key":"ref_49","unstructured":"Jenoe, P., Bonati, L., Engelter, S., and Lyrer, P. (2019). Combined transcriptomic and proteomic analyses of cerebral frontal lobe tissue identified RNA metabolism dysregulation as one potential pathogenic mechanism in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Curr. Neurovasc. Res., 478\u2013490."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Mui\u00f1o, E., Maisterra, O., Balado, J.J., Cullell, N., Carrera, C., Aguila, N.P.T., M\u00e1rquez, J.C., Fabrega, C.G., Lled\u00f3s, M., and S\u00e1nchez, J.G. (2021). Genome-wide transcriptome study in skin biopsies reveals an association of E2F4 with cadasil and cognitive impairment. Sci. Rep., 1\u201312.","DOI":"10.1038\/s41598-021-86349-1"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"12988","DOI":"10.1073\/pnas.0704754104","article-title":"Distinct roles of E2F proteins in vascular smooth muscle cell proliferation and intimal hyperplasia","volume":"104","author":"Giangrande","year":"2007","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"240","DOI":"10.3164\/jcbn.19-22","article-title":"Analysis of gut microbiota in patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy","volume":"65","author":"Matsuura","year":"2019","journal-title":"J. Clin. Biochem. Nutr."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Chabriat, H., Herv\u00e9, D., Duering, M., Godin, O., Jouvent, E., Opherk, C., Alili, N., Reyes, S., Jabouley, A., and Zieren, N. (2015). Predictors of clinical worsening in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy: Prospective cohort study. Stroke, 4\u201311.","DOI":"10.1161\/STROKEAHA.115.010696"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"46","DOI":"10.1002\/acn3.678","article-title":"Serum neurofilament light correlates with CADASIL disease severity and survival","volume":"6","author":"Gravesteijn","year":"2019","journal-title":"Ann. Clin. Transl. Neurol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"968","DOI":"10.1161\/STROKEAHA.113.004461","article-title":"Genome-wide genotyping demonstrates a polygenic risk score associated with white matter hyperintensity volume in CADASIL","volume":"45","author":"Opherk","year":"2014","journal-title":"Stroke"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1482","DOI":"10.1161\/STROKEAHA.114.008540","article-title":"Common NOTCH3 variants and cerebral small-vessel disease","volume":"46","author":"Traylor","year":"2015","journal-title":"Stroke"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"520","DOI":"10.1161\/STROKEAHA.116.012888","article-title":"New insight into the pathogenesis of cerebral small-vessel diseases","volume":"48","author":"Courtois","year":"2017","journal-title":"Stroke"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1964","DOI":"10.1212\/WNL.0000000000002694","article-title":"Distinct molecular mechanisms of HTRA1 mutants in manifesting heterozygotes with CARASIL","volume":"86","author":"Nozaki","year":"2016","journal-title":"Neurology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1371\/journal.pone.0146645","article-title":"The histone demethylase PHF8 is essential for endothelial cell migration","volume":"11","author":"Gu","year":"2016","journal-title":"PLoS ONE"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1016\/S0092-8674(02)00801-2","article-title":"E2F4\/5 and P107 as Smad cofactors linking the TGF\u03b2 receptor to c-myc repression","volume":"110","author":"Chen","year":"2002","journal-title":"Cell"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7357\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T06:27:53Z","timestamp":1760164073000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/14\/7357"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,7,8]]},"references-count":60,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2021,7]]}},"alternative-id":["ijms22147357"],"URL":"https:\/\/doi.org\/10.3390\/ijms22147357","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,7,8]]}}}