{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,3]],"date-time":"2026-03-03T14:32:15Z","timestamp":1772548335483,"version":"3.50.1"},"reference-count":53,"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":[{"name":"Italian Ministry of University","award":["PRIN \u2013 201534HNXC"],"award-info":[{"award-number":["PRIN \u2013 201534HNXC"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of the corticospinal motor neurons, which ultimately leads to death. The repeat expansion in chromosome 9 open reading frame 72 (C9ORF72) represents the most common genetic cause of ALS and it is also involved in the pathogenesis of other neurodegenerative disorders. To offer insights into C9ORF72-mediated pathogenesis, we quantitatively analyzed the proteome of patient-derived primary skin fibroblasts from ALS patients carrying the C9ORF72 mutation compared with ALS patients who tested negative for it. Differentially expressed proteins were identified, used to generate a protein-protein interaction network and subjected to a functional enrichment analysis to unveil altered molecular pathways. ALS patients were also compared with patients affected by frontotemporal dementia carrying the C9ORF72 repeat expansion. As a result, we demonstrated that the molecular pathways mainly altered in fibroblasts (e.g., protein homeostasis) mirror the alterations observed in C9ORF72-mutated neurons. Moreover, we highlighted novel molecular pathways (nuclear and mitochondrial transports, vesicle trafficking, mitochondrial bioenergetics, glucose metabolism, ER-phagosome crosstalk and Slit\/Robo signaling pathway) which might be further investigated as C9ORF72-specific pathogenetic mechanisms. Data are available via ProteomeXchange with the identifier PXD023866.<\/jats:p>","DOI":"10.3390\/ijms221910385","type":"journal-article","created":{"date-parts":[[2021,9,27]],"date-time":"2021-09-27T04:55:33Z","timestamp":1632718533000},"page":"10385","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["C9ORF72 Repeat Expansion Affects the Proteome of Primary Skin Fibroblasts in ALS"],"prefix":"10.3390","volume":"22","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0704-3439","authenticated-orcid":false,"given":"Marta","family":"Lualdi","sequence":"first","affiliation":[{"name":"Biochemistry and Functional Proteomics Laboratory, Department of Science and High Technology, Center of Bioinformatics and Center of Neuroscience, University of Insubria, I-21052 Busto Arsizio, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Adeena","family":"Shafique","sequence":"additional","affiliation":[{"name":"Biochemistry and Functional Proteomics Laboratory, Department of Science and High Technology, Center of Bioinformatics and Center of Neuroscience, University of Insubria, I-21052 Busto Arsizio, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Edoardo","family":"Pedrini","sequence":"additional","affiliation":[{"name":"Biochemistry and Functional Proteomics Laboratory, Department of Science and High Technology, Center of Bioinformatics and Center of Neuroscience, University of Insubria, I-21052 Busto Arsizio, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7141-1817","authenticated-orcid":false,"given":"Luisa","family":"Pieroni","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomic Laboratory, Experimental Neuroscience Department, S. Lucia Foundation IRCCS, I-00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4521-0020","authenticated-orcid":false,"given":"Viviana","family":"Greco","sequence":"additional","affiliation":[{"name":"Department of Basic Biotechnological Sciences, Intensivological and Perioperative Clinics, Universit\u00e0 Cattolica del Sacro Cuore, I-00168 Rome, Italy"},{"name":"Molecular and Genomic Diagnostics Unit, Fondazione Policlinico Universitario \u201cA. Gemelli\u201d IRCCS, I-00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Massimo","family":"Castagnola","sequence":"additional","affiliation":[{"name":"Proteomics and Metabolomic Laboratory, Experimental Neuroscience Department, S. Lucia Foundation IRCCS, I-00168 Rome, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Giorgia","family":"Cucina","sequence":"additional","affiliation":[{"name":"Biochemistry and Functional Proteomics Laboratory, Department of Science and High Technology, Center of Bioinformatics and Center of Neuroscience, University of Insubria, I-21052 Busto Arsizio, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lucia","family":"Corrado","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Eastern Piedmont \u201cA. Avogadro\u201d, I-28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alice","family":"Di Pierro","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Eastern Piedmont \u201cA. Avogadro\u201d, I-28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0197-1880","authenticated-orcid":false,"given":"Fabiola","family":"De Marchi","sequence":"additional","affiliation":[{"name":"Department of Translational Medicine, University of Eastern Piedmont \u201cA. Avogadro\u201d, I-28100 Novara, Italy"},{"name":"Department of Neurology and ALS Centre, \u201cMaggiore della Carit\u00e0\u201d Hospital, I-28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2148-3454","authenticated-orcid":false,"given":"Lara","family":"Camillo","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Eastern Piedmont \u201cA. Avogadro\u201d, I-28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Claudia","family":"Colombrita","sequence":"additional","affiliation":[{"name":"Department of Neurology-Stroke Unit and Laboratory of Neuroscience, Istituto Auxologico Italiano IRCCS, I-20149 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8625-6506","authenticated-orcid":false,"given":"Marianna","family":"D\u2019Anca","sequence":"additional","affiliation":[{"name":"Neurodegenerative Disease Unit, Fondazione Ca\u2019 Granda IRCCS, Policlinico Hospital, I-20122 Milan, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6065-6699","authenticated-orcid":false,"given":"Tiziana","family":"Alberio","sequence":"additional","affiliation":[{"name":"Biochemistry and Functional Proteomics Laboratory, Department of Science and High Technology, Center of Bioinformatics and Center of Neuroscience, University of Insubria, I-21052 Busto Arsizio, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandra","family":"D\u2019Alfonso","sequence":"additional","affiliation":[{"name":"Department of Health Sciences, University of Eastern Piedmont \u201cA. Avogadro\u201d, I-28100 Novara, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0628-5871","authenticated-orcid":false,"given":"Mauro","family":"Fasano","sequence":"additional","affiliation":[{"name":"Biochemistry and Functional Proteomics Laboratory, Department of Science and High Technology, Center of Bioinformatics and Center of Neuroscience, University of Insubria, I-21052 Busto Arsizio, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,9,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1097\/WCO.0b013e32835a3efb","article-title":"How Do C9ORF72 Repeat Expansions Cause ALS and FTD: Can We Learn from Other Non-Coding Repeat Expansion Disorders?","volume":"25","author":"Rademakers","year":"2012","journal-title":"Curr. Opin. Neurol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1016\/j.amjmed.2018.07.012","article-title":"Motor Neuron Disease: Pathophysiology, Diagnosis, and Management","volume":"132","author":"Foster","year":"2019","journal-title":"Am. J. Med."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1016\/j.neuron.2011.09.011","article-title":"Expanded GGGGCC Hexanucleotide Repeat in Non-Coding Region of C9ORF72 Causes Chromosome 9p-Linked Frontotemporal Dementia and Amyotrophic Lateral Sclerosis","volume":"72","author":"Mackenzie","year":"2011","journal-title":"Neuron"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"242.e7","DOI":"10.1016\/j.neurobiolaging.2019.02.026","article-title":"C9ORF72 Hexanucleotide Repeat Length in Older Population: Normal Variation and Effects on Cognition","volume":"84","author":"Kaivola","year":"2019","journal-title":"Neurobiol. 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Mol. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1610","DOI":"10.1038\/nn.4407","article-title":"C9ORF72 Interaction with Cofilin Modulates Actin Dynamics in Motor Neurons","volume":"19","author":"Sivadasan","year":"2016","journal-title":"Nat. Neurosci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"3062","DOI":"10.1007\/s12035-016-9850-1","article-title":"C9ORF72 Regulates Stress Granule Formation and Its Deficiency Impairs Stress Granule Assembly, Hypersensitizing Cells to Stress","volume":"54","author":"Maharjan","year":"2017","journal-title":"Mol. Neurobiol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"134523","DOI":"10.1016\/j.neulet.2019.134523","article-title":"C9ORF72 Protein Function and Immune Dysregulation in Amyotrophic Lateral Sclerosis","volume":"713","author":"Lai","year":"2019","journal-title":"Neurosci. Lett."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1016\/j.neuron.2011.09.010","article-title":"A Hexanucleotide Repeat Expansion in C9ORF72 Is the Cause of Chromosome 9p21-Linked ALS-FTD","volume":"72","author":"Renton","year":"2011","journal-title":"Neuron"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"544","DOI":"10.1038\/s41582-018-0047-2","article-title":"C9ORF72-Mediated ALS and FTD: Multiple Pathways to Disease","volume":"14","author":"Balendra","year":"2018","journal-title":"Nat. Rev. Neurol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"339","DOI":"10.1016\/j.ncl.2017.01.008","article-title":"Frontotemporal Dementia","volume":"35","author":"Olney","year":"2017","journal-title":"Neurol. Clin."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"72","DOI":"10.1016\/j.jns.2015.02.039","article-title":"Motor Neuron Dysfunctions in the Frontotemporal Lobar Degeneration Spectrum: A Clinical and Neurophysiological Study","volume":"351","author":"Cerami","year":"2015","journal-title":"J. Neurol. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1212\/WNL.59.7.1077","article-title":"The Overlap of Amyotrophic Lateral Sclerosis and Frontotemporal Dementia","volume":"59","author":"Anderson","year":"2002","journal-title":"Neurology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1590\/0004-282X20140229","article-title":"C9ORF72-Related Disorders: Expanding the Clinical and Genetic Spectrum of Neurodegenerative Diseases","volume":"73","author":"Souza","year":"2015","journal-title":"Arq. Neuropsiquiatr."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"575","DOI":"10.1002\/mdc3.12677","article-title":"C9ORF72 and Its Relevance in Parkinsonism and Movement Disorders: A Comprehensive Review of the Literature","volume":"5","author":"Bourinaris","year":"2018","journal-title":"Mov. Disord. Clin. Pract."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1007\/s12035-012-8245-1","article-title":"Primary Skin Fibroblasts as a Model of Parkinson\u2019s Disease","volume":"46","author":"Auburger","year":"2012","journal-title":"Mol. Neurobiol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1007\/s12640-015-9532-1","article-title":"Evaluation of Skin Fibroblasts from Amyotrophic Lateral Sclerosis Patients for the Rapid Study of Pathological Features","volume":"28","author":"Yang","year":"2015","journal-title":"Neurotox. Res."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"12","DOI":"10.1016\/j.ceca.2015.11.002","article-title":"Endoplasmic Reticulum and Lysosomal Ca2+ Stores Are Remodelled in GBA1-Linked Parkinson Disease Patient Fibroblasts","volume":"59","author":"Kilpatrick","year":"2016","journal-title":"Cell Calcium"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Keskin, I., Forsgren, E., Lange, D.J., Weber, M., Birve, A., Synofzik, M., Gilthorpe, J.D., Andersen, P.M., and Marklund, S.L. (2016). Effects of Cellular Pathway Disturbances on Misfolded Superoxide Dismutase-1 in Fibroblasts Derived from ALS Patients. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0150133"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"228","DOI":"10.1038\/s41593-017-0047-3","article-title":"TDP-43 Pathology Disrupts Nuclear Pore Complexes and Nucleocytoplasmic Transport in ALS\/FTD","volume":"21","author":"Chou","year":"2018","journal-title":"Nat. Neurosci."},{"key":"ref_25","first-page":"4388","article-title":"Distinction of Sporadic and Familial Forms of ALS Based on Mitochondrial Characteristics","volume":"33","author":"Walczak","year":"2019","journal-title":"FASEB J. Off. Publ. Fed. Am. Soc. Exp. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"105051","DOI":"10.1016\/j.nbd.2020.105051","article-title":"Chronic Stress Induces Formation of Stress Granules and Pathological TDP-43 Aggregates in Human ALS Fibroblasts and IPSC-Motoneurons","volume":"145","author":"Ratti","year":"2020","journal-title":"Neurobiol. Dis."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"423","DOI":"10.3389\/fcell.2020.00423","article-title":"Exploring the Impact of PARK2 Mutations on the Total and Mitochondrial Proteome of Human Skin Fibroblasts","volume":"8","author":"Zilocchi","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1016\/j.neuron.2013.07.033","article-title":"Converging Mechanisms in ALS and FTD: Disrupted RNA and Protein Homeostasis","volume":"79","author":"Ling","year":"2013","journal-title":"Neuron"},{"key":"ref_29","first-page":"5298","article-title":"Widespread Intron Retention Impairs Protein Homeostasis in C9ORF72 ALS Brains","volume":"26","author":"Wang","year":"2020","journal-title":"Genome Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1186\/s40478-019-0797-0","article-title":"Extensive Transcriptomic Study Emphasizes Importance of Vesicular Transport in C9ORF72 Expansion Carriers","volume":"7","author":"Dickson","year":"2019","journal-title":"Acta Neuropathol. Commun."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"548","DOI":"10.3389\/fnins.2019.00548","article-title":"Proteomics Approaches for Biomarker and Drug Target Discovery in ALS and FTD","volume":"13","author":"Hedl","year":"2019","journal-title":"Front. Neurosci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"453","DOI":"10.2217\/bmm-2016-0025","article-title":"Identification of Apo B48 and Other Novel Biomarkers in Amyotrophic Lateral Sclerosis Patient Fibroblasts","volume":"10","author":"Narayan","year":"2016","journal-title":"Biomark. Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2845","DOI":"10.1038\/s41467-018-05049-z","article-title":"Abnormal RNA Stability in Amyotrophic Lateral Sclerosis","volume":"9","author":"Tank","year":"2018","journal-title":"Nat. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13024-017-0217-5","article-title":"Fibroblast Bioenergetics to Classify Amyotrophic Lateral Sclerosis Patients","volume":"12","author":"Konrad","year":"2017","journal-title":"Mol. Neurodegener."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s00401-020-02252-5","article-title":"Mitochondrial Bioenergetic Deficits in C9ORF72 Amyotrophic Lateral Sclerosis Motor Neurons Cause Dysfunctional Axonal Homeostasis","volume":"141","author":"Mehta","year":"2021","journal-title":"Acta Neuropathol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"97","DOI":"10.3389\/fncel.2021.653688","article-title":"The Role of Mitochondrial Dysfunction and ER Stress in TDP-43 and C9ORF72 ALS","volume":"15","author":"Dafinca","year":"2021","journal-title":"Front. Cell. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"2694","DOI":"10.7150\/jca.31877","article-title":"The Role of the Slit\/Robo Signaling Pathway","volume":"10","author":"Tong","year":"2019","journal-title":"J. Cancer"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"178","DOI":"10.1016\/j.ydbio.2017.09.038","article-title":"Motor Axons Are Guided to Exit Points in the Spinal Cord by Slit and Netrin Signals","volume":"432","author":"Kim","year":"2017","journal-title":"Dev. Biol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"618","DOI":"10.1126\/sciadv.aav0618","article-title":"New Neurons Use Slit-Robo Signaling to Migrate through the Glial Meshwork and Approach a Lesion for Functional Regeneration","volume":"4","author":"Kaneko","year":"2018","journal-title":"Sci. Adv."},{"key":"ref_40","first-page":"150375","article-title":"Non-Cell Autonomous Control of Precerebellar Neuron Migration by Slit and Robo Proteins","volume":"145","author":"Dominici","year":"2018","journal-title":"Dev. Camb. Engl."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"137","DOI":"10.3389\/fcell.2020.00137","article-title":"Exploring the HeLa Dark Mitochondrial Proteome","volume":"8","author":"Marini","year":"2020","journal-title":"Front. Cell Dev. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"795","DOI":"10.1038\/nprot.2016.042","article-title":"Label-Free Quantification in Ion Mobility-Enhanced Data-Independent Acquisition Proteomics","volume":"11","author":"Distler","year":"2016","journal-title":"Nat. Protoc."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1074\/mcp.M500230-MCP200","article-title":"Absolute Quantification of Proteins by LCMSE: A Virtue of Parallel MS Acquisition","volume":"5","author":"Silva","year":"2006","journal-title":"Mol. Cell. Proteom. MCP"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"D442","DOI":"10.1093\/nar\/gky1106","article-title":"The PRIDE Database and Related Tools and Resources in 2019: Improving Support for Quantification Data","volume":"47","author":"Csordas","year":"2019","journal-title":"Nucleic Acids Res."},{"key":"ref_45","unstructured":"Bolstad, B. (2021, September 21). Preprocesscore: A Collection of Pre-Processing Functions. R Package Version 1.54.0. Available online: https:\/\/github.com\/bmbolstad\/preprocessCore."},{"key":"ref_46","unstructured":"Wickham, H. (2016). Ggplot2: Elegant Graphics for Data Analysis, Springer International Publishing. [2nd ed.]."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"2847","DOI":"10.1093\/bioinformatics\/btw313","article-title":"Complex Heatmaps Reveal Patterns and Correlations in Multidimensional Genomic Data","volume":"32","author":"Gu","year":"2016","journal-title":"Bioinformatics"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"2498","DOI":"10.1101\/gr.1239303","article-title":"Cytoscape: A Software Environment for Integrated Models of Biomolecular Interaction Networks","volume":"13","author":"Shannon","year":"2003","journal-title":"Genome Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"3135","DOI":"10.1093\/bioinformatics\/btq596","article-title":"GLay: Community Structure Analysis of Biological Networks","volume":"26","author":"Su","year":"2010","journal-title":"Bioinforma. Oxf. Engl."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"8488","DOI":"10.1073\/pnas.1314810111","article-title":"Visual Account of Protein Investment in Cellular Functions","volume":"111","author":"Liebermeister","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Rohart, F., Gautier, B., Singh, A., and Cao, K.-A.L. (2017). MixOmics: An R Package for \u2018omics Feature Selection and Multiple Data Integration. PLoS Comput. Biol., 13.","DOI":"10.1101\/108597"},{"key":"ref_52","unstructured":"R Core Team (2020). R: A Language and Environment for Statistical Computing, R Foundation for Statistical Computing."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Lualdi, M., Alberio, T., and Fasano, M. (2020). Proteostasis and Proteotoxicity in the Network Medicine Era. Int. J. Mol. Sci., 21.","DOI":"10.3390\/ijms21176405"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10385\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:05:33Z","timestamp":1760166333000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/22\/19\/10385"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,9,27]]},"references-count":53,"journal-issue":{"issue":"19","published-online":{"date-parts":[[2021,10]]}},"alternative-id":["ijms221910385"],"URL":"https:\/\/doi.org\/10.3390\/ijms221910385","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,9,27]]}}}