{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,27]],"date-time":"2026-05-27T15:08:47Z","timestamp":1779894527574,"version":"3.53.1"},"reference-count":60,"publisher":"MDPI AG","issue":"23","license":[{"start":{"date-parts":[[2019,11,22]],"date-time":"2019-11-22T00:00:00Z","timestamp":1574380800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2018YFD0900504"],"award-info":[{"award-number":["2018YFD0900504"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science and Technology Program of Guangzhou","award":["201804010096"],"award-info":[{"award-number":["201804010096"]}]},{"DOI":"10.13039\/501100012243","name":"Foundation for Distinguished Young Talents in Higher Education of Guangdong","doi-asserted-by":"publisher","award":["KA18058C3"],"award-info":[{"award-number":["KA18058C3"]}],"id":[{"id":"10.13039\/501100012243","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Iron is an essential element, closely linked with host immune responses. Nevertheless, the relationship between iron metabolism and virus infection is still unclear in aquatic vertebrates. To address this issue, we employed grass carp (Ctenopharyngodon idella) and its lethal virus, grass carp reovirus (GCRV), a double-strand RNA virus, as models. Our results demonstrate that GCRV infection increases the iron content and alters the expression of iron metabolism-related genes both in vivo and in vitro. Of note, the expression of C. idella transferrin receptor 1 (CiTfR1) rather than transferrin is upregulated upon GCRV infection. To clarify the implications of CiTfR1 upregulation for antiviral immunity, we proved that CiTfR1 was not a helper for GCRV invasion, but instead, it inhibited GCRV infection and promoted cell proliferation by facilitating the accumulation of intracellular labile iron pool (LIP), which increases intracellular oxidative stress. Interestingly, we found that CiTfR1 overexpression inhibited the mRNA expression of C. idella interferon 1 (CiIFN1) and CiIFN3. The present study reveals a novel antiviral defense mechanism in teleost where TfR1 induces the accumulation of LIP, leading to the suppression of virus infection and the proliferation of host cells, indicating that iron can be used as a medicated feed additive for the control of animal viral disease.<\/jats:p>","DOI":"10.3390\/ijms20235857","type":"journal-article","created":{"date-parts":[[2019,11,22]],"date-time":"2019-11-22T09:02:52Z","timestamp":1574413372000},"page":"5857","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Transferrin Receptor 1-Associated Iron Accumulation and Oxidative Stress Provides a Way for Grass Carp to Fight against Reovirus Infection"],"prefix":"10.3390","volume":"20","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4227-1530","authenticated-orcid":false,"given":"Quanyuan","family":"Wan","sequence":"first","affiliation":[{"name":"College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China"},{"name":"Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhiwei","family":"Liao","sequence":"additional","affiliation":[{"name":"College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Youliang","family":"Rao","sequence":"additional","affiliation":[{"name":"College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chunrong","family":"Yang","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianfei","family":"Ji","sequence":"additional","affiliation":[{"name":"College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaohui","family":"Chen","sequence":"additional","affiliation":[{"name":"College of Animal Science and Technology, Northwest A&amp;F University, Yangling, Xianyang 712100, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9083-0715","authenticated-orcid":false,"given":"Jianguo","family":"Su","sequence":"additional","affiliation":[{"name":"College of Fisheries, Huazhong Agricultural University, Wuhan 430070, China"},{"name":"Laboratory for Marine Biology and Biotechnology, Pilot National Laboratory for Marine Science and Technology (Qingdao), Qingdao 266237, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,11,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1126\/science.1183021","article-title":"Regulation of adaptive immunity by the innate immune system","volume":"327","author":"Iwasaki","year":"2010","journal-title":"Science"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"783","DOI":"10.1016\/j.cell.2006.02.015","article-title":"Pathogen recognition and innate immunity","volume":"124","author":"Akira","year":"2006","journal-title":"Cell"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"525","DOI":"10.1038\/nrmicro2836","article-title":"Nutritional immunity: Transition metals at the pathogen-host interface","volume":"10","author":"Hood","year":"2012","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"509","DOI":"10.1016\/j.chom.2013.04.010","article-title":"Iron in infection and immunity","volume":"13","author":"Cassat","year":"2013","journal-title":"Cell Host Microbe"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"11","DOI":"10.4049\/jimmunol.1800325","article-title":"Innate nutritional immunity","volume":"201","author":"Sakamoto","year":"2018","journal-title":"J. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"541","DOI":"10.1038\/nrmicro1930","article-title":"Viral infection and iron metabolism","volume":"6","author":"Drakesmith","year":"2008","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1077","DOI":"10.1016\/j.molmed.2016.10.005","article-title":"Siderophores in iron metabolism: From mechanism to therapy potential","volume":"22","author":"Wilson","year":"2016","journal-title":"Trends Mol. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1083","DOI":"10.1128\/JVI.02318-14","article-title":"White spot syndrome virus protein kinase 1 defeats the host cell\u2032s iron-withholding defense mechanism by interacting with host ferritin","volume":"89","author":"Lin","year":"2015","journal-title":"J. Virol."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1159\/000484722","article-title":"Echinochrome a release by red spherule cells is an iron-withholding strategy of sea urchin innate immunity","volume":"10","author":"Coates","year":"2018","journal-title":"J. Innate Immun."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.fsi.2016.04.128","article-title":"Identification and characterization of a ferritin gene involved in the immune defense response of scallop Chlamys farreri","volume":"55","author":"Chen","year":"2016","journal-title":"Fish Shellfish Immunol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.fsi.2014.10.039","article-title":"Ferritin protect shrimp Litopenaeus vannamei from WSSV infection by inhibiting virus replication","volume":"42","author":"Ye","year":"2015","journal-title":"Fish Shellfish Immunol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1016\/j.imbio.2006.02.004","article-title":"Iron-withholding strategy in innate immunity","volume":"211","author":"Ong","year":"2006","journal-title":"Immunobiology"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"3241","DOI":"10.1007\/s00018-009-0051-1","article-title":"Mammalian iron transport","volume":"66","author":"Anderson","year":"2009","journal-title":"Cell. Mol. Life Sci."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"24934","DOI":"10.1074\/jbc.M604592200","article-title":"The crystal structure of iron-free human serum transferrin provides insight into inter-lobe communication and receptor binding","volume":"281","author":"Wally","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"2137","DOI":"10.1016\/j.biocel.2004.02.007","article-title":"Transferrin receptor 1","volume":"36","author":"Aisen","year":"2004","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"875","DOI":"10.1016\/j.cell.2005.10.021","article-title":"TTP specifically regulates the internalization of the transferrin receptor","volume":"123","author":"Tosoni","year":"2005","journal-title":"Cell"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1016\/S0092-8674(04)00130-8","article-title":"Structure of the human transferrin receptor-transferrin complex","volume":"116","author":"Cheng","year":"2004","journal-title":"Cell"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1038\/nchembio.1416","article-title":"The role of iron and reactive oxygen species in cell death","volume":"10","author":"Dixon","year":"2014","journal-title":"Nat. Chem. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1060","DOI":"10.1016\/j.cell.2012.03.042","article-title":"Ferroptosis: An iron-dependent form of nonapoptotic cell death","volume":"149","author":"Dixon","year":"2012","journal-title":"Cell"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1089\/ars.2007.9.245","article-title":"A role for reactive oxygen\/nitrogen species and iron on neuronal synaptic plasticity","volume":"9","author":"Hidalgo","year":"2007","journal-title":"Antioxid. Redox Sign."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"300","DOI":"10.1016\/j.dci.2016.09.004","article-title":"Contributions of transferrin to acute inflammation in the goldfish, C. auratus","volume":"67","author":"Trites","year":"2017","journal-title":"Dev. Comp. Immunol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"290","DOI":"10.1016\/j.dci.2014.12.010","article-title":"The Megalobrama amblycephala transferrin and transferrin receptor genes: Molecular cloning, characterization and expression during early development and after Aeromonas hydrophila infection","volume":"49","author":"Ding","year":"2015","journal-title":"Dev. Comp. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.1016\/j.fsi.2013.08.012","article-title":"A teleostean counterpart of ferritin M subunit from rock bream (Oplegnathus fasciatus): An active constituent in iron chelation and DNA protection against oxidative damage, with a modulated expression upon pathogen stress","volume":"35","author":"Elvitigala","year":"2013","journal-title":"Fish Shellfish Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"411","DOI":"10.1016\/j.fsi.2017.05.032","article-title":"Comparative analysis of two ferritin subunits from blunt snout bream (Megalobrama amblycephala): Characterization, expression, iron depriving and bacteriostatic activity","volume":"66","author":"Ding","year":"2017","journal-title":"Fish Shellfish Immunol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"4265","DOI":"10.1038\/s41598-017-04069-x","article-title":"Coordination of bactericidal and iron regulatory functions of hepcidin in innate antimicrobial immunity in a zebrafish model","volume":"7","author":"Jiang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"274","DOI":"10.1016\/j.fsi.2018.02.023","article-title":"Hepcidin protects grass carp (Ctenopharyngodon idellus) against Flavobacterium columnare infection via regulating iron distribution and immune gene expression","volume":"75","author":"Wei","year":"2018","journal-title":"Fish Shellfish Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"138","DOI":"10.1016\/j.molimm.2016.04.007","article-title":"Differences in gene expression in Atlantic salmon parr and smolt after challenge with Piscine orthoreovirus (PRV)","volume":"73","author":"Johansen","year":"2016","journal-title":"Mol. Immunol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Chen, G., He, L., Luo, L., Huang, R., Liao, L., Li, Y., Zhu, Z., and Wang, Y. (2018). Transcriptomics sequencing provides insights into understanding the mechanism of grass carp reovirus infection. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19020488"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"492","DOI":"10.1016\/j.immuni.2016.02.016","article-title":"Macrophages and iron metabolism","volume":"44","author":"Soares","year":"2016","journal-title":"Immunity"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"776","DOI":"10.1038\/35001596","article-title":"Positional cloning of zebrafish ferroportin1 identifies a conserved vertebrate iron exporter","volume":"403","author":"Donovan","year":"2000","journal-title":"Nature"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Byrne, S.L., Buckett, P.D., Kim, J., Luo, F., Sanford, J., Chen, J., Enns, C., and Wessling-Resnick, M. (2013). Ferristatin II promotes degradation of transferrin receptor-1 in vitro and in vivo. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0070199"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"92","DOI":"10.1038\/nature05539","article-title":"Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses","volume":"446","author":"Radoshitzky","year":"2007","journal-title":"Nature"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"10777","DOI":"10.1073\/pnas.1301764110","article-title":"Identification of transferrin receptor 1 as a hepatitis C virus entry factor","volume":"110","author":"Martin","year":"2013","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2829","DOI":"10.1074\/jbc.M115.690941","article-title":"Transferrin receptor 1 facilitates poliovirus permeation of mouse brain capillary endothelial cells","volume":"291","author":"Mizutani","year":"2016","journal-title":"J. Biol. Chem."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"4551","DOI":"10.1038\/s41598-017-03990-5","article-title":"The destiny of the resistance\/susceptibility against GCRV is controlled by epigenetic mechanisms in CIK cells","volume":"7","author":"Shang","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"194586","DOI":"10.1155\/2011\/194586","article-title":"Strategies for reducing or preventing the generation of oxidative stress","volume":"2011","author":"Poljsak","year":"2011","journal-title":"Oxidative Med. Cell. Longev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1002\/cphy.c120016","article-title":"Iron homeostasis in the liver","volume":"3","author":"Anderson","year":"2013","journal-title":"Compr. Physiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"995","DOI":"10.1016\/j.jhep.2010.04.044","article-title":"Iron inhibits replication of infectious hepatitis C virus in permissive Huh7.5.1 cells","volume":"53","author":"Fillebeen","year":"2010","journal-title":"J. Hepatol."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"17387","DOI":"10.1074\/jbc.RA118.003840","article-title":"ROS-induced HSP70 promotes cytoplasmic translocation of high-mobility group box 1b and stimulates antiviral autophagy in grass carp kidney cells","volume":"293","author":"Rao","year":"2018","journal-title":"J. Biol. Chem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"750","DOI":"10.1007\/s13238-014-0083-7","article-title":"Essential functions of iron-requiring proteins in DNA replication, repair and cell cycle control","volume":"5","author":"Zhang","year":"2014","journal-title":"Protein Cell"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"6225","DOI":"10.1242\/dev.01540","article-title":"The Chianti zebrafish mutant provides a model for erythroid-specific disruption of transferrin receptor 1","volume":"131","author":"Wingert","year":"2004","journal-title":"Development"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S0145-305X(02)00138-6","article-title":"Transferrin and the innate immune response of fish: Identification of a novel mechanism of macrophage activation","volume":"27","author":"Stafford","year":"2003","journal-title":"Dev. Comp. Immunol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"15481","DOI":"10.3390\/ijms160715481","article-title":"Overexpression of the MRI reporter genes ferritin and transferrin receptor affect iron homeostasis and produce limited contrast in mesenchymal stem cells","volume":"16","author":"Pereira","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/j.hepres.2005.02.001","article-title":"Up-regulation of transferrin receptor 1 in chronic hepatitis C: Implication in excess hepatic iron accumulation","volume":"31","author":"Saito","year":"2005","journal-title":"Hepatol. Res."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"431","DOI":"10.1146\/annurev-nutr-082117-051749","article-title":"Crossing the iron gate: Why and how transferrin receptors mediate viral entry","volume":"38","year":"2018","journal-title":"Annu. Rev. Nutr."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1675","DOI":"10.4049\/jimmunol.154.4.1675","article-title":"Transferrin receptor induces tyrosine phosphorylation in T cells and is physically associated with the TCR zeta-chain","volume":"154","author":"Borroto","year":"1995","journal-title":"J. Immunol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1851","DOI":"10.1002\/eji.201344234","article-title":"KLRG1 activity is regulated by association with the transferrin receptor","volume":"44","author":"Schweier","year":"2014","journal-title":"Eur. J. Immunol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.virusres.2014.03.021","article-title":"Grass carp reovirus induces apoptosis and oxidative stress in grass carp (Ctenopharyngodon idellus) kidney cell line","volume":"185","author":"Jia","year":"2014","journal-title":"Virus Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"1296","DOI":"10.3389\/fimmu.2018.01296","article-title":"Iron overload is associated with oxidative stress and nutritional immunity during viral infection in fish","volume":"9","author":"Aguilar","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/j.dci.2016.03.020","article-title":"Bioinformatics analysis of organizational and expressional characterizations of the IFNs, IRFs and CRFBs in grass carp Ctenopharyngodon idella","volume":"61","author":"Liao","year":"2016","journal-title":"Dev. Comp. Immunol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"349","DOI":"10.1016\/j.fsi.2010.04.001","article-title":"Identification and expression profiling analysis of grass carp Ctenopharyngodon idella LGP2 cDNA","volume":"29","author":"Huang","year":"2010","journal-title":"Fish Shellfish Immunol."},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Hu, Y., Wei, X., Liao, Z., Gao, Y., Liu, X., Su, J., and Yuan, G. (2018). Transcriptome analysis provides insights into the markers of resting and LPS-activated macrophages in grass carp (Ctenopharyngodon idella). Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19113562"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"224","DOI":"10.1007\/s00436-005-1340-8","article-title":"Identification of immune genes in grass carp Ctenopharyngodon idella in response to infection of the parasitic copepod Sinergasilus major","volume":"96","author":"Chang","year":"2005","journal-title":"Parasitol. Res."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Peng, L., Yang, C., and Su, J. (2012). Protective roles of grass carp Ctenopharyngodon idella Mx isoforms against grass carp reovirus. PLoS ONE, 7.","DOI":"10.1371\/journal.pone.0052142"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1038\/ng.3280","article-title":"The draft genome of the grass carp (Ctenopharyngodon idellus) provides insights into its evolution and vegetarian adaptation","volume":"47","author":"Wang","year":"2015","journal-title":"Nat. Genet."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"7573","DOI":"10.4049\/jimmunol.1002401","article-title":"Characterization of fish IRF3 as an IFN-inducible protein reveals evolving regulation of IFN response in vertebrates","volume":"185","author":"Sun","year":"2010","journal-title":"J. Immunol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"573","DOI":"10.4049\/jimmunol.1701149","article-title":"Teleost-specific TLR19 localizes to endosome, recognizes dsRNA, recruits TRIF, triggers both IFN and NF-kappaB pathways, and protects cells from grass carp reovirus infection","volume":"200","author":"Ji","year":"2018","journal-title":"J. Immunol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"830","DOI":"10.1016\/j.fsi.2011.01.006","article-title":"Evaluation of internal control genes for qRT-PCR normalization in tissues and cell culture for antiviral studies of grass carp (Ctenopharyngodon idella)","volume":"30","author":"Su","year":"2011","journal-title":"Fish Shellfish Immunol."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1373\/49.1.175","article-title":"Total Iron-binding capacity calculated from serum transferrin concentration or serum iron concentration and unsaturated iron-binding capacity","volume":"49","author":"Yamanishi","year":"2003","journal-title":"Clin. Chem."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"489","DOI":"10.1515\/BC.2002.051","article-title":"The chelatable iron pool in living cells: A methodically defined quantity","volume":"383","author":"Petrat","year":"2002","journal-title":"Biol. Chem."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/23\/5857\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T13:36:37Z","timestamp":1760189797000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/23\/5857"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,11,22]]},"references-count":60,"journal-issue":{"issue":"23","published-online":{"date-parts":[[2019,12]]}},"alternative-id":["ijms20235857"],"URL":"https:\/\/doi.org\/10.3390\/ijms20235857","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,11,22]]}}}