{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T12:32:28Z","timestamp":1766579548893,"version":"3.48.0"},"reference-count":57,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2025,12,20]],"date-time":"2025-12-20T00:00:00Z","timestamp":1766188800000},"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>Studies in human medicine have demonstrated that rotavirus infection can also affect extraintestinal sites due to its systemic effects. However, in veterinary medicine, the injury caused by rotavirus diarrhea is limited to the intestines, and its effects on various systemic structures remain poorly understood. In this observational case\u2013control study, we aimed to determine the effects of HSP-27, Caspase-3, IL-2, \u03b3-H2AX, HMGB-1, SP-D, and GDH (or GLDH) on the pathogenesis of rotavirus infection by using biomarkers for diagnostic purposes in lung and liver injury in neonate diarrheic calves naturally infected with rotavirus, both alive and post-mortem. Fifty-two Simmental calves (1\u201328 days old) of both sexes, 40 infected with rotavirus and 12 healthy, were studied. Twenty-eight out of 40 survived, while the remainder underwent necropsy for histopathological and immunopathological (HSP-27, Caspase-3, IL-2, \u03b3-H2AX) examination of the lungs and livers. Lung and liver-specific serum E-selectin, glutamate dehydrogenase, surfactant protein-D, and high mobility group box-1 were analyzed by a bovine-specific ELISA kit (Shanghai Coon Koon Biotech Co., Ltd., China). Histopathological and immunohistochemical analyses confirmed lung and liver injury in naturally infected calves. HMGB-1, SP-D, and GDH concentrations were significantly higher in naturally infected calves than in the control group (p &lt; 0.001, p &lt; 0.001, and p &lt; 0.05, respectively), showing an excellent diagnostic predictive capacity for lung and liver injury. Also, IL-2, HSP-27, CASP-3, and \u03b3-H2AX were significantly expressed in the lungs (p &lt; 0.001, p &lt; 0.001, p &lt; 0.001, and p &lt; 0.05, respectively) and liver (p &lt; 0.001, p &lt; 0.001, p &lt; 0.01, and p &lt; 0.01, respectively). All these observations led us to hypothesize that oxidative stress, apoptosis, and DNA damage may underlie the pathogenesis of this condition. Nevertheless, further studies on large populations of rotavirus-infected calves are needed to confirm the data reported in the current study.<\/jats:p>","DOI":"10.3390\/ijms27010065","type":"journal-article","created":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T12:22:27Z","timestamp":1766578947000},"page":"65","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Evaluation of Systemic Injury in Calves with Rotavirus-Induced Diarrhea Using Sensitive Biomarkers and Immunopathology"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9294-1825","authenticated-orcid":false,"given":"Murat","family":"Uztim\u00fcr","sequence":"first","affiliation":[{"name":"Faculty of Veterinary Medicine, Department of Internal Medicine, Bing\u00f6l University, Bingol 12200, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cennet Nur","family":"\u00dcnal","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary Medicine, Department of Internal Medicine, Bing\u00f6l University, Bingol 12200, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5777-964X","authenticated-orcid":false,"given":"Muhammet Bahaddin","family":"D\u00f6rtbudak","sequence":"additional","affiliation":[{"name":"Faculty of Veterinary Medicine, Department of Pathology, Harran University, \u015eanl\u0131urfa 63290, T\u00fcrkiye"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Davide","family":"Bisanti","sequence":"additional","affiliation":[{"name":"San Francesco Veterinary Clinic, 73016 San Cesario di Lecce, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8122-9170","authenticated-orcid":false,"given":"Alessandro","family":"Di Cerbo","sequence":"additional","affiliation":[{"name":"School of Biosciences and Veterinary Medicine, University of Camerino, 62024 Matelica, Italy"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,20]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"110728","DOI":"10.1016\/j.vetimm.2024.110728","article-title":"Immunophenotyping of peripheral circulating lymphocytes and serum selenium levels in calves with neonatal diarrhea","volume":"269","author":"Uztimur","year":"2024","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"110947","DOI":"10.1016\/j.vetimm.2025.110947","article-title":"Evaluation of serum serotonin as a biomarker of intestinal inflammation in calves","volume":"284","author":"Uztimur","year":"2025","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1","DOI":"10.4142\/jvs.2014.15.1.1","article-title":"An overview of calf diarrhea\u2014Infectious etiology, diagnosis, and intervention","volume":"15","author":"Cho","year":"2014","journal-title":"J. Vet. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1186\/s43088-022-00309-w","article-title":"Clinical, hematological and some biochemical alterations during diarrhea in Friesian calves naturally infected with E. coli and Salmonella","volume":"11","author":"Shehta","year":"2022","journal-title":"Beni Suef Univ. J. Basic Appl. Sci."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"139","DOI":"10.2460\/ajvr.81.2.139","article-title":"Use of intestine-related biomarkers for detecting intestinal epithelial damage in neonatal calves with diarrhea","volume":"81","author":"Ok","year":"2020","journal-title":"Am. J. Vet. Res."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"4","DOI":"10.1097\/01.shk.0000188710.04777.9e","article-title":"Hmgb-1 as a therapeutic target for infectious and inflammatory disorders","volume":"25","author":"Mantell","year":"2006","journal-title":"Shock"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"565","DOI":"10.1084\/jem.192.4.565","article-title":"High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes","volume":"192","author":"Andersson","year":"2000","journal-title":"J. Exp. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"7370","DOI":"10.1074\/jbc.M306793200","article-title":"Involvement of toll-like receptors 2 and 4 in cellular activation by high mobility group box 1 protein","volume":"279","author":"Park","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"331","DOI":"10.1038\/nri1594","article-title":"High-mobility group box 1 protein (HMGB1): Nuclear weapon in the immune arsenal","volume":"5","author":"Lotze","year":"2005","journal-title":"Nat. Rev. Immunol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1038\/nm1124","article-title":"Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis","volume":"10","author":"Wang","year":"2004","journal-title":"Nat. Med."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"248","DOI":"10.1126\/science.285.5425.248","article-title":"HMG-1 as a late mediator of endotoxin lethality in mice","volume":"285","author":"Wang","year":"1999","journal-title":"Science"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1194\/jlr.C400018-JLR200","article-title":"Suppression of HMGB1 release by stearoyl lysophosphatidylcholine:an additional mechanism for its therapeutic effects in experimental sepsis","volume":"46","author":"Chen","year":"2005","journal-title":"J. Lipid Res."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"589","DOI":"10.2174\/138161206775474387","article-title":"Pulmonary surfactant proteins A and D: Innate immune functions and biomarkers for lung diseases","volume":"12","author":"Takahashi","year":"2006","journal-title":"Curr. Pharm. Des."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Park, J., Pabon, M., Choi, A.M.K., Siempos, I.I., Fredenburgh, L.E., Baron, R.M., Jeon, K., Chung, C.R., Yang, J.H., and Park, C.M. (2017). Plasma surfactant protein-D as a diagnostic biomarker for acute respiratory distress syndrome: Validation in US and Korean cohorts. BMC Pulm. Med., 17.","DOI":"10.1186\/s12890-017-0532-1"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Peukert, K., Seeliger, B., Fox, M., Feuerborn, C., Sauer, A., Schuss, P., Schneider, M., David, S., Welte, T., and Putensen, C. (2021). SP-D Serum Levels Reveal Distinct Epithelial Damage in Direct Human ARDS. J. Clin. Med., 10.","DOI":"10.3390\/jcm10040737"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"25","DOI":"10.1007\/s00408-014-9669-3","article-title":"Serum surfactant protein D (SP-D) is a prognostic marker of poor outcome in patients with A\/H1N1 virus infection","volume":"193","author":"Delgado","year":"2015","journal-title":"Lung"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"20","DOI":"10.1097\/00003246-200301000-00003","article-title":"Prognostic value of surfactant proteins A and D in patients with acute lung injury","volume":"31","author":"Cheng","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1447","DOI":"10.1378\/chest.07-0864","article-title":"Surfactant protein-D and surfactant inhibit endotoxin-induced pulmonary inflammation","volume":"132","author":"Ikegami","year":"2007","journal-title":"Chest"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"7815","DOI":"10.1007\/s11033-023-08666-0","article-title":"Biomarkers of liver diseases","volume":"50","author":"Tamber","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1582","DOI":"10.1111\/liv.13441","article-title":"The transformation in biomarker detection and management of drug-induced liver injury","volume":"37","author":"Church","year":"2017","journal-title":"Liver Int."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"461","DOI":"10.1080\/1354750X.2016.1269131","article-title":"A longitudinal assessment of miR-122 and GLDH as biomarkers of drug-induced liver injury in the rat","volume":"22","author":"Thulin","year":"2017","journal-title":"Biomarkers"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"131","DOI":"10.1016\/j.taap.2014.03.015","article-title":"Liver biomarker and in vitro assessment confirm the hepatic origin of aminotransferase elevations lacking histopathological correlate in beagle dogs treated with GABAA receptor antagonist NP260","volume":"277","author":"Harrill","year":"2014","journal-title":"Toxicol. Appl. Pharmacol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2464","DOI":"10.1002\/1097-0142(20000601)88:11<2464::AID-CNCR6>3.0.CO;2-W","article-title":"Prognostic significance of heat shock protein-27 expression in hepatocellular carcinoma and its relation to histologic grading and survival","volume":"88","author":"King","year":"2000","journal-title":"Cancer"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1633","DOI":"10.1002\/bab.2233","article-title":"Caspase-3: Structure, function, and biotechnological aspects","volume":"69","author":"Asadi","year":"2022","journal-title":"Biotechnol. Appl. Biochem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"245","DOI":"10.1146\/annurev.iy.11.040193.001333","article-title":"The IL-2 receptor complex: Its structure, function, and target genes","volume":"11","author":"Minami","year":"1993","journal-title":"Annu. Rev. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1010428317695931","DOI":"10.1177\/1010428317695931","article-title":"gamma-H2AX: Can it be established as a classical cancer prognostic factor?","volume":"39","author":"Palla","year":"2017","journal-title":"Tumour Biol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"309","DOI":"10.2147\/OTT.S36995","article-title":"gamma-H2AX expression detected by immunohistochemistry correlates with prognosis in early operable non-small cell lung cancer","volume":"5","author":"Matthaios","year":"2012","journal-title":"Onco Targets Ther."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"758","DOI":"10.1053\/jhep.2001.28229","article-title":"Caspase activation correlates with the degree of inflammatory liver injury in chronic hepatitis C virus infection","volume":"34","author":"Bantel","year":"2001","journal-title":"Hepatology"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.jcpa.2003.12.008","article-title":"Immunohistochemical labelling of cytokines in lung lesions of pigs naturally infected with Mycoplasma hyopneumoniae","volume":"130","author":"Rodriguez","year":"2004","journal-title":"J. Comp. Pathol."},{"key":"ref_30","first-page":"3775","article-title":"Expression of HSP27 in Hepatocellular Carcinoma","volume":"36","author":"Eto","year":"2016","journal-title":"Anticancer. Res."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"597095","DOI":"10.1155\/2013\/597095","article-title":"DNA damage sensor gamma -H2AX is increased in preneoplastic lesions of hepatocellular carcinoma","volume":"2013","author":"Matsuda","year":"2013","journal-title":"Sci. World J."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"2836","DOI":"10.18632\/aging.101956","article-title":"Hepatic histopathology and apoptosis in diet-induced-obese mice under Escherichia coli pneumonia","volume":"11","author":"Song","year":"2019","journal-title":"Aging"},{"key":"ref_33","first-page":"1043","article-title":"Emerging Roles of High-mobility Group Box-1 in Liver Disease","volume":"12","author":"Wang","year":"2024","journal-title":"J. Clin. Transl. Hepatol."},{"key":"ref_34","doi-asserted-by":"crossref","unstructured":"Kim, S.H., Choi, Y., Miguel, M.A., Lee, S.J., Lee, S.S., and Lee, S.S. (2023). Analysis of Fecal Microbial Changes in Young Calves Following Bovine Rotavirus Infection. Vet. Sci., 10.","DOI":"10.3390\/vetsci10080496"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1093\/toxsci\/kfp235","article-title":"High-mobility group box-1 protein and keratin-18, circulating serum proteins informative of acetaminophen-induced necrosis and apoptosis in vivo","volume":"112","author":"Antoine","year":"2009","journal-title":"Toxicol. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","unstructured":"de Andres, P.J., Ferreiro, S., Flores, A., Garcia, A., and Henriquez-Camacho, C. (2024). Histological Assessment of Respiratory Tract and Liver of BALB\/c Mice Nebulized with Tocilizumab. Pharmaceutics, 16.","DOI":"10.3390\/pharmaceutics16070862"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Abou-Zeid, S.M., Aljuaydi, S.H., AbuBakr, H.O., Tahoun, E.A., Di Cerbo, A., Alagawany, M., Khalil, S.R., and Farag, M.R. (2021). Astaxanthin Mitigates Thiacloprid-Induced Liver Injury and Immunotoxicity in Male Rats. Mar. Drugs, 19.","DOI":"10.3390\/md19090525"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"276","DOI":"10.1093\/toxsci\/kft009","article-title":"Assessment of emerging biomarkers of liver injury in human subjects","volume":"132","author":"Schomaker","year":"2013","journal-title":"Toxicol. Sci."},{"key":"ref_39","unstructured":"Harris, R.J.C. (1962). Two viruses causing diarrhoea in infant mice. The Problems of Laboratory Animal Disease, Academic Press Inc."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"291","DOI":"10.1016\/j.vetmic.2011.05.017","article-title":"Intestinal and extra-intestinal pathogenicity of a bovine reassortant rotavirus in calves and piglets","volume":"152","author":"Kim","year":"2011","journal-title":"Vet. Microbiol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/0378-1135(83)90017-2","article-title":"Intestinal changes associated with rotavirus and enterotoxigenic Escherichia coli infection in calves","volume":"8","author":"Tzipori","year":"1983","journal-title":"Vet. Microbiol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1177\/002215540405200104","article-title":"Expression of cytokines (TNF-alpha, IL-1alpha, and IL-2) in chronic hepatitis C: Comparative hybridocytochemical and immunocytochemical study in children and adult patients","volume":"52","author":"Kasprzak","year":"2004","journal-title":"J. Histochem. Cytochem."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"4820","DOI":"10.1128\/JVI.80.10.4820-4832.2006","article-title":"Rotavirus viremia and extraintestinal viral infection in the neonatal rat model","volume":"80","author":"Crawford","year":"2006","journal-title":"J. Virol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"777","DOI":"10.1002\/hep.26294","article-title":"Mechanistic biomarkers provide early and sensitive detection of acetaminophen-induced acute liver injury at first presentation to hospital","volume":"58","author":"Antoine","year":"2013","journal-title":"Hepatology"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1038\/modpathol.3800146","article-title":"Overexpression of caspase-3 in hepatocellular carcinomas","volume":"17","author":"Persad","year":"2004","journal-title":"Mod. Pathol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"114921","DOI":"10.1016\/j.bios.2022.114921","article-title":"A microfluidic device for assessment of E-selectin-mediated neutrophil recruitment to inflamed endothelium and prediction of therapeutic response in sickle cell disease","volume":"222","author":"Man","year":"2023","journal-title":"Biosens. Bioelectron."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"113","DOI":"10.1016\/j.theriogenology.2022.01.019","article-title":"Serum sRAGE and sE-selectin levels are useful biomarkers of lung injury and prediction of mortality in calves with perinatal asphyxia","volume":"181","author":"Ider","year":"2022","journal-title":"Theriogenology"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1347","DOI":"10.2460\/ajvr.2004.65.1347","article-title":"Evaluation of hepatosplanchnic circulation and intestinal oxygenation in dogs with a condition that mimicked septic shock induced by continuous infusion of a low dose of lipopolysaccharide","volume":"65","author":"Sakaue","year":"2004","journal-title":"Am. J. Vet. Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"110979","DOI":"10.1016\/j.vetimm.2025.110979","article-title":"Investigation of the relationship between serum endocan level and interleukin-6, procalcitonin, e-selectin in calves with diarrhea, according to the etiological factor","volume":"286","author":"Unal","year":"2025","journal-title":"Vet. Immunol. Immunopathol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Wei, X., Wang, W., Dong, Z., Cheng, F., Zhou, X., Li, B., and Zhang, J. (2020). Detection of Infectious Agents Causing Neonatal Calf Diarrhea on Two Large Dairy Farms in Yangxin County, Shandong Province, China. Front. Vet. Sci., 7.","DOI":"10.3389\/fvets.2020.589126"},{"key":"ref_51","doi-asserted-by":"crossref","unstructured":"Berber, E., Canakoglu, N., Sozdutmaz, I., Simsek, E., Sursal, N., Ekinci, G., Kokkaya, S., Arikan, E., Ambarcioglu, P., and Goksu, A.G. (2021). Seasonal and Age-Associated Pathogen Distribution in Newborn Calves with Diarrhea Admitted to ICU. Vet. Sci., 8.","DOI":"10.3390\/vetsci8070128"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Canelli, E., Ferrari, L., Borghetti, P., Candela, F., Abiakam, N.S., Bianchera, A., Buttini, F., Magi, G.E., Sonvico, F., and Martelli, P. (2023). Nano-adjuvanted dry powder vaccine for the mucosal immunization against airways pathogens. Front. Vet. Sci., 10.","DOI":"10.3389\/fvets.2023.1116722"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"105043","DOI":"10.1016\/j.rvsc.2023.105043","article-title":"Evaluation of brain injury in goats naturally infected with Coenurus cerebralis; brain specific biomarkers, acute inflammation, and DNA oxidation","volume":"165","author":"Uztimur","year":"2023","journal-title":"Res. Vet. Sci."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"106269","DOI":"10.1016\/j.tvjl.2024.106269","article-title":"Assessment of brain injury in cattle with Theileria annulata: Neuron-specific biomarkers, inflammation, oxidative stress and apoptosis","volume":"309","author":"Uztimur","year":"2025","journal-title":"Vet. J."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Magi, G.E., Mariotti, F., Pallotta, L., Di Cerbo, A., and Venanzi, F.M. (2022). Immunohistochemical Expression of p62 in Feline Mammary Carcinoma and Non-Neoplastic Mammary Tissue. Animals, 12.","DOI":"10.3390\/ani12151964"},{"key":"ref_56","doi-asserted-by":"crossref","unstructured":"Ozturk, Y., Ozturk, M., Dortbudak, M.B., Mariotti, F., Magi, G.E., and Di Cerbo, A. (2025). Astaxanthin Mitigates 5-Fluorouracil-Induced Hepatotoxicity and Oxidative Stress in Male Rats. Nutrients, 17.","DOI":"10.3390\/nu17071230"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1763","DOI":"10.1213\/ANE.0000000000002864","article-title":"Correlation Coefficients: Appropriate Use and Interpretation","volume":"126","author":"Schober","year":"2018","journal-title":"Anesth. Analg."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/65\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,24]],"date-time":"2025-12-24T12:25:01Z","timestamp":1766579101000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/1\/65"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,20]]},"references-count":57,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["ijms27010065"],"URL":"https:\/\/doi.org\/10.3390\/ijms27010065","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,20]]}}}