{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T05:15:10Z","timestamp":1787030110880,"version":"build-2736575974"},"reference-count":65,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2022,1,7]],"date-time":"2022-01-07T00:00:00Z","timestamp":1641513600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Health","award":["P20GM103629"],"award-info":[{"award-number":["P20GM103629"]}]},{"name":"Tulane University Faculty Research Enhancement Funds","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100006952","name":"Louisiana Board of Regents","doi-asserted-by":"publisher","award":["(2017-22)-GF-11"],"award-info":[{"award-number":["(2017-22)-GF-11"]}],"id":[{"id":"10.13039\/100006952","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>Glioblastoma (GBM) is an aggressive primary central nervous system neoplasia with limited therapeutic options and poor prognosis. Following reports of cytomegalovirus (HCMV) in GBM tumors, the anti-viral drug Valganciclovir was administered and found to significantly increase the longevity of GBM patients. While these findings suggest a role for HCMV in GBM, the relationship between them is not clear and remains controversial. Treatment with anti-viral drugs may prove clinically useful; however, their results do not explain the underlying mechanism between HCMV infection and GBM progression. We hypothesized that HCMV infection would metabolically reprogram GBM cells and that these changes would allow for increased tumor progression. We infected LN-18 GBM cells and employed a Seahorse Bioanalyzer to characterize cellular metabolism. Increased mitochondrial respiration and glycolytic rates were observed following infection. These changes were accompanied by elevated production of reactive oxygen species and lactate. Due to lactate\u2019s numerous tumor-promoting effects, we examined the impact of paracrine signaling of HCMV-infected GBM cells on uninfected stromal cells. Our results indicated that, independent of viral transmission, the secretome of HCMV-infected GBM cells was able to alter the expression of key metabolic proteins and epigenetic markers. This suggests a mechanism of action where reprogramming of GBM cells alters the surrounding tumor microenvironment to be permissive to tumor progression in a manner akin to the Reverse-Warburg Effect. Overall, this suggests a potential oncomodulatory role for HCMV in the context of GBM.<\/jats:p>","DOI":"10.3390\/v14010103","type":"journal-article","created":{"date-parts":[[2022,1,9]],"date-time":"2022-01-09T23:35:09Z","timestamp":1641771309000},"page":"103","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Metabolic Reprogramming of Glioblastoma Cells during HCMV Infection Induces Secretome-Mediated Paracrine Effects in the Microenvironment"],"prefix":"10.3390","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4685-3757","authenticated-orcid":false,"given":"Mark A. 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Rep."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"De Vleeschouwer, S. (2017). Current Standards of Care in Glioblastoma Therapy. Glioblastoma, Codon Publications.","DOI":"10.15586\/codon.glioblastoma.2017"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1865","DOI":"10.1126\/science.7997879","article-title":"Identification of herpesvirus-like DNA sequences in AIDS-associated Kaposi\u2019s sarcoma","volume":"266","author":"Chang","year":"1994","journal-title":"Science"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"702","DOI":"10.1016\/S0140-6736(64)91524-7","article-title":"Virus Particles in Cultured Lymphoblasts from Burkitt\u2019s Lymphoma","volume":"1","author":"Epstein","year":"1964","journal-title":"Lancet"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Chang, Y., Moore, P.S., and Weiss, R.A. (2017). Human oncogenic viruses: Nature and discovery. Philos. Trans. R. Soc. Lond. B Biol. Sci., 372.","DOI":"10.1098\/rstb.2016.0264"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1007\/s11060-011-0658-6","article-title":"The roles of viruses in brain tumor initiation and oncomodulation","volume":"105","author":"Kofman","year":"2011","journal-title":"J. NeuroOncol."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"387","DOI":"10.1007\/s11481-010-9204-0","article-title":"Chronic viral infection and primary central nervous system malignancy","volume":"5","author":"Crawford","year":"2010","journal-title":"J. Neuroimmune Pharmacol."},{"key":"ref_8","first-page":"3347","article-title":"Human cytomegalovirus infection and expression in human malignant glioma","volume":"62","author":"Cobbs","year":"2002","journal-title":"Cancer Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1266","DOI":"10.1002\/jmv.25673","article-title":"Human cytomegalovirus infection in Iranian glioma patients correlates with aging and tumor aggressiveness","volume":"92","author":"Maleki","year":"2020","journal-title":"J. Med. Virol."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"10","DOI":"10.1215\/15228517-2007-035","article-title":"Sensitive detection of human cytomegalovirus in tumors and peripheral blood of patients diagnosed with glioblastoma","volume":"10","author":"Mitchell","year":"2008","journal-title":"Neuro Oncol."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"79","DOI":"10.1007\/s00401-008-0359-1","article-title":"Detection of human cytomegalovirus in different histological types of gliomas","volume":"116","author":"Scheurer","year":"2008","journal-title":"Acta NeuroPathol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1016\/j.jcv.2012.12.018","article-title":"Human cytomegalovirus infection levels in glioblastoma multiforme are of prognostic value for survival","volume":"57","author":"Rahbar","year":"2013","journal-title":"J. Clin. Virol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Libard, S., Popova, S.N., Amini, R.M., Karja, V., Pietilainen, T., Hamalainen, K.M., Sundstrom, C., Hesselager, G., Bergqvist, M., and Ekman, S. (2014). Human cytomegalovirus tegument protein pp65 is detected in all intra- and extra-axial brain tumours independent of the tumour type or grade. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0108861"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"6815","DOI":"10.1128\/JVI.00015-12","article-title":"Genetic analysis of cytomegalovirus in malignant gliomas","volume":"86","author":"Bhattacharjee","year":"2012","journal-title":"J. Virol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"854","DOI":"10.1128\/JVI.06097-11","article-title":"Significant association of multiple human cytomegalovirus genomic Loci with glioblastoma multiforme samples","volume":"86","author":"Ranganathan","year":"2012","journal-title":"J. Virol."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"231","DOI":"10.1007\/s11060-010-0383-6","article-title":"The detection of CMV pp65 and IE1 in glioblastoma multiforme","volume":"103","author":"Lucas","year":"2011","journal-title":"J. NeuroOncol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"838","DOI":"10.1038\/modpathol.3800352","article-title":"Lack of association of cytomegalovirus with human brain tumors","volume":"18","author":"Lau","year":"2005","journal-title":"Mod. Pathol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1469","DOI":"10.1093\/neuonc\/nou167","article-title":"Human cytomegalovirus infection in tumor cells of the nervous system is not detectable with standardized pathologico-virological diagnostics","volume":"16","author":"Baumgarten","year":"2014","journal-title":"Neuro Oncol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"4031","DOI":"10.1158\/1078-0432.CCR-20-0369","article-title":"Valganciclovir as Add-on to Standard Therapy in Glioblastoma Patients","volume":"26","author":"Stragliotto","year":"2020","journal-title":"Clin. Cancer Res."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1204","DOI":"10.1002\/ijc.28111","article-title":"Effects of valganciclovir as an add-on therapy in patients with cytomegalovirus-positive glioblastoma: A randomized, double-blind, hypothesis-generating study","volume":"133","author":"Stragliotto","year":"2013","journal-title":"Int. J. Cancer"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.1086\/508173","article-title":"Seroprevalence of cytomegalovirus infection in the United States, 1988\u20131994","volume":"43","author":"Staras","year":"2006","journal-title":"Clin. Infect. Dis."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"587","DOI":"10.1093\/ije\/29.3.587","article-title":"Human cytomegalovirus seroprevalence in three socioeconomically different urban areas during the first trimester: A population-based cohort study","volume":"29","author":"Mustakangas","year":"2000","journal-title":"Int. J. Epidemiol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"202","DOI":"10.1002\/rmv.655","article-title":"Review of cytomegalovirus seroprevalence and demographic characteristics associated with infection","volume":"20","author":"Cannon","year":"2010","journal-title":"Rev. Med. Virol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e3078","DOI":"10.1038\/cddis.2017.461","article-title":"Essential role of HCMV deubiquitinase in promoting oncogenesis by targeting anti-viral innate immune signaling pathways","volume":"8","author":"Kumari","year":"2017","journal-title":"Cell Death Dis."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"107","DOI":"10.1186\/1423-0127-16-107","article-title":"Human cytomegalovirus UL76 induces chromosome aberrations","volume":"16","author":"Siew","year":"2009","journal-title":"J. Biomed. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"19","DOI":"10.4049\/jimmunol.180.1.19","article-title":"Immune modulation by the human cytomegalovirus-encoded molecule UL18, a mystery yet to be solved","volume":"180","author":"Wagner","year":"2008","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"1179","DOI":"10.1038\/nbt.1500","article-title":"Systems-level metabolic flux profiling identifies fatty acid synthesis as a target for antiviral therapy","volume":"26","author":"Munger","year":"2008","journal-title":"Nat. Biotechnol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Munger, J., Bajad, S.U., Coller, H.A., Shenk, T., and Rabinowitz, J.D. (2006). Dynamics of the cellular metabolome during human cytomegalovirus infection. PLoS Pathog, 2.","DOI":"10.1371\/journal.ppat.0020132"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1573","DOI":"10.1128\/JVI.01967-10","article-title":"Human cytomegalovirus activates glucose transporter 4 expression to increase glucose uptake during infection","volume":"85","author":"Yu","year":"2011","journal-title":"J. Virol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"935","DOI":"10.1016\/j.mito.2011.08.008","article-title":"Human cytomegalovirus infection increases mitochondrial biogenesis","volume":"11","author":"Kaarbo","year":"2011","journal-title":"Mitochondrion"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e01183-19","DOI":"10.1128\/JVI.01183-19","article-title":"Human Cytomegalovirus Alters Host Cell Mitochondrial Function during Acute Infection","volume":"94","author":"Combs","year":"2020","journal-title":"J. Virol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e2101675118","DOI":"10.1073\/pnas.2101675118","article-title":"The human cytomegalovirus protein pUL13 targets mitochondrial cristae architecture to increase cellular respiration during infection","volume":"118","author":"Betsinger","year":"2021","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"646","DOI":"10.1016\/j.cell.2011.02.013","article-title":"Hallmarks of cancer: The next generation","volume":"144","author":"Hanahan","year":"2011","journal-title":"Cell"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"269","DOI":"10.1126\/science.124.3215.269","article-title":"On respiratory impairment in cancer cells","volume":"124","author":"Warburg","year":"1956","journal-title":"Science"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1085\/jgp.8.6.519","article-title":"The Metabolism of Tumors in the Body","volume":"8","author":"Warburg","year":"1927","journal-title":"J. Gen. Physiol."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"3984","DOI":"10.4161\/cc.8.23.10238","article-title":"The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma","volume":"8","author":"Pavlides","year":"2009","journal-title":"Cell Cycle"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14E.3.1","DOI":"10.1002\/9780471729259.mc14e03s18","article-title":"Human cytomegalovirus: Propagation, quantification, and storage","volume":"18","author":"Britt","year":"2010","journal-title":"Curr. Protoc. MicroBiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1671","DOI":"10.1172\/JCI123375","article-title":"Cytomegalovirus promotes murine glioblastoma growth via pericyte recruitment and angiogenesis","volume":"129","author":"Krenzlin","year":"2019","journal-title":"J. Clin. Investig."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"71","DOI":"10.1191\/0960327102ht213oa","article-title":"Reactive oxygen species as double-edged swords in cellular processes: Low-dose cell signaling versus high-dose toxicity","volume":"21","author":"Martin","year":"2002","journal-title":"Hum. Exp. Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","unstructured":"Rodriguez-Sanchez, I., Schafer, X.L., Monaghan, M., and Munger, J. (2019). The Human Cytomegalovirus UL38 protein drives mTOR-independent metabolic flux reprogramming by inhibiting TSC2. PLoS Pathog., 15.","DOI":"10.1371\/journal.ppat.1007569"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"5001","DOI":"10.1158\/1078-0432.CCR-13-2499","article-title":"Molecular pathways: Deregulation of histone h3 lysine 27 methylation in cancer-different paths, same destination","volume":"20","author":"Ezponda","year":"2014","journal-title":"Clin. Cancer Res."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ngollo, M., Lebert, A., Daures, M., Judes, G., Rifai, K., Dubois, L., Kemeny, J.L., Penault-Llorca, F., Bignon, Y.J., and Guy, L. (2017). Global analysis of H3K27me3 as an epigenetic marker in prostate cancer progression. BMC Cancer, 17.","DOI":"10.1186\/s12885-017-3256-y"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"440","DOI":"10.21037\/atm.2018.10.21","article-title":"H3K27me3 induces multidrug resistance in small cell lung cancer by affecting HOXA1 DNA methylation via regulation of the lncRNA HOTAIR","volume":"6","author":"Fang","year":"2018","journal-title":"Ann. Transl. Med."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"5369","DOI":"10.18632\/oncotarget.3030","article-title":"Global analysis of H3K4me3 and H3K27me3 profiles in glioblastoma stem cells and identification of SLC17A7 as a bivalent tumor suppressor gene","volume":"6","author":"Lin","year":"2015","journal-title":"Oncotarget"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1007\/s11060-015-1734-0","article-title":"Cytomegalovirus and glioblastoma; controversies and opportunities","volume":"123","author":"Lawler","year":"2015","journal-title":"J. NeuroOncol."},{"key":"ref_46","doi-asserted-by":"crossref","unstructured":"Stragliotto, G., Pantalone, M.R., Rahbar, A., and Soderberg-Naucler, C. (2020). Valganciclovir as Add-On to Standard Therapy in Secondary Glioblastoma. Microorganisms, 8.","DOI":"10.3390\/microorganisms8101471"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"827","DOI":"10.1016\/j.cmet.2012.05.001","article-title":"Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo","volume":"15","author":"Yang","year":"2012","journal-title":"Cell Metab."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1002\/nbm.2794","article-title":"Metabolism of [U-13 C]glucose in human brain tumors in vivo","volume":"25","author":"Maher","year":"2012","journal-title":"NMR Biomed."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"109024","DOI":"10.1016\/j.celrep.2021.109024","article-title":"Inhibition of mitochondrial translation suppresses glioblastoma stem cell growth","volume":"35","author":"Sighel","year":"2021","journal-title":"Cell Rep."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/1177271918755391","article-title":"Reactive Oxygen Species: A Key Constituent in Cancer Survival","volume":"13","author":"Kumari","year":"2018","journal-title":"Biomark Insights"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"479","DOI":"10.3109\/10715761003667554","article-title":"Reactive oxygen species in cancer","volume":"44","author":"Liou","year":"2010","journal-title":"Free Radic. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"20336","DOI":"10.1074\/jbc.M111899200","article-title":"Reversible inactivation of the tumor suppressor PTEN by H2O2","volume":"277","author":"Lee","year":"2002","journal-title":"J. Biol. Chem."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"105159","DOI":"10.1016\/j.antiviral.2021.105159","article-title":"Inhibiting cytomegalovirus replication through targeting the host electron transport chain","volume":"194","author":"Combs","year":"2021","journal-title":"Antiviral Res."},{"key":"ref_54","doi-asserted-by":"crossref","unstructured":"Sanzey, M., Abdul Rahim, S.A., Oudin, A., Dirkse, A., Kaoma, T., Vallar, L., Herold-Mende, C., Bjerkvig, R., Golebiewska, A., and Niclou, S.P. (2015). Comprehensive analysis of glycolytic enzymes as therapeutic targets in the treatment of glioblastoma. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0123544"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"67966","DOI":"10.18632\/oncotarget.11817","article-title":"Human cytomegalovirus encoded chemokine receptor US28 activates the HIF-1alpha\/PKM2 axis in glioblastoma cells","volume":"7","author":"Siderius","year":"2016","journal-title":"Oncotarget"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1038\/cdd.2010.150","article-title":"Acidic stress promotes a glioma stem cell phenotype","volume":"18","author":"Hjelmeland","year":"2011","journal-title":"Cell Death Differ."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Lai, S.W., Lin, H.J., Liu, Y.S., Yang, L.Y., and Lu, D.Y. (2020). Monocarboxylate Transporter 4 Regulates Glioblastoma Motility and Monocyte Binding Ability. Cancers, 12.","DOI":"10.3390\/cancers12020380"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"3970","DOI":"10.18632\/oncotarget.2147","article-title":"The nutritional phenome of EMT-induced cancer stem-like cells","volume":"5","author":"Cuyas","year":"2014","journal-title":"Oncotarget"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1143","DOI":"10.3389\/fonc.2019.01143","article-title":"Lactate in the Regulation of Tumor Microenvironment and Therapeutic Approaches","volume":"9","year":"2019","journal-title":"Front. Oncol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.semcdb.2015.02.011","article-title":"Extracellular vesicles in the biology of brain tumour stem cells\u2014Implications for inter-cellular communication, therapy and biomarker development","volume":"40","author":"Nakano","year":"2015","journal-title":"Semin. Cell Dev. Biol."},{"key":"ref_61","doi-asserted-by":"crossref","unstructured":"Seo, J.Y., and Cresswell, P. (2013). Viperin regulates cellular lipid metabolism during human cytomegalovirus infection. PLoS Pathog, 9.","DOI":"10.1371\/journal.ppat.1003497"},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1093\/neuonc\/now128","article-title":"Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells","volume":"19","author":"Lin","year":"2017","journal-title":"Neuro Oncol."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"1556","DOI":"10.1038\/ncb3272","article-title":"Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma","volume":"17","author":"Tardito","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"9030","DOI":"10.1074\/jbc.M511397200","article-title":"The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism","volume":"281","author":"Ullah","year":"2006","journal-title":"J. Biol. Chem."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Liu, C., Clark, P.A., Kuo, J.S., and Kalejta, R.F. (2017). Human Cytomegalovirus-Infected Glioblastoma Cells Display Stem Cell-Like Phenotypes. mSphere, 2.","DOI":"10.1128\/mSphere.00137-17"}],"container-title":["Viruses"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/1\/103\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,13]],"date-time":"2025-10-13T13:27:04Z","timestamp":1760362024000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1999-4915\/14\/1\/103"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,7]]},"references-count":65,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2022,1]]}},"alternative-id":["v14010103"],"URL":"https:\/\/doi.org\/10.3390\/v14010103","relation":{},"ISSN":["1999-4915"],"issn-type":[{"value":"1999-4915","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,7]]}}}