{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,13]],"date-time":"2026-11-13T09:57:46Z","timestamp":1794563866395,"version":"4.9.1"},"reference-count":59,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T00:00:00Z","timestamp":1506384000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004271","name":"Sapienza Universit\u00e0 di Roma","doi-asserted-by":"publisher","award":["Ateneo Federato 2014"],"award-info":[{"award-number":["Ateneo Federato 2014"]}],"id":[{"id":"10.13039\/501100004271","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Antioxidants"],"abstract":"<jats:p>Alpha-lipoic acid (ALA) is a pleiotropic molecule with antioxidant and anti-inflammatory properties, of which the effects are exerted through the modulation of NF-kB. This nuclear factor, in fact, modulates different inflammatory cytokines, including IL-1b and IL-6, in different tissues and cell types. We recently showed that IL-1b and IL-6 DNA methylation is modulated in the brain of Alzheimer\u2019s disease patients, and that IL-1b expression is associated to DNA methylation in the brain of patients with tuberous sclerosis complex. These results prompted us to ask whether ALA-induced repression of IL-1b and IL-6 was dependent on DNA methylation. Therefore, we profiled DNA methylation in the 5\u2019-flanking region of the two aforementioned genes in SK-N-BE human neuroblastoma cells cultured in presence of ALA 0.5 mM. Our experimental data pointed out that the two promoters are hypermethylated in cells supplemented with ALA, both at CpG and non-CpG sites. Moreover, the observed hypermethylation is associated with decreased mRNA expression and decreased cytokine release. These results reinforce previous findings indicating that IL-1b and IL-6 undergo DNA methylation-dependent modulation in neural models and pave the road to study the epigenetic mechanisms triggered by ALA.<\/jats:p>","DOI":"10.3390\/antiox6040074","type":"journal-article","created":{"date-parts":[[2017,9,26]],"date-time":"2017-09-26T16:14:45Z","timestamp":1506442485000},"page":"74","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["Alpha-Lipoic Acid Downregulates IL-1\u03b2 and IL-6 by DNA Hypermethylation in SK-N-BE Neuroblastoma Cells"],"prefix":"10.3390","volume":"6","author":[{"given":"Simona","family":"Dinicola","sequence":"first","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sara","family":"Proietti","sequence":"additional","affiliation":[{"name":"Department of Surgery \u201cPietro Valdoni\u201d, Sapienza University of Rome, Via Antonio Scarpa 16, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5469-6419","authenticated-orcid":false,"given":"Alessandra","family":"Cucina","sequence":"additional","affiliation":[{"name":"Department of Surgery \u201cPietro Valdoni\u201d, Sapienza University of Rome, Via Antonio Scarpa 16, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0408-4136","authenticated-orcid":false,"given":"Mariano","family":"Bizzarri","sequence":"additional","affiliation":[{"name":"Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andrea","family":"Fuso","sequence":"additional","affiliation":[{"name":"Department of Surgery \u201cPietro Valdoni\u201d, Sapienza University of Rome, Via Antonio Scarpa 16, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2017,9,26]]},"reference":[{"key":"ref_1","first-page":"570","article-title":"Lipoic acid\u2014The drug of the future?","volume":"57","author":"Bilska","year":"2005","journal-title":"Pharmacol. Rep."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1002\/biof.5520170120","article-title":"Lipoic acid: A multifunctional antioxidant","volume":"17","author":"Bast","year":"2003","journal-title":"Biofactors"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"315","DOI":"10.1016\/S0306-3623(96)00474-0","article-title":"The pharmacology of the antioxidant lipoic acid","volume":"29","author":"Biewenga","year":"1997","journal-title":"Gen. Pharmacol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"227","DOI":"10.1016\/0891-5849(95)00017-R","article-title":"Alpha-Lipoic acid as a biological antioxidant","volume":"19","author":"Packer","year":"1995","journal-title":"Free Radic. Biol. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"802","DOI":"10.1248\/bpb.b12-00977","article-title":"Cytoprotective effect of alpha-lipoic acid on paraquat-exposed human bronchial epithelial cells via activation of nuclear factor erythroid related factor-2 pathway","volume":"36","author":"Kim","year":"2013","journal-title":"Biol. Pharm. Bull."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/j.brainres.2012.12.041","article-title":"Protective effect of lipoic acid against oxidative stress is mediated by Keap1\/Nrf2-dependent heme oxygenase-1 induction in the RGC-5 cell line","volume":"1499","author":"Koriyama","year":"2013","journal-title":"Brain Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1007\/s00011-010-0256-7","article-title":"Evidence that \u03b1-lipoic acid inhibits NF-\u03baB activation independent of its antioxidant function","volume":"60","author":"Ying","year":"2011","journal-title":"Inflamm. Res."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"106","DOI":"10.1038\/emm.2007.12","article-title":"Alpha-lipoic acid inhibits matrix metalloproteinase-9 expression by inhibiting NF-kB transcriptional activity","volume":"39","author":"Kim","year":"2007","journal-title":"Exp. Mol. Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1695","DOI":"10.1080\/17425247.2016.1200556","article-title":"Immunomodulatory activities of alpha lipoic acid with a special focus on its efficacy in preventing miscarriage","volume":"13","author":"Monastra","year":"2016","journal-title":"Expert Opin. Drug Deliv."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"245","DOI":"10.3109\/03602539808996311","article-title":"Alpha-Lipoic acid: A metabolic antioxidant which regulates NF-kappa B signal transduction and protects against oxidative injury","volume":"30","author":"Packer","year":"1998","journal-title":"Drug Metab. Rev."},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Devi, Y.S., DeVine, M., DeKuiper, J., Ferguson, S., and Fazleabas, A.T. (2015). Inhibition of IL-6 signaling pathway by curcumin in uterine decidual cells. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0125627"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.jsbmb.2015.05.001","article-title":"Lazaroid U-74389G inhibits the osteoblastic differentiation of IL-1\u03b2-indcued aortic valve interstitial cells through glucocorticoid receptor and inhibition of NF-\u03baB pathway","volume":"152","author":"Sun","year":"2015","journal-title":"J. Steroid Biochem. Mol. Biol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1794","DOI":"10.1007\/s10753-015-0157-6","article-title":"NLRC5 Mediates IL-6 and IL-1\u03b2 Secretion in LX-2 Cells and Modulated by the NF-\u03baB\/Smad3 Pathway","volume":"38","author":"Xu","year":"2015","journal-title":"Inflammation"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"223","DOI":"10.1016\/j.yexcr.2014.08.040","article-title":"IL-1\u03b2 induces IL-6 production in retinal M\u00fcller cells predominantly through the activation of p38 MAPK\/NF-\u03baB signaling pathway","volume":"33","author":"Liu","year":"2015","journal-title":"Exp. Cell. Res."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.3892\/ijmm.2014.1863","article-title":"Dexmedetomidine suppresses interleukin-1\u03b2-induced interleukin-6 synthesis in rat glial cells","volume":"34","author":"Tanabe","year":"2014","journal-title":"Int. J. Mol. Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"510","DOI":"10.1007\/s10753-014-9957-3","article-title":"Alpha-lipoic acid exerts anti-inflammatory effects on lipopolysaccharide-stimulated rat mesangial cells via inhibition of nuclear factor kappa B (NF-\u03baB) signaling pathway","volume":"38","author":"Li","year":"2015","journal-title":"Inflammation"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"458","DOI":"10.2174\/1568026615666150114161358","article-title":"Lipoic Acid: Its antioxidant and anti-inflammatory role and clinical applications","volume":"15","author":"Moura","year":"2015","journal-title":"Curr. Top. Med. Chem."},{"key":"ref_18","first-page":"2766","article-title":"Peripheral neuropathy in obstetrics: Efficacy and safety of \u03b1-lipoic acid supplementation","volume":"18","author":"Costantino","year":"2014","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_19","first-page":"133","article-title":"Treatment of carpal tunnel syndrome with alpha-lipoic acid","volume":"13","author":"Caccese","year":"2009","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"B788","DOI":"10.1093\/gerona\/58.9.B788","article-title":"Effect of dl-alpha-lipoic acid on the status of lipid peroxidation and lipids in aged rats","volume":"58","author":"Arivazhagan","year":"2003","journal-title":"J. Gerontol. A. Biol. Sci. Med. Sci."},{"key":"ref_21","unstructured":"(2017, July 26). World Alzheimer Report 2016. Available online: https:\/\/www.alz.co.uk\/research\/world-report-2016."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"38","DOI":"10.1111\/j.1582-4934.2008.00225.x","article-title":"Alzheimer neurofibrillary degeneration: Significance, etiopathogenesis, therapeutics and prevention","volume":"12","author":"Iqbal","year":"2008","journal-title":"J. Cell. Mol. Med."},{"key":"ref_23","first-page":"132","article-title":"IANA task force on nutrition and cognitive decline with aging","volume":"11","author":"Andrieu","year":"2007","journal-title":"J. Nutr. Health Aging"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1016\/S0197-4580(00)00124-X","article-title":"Inflammation and Alzheimer\u2019s disease","volume":"21","author":"Akiyama","year":"2000","journal-title":"Neurobiol. Aging"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1196\/annals.1332.007","article-title":"Inflammation and the degenerative diseases of aging","volume":"1035","author":"McGeer","year":"2004","journal-title":"Ann. N. Y. Acad. Sci."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1539","DOI":"10.1007\/s12272-010-1006-7","article-title":"Inflammation and Alzheimer\u2019s disease","volume":"33","author":"Lee","year":"2010","journal-title":"Arch. Pharm. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1097\/NEN.0000000000000176","article-title":"Neuroinflammatory signals in Alzheimer disease and APP\/PS1 transgenic mice: Correlations with plaques, tangles, and oligomeric species","volume":"74","author":"Aso","year":"2015","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_28","doi-asserted-by":"crossref","unstructured":"Rubio-Perez, J.M., and Morillas-Ruiz, J.M. (2012). A review: Inflammatory process in Alzheimer\u2019s disease, role of cytokines. Scientific World J.","DOI":"10.1100\/2012\/756357"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1016\/j.jneuroim.2015.04.014","article-title":"The interleukin 1 alpha, interleukin 1 beta, interleukin 6 and alpha-2-macroglobulin serum levels in patients with early or late onset Alzheimer\u2019s disease, mild cognitive impairment or Parkinson\u2019s disease","volume":"283","author":"Dursun","year":"2015","journal-title":"J. Neuroimmunol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"3219","DOI":"10.3892\/mmr.2015.3183","article-title":"Exploring the association between interleukin-1\u03b2 and its interacting proteins in Alzheimer\u2019s disease","volume":"11","author":"Xie","year":"2015","journal-title":"Mol. Med. Rep."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1218","DOI":"10.1016\/j.bbamcr.2016.03.018","article-title":"The role of interleukin-6 signaling in nervous tissue","volume":"1863","author":"Rothaug","year":"2016","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_32","first-page":"27","article-title":"DNA Methylation Profiles of Selected Pro-Inflammatory Cytokines in Alzheimer Disease","volume":"76","author":"Nicolia","year":"2017","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"252","DOI":"10.1016\/j.bbrc.2011.09.066","article-title":"The involvement of DNA and histone methylation in the repression of IL-1\u03b2-induced MCP-1 production by hypoxia","volume":"414","author":"Aoi","year":"2011","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1007\/s00262-012-1340-3","article-title":"DNA methylation at promoter regions of interleukin 1B, interleukin 6, and interleukin 8 in non-small cell lung cancer","volume":"62","author":"Tekpli","year":"2013","journal-title":"Cancer Immunol. Immunother."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3303","DOI":"10.1002\/art.24882","article-title":"DNA demethylation at specific CpG sites in the IL1B promoter in response to inflammatory cytokines in human articular chondrocytes","volume":"60","author":"Hashimoto","year":"2009","journal-title":"Arthritis Rheum."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"807","DOI":"10.1523\/JNEUROSCI.2939-14.2015","article-title":"SIRT1 deficiency in microglia contributes to cognitive decline in aging and neurodegeneration via epigenetic regulation of IL-1\u03b2","volume":"35","author":"Cho","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"464","DOI":"10.1007\/s12031-016-0750-7","article-title":"Promoter-specific hypomethylation correlates with IL-1\u03b2 overexpression in Tuberous Sclerosis Complex (TSC)","volume":"59","author":"Fuso","year":"2016","journal-title":"J. Mol. Neurosci."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"77","DOI":"10.1016\/j.phanu.2017.06.002","article-title":"Alpha-lipoic acid represses IL-1B and IL-6 through DNA methylation in ovarian cells","volume":"5","author":"Dinicola","year":"2017","journal-title":"PharmaNutrition"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.jnutbio.2010.01.010","article-title":"DNA methylase and demethylase activities are modulated by one-carbon metabolism in Alzheimer\u2019s disease models","volume":"22","author":"Fuso","year":"2011","journal-title":"J. Nutr. Biochem."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"275","DOI":"10.3233\/JAD-2007-11303","article-title":"Gamma-Secretase is differentially modulated by alterations of homocysteine cycle in neuroblastoma and glioblastoma cells","volume":"11","author":"Fuso","year":"2007","journal-title":"J. Alzheimers Dis."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1016\/S0014-5793(03)00277-1","article-title":"Presenilin 1 gene silencing by S-adenosylmethionine: A treatment for Alzheimer disease?","volume":"541","author":"Scarpa","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Fuso, A., Ferraguti, G., Scarpa, S., Ferrer, I., and Lucarelli, M. (2015). Disclosing bias in bisulfite assay: MethPrimers underestimate high DNA methylation. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0118318"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"3965","DOI":"10.4161\/cc.9.19.13193","article-title":"Early demethylation of non-CpG, CpC-rich, elements in the myogenin 5\u2032-flanking region: A priming effect on the spreading of active demethylation","volume":"9","author":"Fuso","year":"2010","journal-title":"Cell Cycle"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"215","DOI":"10.1038\/nn.3607","article-title":"Distribution, recognition and regulation of non-CpG methylation in the adult mammalian brain","volume":"17","author":"Guo","year":"2014","journal-title":"Nat. Neurosci."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"816","DOI":"10.1016\/j.cell.2011.12.035","article-title":"Base-resolution analyses of sequence and parent-of-origin dependent DNA methylation in the mouse genome","volume":"148","author":"Xie","year":"2012","journal-title":"Cell"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"1134","DOI":"10.1016\/j.cell.2013.04.022","article-title":"Epigenomic analysis of multilineage differentiation of human embryonic stem cells","volume":"153","author":"Xie","year":"2013","journal-title":"Cell"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1237905","DOI":"10.1126\/science.1237905","article-title":"Global epigenomic reconfiguration during mammalian brain development","volume":"341","author":"Lister","year":"2013","journal-title":"Science"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"3009","DOI":"10.1093\/nar\/gkt1306","article-title":"Characterizing the strand-specific distribution of non-CpG methylation in human pluripotent cells","volume":"42","author":"Guo","year":"2014","journal-title":"Nucleic Acids Res."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"823","DOI":"10.4161\/epi.28741","article-title":"The evidence for functional non-CpG methylation in mammalian cells","volume":"9","author":"Patil","year":"2014","journal-title":"Epigenetics"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.gene.2016.03.028","article-title":"Non-random distribution of methyl-CpG sites and non-CpG methylation in the human rDNA promoter identified by next generation bisulfite sequencing","volume":"585","author":"Pietrzak","year":"2016","journal-title":"Gene"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"148","DOI":"10.3390\/genes8060148","article-title":"CpG and Non-CpG Methylation in Epigenetic Gene Regulation and Brain Function","volume":"8","author":"Jang","year":"2017","journal-title":"Genes"},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1515\/cclm-2012-0618","article-title":"The \u201cgolden age\u201d of DNA methylation in neurodegenerative diseases","volume":"51","author":"Fuso","year":"2013","journal-title":"Clin. Chem. Lab. Med."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Wen, K.X., Mili\u00e7, J., El-Khodor, B., Dhana, K., Nano, J., Pulido, T., Kraja, B., Zaciragic, A., Bramer, W.M., and Troup, J. (2016). The Role of DNA Methylation and Histone Modifications in Neurodegenerative Diseases: A Systematic Review. PLoS ONE, 11.","DOI":"10.1371\/journal.pone.0167201"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"1043","DOI":"10.3892\/mmr.2016.5390","article-title":"Neurogenesis-based epigenetic therapeutics for Alzheimer\u2019s disease (Review)","volume":"14","author":"Li","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"30483","DOI":"10.3390\/ijms161226236","article-title":"Epigenetics of Aging and Alzheimer\u2019s Disease: Implications for Pharmacogenomics and Drug Response","volume":"16","author":"Cacabelos","year":"2015","journal-title":"Int. J. Mol. Sci."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"21","DOI":"10.1016\/j.pneurobio.2015.05.002","article-title":"The epigenetics of aging and neurodegeneration","volume":"131","author":"Lardenoije","year":"2015","journal-title":"Prog. Neurobiol."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"1425","DOI":"10.4161\/cbt.22003","article-title":"Lipoic acid inhibits cell proliferation of tumor cells in vitro and in vivo","volume":"13","author":"Feuerecker","year":"2012","journal-title":"Cancer Biol. Ther."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1003","DOI":"10.1016\/j.neuint.2011.09.005","article-title":"\u03b1-Lipoic acid (LA) enantiomers protect SH-SY5Y cells against glutathione depletion","volume":"59","author":"Yamada","year":"2011","journal-title":"Neurochem. Int."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"790","DOI":"10.1007\/s11064-007-9496-5","article-title":"Potent upregulation of glutathione and NAD(P)H: Quinone oxidoreductase 1 by alpha-lipoic acid in human neuroblastoma SH-SY5Y cells: protection against neurotoxicant-elicited cytotoxicity","volume":"33","author":"Jia","year":"2008","journal-title":"Neurochem. Res."}],"container-title":["Antioxidants"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-3921\/6\/4\/74\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T18:45:58Z","timestamp":1760208358000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-3921\/6\/4\/74"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,9,26]]},"references-count":59,"journal-issue":{"issue":"4","published-online":{"date-parts":[[2017,12]]}},"alternative-id":["antiox6040074"],"URL":"https:\/\/doi.org\/10.3390\/antiox6040074","relation":{},"ISSN":["2076-3921"],"issn-type":[{"value":"2076-3921","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,9,26]]}}}