{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T05:36:50Z","timestamp":1791005810836,"version":"4.1.0"},"reference-count":51,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T00:00:00Z","timestamp":1554336000000},"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>Acute lung injury (ALI) is a life-threatening syndrome characterized by acute and severe hypoxemic respiratory failure. Visfatin, which is known as an obesity-related cytokine with pro-inflammatory activities, plays a role in regulation of inflammatory cytokines. The mechanisms of ALI remain unclear in critically ill patients. Survival in ALI patients appear to be influenced by the stress generated by mechanical ventilation and by ALI-associated factors that initiate the inflammatory response. The objective for this study was to understand the mechanisms of how visfatin regulates inflammatory cytokines and promotes ALI. The expression of visfatin was evaluated in ALI patients and mouse sepsis models. Moreover, the underlying mechanisms were investigated using human bronchial epithelial cell lines, BEAS-2B and NL-20. An increase of serum visfatin was discovered in ALI patients compared to normal controls. Results from hematoxylin and eosin (H&amp;E) and immunohistochemistry staining also showed that visfatin protein was upregulated in mouse sepsis models. Moreover, lipopolysaccharide (LPS) induced visfatin expression, activated the STAT3\/NF\u03baB pathway, and increased the expression of pro-inflammatory cytokines, including IL1-\u03b2, IL-6, and TNF-\u03b1 in human bronchial epithelial cell lines NL-20 and BEAS-2B. Co-treatment of visfatin inhibitor FK866 reversed the activation of the STAT3\/NF\u03baB pathway and the increase of pro-inflammatory cytokines induced by LPS. Our study provides new evidence for the involvement of visfatin and down-stream events in acute lung injury. Further studies are required to confirm whether the anti-visfatin approaches can improve ALI patient survival by alleviating the pro-inflammatory process.<\/jats:p>","DOI":"10.3390\/ijms20071678","type":"journal-article","created":{"date-parts":[[2019,4,4]],"date-time":"2019-04-04T11:31:57Z","timestamp":1554377517000},"page":"1678","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Essential Role of Visfatin in Lipopolysaccharide and Colon Ascendens Stent Peritonitis-Induced Acute Lung Injury"],"prefix":"10.3390","volume":"20","author":[{"given":"Yi-Chen","family":"Lee","sequence":"first","affiliation":[{"name":"Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Anatomy, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5640-4969","authenticated-orcid":false,"given":"Chun-Yu","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center of Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Division of Infectious Diseases, Department of Internal Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Hsu","family":"Chen","sequence":"additional","affiliation":[{"name":"School of Medicine, Graduate Institute of Medicine, Sepsis Research Center, Center of Dengue Fever Control and Research, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Internal Medicine, Kaohsiung Municipal Ta-Tung Hospital, Kaohsiung 801, Taiwan"},{"name":"Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu 300, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wen-Chin","family":"Chiu","sequence":"additional","affiliation":[{"name":"Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Division of Thoracic Surgery, Department of Surgery, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yen-Yun","family":"Wang","sequence":"additional","affiliation":[{"name":"School of Dentistry, College of Dental Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chin","family":"Hsu","sequence":"additional","affiliation":[{"name":"Department of Physiology, School of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen Chu-Sung","family":"Hu","sequence":"additional","affiliation":[{"name":"Department of Dermatology, Kaohsiung Medical University Hospital, Kaohsiung, Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yu-Han","family":"Su","sequence":"additional","affiliation":[{"name":"Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4753-788X","authenticated-orcid":false,"given":"Shyng-Shiou F.","family":"Yuan","sequence":"additional","affiliation":[{"name":"Translational Research Center, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Department of Biological Science and Technology, College of Biological Science and Technology, National Chiao Tung University, Hsinchu 300, Taiwan"},{"name":"Department of Medical Research and Department of Obstetrics and Gynecology, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Graduate Institute of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan"},{"name":"Center for Intelligent Drug Systems and Smart Bio-devices (IDS2B), National Chiao Tung University, Hsinchu 300, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2019,4,4]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"319","DOI":"10.1165\/rcmb.F305","article-title":"Acute lung injury and the acute respiratory distress syndrome: Four decades of inquiry into pathogenesis and rational management","volume":"33","author":"Matthay","year":"2005","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_2","first-page":"1823","article-title":"Acute respiratory distress syndrome","volume":"65","author":"Mortelliti","year":"2002","journal-title":"Am. Fam. Phys."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1027","DOI":"10.1164\/rccm.200208-966WS","article-title":"Future research directions in acute lung injury: Summary of a National Heart, Lung, and Blood Institute working group","volume":"167","author":"Matthay","year":"2003","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1056\/NEJMoa050333","article-title":"Incidence and outcomes of acute lung injury","volume":"353","author":"Rubenfeld","year":"2005","journal-title":"New Engl. J. Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1097\/01.CCM.0000063475.65751.1D","article-title":"Incidence of acute lung injury in the United States","volume":"31","author":"Goss","year":"2003","journal-title":"Crit. Care Med."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"743","DOI":"10.1007\/BF02730667","article-title":"Acute lung injury and acute respiratory distress syndrome","volume":"71","author":"Vasudevan","year":"2004","journal-title":"Indian J. Pediatrics"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1334","DOI":"10.1056\/NEJM200005043421806","article-title":"The acute respiratory distress syndrome","volume":"342","author":"Ware","year":"2000","journal-title":"New Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"337","DOI":"10.1055\/s-2006-948288","article-title":"Pathophysiology of acute lung injury and the acute respiratory distress syndrome","volume":"27","author":"Ware","year":"2006","journal-title":"Semin. Respir. Crit. Care Med."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1631\/jzus.2007.B0060","article-title":"Acute lung injury\/acute respiratory distress syndrome (ALI\/ARDS): The mechanism, present strategies and future perspectives of therapies","volume":"8","author":"Luh","year":"2007","journal-title":"J. Zhejiang Univ. Sci. B"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"243","DOI":"10.1089\/jamp.2009.0775","article-title":"Acute lung injury: Epidemiology, pathogenesis, and treatment","volume":"23","author":"Johnson","year":"2010","journal-title":"J. Aerosol Med. Pulm. Drug Deliv."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1378\/chest.06-1743","article-title":"Nonventilatory treatments for acute lung injury and ARDS","volume":"131","author":"Calfee","year":"2007","journal-title":"Chest"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1644","DOI":"10.1097\/CCM.0b013e3181e795ee","article-title":"Therapeutic strategies for severe acute lung injury","volume":"38","author":"Diaz","year":"2010","journal-title":"Crit. Care Med."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1280","DOI":"10.1128\/IAI.01127-10","article-title":"Model of polymicrobial peritonitis that induces the proinflammatory and immunosuppressive phases of sepsis","volume":"79","author":"Barrera","year":"2011","journal-title":"Infect. Immun."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1046\/j.1365-2567.2003.01674.x","article-title":"Effects of functional Toll-like receptor-4 mutations on the immune response to human and experimental sepsis","volume":"109","author":"Feterowski","year":"2003","journal-title":"Immunology"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1016\/S0272-5231(05)70159-3","article-title":"Mediators and mechanisms of acute lung injury","volume":"21","author":"Parsons","year":"2000","journal-title":"Clin. Chest Med."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"145","DOI":"10.1002\/path.1491","article-title":"Role of inflammatory mediators in the pathophysiology of acute respiratory distress syndrome","volume":"202","author":"Bhatia","year":"2004","journal-title":"J. Pathol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"L665","DOI":"10.1152\/ajplung.00232.2013","article-title":"Novel concepts of acute lung injury and alveolar-capillary barrier dysfunction","volume":"305","author":"Herold","year":"2013","journal-title":"Am. J. Physiology. Lung Cell. Mol. Physiol."},{"key":"ref_18","first-page":"1431","article-title":"Cloning and characterization of the cDNA encoding a novel human pre-B-cell colony-enhancing factor","volume":"14","author":"Samal","year":"1994","journal-title":"Mol. Cell. Biol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"15","DOI":"10.1186\/1476-9255-5-15","article-title":"Augmentation of Pulmonary Epithelial Cell IL-8 Expression and Permeability by Pre-B-cell Colony Enhancing Factor","volume":"5","author":"Li","year":"2008","journal-title":"J. Inflamm."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1016\/S0014-5793(03)00476-9","article-title":"Growth phase-dependent changes in the subcellular localization of pre-B-cell colony-enhancing factor","volume":"544","author":"Kitani","year":"2003","journal-title":"FEBS Lett."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"1318","DOI":"10.1172\/JCI19930","article-title":"Pre-B cell colony-enhancing factor inhibits neutrophil apoptosis in experimental inflammation and clinical sepsis","volume":"113","author":"Jia","year":"2004","journal-title":"J. Clin. Investig."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1016\/j.cytogfr.2013.05.006","article-title":"Pre-B cell colony enhancing factor (PBEF), a cytokine with multiple physiological functions","volume":"24","author":"Sun","year":"2013","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_23","first-page":"9","article-title":"Visfatin\u2014A review","volume":"15","author":"Sonoli","year":"2011","journal-title":"Eur. Rev. Med Pharmacol. Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"50754","DOI":"10.1074\/jbc.M408388200","article-title":"The NAD biosynthesis pathway mediated by nicotinamide phosphoribosyltransferase regulates Sir2 activity in mammalian cells","volume":"279","author":"Revollo","year":"2004","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"3225","DOI":"10.1002\/1521-4141(200211)32:11<3225::AID-IMMU3225>3.0.CO;2-L","article-title":"Pre-B-cell colony-enhancing factor, whose expression is up-regulated in activated lymphocytes, is a nicotinamide phosphoribosyltransferase, a cytosolic enzyme involved in NAD biosynthesis","volume":"32","author":"Rongvaux","year":"2002","journal-title":"Eur. J. Immunol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1067\/mob.2002.126295","article-title":"Pre-B-cell colony-enhancing factor, a novel cytokine of human fetal membranes","volume":"187","author":"Ognjanovic","year":"2002","journal-title":"Am. J. Obstet. Gynecol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"426","DOI":"10.1126\/science.1097243","article-title":"Visfatin: A protein secreted by visceral fat that mimics the effects of insulin","volume":"307","author":"Fukuhara","year":"2005","journal-title":"Science"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"1748","DOI":"10.4049\/jimmunol.178.3.1748","article-title":"Visfatin, an adipocytokine with proinflammatory and immunomodulating properties","volume":"178","author":"Moschen","year":"2007","journal-title":"J. Immunol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1016\/j.mvr.2005.08.003","article-title":"Pre-B-cell-colony-enhancing factor is critically involved in thrombin-induced lung endothelial cell barrier dysregulation","volume":"70","author":"Ye","year":"2005","journal-title":"Microvasc. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2084","DOI":"10.1002\/art.21942","article-title":"Regulation of pre-B cell colony-enhancing factor by STAT-3-dependent interleukin-6 trans-signaling: Implications in the pathogenesis of rheumatoid arthritis","volume":"54","author":"Nowell","year":"2006","journal-title":"Arthritis Rheum."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"972","DOI":"10.1161\/CIRCULATIONAHA.106.665893","article-title":"Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: Possible role in inflammation and plaque destabilization","volume":"115","author":"Dahl","year":"2007","journal-title":"Circulation"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"605","DOI":"10.1164\/rccm.200712-1822OC","article-title":"Essential role of pre-B-cell colony enhancing factor in ventilator-induced lung injury","volume":"178","author":"Hong","year":"2008","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"361","DOI":"10.1164\/rccm.200404-563OC","article-title":"Pre-B-cell colony-enhancing factor as a potential novel biomarker in acute lung injury","volume":"171","author":"Ye","year":"2005","journal-title":"Am. J. Respir. Crit. Care Med."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"63","DOI":"10.1586\/1744666X.5.1.63","article-title":"Role of the pulmonary epithelium and inflammatory signals in acute lung injury","volume":"5","author":"Manicone","year":"2009","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wu, M.H., Tsai, C.H., Huang, Y.L., Fong, Y.C., and Tang, C.H. (2018). Visfatin Promotes IL-6 and TNF-alpha Production in Human Synovial Fibroblasts by Repressing miR-199a-5p through ERK, p38 and JNK Signaling Pathways. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19010190"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"59","DOI":"10.1097\/SHK.0b013e31802e454f","article-title":"Colon ascendens stent peritonitis\u2014A model of sepsis adopted to the rat: Physiological, microcirculatory and laboratory changes","volume":"28","author":"Lustig","year":"2007","journal-title":"Shock"},{"key":"ref_37","doi-asserted-by":"crossref","unstructured":"Traeger, T., Koerner, P., Kessler, W., Cziupka, K., Diedrich, S., Busemann, A., Heidecke, C.D., and Maier, S. (2010). Colon ascendens stent peritonitis (CASP)\u2014A standardized model for polymicrobial abdominal sepsis. J. Vis. Exp. JoVE.","DOI":"10.3791\/2299"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1007","DOI":"10.1097\/SLA.0000000000000329","article-title":"FK866, a visfatin inhibitor, protects against acute lung injury after intestinal ischemia-reperfusion in mice via NF-kappaB pathway","volume":"259","author":"Matsuda","year":"2014","journal-title":"Ann. Surg."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.bbrc.2015.01.111","article-title":"FK866-induced NAMPT inhibition activates AMPK and downregulates mTOR signaling in hepatocarcinoma cells","volume":"458","author":"Schuster","year":"2015","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1759","DOI":"10.1016\/j.bbamcr.2009.09.006","article-title":"Visfatin through STAT3 activation enhances IL-6 expression that promotes endothelial angiogenesis","volume":"1793","author":"Kim","year":"2009","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"119","DOI":"10.4161\/cbt.10.2.12581","article-title":"Nampt\/PBEF\/visfatin and cancer","volume":"10","author":"Bi","year":"2010","journal-title":"Cancer Biol. Ther."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"4478","DOI":"10.1158\/1078-0432.CCR-15-2704","article-title":"Extracellular Visfatin-Promoted Malignant Behavior in Breast Cancer Is Mediated Through c-Abl and STAT3 Activation","volume":"22","author":"Hung","year":"2016","journal-title":"Clin. Cancer Res. Off. J. Am. Assoc. Cancer Res."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"34833","DOI":"10.1074\/jbc.M805866200","article-title":"Extracellular Nampt promotes macrophage survival via a nonenzymatic interleukin-6\/STAT3 signaling mechanism","volume":"283","author":"Li","year":"2008","journal-title":"J. Biol. Chem."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"619","DOI":"10.1007\/s00424-009-0752-1","article-title":"Visfatin induces oxidative stress in differentiated C2C12 myotubes in an Akt- and MAPK-independent, NFkB-dependent manner","volume":"459","author":"Oita","year":"2010","journal-title":"Pflug. Arch. Eur. J. Physiol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"13135","DOI":"10.1038\/srep13135","article-title":"Unique Toll-Like Receptor 4 Activation by NAMPT\/PBEF Induces NFkappaB Signaling and Inflammatory Lung Injury","volume":"5","author":"Camp","year":"2015","journal-title":"Sci. Rep."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"7290","DOI":"10.1021\/jm300740t","article-title":"Carboranes increase the potency of small molecule inhibitors of nicotinamide phosphoribosyltranferase","volume":"55","author":"Lee","year":"2012","journal-title":"J. Med. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"629","DOI":"10.2147\/DDDT.S125349","article-title":"MC-PPEA as a new and more potent inhibitor of CLP-induced sepsis and pulmonary inflammation than FK866","volume":"11","author":"Huang","year":"2017","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"762","DOI":"10.1001\/jama.2016.0288","article-title":"Assessment of Clinical Criteria for Sepsis: For the Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3)","volume":"315","author":"Seymour","year":"2016","journal-title":"JAMA"},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"554","DOI":"10.1378\/chest.06-1976","article-title":"Epidemiology and outcomes of acute lung injury","volume":"131","author":"Rubenfeld","year":"2007","journal-title":"Chest"},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"680","DOI":"10.1021\/acs.jproteome.7b00730","article-title":"Colon Ascendens Stent Peritonitis (CASP) Induces Excessive Inflammation and Systemic Metabolic Dysfunction in a Septic Rat Model","volume":"17","author":"Zhang","year":"2018","journal-title":"J. Proteome Res."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"862","DOI":"10.1093\/ajcp\/aqw076","article-title":"Performances of the H-Score for Diagnosis of Hemophagocytic Lymphohistiocytosis in Adult and Pediatric Patients","volume":"145","author":"Debaugnies","year":"2016","journal-title":"Am. J. Clin. Pathol."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1678\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T12:42:51Z","timestamp":1760186571000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/20\/7\/1678"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2019,4,4]]},"references-count":51,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2019,4]]}},"alternative-id":["ijms20071678"],"URL":"https:\/\/doi.org\/10.3390\/ijms20071678","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2019,4,4]]}}}