{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T02:52:36Z","timestamp":1775271156129,"version":"3.50.1"},"reference-count":59,"publisher":"MDPI AG","issue":"11","license":[{"start":{"date-parts":[[2018,11,14]],"date-time":"2018-11-14T00:00:00Z","timestamp":1542153600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1150816"],"award-info":[{"award-number":["1150816"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100002850","name":"Fondo Nacional de Desarrollo Cient\u00edfico y Tecnol\u00f3gico","doi-asserted-by":"publisher","award":["1180337"],"award-info":[{"award-number":["1180337"]}],"id":[{"id":"10.13039\/501100002850","id-type":"DOI","asserted-by":"publisher"}]},{"name":"European Union\u2019s Horizon 2020 research and innovation programme (RISE) under the Marie Sk\u0142odowska-Curie grant agreement","award":["734825"],"award-info":[{"award-number":["734825"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Niemann\u2013Pick type C (NPC) disease is a rare neurovisceral cholesterol storage disorder that arises from loss of function mutations in the NPC1 or NPC2 genes. Soon after birth, some patients present with an aggressive hepatosplenomegaly and cholestatic signs. Histopathologically, the liver presents with large numbers of foam cells; however, their role in disease pathogenesis has not been explored in depth. Here, we studied the consequences of gadolinium chloride (GdCl3) treatment, a well-known Kupffer\/foam cell inhibitor, at late stages of NPC liver disease and compared it with NPC1 genetic rescue in hepatocytes in vivo. GdCl3 treatment successfully blocked the endocytic capacity of hepatic Kupffer\/foam measured by India ink endocytosis, decreased the levels CD68\u2014A marker of Kupffer cells in the liver\u2014and normalized the transaminase levels in serum of NPC mice to a similar extent to those obtained by genetic Npc1 rescue of liver cells. Gadolinium salts are widely used as magnetic resonance imaging (MRI) contrasts. This study opens the possibility of targeting foam cells with gadolinium or by other means for improving NPC liver disease. Synopsis: Gadolinium chloride can effectively rescue some parameters of liver dysfunction in NPC mice and its potential use in patients should be carefully evaluated.<\/jats:p>","DOI":"10.3390\/ijms19113599","type":"journal-article","created":{"date-parts":[[2018,11,14]],"date-time":"2018-11-14T10:58:22Z","timestamp":1542193102000},"page":"3599","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Gadolinium Chloride Rescues Niemann\u2013Pick Type C Liver Damage"],"prefix":"10.3390","volume":"19","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9951-2174","authenticated-orcid":false,"given":"Andr\u00e9s D.","family":"Klein","sequence":"first","affiliation":[{"name":"Centro de Gen\u00e9tica y Gen\u00f3mica, Facultad de Medicina, Cl\u00ednica Alemana Universidad del Desarrollo, Santiago 7590943, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Juan Esteban","family":"Oyarz\u00fan","sequence":"additional","affiliation":[{"name":"Departamento de Gastroenterolog\u00eda, Facultad de Medicina, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1887-0808","authenticated-orcid":false,"given":"Cristian","family":"Cortez","sequence":"additional","affiliation":[{"name":"Center for Genomic and Bioinformatic, Faculty of Sciences, Universidad Mayor, Santiago 8580745, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8383-9829","authenticated-orcid":false,"given":"Silvana","family":"Zanlungo","sequence":"additional","affiliation":[{"name":"Departamento de Gastroenterolog\u00eda, Facultad de Medicina, Pontificia Universidad Cat\u00f3lica de Chile, Santiago 8331150, Chile"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2018,11,14]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1213","DOI":"10.1016\/j.cell.2009.03.049","article-title":"Structure of N-Terminal Domain of NPC1 Reveals Distinct Subdomains for Binding and Transfer of Cholesterol","volume":"137","author":"Kwon","year":"2009","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"50","DOI":"10.1186\/s13023-018-0785-7","article-title":"Consensus clinical management guidelines for Niemann\u2013Pick disease type C","volume":"13","author":"Geberhiwot","year":"2018","journal-title":"Orphanet J. Rare Dis."},{"key":"ref_3","first-page":"166","article-title":"The unique case of the Niemann\u2013Pick type C cholesterol storage disorder","volume":"12","author":"Klein","year":"2014","journal-title":"Pediatr. Endocrinol. Rev."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"1669","DOI":"10.1007\/s00431-017-3020-y","article-title":"Niemann\u2013Pick disease type C in the newborn period: A single-center experience","volume":"176","author":"Gumus","year":"2017","journal-title":"Eur. J. Pediatr."},{"key":"ref_5","first-page":"44","article-title":"Niemann\u2013Pick disease type C in neonatal cholestasis at a North American Center","volume":"35","author":"Yerushalmi","year":"2002","journal-title":"J. Pediatr. Gastroenterol. Nutr."},{"key":"ref_6","first-page":"57","article-title":"[Three Chinese children with Niemann\u2013Pick disease type C with neonatal cholestasis as initial presentation]","volume":"53","author":"Yang","year":"2015","journal-title":"Zhonghua er ke za zhi (Chin. J. Pediatr.)"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/S0022-3476(05)81695-6","article-title":"Niemann\u2013Pick disease type C: Diagnosis and outcome in children, with particular reference to liver disease","volume":"123","author":"Kelly","year":"1993","journal-title":"J. Pediatr."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"1504","DOI":"10.1002\/hep.22327","article-title":"In vivo antisense oligonucleotide reduction of NPC1 expression as a novel mouse model for Niemann Pick Type C- associated liver disease","volume":"47","author":"Rimkunas","year":"2008","journal-title":"Hepatology"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"327","DOI":"10.1194\/jlr.M800415-JLR200","article-title":"TNF-\u03b1 plays a role in hepatocyte apoptosis in Niemann\u2013Pick type C liver disease","volume":"50","author":"Rimkunas","year":"2009","journal-title":"J. Lipid Res."},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"V\u00e1zquez, M.C., del Pozo, T., Robledo, F.A., Carrasco, G., Pavez, L., Olivares, F., Gonz\u00e1lez, M., and Zanlungo, S. (2011). Alteration of gene expression profile in Niemann\u2013Pick type C mice correlates with tissue damage and oxidative stress. PLoS ONE, 6.","DOI":"10.1371\/journal.pone.0028777"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1717","DOI":"10.1016\/B978-0-444-59565-2.00041-1","article-title":"Niemann\u2013Pick diseases","volume":"113","author":"Vanier","year":"2013","journal-title":"Handb. Clin. Neurol."},{"key":"ref_12","first-page":"624","article-title":"Electron microscopic study of Kupffer-cell phagocytosis blockade induced by gadolinium chloride","volume":"61","author":"Husztik","year":"1980","journal-title":"Br. J. Exp. Pathol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"347","DOI":"10.2337\/db09-0016","article-title":"Depletion of liver Kupffer cells prevents the development of diet-induced hepatic steatosis and insulin resistance","volume":"59","author":"Huang","year":"2010","journal-title":"Diabetes"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wang, B., Zhang, Q., Zhu, B., Cui, Z., and Zhou, J. (2013). Protective Effect of Gadolinium Chloride on Early Warm Ischemia\/Reperfusion Injury in Rat Bile Duct during Liver Transplantation. PLoS ONE, 8.","DOI":"10.1371\/journal.pone.0052743"},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"219","DOI":"10.4149\/gpb_2016041","article-title":"Inhibition of Kupffer cell functions modulates arsenic intoxication in Wistar rats","volume":"2","author":"Adeyemi","year":"2017","journal-title":"Gen. Physiol. Biophys."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1002\/jat.3141","article-title":"Establishment of a mouse model for amiodarone-induced liver injury and analyses of its hepatotoxic mechanism","volume":"36","author":"Takai","year":"2016","journal-title":"J. Appl. Toxicol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"414","DOI":"10.1007\/s12026-018-9002-y","article-title":"The class D scavenger receptor CD68 contributes to mouse chronic liver injury","volume":"3","author":"Yang","year":"2018","journal-title":"Immunol. Res."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"56","DOI":"10.1016\/S1499-3872(14)60291-5","article-title":"Effects of Kupffer cell inactivation on graft survival and liver regeneration after partial liver transplantation in rats","volume":"1","author":"Luo","year":"2015","journal-title":"Hepatobiliary Pancreat. Dis. Int."},{"key":"ref_19","first-page":"6357","article-title":"Kupffer cell depletion by gadolinium chloride aggravates liver injury after brain death in rats","volume":"17","author":"Zhu","year":"2018","journal-title":"Mol. Med. Rep."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1097","DOI":"10.3389\/fimmu.2017.01097","article-title":"Regulation of human Macrophage M1-M2 Polarization Balance by hypoxia and the Triggering receptor expressed on Myeloid cells-1","volume":"8","author":"Raggi","year":"2017","journal-title":"Front. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"507","DOI":"10.1007\/s00247-017-3806-0","article-title":"Gadolinium-based contrast agents in pediatric magnetic resonance imaging","volume":"47","author":"Gale","year":"2017","journal-title":"Pediatr. Radiol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"296","DOI":"10.1002\/jlb.52.3.296","article-title":"Heterogeneity of rat liver and spleen macrophages in gadolinium chloride-induced elimination and repopulation","volume":"52","author":"Hardonk","year":"1992","journal-title":"J. Leukoc. Biol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2946","DOI":"10.1093\/hmg\/dds126","article-title":"Neuronal and epithelial cell rescue resolves chronic systemic inflammation in the lipid storage disorder Niemann\u2013Pick C","volume":"21","author":"Lopez","year":"2012","journal-title":"Hum. Mol. Genet."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"4367","DOI":"10.1523\/JNEUROSCI.5981-10.2011","article-title":"Anatomically defined neuron-based rescue of neurodegenerative Niemann\u2013Pick type C disorder","volume":"31","author":"Lopez","year":"2011","journal-title":"J. Neurosci."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"201","DOI":"10.1006\/jsre.2001.6217","article-title":"Inhibition of Kupffer cells reduced CXC chemokine production and liver injury","volume":"99","author":"Mosher","year":"2001","journal-title":"J. Surg. Res."},{"key":"ref_26","first-page":"1208","article-title":"Selective depletion of hepatic kupffer cells significantly alleviated hepatosteatosis and intrahepatic inflammation induced by high fat diet","volume":"59","author":"Chen","year":"2012","journal-title":"Hepatogastroenterology."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"216","DOI":"10.1186\/1742-2094-9-216","article-title":"Complement is dispensable for neurodegeneration in Niemann\u2013Pick disease type C","volume":"9","author":"Lopez","year":"2012","journal-title":"J. Neuroinflammation"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"e2147","DOI":"10.1038\/cddis.2016.16","article-title":"Necroptosis in Niemann\u2013Pick disease, type C1: A potential therapeutic target","volume":"7","author":"Cougnoux","year":"2016","journal-title":"Cell Death Dis."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"242","DOI":"10.1016\/j.nbd.2009.07.010","article-title":"Beneficial effects of anti-inflammatory therapy in a mouse model of Niemann\u2013Pick disease type C1","volume":"36","author":"Smith","year":"2009","journal-title":"Neurobiol. Dis."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1016\/j.ymgmr.2018.05.001","article-title":"Controversies on the potential therapeutic use of rapamycin for treating a lysosomal cholesterol storage disease","volume":"15","author":"Klein","year":"2018","journal-title":"Mol. Genet. Metab. Reports"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1111\/jnc.13138","article-title":"Immune dysfunction in Niemann\u2013Pick disease type C","volume":"136","author":"Platt","year":"2016","journal-title":"J. Neurochem."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"944","DOI":"10.1124\/mol.51.6.944","article-title":"Gadolinium chloride blocks alcohol-dependent liver toxicity in rats treated chronically with intragastric alcohol despite the induction of CYP2E1","volume":"51","author":"Koop","year":"1997","journal-title":"Mol. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"186","DOI":"10.1002\/hep.510300104","article-title":"Pretreatment of mice with macrophage inactivators decreases acetaminophen hepatotoxicity and the formation of reactive oxygen and nitrogen species","volume":"30","author":"Michael","year":"1999","journal-title":"Hepatology"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1234","DOI":"10.1016\/j.bcp.2011.07.090","article-title":"Amiodarone impairs trafficking through late endosomes inducing a Niemann\u2013Pick C-like phenotype","volume":"82","author":"Piccoli","year":"2011","journal-title":"Biochem. Pharmacol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1016\/j.ab.2007.02.020","article-title":"Metabolic profiling of serum from gadolinium chloride-treated rats by1H NMR spectroscopy","volume":"364","author":"Liao","year":"2007","journal-title":"Anal. Biochem."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1394","DOI":"10.1016\/j.mri.2016.09.005","article-title":"Gadolinium toxicity and treatment","volume":"34","author":"Ramalho","year":"2016","journal-title":"Magn. Reson. Imaging"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"229","DOI":"10.1007\/s40263-018-0500-1","article-title":"Gadolinium-Based Contrast Agent-Related Toxicities","volume":"32","author":"Pasquini","year":"2018","journal-title":"CNS Drugs"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"779","DOI":"10.1016\/j.mric.2017.06.009","article-title":"Safety of Contrast Material Use in Children","volume":"25","author":"Soares","year":"2017","journal-title":"Magn. Reson. Imaging Clin. N. Am."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"765","DOI":"10.1016\/j.mric.2017.06.007","article-title":"Gadolinium Deposition and Chronic Toxicity","volume":"25","author":"Ramalho","year":"2017","journal-title":"Magn. Reson. Imaging Clin. N. Am."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"43","DOI":"10.1097\/00024382-199401000-00008","article-title":"Role of Kupffer cells in interleukin-6 release following trauma-hemorrhage and resuscitation","volume":"1","author":"Ayala","year":"1994","journal-title":"Shock"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"723","DOI":"10.1002\/jlb.55.6.723","article-title":"Blockade of liver macrophages by gadolinium chloride reduces lethality in endotoxemic rats\u2014Analysis of mechanisms of lethality in endotoxemia","volume":"55","author":"Iimuro","year":"1994","journal-title":"J. Leukoc. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"434","DOI":"10.1097\/00024382-199612000-00008","article-title":"Modulation of Kupffer cell activity by gadolinium chloride in endotoxemic rats","volume":"6","author":"Vollmar","year":"1996","journal-title":"Shock"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"1684","DOI":"10.1097\/00007890-199712270-00009","article-title":"In vitro analysis of gadolinium chloride abrogation of the systemic tolerance induced by portal venous administration of ultraviolet B-irradiated donor cells","volume":"64","author":"Yu","year":"1997","journal-title":"In Transplantation;"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Vincent, M., Sayre, N.L., Graham, M.J., Crooke, R.M., Shealy, D.J., and Liscum, L. (2010). Evaluation of an anti-tumor necrosis factor therapeutic in a mouse model of Niemann\u2013Pick C liver disease. PLoS ONE, 5.","DOI":"10.1371\/journal.pone.0012941"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.nbd.2004.09.004","article-title":"Enhanced calcium release in the acute neuronopathic form of Gaucher disease","volume":"18","author":"Pelled","year":"2005","journal-title":"Neurobiol. Dis."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"133","DOI":"10.1038\/nrd.2017.214","article-title":"Emptying the stores: Lysosomal diseases and therapeutic strategies","volume":"17","author":"Platt","year":"2018","journal-title":"Nat. Rev. Drug Discov."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"e10616","DOI":"10.7554\/eLife.10616","article-title":"Intracellular sphingosine releases calcium from lysosomes","volume":"4","author":"Haberkant","year":"2015","journal-title":"Elife"},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"288","DOI":"10.1038\/ncb3114","article-title":"Lysosomal calcium signalling regulates autophagy through calcineurin and TFEB","volume":"17","author":"Medina","year":"2015","journal-title":"Nat. Cell Biol."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"731","DOI":"10.1038\/ncomms1735","article-title":"Lipid storage disorders block lysosomal trafficking by inhibiting a TRP channel and lysosomal calcium release","volume":"3","author":"Shen","year":"2012","journal-title":"Nat. Commun."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"679","DOI":"10.1085\/jgp.95.4.679","article-title":"Blockade of current through single calcium channels by trivalent lanthanide cations. Effect of ionic radius on the rates of ion entry and exit","volume":"95","author":"Lansman","year":"1990","journal-title":"J. Gen. Physiol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1007\/s12011-008-8121-z","article-title":"Lysosomes of the liver and the duodenal enterocytes, a site of handling of two rare earths. Ultrastructural and microanalytical study","volume":"124","author":"Ahlem","year":"2008","journal-title":"Biol. Trace Elem. Res."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"323","DOI":"10.2220\/biomedres.28.323","article-title":"Gadolinium chloride suppresses styrene-induced cytochrome P450s expression in rat liver","volume":"28","author":"Hirasawa","year":"2007","journal-title":"Biomed. Res"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"1376","DOI":"10.1021\/tx900086v","article-title":"Macrophages and inflammatory mediators in chemical toxicity: A battle of forces","volume":"22","author":"Laskin","year":"2009","journal-title":"Chem. Res. Toxicol."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"326ra23","DOI":"10.1126\/scitranslmed.aad9407","article-title":"Chronic administration of an HDAC inhibitor treats both neurological and systemic Niemann\u2013Pick type C disease in a mouse model","volume":"8","author":"Alam","year":"2016","journal-title":"Sci. Transl. Med."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Ebner, L., Gl\u00e4ser, A., Br\u00e4uer, A., Witt, M., Wree, A., Rolfs, A., Frank, M., Vollmar, B., and Kuhla, A. (2018). Evaluation of two liver treatment strategies in a mouse model of niemann\u2013pick-disease type C1. Int. J. Mol. Sci., 19.","DOI":"10.3390\/ijms19040972"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"819","DOI":"10.1053\/jhep.2002.35617","article-title":"Relevance of Niemann\u2013Pick type C1 protein expression in controlling plasma cholesterol and biliary lipid secretion in mice","volume":"36","author":"Amigo","year":"2002","journal-title":"Hepatology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"345","DOI":"10.1080\/13510002.1996.11747071","article-title":"Inhibitory effect of phenyl N-terf-butyl nitrone on Kupffer cell phagocytosis","volume":"2","author":"Janzen","year":"1996","journal-title":"Redox Rep."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"613","DOI":"10.1016\/j.celrep.2016.07.085","article-title":"Identification of Modifier Genes in a Mouse Model of Gaucher Disease","volume":"16","author":"Klein","year":"2016","journal-title":"Cell Rep."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"671","DOI":"10.1038\/nmeth.2089","article-title":"NIH Image to ImageJ: 25 years of image analysis","volume":"9","author":"Schneider","year":"2012","journal-title":"Nat. Methods"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/11\/3599\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T02:01:09Z","timestamp":1775268069000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/19\/11\/3599"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2018,11,14]]},"references-count":59,"journal-issue":{"issue":"11","published-online":{"date-parts":[[2018,11]]}},"alternative-id":["ijms19113599"],"URL":"https:\/\/doi.org\/10.3390\/ijms19113599","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2018,11,14]]}}}