{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,13]],"date-time":"2026-06-13T20:25:33Z","timestamp":1781382333241,"version":"3.54.1"},"reference-count":58,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2020,9,19]],"date-time":"2020-09-19T00:00:00Z","timestamp":1600473600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Seventh Framework Programme","award":["FP7-NMP-2013-LARGE-7"],"award-info":[{"award-number":["FP7-NMP-2013-LARGE-7"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nanomaterials"],"abstract":"<jats:p>TiO2 nanomaterials are among the most commonly produced and used engineered nanomaterials (NMs) in the world. There is controversy regarding their ability to induce inflammation-mediated lung injuries following inhalation exposure. Activation of the NACHT, LRR and PYD domains-containing protein 3 (NALP3) inflammasome and subsequent release of the cytokine interleukin (IL)-1\u03b2 in pulmonary macrophages has been postulated as an essential pathway for the inflammatory and associated tissue-remodeling effects of toxic particles. Our study aim was to determine and rank the IL-1\u03b2 activating properties of TiO2 NMs by comparing a large panel of different samples against each other as well as against fine TiO2, synthetic amorphous silica and crystalline silica (DQ12 quartz). Effects were evaluated in primary bone marrow derived macrophages (BMDMs) from NALP3-deficient and proficient mice as well as in the rat alveolar macrophage cell line NR8383. Our results show that specific TiO2 NMs can activate the inflammasome in macrophages albeit with a markedly lower potency than amorphous SiO2 and quartz. The heterogeneity in IL-1\u03b2 release observed in our study among 19 different TiO2 NMs underscores the relevance of case-by-case evaluation of nanomaterials of similar chemical composition. Our findings also further promote the NR8383 cell line as a promising in vitro tool for the assessment of the inflammatory and inflammasome activating properties of NMs.<\/jats:p>","DOI":"10.3390\/nano10091876","type":"journal-article","created":{"date-parts":[[2020,9,19]],"date-time":"2020-09-19T07:06:09Z","timestamp":1600499169000},"page":"1876","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":18,"title":["Evaluation of the NLRP3 Inflammasome Activating Effects of a Large Panel of TiO2 Nanomaterials in Macrophages"],"prefix":"10.3390","volume":"10","author":[{"given":"Julia","family":"Kolling","sequence":"first","affiliation":[{"name":"IUF\u2014Leibniz Research Institute for Environmental Medicine, Auf\u2019m Hennekamp 50, 40225 DE D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonas","family":"Tigges","sequence":"additional","affiliation":[{"name":"IUF\u2014Leibniz Research Institute for Environmental Medicine, Auf\u2019m Hennekamp 50, 40225 DE D\u00fcsseldorf, Germany"},{"name":"Bundeswehr Institute of Pharmacology and Toxicology, Neuherbergstra\u00dfe 11, 80937 DE Munich, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Bryan","family":"Hellack","sequence":"additional","affiliation":[{"name":"Institute of Energy and Environmental Technology e.V. (IUTA), Bliersheimer Str. 60, 47229 Duisburg, Germany"},{"name":"UBA\u2014German Environment Agency, Paul-Ehrlich-Str. 29, 63225 Langen, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Catrin","family":"Albrecht","sequence":"additional","affiliation":[{"name":"IUF\u2014Leibniz Research Institute for Environmental Medicine, Auf\u2019m Hennekamp 50, 40225 DE D\u00fcsseldorf, Germany"},{"name":"State Office for Consumer Protection Saxony-Anhalt, 39576 Stendal, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roel P. F.","family":"Schins","sequence":"additional","affiliation":[{"name":"IUF\u2014Leibniz Research Institute for Environmental Medicine, Auf\u2019m Hennekamp 50, 40225 DE D\u00fcsseldorf, Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,9,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"4227","DOI":"10.1021\/es8032549","article-title":"Estimates of upper bounds and trends in nano-TiO2 production as a basis for exposure assessment","volume":"43","author":"Robichaud","year":"2009","journal-title":"Environ. Sci. Technol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s12951-018-0376-8","article-title":"Critical review of the safety assessment of titanium dioxide additives in food","volume":"16","author":"Winkler","year":"2018","journal-title":"J. Nanobiotechnol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/S0003-4878(98)00044-1","article-title":"The Quartz Hazard: A Variable Entity","volume":"42","author":"Donaldson","year":"1998","journal-title":"Ann. Occup. Hyg."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"292","DOI":"10.1165\/rcmb.2003-0300OC","article-title":"Inflammatory time course after quartz instillation: Role of tumor necrosis factor-alpha and particle surface","volume":"31","author":"Albrecht","year":"2004","journal-title":"Am. J. Respir. Cell Mol. Biol."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1016\/S0003-4878(98)00066-0","article-title":"Surface Chemistry and Quartz Hazard","volume":"42","author":"Fubini","year":"1998","journal-title":"Ann. Occup. Hyg."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"111","DOI":"10.1016\/j.toxlet.2011.01.025","article-title":"Titanium dioxide nanoparticles impair lung mitochondrial function","volume":"202","author":"Torres","year":"2011","journal-title":"Toxicol. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"397","DOI":"10.1289\/ehp.9469","article-title":"Inhalation exposure study of titanium dioxide nanoparticles with a primary particle size of 2 to 5 nm","volume":"115","author":"Grassian","year":"2007","journal-title":"Environ. Health Perspect."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"160","DOI":"10.1016\/j.bbrc.2009.12.178","article-title":"Titanium dioxide induces different levels of IL-1beta production dependent on its particle characteristics through caspase-1 activation mediated by reactive oxygen species and cathepsin B","volume":"392","author":"Morishige","year":"2010","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_9","first-page":"173","article-title":"Correlation between particle size, in vivo particle persistence, and lung injury","volume":"102","author":"Ferin","year":"1994","journal-title":"Environ. Health Perspect."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"141","DOI":"10.1016\/j.taap.2007.05.001","article-title":"Endocytosis, oxidative stress and IL-8 expression in human lung epithelial cells upon treatment with fine and ultrafine TiO2: Role of the specific surface area and of surface methylation of the particles","volume":"222","author":"Singh","year":"2007","journal-title":"Toxicol. Appl. Pharm."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/1743-8977-5-1","article-title":"Nanoparticle inhalation augments particle-dependent systemic microvascular dysfunction","volume":"5","author":"Nurkiewicz","year":"2008","journal-title":"Part. Fibre Toxicol."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"9035","DOI":"10.1073\/pnas.0803933105","article-title":"The Nalp3 inflammasome is essential for the development of silicosis","volume":"105","author":"Cassel","year":"2008","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"674","DOI":"10.1126\/science.1156995","article-title":"Innate immune activation through Nalp3 inflammasome sensing of asbestos and silica","volume":"320","author":"Dostert","year":"2008","journal-title":"Science"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"847","DOI":"10.1038\/ni.1631","article-title":"Silica crystals and aluminum salts activate the NALP3 inflammasome through phagosomal destabilization","volume":"9","author":"Hornung","year":"2008","journal-title":"Nat. Immunol."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"417","DOI":"10.1016\/S1097-2765(02)00599-3","article-title":"The Inflammasome","volume":"10","author":"Martinon","year":"2002","journal-title":"Mol. Cell"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1016\/j.freeradbiomed.2007.12.027","article-title":"Silica binding and toxicity in alveolar macrophages","volume":"44","author":"Hamilton","year":"2008","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1186\/s12989-016-0150-8","article-title":"The complex cascade of cellular events governing inflammasome activation and IL-1\u03b2 processing in response to inhaled particles","volume":"13","author":"Rabolli","year":"2016","journal-title":"Part. Fibre Toxicol."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"22","DOI":"10.1186\/1743-8977-7-22","article-title":"Nanomaterial cytotoxicity is composition, size, and cell type dependent","volume":"7","author":"Sohaebuddin","year":"2010","journal-title":"Part. Fibre Toxicol."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1186\/s12989-014-0058-0","article-title":"Silica-induced NLRP3 inflammasome activation in vitro and in rat lungs","volume":"11","author":"Peeters","year":"2014","journal-title":"Part. Fibre Toxicol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e1629","DOI":"10.1038\/cddis.2014.576","article-title":"The NLRP3 inflammasome is activated by nanoparticles through ATP, ADP and adenosine","volume":"6","author":"Baron","year":"2015","journal-title":"Cell Death Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"51","DOI":"10.1186\/s12989-017-0232-2","article-title":"Pro-inflammatory adjuvant properties of pigment-grade titanium dioxide particles are augmented by a genotype that potentiates interleukin 1\u03b2 processing","volume":"14","author":"Riedle","year":"2017","journal-title":"Part. Fibre Toxicol."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1216","DOI":"10.1136\/gutjnl-2015-310297","article-title":"Titanium dioxide nanoparticles exacerbate DSS-induced colitis: Role of the NLRP3 inflammasome","volume":"66","author":"Ruiz","year":"2017","journal-title":"Gut"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"326","DOI":"10.3109\/17435390.2010.506957","article-title":"Activation of the inflammasome by amorphous silica and TiO2 nanoparticles in murine dendritic cells","volume":"5","author":"Winter","year":"2011","journal-title":"Nanotoxicology"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"21844","DOI":"10.1074\/jbc.M111.238519","article-title":"Induction of inflammasome-dependent pyroptosis by carbon black nanoparticles","volume":"286","author":"Reisetter","year":"2011","journal-title":"J. Biol. Chem."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1186\/1743-8977-8-31","article-title":"Contrasting macrophage activation by fine and ultrafine titanium dioxide particles is associated with different uptake mechanisms","volume":"8","author":"Scherbart","year":"2011","journal-title":"Part. Fibre Toxicol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"11","DOI":"10.1186\/s12989-017-0192-6","article-title":"SiO2 and TiO2 nanoparticles synergistically trigger macrophage inflammatory responses","volume":"14","author":"Tsugita","year":"2017","journal-title":"Part. Fibre Toxicol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"89559","DOI":"10.1039\/C5RA14303A","article-title":"A comparative study on the efficacy of different probes to predict the photo-activity of nano-titanium dioxide toward biomolecules","volume":"5","author":"Marucco","year":"2015","journal-title":"RSC Adv."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1039\/C2CP42381B","article-title":"Shape-controlled TiO2nanoparticles and TiO2 P25 interacting with CO and H2O2 molecular probes: A synergic approach for surface structure recognition and physico-chemical understanding","volume":"15","author":"Deiana","year":"2013","journal-title":"Phys. Chem. Chem. Phys."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"70501","DOI":"10.1039\/C6RA09686G","article-title":"Shape engineered TiO2 nanoparticles in Caenorhabditis elegans: A Raman imaging based approach to assist tissue-specific toxicological studies","volume":"6","author":"Iannarelli","year":"2016","journal-title":"RSC Adv."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/10937404.2015.1126210","article-title":"A Multilaboratory Toxicological Assessment of a Panel of 10 Engineered Nanomaterials to Human Health\u2014ENPRA Project\u2014The Highlights, Limitations, and Current and Future Challenges","volume":"19","author":"Kermanizadeh","year":"2016","journal-title":"J. Toxicol. Environ. Health B Crit. Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"105","DOI":"10.1093\/mutage\/gew056","article-title":"Oxidant generation, DNA damage and cytotoxicity by a panel of engineered nanomaterials in three different human epithelial cell lines","volume":"32","author":"Thongkam","year":"2017","journal-title":"Mutagenesis"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"58","DOI":"10.1016\/j.taap.2017.01.012","article-title":"Phagolysosome acidification is required for silica and engineered nanoparticle-induced lysosome membrane permeabilization and resultant NLRP3 inflammasome activity","volume":"318","author":"Jessop","year":"2017","journal-title":"Toxicol. Appl. Pharm."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"37","DOI":"10.1006\/taap.2002.9500","article-title":"In Vitro and in Vivo Activation of Extracellular Signal-Regulated Kinases by Coal Dusts and Quartz Silica","volume":"184","author":"Albrecht","year":"2002","journal-title":"Toxicol. Appl. Pharm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"2006","DOI":"10.4049\/jimmunol.1201065","article-title":"NLRP1-dependent pyroptosis leads to acute lung injury and morbidity in mice","volume":"189","author":"Kovarova","year":"2012","journal-title":"J. Immunol."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"519","DOI":"10.1146\/annurev.immunol.021908.132612","article-title":"Immunological and inflammatory functions of the interleukin-1 family","volume":"27","author":"Dinarello","year":"2009","journal-title":"Annu. Rev. Immunol."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"3734","DOI":"10.4049\/jimmunol.1200136","article-title":"The IL-1-dependent sterile inflammatory response has a substantial caspase-1-independent component that requires cathepsin C","volume":"189","author":"Kono","year":"2012","journal-title":"J. Immunol."},{"key":"ref_38","doi-asserted-by":"crossref","unstructured":"Kusaka, T., Nakayama, M., Nakamura, K., Ishimiya, M., Furusawa, E., and Ogasawara, K. (2014). Effect of silica particle size on macrophage inflammatory responses. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0092634"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"69","DOI":"10.1186\/s12989-014-0069-x","article-title":"The alarmin IL-1\u03b1 is a master cytokine in acute lung inflammation induced by silica micro- and nanoparticles","volume":"11","author":"Rabolli","year":"2014","journal-title":"Part. Fibre Toxicol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"32","DOI":"10.1186\/1743-8977-9-32","article-title":"Comparison of non-crystalline silica nanoparticles in IL-1\u03b2 release from macrophages","volume":"9","author":"Sandberg","year":"2012","journal-title":"Part. Fibre Toxicol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"567","DOI":"10.1007\/BF02620974","article-title":"From growth factor dependence to growth factor responsiveness: The genesis of an alveolar macrophage cell line","volume":"23","author":"Helmke","year":"1987","journal-title":"Vitr. Cell. Dev. Biol."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1021\/tx1003003","article-title":"Surface iron inhibits quartz-induced cytotoxic and inflammatory responses in alveolar macrophages","volume":"24","author":"Ghiazza","year":"2011","journal-title":"Chem. Res. Toxicol."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"459","DOI":"10.1007\/s00204-007-0178-5","article-title":"Actin plays a crucial role in the phagocytosis and biological response to respirable quartz particles in macrophages","volume":"81","author":"Haberzettl","year":"2007","journal-title":"Arch. Toxicol."},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Bannuscher, A., Hellack, B., Bahl, A., Laloy, J., Herman, H., Stan, M.S., Dinischiotu, A., Giusti, A., Krause, B.-C., and Tentschert, J. (2020). Metabolomics profiling to investigate nanomaterial toxicity in vitro and in vivo. Nanotoxicology, 1\u201320.","DOI":"10.1080\/17435390.2020.1764123"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"861","DOI":"10.1080\/17435390.2019.1592258","article-title":"Comparison of the effects of multiwall carbon nanotubes on the epithelial cells and macrophages","volume":"13","author":"Horie","year":"2019","journal-title":"Nanotoxicology"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"16","DOI":"10.1186\/s12951-016-0164-2","article-title":"An in vitro alveolar macrophage assay for predicting the short-term inhalation toxicity of nanomaterials","volume":"14","author":"Wiemann","year":"2016","journal-title":"J. Nanobiotechnol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"13","DOI":"10.1186\/1743-8977-7-13","article-title":"NF-kappaB dependent and independent mechanisms of quartz-induced proinflammatory activation of lung epithelial cells","volume":"7","author":"Knaapen","year":"2010","journal-title":"Part. Fibre Toxicol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"1685","DOI":"10.1016\/j.freeradbiomed.2010.08.031","article-title":"Neutrophil-derived ROS contribute to oxidative DNA damage induction by quartz particles","volume":"49","author":"Wessels","year":"2010","journal-title":"Free. Radic. Biol. Med."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"258","DOI":"10.1002\/em.10120","article-title":"Overexpression of heme oxygenase-1 (HO-1) in V79 cells results in increased resistance to hyperbaric oxygen (HBO)-induced DNA damage","volume":"40","author":"Rothfuss","year":"2002","journal-title":"Environ. Mol. Mutagen."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"101261","DOI":"10.1016\/j.redox.2019.101261","article-title":"Self-defence of macrophages against oxidative injury: Fighting for their own survival","volume":"26","author":"Regdon","year":"2019","journal-title":"Redox Biol."},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"L485","DOI":"10.1152\/ajplung.00427.2001","article-title":"Enhanced nitric oxide and reactive oxygen species production and damage after inhalation of silica","volume":"283","author":"Porter","year":"2002","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.colsurfb.2008.09.014","article-title":"Agglomeration and sedimentation of TiO2 nanoparticles in cell culture medium","volume":"68","author":"Allouni","year":"2009","journal-title":"Colloids Surf. B Biointerfaces"},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"259","DOI":"10.3109\/17435390.2011.652206","article-title":"Screening of different metal oxide nanoparticles reveals selective toxicity and inflammatory potential of silica nanoparticles in lung epithelial cells and macrophages","volume":"7","author":"Panas","year":"2013","journal-title":"Nanotoxicology"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s00204-016-1673-3","article-title":"Impact of serum as a dispersion agent for in vitro and in vivo toxicological assessments of TiO2 nanoparticles","volume":"91","author":"Vranic","year":"2017","journal-title":"Arch. Toxicol."},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"871","DOI":"10.1007\/s00204-019-02422-9","article-title":"The protein corona suppresses the cytotoxic and pro-inflammatory response in lung epithelial cells and macrophages upon exposure to nanosilica","volume":"93","author":"Leibe","year":"2019","journal-title":"Arch. Toxicol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"144","DOI":"10.1080\/17435390802318349","article-title":"A biocompatible medium for nanoparticle dispersion","volume":"2","author":"Porter","year":"2008","journal-title":"Nanotoxicology"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1080\/17435390.2019.1687775","article-title":"Length-dependent toxicity of TiO2 nanofibers: Mitigation via shortening","volume":"14","author":"Bianchi","year":"2020","journal-title":"Nanotoxicology"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"179","DOI":"10.1093\/toxsci\/kfs261","article-title":"Differential mouse pulmonary dose and time course responses to titanium dioxide nanospheres and nanobelts","volume":"131","author":"Porter","year":"2013","journal-title":"Toxicol. Sci."}],"container-title":["Nanomaterials"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2079-4991\/10\/9\/1876\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T10:11:33Z","timestamp":1760177493000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2079-4991\/10\/9\/1876"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,9,19]]},"references-count":58,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2020,9]]}},"alternative-id":["nano10091876"],"URL":"https:\/\/doi.org\/10.3390\/nano10091876","relation":{},"ISSN":["2079-4991"],"issn-type":[{"value":"2079-4991","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,9,19]]}}}