Journal of Applied Toxicology最新文献

{"title":"Nebivolol hydrochloride and its impurities induce pseudo‐allergic reactions via mast cell activation","authors":"Liju Yu, Yi Shan, Jiayu Lu, Huaizhen He","doi":"10.1002/jat.4699","DOIUrl":"https://doi.org/10.1002/jat.4699","url":null,"abstract":"Nebivolol hydrochloride is a third‐generation β‐blocker commonly used to treat cardiovascular diseases. However, it has been reported to induce allergic reactions in clinical use which deserves much attention. Therefore, this study focused on the ability of two isomers of nebivolol and chiral isomer impurities to induce allergic reactions. Our findings demonstrate that both nebivolol and two isomeric impurities can activate mast cell degranulation in vitro and show significant retention on Mas‐related G‐protein‐coupled receptor X2 (MRGPRX2)‐HEK293 cell membrane chromatography. These effects were further validated in vivo, where nebivolol and impurity IP‐3 were observed to cause toe swelling and mast cell degranulation in mice. Molecular docking studies revealed interactions between these compounds and key amino acids of MRGPRX2, suggesting a mechanism for the induced allergic reactions. This work lays the foundation for improving the clinical safety of nebivolol.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"47 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261860","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nuciferine protects hyperandrogen‐injured ovarian granulosa cells by inhibiting ferroptosis via SOX2‐mediated activation of the SLC7A11/GPX4 axis","authors":"Hongyu Yang, Shichao Chen, Shanshan Yin, Qi Ding","doi":"10.1002/jat.4697","DOIUrl":"https://doi.org/10.1002/jat.4697","url":null,"abstract":"Polycystic ovary syndrome (PCOS) is a common endocrine disorder that can cause menstrual irregularities, infertility, polycystic ovaries, and metabolic abnormalities. Female reproductive health and quality of life are significantly affected by PCOS, which has recently been associated with ferroptosis in granulosa cells (GCs). Nuciferine (NF) is a naturally extracted substance with multiple pharmacological activities, which is reported with anti‐ferroptosis function. Herein, the influence of NF for androgen‐induced ferroptosis in GCs was investigated to explore the potential value of NF on treating PCOS. 10 μM NF and 20 μM NF were employed for treating KGN cells according to cell viability results. KGN cells were treated with 10 μM dehydroepiandrosterone (DHEA) for 1 day, followed by introducing 10 μM NF and 20 μM NF for 24 h. Strikingly reduced cell viability, increased lactate dehydrogenase release and reactive oxygen species (ROS) production, enhanced apoptosis, upregulated Bax, downregulated Bcl‐2, restrained malondialdehyde contents, and declined superoxide dismutase activity were observed in DHEA‐treated KGN cells, which were significantly reversed by NF. Significantly repressed GPX4, SLC7A11, and SOX2 levels, as well as increased ACSL4 levels and Fe<jats:sup>2+</jats:sup> levels in DHEA‐treated KGN cells, were notably rescued by NF. Furthermore, the inhibitory effect of NF on ROS production and ferroptosis in DHEA‐treated KGN cells was partially abrogated by silencing SOX2. Collectively, NF protected DHEA‐injured ovarian GCs by inhibiting ferroptosis via upregulating SOX2.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"88 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261861","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The ameliorative potential of metformin against aluminum‐induced neurotoxicity: Insights from in vitro studies","authors":"Sonia Sanajou, Anil Yirün, Göksun Demirel, Pinar Erkekoğlu, Gönül Şahin, Terken Baydar","doi":"10.1002/jat.4695","DOIUrl":"https://doi.org/10.1002/jat.4695","url":null,"abstract":"Alzheimer's disease (AD) is increasingly recognized as a metabolic disorder, often referred to as type 3 diabetes, due to its strong association with insulin resistance. Chronic exposure to aluminum, a known neurotoxin, has been identified as a significant risk factor in the development and progression of AD. This study explores the potential of metformin, a common anti‐diabetic drug, to mitigate aluminum‐induced neurotoxicity in an in vitro model of AD. Our findings reveal that metformin significantly reduces oxidative stress markers such as malonaldehyde, carbonyl groups, and reactive oxygen species while enhancing antioxidant defenses. Metformin modulates critical signaling pathways, including glycogen synthase kinase 3 beta (GSK3‐β)/RAC‐alpha serine/threonine protein kinase (RAC‐alpha serine/threonine protein kinase (Akt1)/protein phosphatase 2A (PP2A) and Wnt/β‐catenin, decreasing Tau protein levels and promoting neurogenesis. These results suggest that metformin may offer a novel therapeutic approach for AD, particularly in cases where aluminum exposure is a contributing factor.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"30 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-09-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142261862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bifidobacterium longum subsp. infantis YLGB‐1496—Toxicological evaluation","authors":"Jian Zhao, Yueyi Guo, Qiuyue Jiang, Hanglian Lan, Wei‐Lian Hung, Barry Lynch","doi":"10.1002/jat.4688","DOIUrl":"https://doi.org/10.1002/jat.4688","url":null,"abstract":"<jats:styled-content style=\"fixed-case\"><jats:italic>Bifidobacterium infantis</jats:italic></jats:styled-content> YLGB‐1496, originally isolated from breast milk from a Taiwanese mother, is under study for use as a probiotic. As part of safety assessment, an Ames, in vivo mouse micronucleus, and in vivo mouse spermatocyte chromosome aberration assay were conducted along with a 13‐week oral rat toxicity study. <jats:styled-content style=\"fixed-case\"><jats:italic>B. infantis</jats:italic></jats:styled-content> YLGB‐1496 had no activity in any of the genotoxicity assays. Administration of the bacteria to Sprague–Dawley rats at doses ranging from 0 to 1.5 g/kg bw/day had no treatment‐related effects on any of the endpoints measured. There appear to be no concerns for translocation or pathogenicity of <jats:styled-content style=\"fixed-case\"><jats:italic>B. infantis</jats:italic></jats:styled-content> YLGB‐1496 based on extensive experience with the species in general. The results of the current investigations support potential use of <jats:styled-content style=\"fixed-case\"><jats:italic>B. infantis</jats:italic></jats:styled-content> YLGB‐1496 as a probiotic in infant formula.","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"4 1","pages":""},"PeriodicalIF":3.3,"publicationDate":"2024-09-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142180242","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Epigenetic alternations in the SYP and DLG4 genes due to low-level methylmercury exposure during neuronal differentiation in vitro","authors":"Hisaka Kurita,&nbsp;Haruka Masuda,&nbsp;Ayu Okuda,&nbsp;Suzuna Go,&nbsp;Kazuki Ohuchi,&nbsp;Hiroki Yoshioka,&nbsp;Masatake Fujimura,&nbsp;Isao Hozumi,&nbsp;Masatoshi Inden","doi":"10.1002/jat.4690","DOIUrl":"10.1002/jat.4690","url":null,"abstract":"<p>Methylmercury (MeHg) is an environmental toxin known to damage the central nervous system. When pregnant women ingest seafood, which may contain accumulated MeHg, fetal development may be affected. The embryonic period, a time of major epigenetic change, is susceptible to epigenetic disruptions due to chemical exposure. Therefore, understanding the molecular mechanism underlying MeHg's effects on neuronal development requires consideration of epigenetic factors. In this study, we investigated epigenetic modifications in the synaptophysin (<i>SYP</i>) and discs large MAGUK scaffold protein 4 (<i>DLG4</i>) genes. LUHMES cells were exposed to 1 nM MeHg for 6 days during days 2–8 of neural differentiation. MeHg exposure significantly reduced the number of spikes observed on day 16 of differentiation. Both mRNA and protein expression levels of SYP and DLG4 were significantly decreased by MeHg exposure. Additionally, MeHg treatment reduced acetyl histone H3 levels associated with transcriptional activity in the <i>SYP</i> gene while increasing histone H3 lysine 27 tri-methylation (H3K27me3) levels related to transcriptional repression. Conversely, regarding the <i>DLG4</i> gene, MeHg exposure increased H3K27me3 levels. Differential changes in DNA methylation (high and low methylation states) were observed in the <i>SYP</i> and <i>DLG4</i> genes due to MeHg exposure depending on CpG site position. In conclusion, this study suggests that epigenetic changes, particularly histone modifications, contribute to decreased MeHg exposure-induced SYP and DLG4 expression during neuronal differentiation.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 12","pages":"1986-1996"},"PeriodicalIF":2.7,"publicationDate":"2024-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142072865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Appearance of sex-determining region Y-box 9 (SOX9)- and glutathione S-transferase placental form (GST-P)-positive hepatocytes as possible carcinogenic events in the early stage of furan-induced hepatocarcinogenesis","authors":"Daisuke Hibi,&nbsp;Meili Soma,&nbsp;Yuta Suzuki,&nbsp;Shinji Takasu,&nbsp;Yuji Ishii,&nbsp;Takashi Umemura","doi":"10.1002/jat.4691","DOIUrl":"10.1002/jat.4691","url":null,"abstract":"<p>Furan, the basic skeleton of various flavoring agents, induces cholangiocellular tumors with higher incidences in the caudate lobe and hepatocellular tumors without the lobe specificity in rats, but the mechanism is unclear. We investigated the lobe distribution of possible carcinogenic events. Furan caused proliferation/infiltration of oval and inflammatory cells prominently in the caudate lobe as early as 4 weeks and cholangiofibrosis in this lobe at 8 weeks. In vivo mutagenicity assays using DNA extracted from the caudate or left lateral lobe of male <i>gpt</i> delta rats, the reporter gene-transgenic rats, treated with 8 mg/kg furan for 4 or 8 weeks showed negative outcomes. The distribution of glutathione <i>S</i>-transferase placental form (GST-P)-positive or sex-determining region Y-box 9 (SOX9)-positive hepatocytes was examined. Significant increases in the number of GST-P-positive hepatocytes were observed in all lobes of furan-treated rats at 8 weeks. By contrast, SOX9-positive hepatocytes, liver injury-inducible progenitor cells, were also found in all lobes of treated rats, the incidences of which were by far the highest in the caudate lobe. In addition, some of these hepatocytes also co-expressed delta like 1 homolog (DLK1), a hepatoblast marker, particularly in areas with a predominant presence of inflammatory cells. Overall, furan induced liver injury, leading to the appearance of SOX9-positive hepatocytes, some of which were subjected to dedifferentiation in the inflammatory microenvironment of a cholangiocarcinoma-prone lobe. Thus, the appearance of SOX9-positive hepatocytes together with GST-P-positive hepatocytes could be initial events in furan-induced hepatocarcinogenesis via non-genotoxic mechanisms.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 12","pages":"1976-1985"},"PeriodicalIF":2.7,"publicationDate":"2024-08-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bacillus subtilis ZB423: 90-Day repeat dose oral (gavage) toxicity study in Wistar rats","authors":"Vijayakumar K. N.,&nbsp;Swati S. Bamne,&nbsp;Johnson Crasta,&nbsp;Satish Kumar C.,&nbsp;Ramakrishna M. Bhat,&nbsp;Bentley M. Shuster,&nbsp;John W. K. Oliver,&nbsp;Zachary D. Abbott","doi":"10.1002/jat.4677","DOIUrl":"10.1002/jat.4677","url":null,"abstract":"<p>The novel genetically modified probiotic <i>Bacillus subtilis</i> ZB423 was assessed in a 90-day repeated-dose oral toxicity study adhering to Good Laboratory Practice (GLP) and Organization for Economic Cooperation and Development (OECD) guidelines. Spray-dried spores at a concentration of 1.1E12 CFU/g were administered at doses of 130, 260, and 519 mg/kg body weight/day correlating to 1.43 × 10¹¹, 2.86 × 10¹¹, and 5.71 × 10¹¹ CFU/kg/day, respectively, by oral gavage to Wistar rats for a period of 90 consecutive days. Results showed no toxicologically relevant findings for <i>B. subtilis</i> ZB423 from measured parameters. The no observed adverse effect level (NOAEL) of <i>B. subtilis</i> ZB423 is 519 mg/kg body weight/day corresponding to 5.71 × 10¹¹ CFU/kg/day for lyophilized <i>B. subtilis</i> ZB423 spores under the test conditions employed.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 12","pages":"1874-1885"},"PeriodicalIF":2.7,"publicationDate":"2024-08-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142017605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Toxicity of soil leaching liquor from coking plant in developmental zebrafish embryos/larvae model","authors":"Guangchao Yang,&nbsp;Jining Liu,&nbsp;Qian Yang,&nbsp;Wen Gu","doi":"10.1002/jat.4692","DOIUrl":"10.1002/jat.4692","url":null,"abstract":"<p>The coking industry in China is the largest coke supplier in the world. Contaminated soil in industrial areas poses a serious threat to human and ecosystems. Most of the studies investigated the toxicity of soil from coking plant on soil microorganisms, while the toxic effects of soil leaching liquor on aquatics are limited. In this study, the composition of soil leaching liquor from a coking plant in Taiyuan (TY) was analyzed, and the developmental toxicity on zebrafish was evaluated. The results showed that a total of 91 polycyclic aromatic hydrocarbons were detected in the leaching liquor, followed by phenols and benzene series. The leaching liquor induced developmental impairment in zebrafish larvae, including delayed incubation, deficits in locomotor behavior, vascular and cardiac dysplasia, and impaired neurodevelopment. The results of metabolomics analysis showed that TY soil leaching liquor induced significant metabolic profile disturbances in zebrafish embryos/larvae. The developmental toxicity of the leaching liquor metabolic disorders may be associated with the leaching liquor-induced abnormalities in zebrafish embryonic development. Metabolic pathways were identified by arginine and proline metabolism, phosphotransferase system, starch and sucrose metabolism, steroid biosynthesis, beta-alanine metabolism, and nucleotide metabolism pathways.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 12","pages":"1962-1975"},"PeriodicalIF":2.7,"publicationDate":"2024-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142008843","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Composition of e-cigarette aerosols: A review and risk assessment of selected compounds.","authors":"Jonathan Heywood, Grayson Abele, Blake Langenbach, Sydney Litvin, Sarah Smallets, Dennis Paustenbach","doi":"10.1002/jat.4683","DOIUrl":"https://doi.org/10.1002/jat.4683","url":null,"abstract":"<p><p>The potential harms and benefits of e-cigarettes, or electronic nicotine delivery systems (ENDS), have received significant attention from public health and regulatory communities. Such products may provide a reduced risk means of nicotine delivery for combustible cigarette smokers while being inappropriately appealing to nicotine naive youth. Numerous authors have examined the chemical complexity of aerosols from various open- and closed-system ENDS. This body of literature is reviewed here, with the risks of ENDS aerosol exposure among users evaluated with a margin of exposure (MoE) approach for two non-carcinogens (methylglyoxal, butyraldehyde) and a cancer risk analysis for the carcinogen N-nitrosonornicotine (NNN). We identified 96 relevant papers, including 17, 13, and 5 reporting data for methylglyoxal, butyraldehyde, and NNN, respectively. Using low-end (minimum aerosol concentration, low ENDS use) and high-end (maximum aerosol concentration, high ENDS use) assumptions, estimated doses for methylglyoxal (1.78 × 10^-3-135 μg/kg-bw/day) and butyraldehyde (1.9 × 10^-4-66.54 μg/kg-bw/day) corresponded to MoEs of 227-17,200,000 and 271-280,000,000, respectively, using identified points of departure (PoDs). Doses of 9.90 × 10^-6-1.99 × 10^-4 μg/kg-bw/day NNN corresponded to 1.4-28 surplus cancers per 100,000 ENDS users, relative to a NNN-attributable surplus of 7440 per 100,000 cigarette smokers. It was concluded that methylglyoxal and butyraldehyde in ENDS aerosols, while not innocuous, did not present a significant risk of irritant effects among ENDS users. The carcinogenic risks of NNN in ENDS aerosols were reduced, but not eliminated, relative to concentrations reported in combustible cigarette smoke.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":" ","pages":""},"PeriodicalIF":2.7,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141988017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Esculin alleviates lipopolysaccharide (LPS)–induced pneumonia by regulating the USP7/MAPK14 axis","authors":"Lijuan Wang,&nbsp;Na Li,&nbsp;Yanan Wang,&nbsp;Xu Chen","doi":"10.1002/jat.4686","DOIUrl":"10.1002/jat.4686","url":null,"abstract":"<p>Pneumonia is a serious and life-threatening lung inflammation with high morbidity and mortality. Accumulating evidence has suggested that esculin, a derivative of coumarin, possesses potent anti-inflammatory effects. This study is designed to explore the pharma role and underlying mechanism of esculin against lipopolysaccharides (LPS)-induced pneumonia. TC-1 cells were stimulated by LPS to mimic the inflammatory injury model <i>in vitro</i>. Cell viability, proliferation, and apoptosis were determined using MTT assay, 5-ethynyl-2′-deoxyuridine assay, and flow cytometry. Interleukin-1β and tumor necrosis factor α levels were analyzed using an enzyme-linked immunosorbent assay. Reactive oxygen species and superoxide dismutase were examined using special assay kits. Macrophage polarization was detected using flow cytometry. Mitogen-activated protein kinase 14 (MAPK14) level was detected by real-time quantitative polymerase chain reaction. MAPK14 and ubiquitin-specific protease 7 (USP7) protein levels were determined using western blot assay. After Ubibrowser database prediction, the interaction between USP7 and MAPK14 was verified using a Co-immunoprecipitation assay. The biological role of esculin was verified in LPS-challenged ALI mice <i>in vivo</i>. Here, we found that esculin significantly relieved LPS-induced TC-1 cell proliferation inhibition, and apoptosis, inflammatory response, oxidative stress, and M1-type macrophage polarization promotion. MAPK14 and USP7 expressions were enhanced in LPS-treated TC-1 cells, which was partly abolished by esculin treatment. Overexpressing MAPK14 attenuated the repression of esculin on LPS-triggered TC-1 cell injury. At the molecular level, USP7 interacted with MAPK14 and maintained its stability by removing ubiquitin. Moreover, esculin repressed the progression of pneumonia <i>in vivo</i> by regulating MAPK14. Taken together, esculin exposure could mitigate LPS-induced TC-1 cell injury partly by targeting the USP7/MAPK14 axis, providing a better understanding of the role of esculin in the anti-inflammatory therapeutics for pneumonia.</p>","PeriodicalId":15242,"journal":{"name":"Journal of Applied Toxicology","volume":"44 12","pages":"1949-1961"},"PeriodicalIF":2.7,"publicationDate":"2024-08-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141982353","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}