Chemical Research in Toxicology最新文献

{"title":"ROS-Dependent Endoplasmic Reticulum Stress Is Involved in Silica-Induced Pulmonary Fibrosis through the GRP78/CHOP/TXNIP/NLRP3 Signaling Pathway in Rats.","authors":"Gui-Zhi Han, Shuang Li, Yuan-Yuan Cui, Bo Shao, Ye Song, Shun-Li Jiang, Zhao-Qiang Zhang","doi":"10.1021/acs.chemrestox.5c00135","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00135","url":null,"abstract":"<p><p>Several studies have suggested that silica-induced reactive oxygen species (ROS) stimulate the endoplasmic reticulum to undergo endoplasmic reticulum stress (ERS), which eventually leads to pulmonary fibrosis. However, the mechanisms by which ROS-dependent ERS leads to silicosis and fibrosis remain unclear. In this study, male rats were intratracheally instilled with a single dose of crystalline silica (SiO2) suspension (100 mg/mL, 1 mL) to establish silicosis and then were injected intravenously with 1 mL of N-Acetylcysteine (NAC) (at the dose of 20, 40, or 80 mg/kg, respectively) daily to inhibit ROS-dependent ERS. Rats given a single intratracheal dose of SiO₂ suspension and subsequently receiving daily intravenous injections of phosphate buffer solution (PBS) served as models, while those given a single intratracheal dose of PBS and subsequently receiving daily intravenous injections of PBS served as controls. After 40 days, lung samples were taken for pathological observation, and the levels of glucose-regulated protein 78(GRP78), CCAAT-enhancer-binding protein homologous protein (CHOP), thioredoxin-interacting protein (TXNIP), and nucleotide-binding oligomerization domain (NOD)-like receptor family pyrin domain containing 3 inflammasome (NLRP3 inflammasome) were assessed. The results showed that compared with the control group, the lung tissues of the model rats exhibited obvious fibrosis and ERS, accompanied by the elevated levels of GRP78, CHOP, TXNIP, and NLRP3 inflammasome. After ROS were inhibited with NAC, the degree of lung fibrosis and ERS was significantly alleviated, and the levels of the aforementioned cytokines were also reduced. Moreover, the higher the dose of NAC intervention, the more pronounced the effects. The results demonstrated that ROS-dependent ERS is deeply involved in silica-induced pulmonary fibrosis through the GRP78/CHOP/TXNIP/NLRP3 signaling pathway in rats.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598907","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Role of Human Aldo-Keto Reductases and Nuclear Factor Erythroid 2-Related Factor 2 in the Metabolic Activation of 1,8-Dinitropyrene and Its Metabolite 1-Amino-8-nitropyrene via Nitroreduction in Human Lung Cells.","authors":"Anthony L Su, Cátia F Marques, Jacek Krzeminski, Karam El-Bayoumy, Trevor M Penning","doi":"10.1021/acs.chemrestox.5c00101","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00101","url":null,"abstract":"<p><p>1,8-Dinitropyrene (1,8-DNP) is a diesel exhaust constituent classified as a possible human carcinogen (Group 2B) by the International Agency for Research on Cancer. Its mutagenic properties can be attributed in part through the formation of covalent DNA adducts that result from mononitroreduction (e.g., <i>N</i>-(deoxyguanosin-8-yl)-1-amino-8-nitropyrene). Recombinant aldo-keto reductases (AKRs) 1C1-1C3 catalyze the nitroreduction of 1,8-DNP, 1-nitropyrene, and 3-nitrobenzanthrone. Although <i>AKR1C1-1C3</i> are induced by nuclear factor erythroid 2-related factor 2 (NRF2), the contribution of NRF2 toward the nitroreduction of 1,8-DNP in human lung cells is currently unknown. We used highly sensitive and specific in-cell fluorescence assays to examine the ability of human lung A549 and HBEC3-KT cells to metabolize 1,8-DNP to yield 1-amino-8-nitropyrene (1,8-ANP) and 1,8-DNP to yield 1,8-diaminopyrene (1,8-DAP) via mono- and bis-nitroreduction, respectively. A549 cells generated both 1,8-ANP and 1,8-DAP from 1,8-DNP. By contrast, HBEC3-KT cells formed 1,8-ANP, but essentially no 1,8-DAP, from 1,8-DNP. We used genetic and pharmacological approaches to investigate the dependence of 1,8-DNP nitroreduction on AKR1C1-1C3 and NRF2. A549 cells with homozygous <i>NFE2L2</i>/NRF2 knockout did not exhibit decreased 1,8-ANP formation but showed decreased 1,8-DAP formation, indicating that the second but not the first nitroreduction step was NRF2-dependent. Treatment of HBEC3-KT cells with NRF2 activators (<i>R</i>-sulforaphane (SFN) or 1-(2-cyano-3,12,28-trioxooleana-1,9(11)-dien-28-yl)-1<i>H</i>-imidazole (CDDO-Im) did not increase the mononitroreduction of 1,8-DNP to 1,8-ANP but increased the conversion of 1,8-ANP to 1,8-DAP consistent with the second step requiring inducible NRF2. AKR1C isoform specific inhibitors showed that these enzymes accounted for the majority of 1,8-ANP and 1,8-DAP formation in both cell lines. The ability of A549 <i>NFE2L2/</i>NRF2 knockout cells to still form 1,8-ANP coupled with their lack of AKR1C isoform expression indicated that a new nitroreductase was expressed as an adaptive response to NRF2 loss. We find that this nitroreductase is not NQO1, thioredoxin reductase, xanthine oxidase, or NADPH-P450 oxidoreductase.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144598906","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of Internal Exposures after Virtual Oral Doses of Disparate Chemicals in Rats and Humans Using Simplified Physiologically Based Pharmacokinetic Models with <i>In Silico-</i>Generated Input Parameters.","authors":"Hiroshi Yamazaki, Makiko Shimizu","doi":"10.1021/acs.chemrestox.5c00157","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00157","url":null,"abstract":"<p><p>Toxicological evaluation of industrial chemicals with a broad range of chemical structures, for example, bioactive food components, toxic food-derived compounds, and drugs, usually involves the estimation of human clearance by allometric extrapolation of traditionally determined <i>in vivo</i> rat profiles. Three general methods are used to utilize and expand observed time-dependent plasma concentration data after single oral doses of chemicals: empirical standard noncompartmental analysis, compartmental modeling, and physiologically based pharmacokinetic (PBPK) modeling. Application of the PBPK model for forward dosimetry (from external to internal concentrations) following oral administrations has recently been simplified by using <i>in silico</i>-generated input parameters to evaluate internal exposures in humans without reference to any experimental data. Human PBPK model input parameters for a diverse range of compounds have been successfully estimated by using <i>in silico</i>-generated chemical descriptors and machine learning tools. Key values for the fraction absorbed × intestinal availability, the absorption constant, the volume of systemic circulation, and the hepatic intrinsic clearance can be generated <i>in silico</i> using mathematical equations to estimate values for sets of approximately 30 physicochemical properties or <i>in silico</i> descriptors. After virtual oral dosing of more than 350 compounds, the plasma and liver concentrations generated by PBPK models (1) using traditionally determined input parameters and (2) using input parameters estimated <i>in silico</i> were correlated in rat models and human models. This approach to pharmacokinetic modeling could potentially be applied in the clinical setting and during computational toxicological assessment of the potential risks of a wide range of general chemicals.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144590053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phthalate Exposure: Prevalence, Health Effects, Regulatory Frameworks, and Remediation.","authors":"Abdulkhalik Mansuri, Charvi Trivedi, Shaivee Chokshi, Keya Jantrania, Ashutosh Kumar","doi":"10.1021/acs.chemrestox.4c00338","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00338","url":null,"abstract":"<p><p>Phthalates, a ubiquitous class of plasticizers, are widely used to enhance the flexibility and durability of plastics. However, their noncovalent association with polymer matrices allows them to leach readily into the environment, raising significant global concerns. This review provides a comprehensive analysis of phthalates, including their chemical structures, properties, and applications, alongside their environmental prevalence and potential health risks. Particular emphasis is placed on the mechanisms of phthalate toxicity, including endocrine disruption, oxidative stress, and epigenetic modifications, with a critical discussion on how these mechanisms contribute to observed health outcomes. The bioaccumulation of phthalates in diverse environments is discussed, highlighting their presence in soil, water, and air. Advanced analytical techniques for phthalate detection are reviewed, with a focus on their strengths and limitations, and the need for more sensitive and accurate methods to monitor environmental contamination is underscored. Epidemiological and laboratory studies are critically examined to provide a detailed understanding of the developmental, reproductive, and systemic health effects associated with phthalate exposure. This review goes beyond summarizing existing knowledge by integrating discussions on regulatory frameworks, current challenges, and future directions for reducing environmental and health risks posed by phthalates. By addressing gaps in recent literature and consolidating diverse findings, this work aims to serve as a valuable resource for researchers and policymakers engaged in mitigating the impacts of phthalates on living organisms and ecosystems.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574455","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Addressing Pitfalls of Metabolomics for Toxicology: A Call for Standardization, Reproducibility and Data Sharing.","authors":"Min Nian, Xing Chen, Mingliang Fang","doi":"10.1021/acs.chemrestox.4c00555","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00555","url":null,"abstract":"<p><p>Metabolomics has emerged as a pivotal tool in toxicology, providing unique insights into biochemical and molecular disruptions upon toxicant exposure. However, its application faces challenges such as metabolite misannotation, insufficient quality assurance and quality control (QA/QC), and limitations in dose-response and time-response studies. Pathway enrichment analysis is often hindered by incomplete databases and irrelevant background metabolites, leading to false positives or missed key pathways, while the lack of robust validation mechanisms can blur distinctions between general stress responses and toxicant-specific mechanisms. Addressing these pitfalls requires standardized protocols for sample preparation, analytical workflows, and data processing to ensure reproducibility. Rigorous QA/QC practices are essential to minimize batch effects, while cross-validation with transcriptomics and proteomics strengthens mechanistic insights. Comprehensive data sharing through public repositories enhances transparency and supports secondary analysis for novel discoveries. By adopting these strategies, metabolomics can achieve greater reliability and advance toxicological research by identifying early biomarkers, elucidating toxicant mechanisms, and improving environmental health assessments.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144574454","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Conformation-Dependent Lesion Bypass and Mutagenicity of Bulky 2-Acetylaminofluorene-Guanine DNA Adduct in Epigenetically Relevant Sequence Contexts.","authors":"Yi-Tzai Chen, Rui Qi, Ang Cai, Bongsup P Cho, Deyu Li","doi":"10.1021/acs.chemrestox.5c00055","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00055","url":null,"abstract":"<p><p>DNA base cytosine can be modified epigenetically by adding a methyl group to form 5-methylcytosine (5mC). 5mC in DNA CpG islands plays a crucial role in mammalian cell development and epigenetic regulation. While 5mC does not block DNA replication and is not mutagenic, the biological consequences of 5mC affecting the flanking guanine with a bulky modification during DNA replication are not well understood. This paper examined the lesion bypass and mutagenicity of the 2-acetylaminofluorene-modified guanine DNA adduct (dG-AAF) in epigenetically relevant sequence contexts in <i>Escherichia coli</i>. The C/5mC context exhibited significantly different bypass and mutagenicity profiles for dG-AAF. The biological outcomes also varied depending on the nature of the 3' flanking base and the lesion bulkiness. In addition, we extensively observed a unique type of -1 G deletion when the lesion was flanked by 3' purines, possibly due to the formation of a stacked slipped mutagenic intermediate. However, there was no such deletion with 3' pyrimidines. Our findings provide a new perspective on the role of epigenetic markers in DNA replication and could help to develop methods to identify mutation patterns associated with specific mutational signatures or spectra in cancer.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144558425","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Acetic Acid Inhalation-Induced Lung Injury: A Common Chemical with Underestimated Risks.","authors":"Puthiyavalappil Rasin, Praveena Prabhakaran","doi":"10.1021/acs.chemrestox.5c00226","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00226","url":null,"abstract":"<p><p>Acetic acid is widely used; however, its inhalation can cause significant respiratory harm. This paper examines its toxicological mechanisms, overlooked health risks, and the need for targeted safety measures to prevent lung injury in both domestic and occupational places.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551433","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Isothiazole Disinfectants Inhibit Neurosteroid Production by Targeting Human and Rat 5α-Reductase Type 1.","authors":"Shufang Qi, Li Cai, Xinmiao Lu, Shaowei Wang, Siming Shao, Nikita Jacintha Hector, Baiping Mao, Yiyan Wang, Ren-Shan Ge, Wangning Shangguan","doi":"10.1021/acs.chemrestox.5c00063","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.5c00063","url":null,"abstract":"<p><p>Isothiazole disinfectants are widely used antimicrobial preservatives found in various consumer products, raising concerns about their potential effects on human health. This study investigated the inhibitory effects of seven isothiazole disinfectants on human and rat steroid 5α-reductase type 1 (SRD5A1), a key enzyme in neurosteroid biosynthesis. Among the tested compounds, dichlorooctylisothiazole exhibited the strongest suppression on human SRD5A1 with an IC₅₀ value of 3.23 μM, followed by octylisothiazole (5.10 μM), butylbenzo[<i>d</i>]isothiazol-3(2H)-one (16.51 μM), benzisothiazole (31.64 μM), and methylchloroisothiazole (42.65 μM). Enzyme kinetics and molecular docking analyses revealed that these compounds acted through mixed/noncompetitive inhibition by binding to the NADPH-binding pocket via van der Waals and hydrogen bonds. Cell-based studies in human SF126 glioblastoma cells confirmed that these compounds penetrated cell membranes and reduced dihydrotestosterone production. Structure-activity relationship analysis showed that compounds with higher LogP, molecular weight, volume, heavy atom number, and apolar desolvation exhibited stronger inhibitory activity. 3D quantitative structure-activity relationship analysis incorporated hydrogen bond acceptor and hydrophobicity domain features. Additionally, dichlorooctylisothiazole showed significant inhibition of rat SRD5A1 with an IC₅₀ of 21.47 μM. In conclusion, these findings reveal some isothiazole disinfectants as potential endocrine disruptors targeting neurosteroid biosynthesis via SRD5A1 and highlight clear structure-activity relationship and species-dependent variance.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144551434","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"AI-Driven Integration of Transcriptomics, Quantum Mechanics, and Physiology for Predicting Drug-Induced Liver Injury in Data-Limited Scenarios.","authors":"Roshan Bhave, Babatunde Bello, Divesh Bhatt, Joseph Machulcz, Jacqueline A R Shea, Maksim Khotimchenko, Weida Tong, Szczepan W Baran, Jyotika Varshney","doi":"10.1021/acs.chemrestox.4c00542","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00542","url":null,"abstract":"<p><p>Drug-induced liver injury (DILI) is a significant concern with prescription medications and supplements. Accordingly, it is crucial to develop tools and approaches that can predict DILI likelihood of existing medications and supplements, as well as potential drug candidates under development. The complexity of liver injury mechanisms and the limited availability of DILI data hamper the development of robust predictive models. In order to overcome these challenges, this study investigated enriching machine learning/artificial intelligence (ML/AI) models that predict the risk of DILI using drug structural parameters along with rat liver transcriptomics data, quantum mechanics-derived features of the drug molecules, and metrics for interspecies variability of drug exposure. The enrichment of ML/AI models with such features dramatically improved ML/AI models' DILI predictive ability, even in a severely data-limited scenario. The approach used in the study, especially the incorporation of knowledge-based features to enrich AI models, holds tremendous promise for not only assessing safety and toxicity assessments of drug candidates but also in other aspects such as target engagement and efficacy of these candidates, early in the development phase.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144537401","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Machine Learning Models Based on Enlarged Chemical Spaces for Screening Carcinogenic Chemicals.","authors":"Chao Wu, Jingwen Chen, Yuxuan Zhang, Zhongyu Wang, Zijun Xiao, Wenjia Liu, Haobo Wang","doi":"10.1021/acs.chemrestox.4c00523","DOIUrl":"https://doi.org/10.1021/acs.chemrestox.4c00523","url":null,"abstract":"<p><p>Machine learning (ML) models for screening carcinogenic chemicals are critical for the sound management of chemicals. Previous models were built on small-scale datasets and lacked applicability domain (AD) characterization that is necessary for regulatory applications of the models. In the current study, an enlarged dataset containing 1697 compounds (940 carcinogens and 757 non-carcinogens) was curated and employed to construct screening models based on 12 types of molecular fingerprints, four ML algorithms, and two graph neural networks. The AD of the optimal model was defined by a state-of-the-art characterization methodology (AD_SAL) based on the analysis of structure-activity landscapes (SALs). Results showed that an optimal model based on the random forest algorithm with the PubChem fingerprints outperformed previous ones, with an area under the receiver operating characteristic curve of 86.2% on the validation set imposed with the AD_SAL. The optimal model, coupled with the AD_SAL, was employed to screen carcinogenic chemicals in the Inventory of Existing Chemical Substances of China (IECSC) and plastic additives datasets, identifying 1282 chemicals from the IECSC and 841 plastic additives as carcinogenic chemicals. The screening model coupled with AD_SAL may serve as a promising tool for prioritizing chemicals of carcinogenic concern, facilitating the sound management of chemicals.</p>","PeriodicalId":31,"journal":{"name":"Chemical Research in Toxicology","volume":" ","pages":""},"PeriodicalIF":3.7,"publicationDate":"2025-06-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144511274","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}