Toxicological Sciences最新文献_第10页

The impact of neonicotinoid pesticides on reproductive health. 新烟碱类杀虫剂对生殖健康的影响。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-02-01 DOI: 10.1093/toxsci/kfae138

Jadesola I Oladosu, Jodi A Flaws

{"title":"The impact of neonicotinoid pesticides on reproductive health.","authors":"Jadesola I Oladosu, Jodi A Flaws","doi":"10.1093/toxsci/kfae138","DOIUrl":"10.1093/toxsci/kfae138","url":null,"abstract":"Neonicotinoids are some of the most widely used insecticides in the world because they broadly target chewing and sucking insects. Neonicotinoids are used in commercial agricultural systems, sold for use in home gardens, and found in veterinary pharmaceuticals in the form of flea and tick preventatives for companion animals. They are also used as crop seed treatments and spread throughout crops as they mature. As a result, humans, wildlife, livestock, and pets are routinely exposed to neonicotinoids through the consumption of contaminated food and water as well as through the use of some veterinary pharmaceuticals. Although several studies indicate that neonicotinoid exposure causes genotoxicity, neurotoxicity, hepatotoxicity, and immunotoxicity in some non-target species, the impact of neonicotinoid pesticides on the male and female reproductive systems in mammals is largely understudied. This review summarizes current insights on the impact of common neonicotinoid pesticides such as acetamiprid, clothianidin, imidacloprid, and thiacloprid on male and female reproductive health in mammals. The review also summarizes the impacts of exposure to mixtures of neonicotinoids on reproductive endpoints. In addition, this review highlights where gaps in research on neonicotinoid pesticides and reproductive health exist so that future studies can be designed to fill current gaps in knowledge.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"131-146"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775419/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142508640","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

In vitro human ion channel assays predictive of drug-induced seizure. 体外人离子通道测定预测药物诱发癫痫发作。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-02-01 DOI: 10.1093/toxsci/kfae148

Jennifer D Cohen, Dahea You, Ashok K Sharma, Takafumi Takai, Hideto Hara, Vicencia T Sales, Tomoya Yukawa, Beibei Cai

{"title":"In vitro human ion channel assays predictive of drug-induced seizure.","authors":"Jennifer D Cohen, Dahea You, Ashok K Sharma, Takafumi Takai, Hideto Hara, Vicencia T Sales, Tomoya Yukawa, Beibei Cai","doi":"10.1093/toxsci/kfae148","DOIUrl":"10.1093/toxsci/kfae148","url":null,"abstract":"Seizure is among the most severe FDA black box warnings of neurotoxicity reported on drug labels. Gaining a better mechanistic understanding of off-targets causative of seizure will improve the identification of potential seizure risks preclinically. In the present study, we evaluated an in vitro panel of 9 investigational (Cav2.1, Cav3.2, GlyRA1, AMPA, HCN1, Kv1.1, Kv7.2/7.3, NaV1.1, Nav1.2) and 2 standard (GABA-A, NMDA) ion channel targets with strong correlative links to seizure, using automated electrophysiology. Each target was assessed with a library of 34 preclinical compounds and 10 approved drugs with known effects of convulsion in vivo and/or in patients. Cav2.1 had the highest frequency of positive hits, 20 compounds with an EC30 or IC30 ≤ 30 µM, and the highest importance score relative to the 11 targets. An additional 35 approved drugs, with categorized low to frequent seizure risk in patients, were evaluated in the Cav2.1 assay. The Cav2.1 assay predicted preclinical compounds to cause convulsion in nonclinical species with a sensitivity of 52% and specificity of 78%, and approved drugs to cause seizure in nonclinical species or in patients with a sensitivity of 48% or 54% and specificity of 71% or 78%, respectively. The integrated panel of 11 ion channel targets predicted preclinical compounds to cause convulsion in nonclinical species with a sensitivity of 68%, specificity of 56%, and accuracy of 65%. This study highlights the utility of expanding the in vitro panel of targets evaluated for seizurogenic activity, in order to reduce compound attrition early on in drug discovery.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"253-268"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775423/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142814238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

A Novel Computational Machine Learning Pipeline to Quantify Similarities in Three-Dimensional Protein Structures. 一种新的计算机器学习管道来量化三维蛋白质结构的相似性。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-01-17 DOI: 10.1093/toxsci/kfaf007

Shreyas U Hirway, Xiao Xu, Fan Fan

{"title":"A Novel Computational Machine Learning Pipeline to Quantify Similarities in Three-Dimensional Protein Structures.","authors":"Shreyas U Hirway, Xiao Xu, Fan Fan","doi":"10.1093/toxsci/kfaf007","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf007","url":null,"abstract":"Animal models are widely used during drug development. The selection of suitable animal model relies on various factors such as target biology, animal resource availability and legacy species. It is imperative that the selected animal species exhibit the highest resemblance to human, in terms of target biology as well as the similarity in the target protein. The current practice to address cross-species protein similarity relies on pair-wise sequence comparison using protein sequences, instead of the biologically relevant 3-dimensional (3D) structure of proteins. We developed a novel quantitative machine learning pipeline using 3D structure-based feature data from the Protein Data Bank, nominal data from UNIPROT and bioactivity data from ChEMBL, all of which were matched for human and animal data. Using the XGBoost regression model, similarity scores between targets were calculated and based on these scores, the best animal species for a target was identified. For real-world application, targets from an alternative source, ie, AlphaFold, were tested using the model, and the animal species that had the most similar protein to the human counterparts were predicted. These targets were then grouped based on their associated phenotype such that the pipeline could predict an optimal animal species.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143012093","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}

引用次数: 0

Integration of the rat liver micronucleus assay into a 28-day treatment protocol: testing the genotoxicity of four small-molecule nitrosamines with different carcinogenic potencies and tumor target specificities. 将大鼠肝脏微核检测整合到28天的治疗方案中：测试四种具有不同致癌效力和肿瘤靶点特异性的小分子亚硝胺的遗传毒性。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-01-03 DOI: 10.1093/toxsci/kfaf002

Xiaoqing Guo, Ji-Eun Seo, Hannah Xu, Jian Yan, Pritpal Malhi, Aisar H Atrakchi, Timothy Mcgovern, Karen L Davis Bruno, Robert H Heflich, Tao Chen

{"title":"Integration of the rat liver micronucleus assay into a 28-day treatment protocol: testing the genotoxicity of four small-molecule nitrosamines with different carcinogenic potencies and tumor target specificities.","authors":"Xiaoqing Guo, Ji-Eun Seo, Hannah Xu, Jian Yan, Pritpal Malhi, Aisar H Atrakchi, Timothy Mcgovern, Karen L Davis Bruno, Robert H Heflich, Tao Chen","doi":"10.1093/toxsci/kfaf002","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf002","url":null,"abstract":"Several potent carcinogenic nitrosamines, including N-nitrosodiethylamine (NDEA) and N-nitrosodimethylamine (NDMA), induce micronuclei in the micronucleated hepatocyte (MNHEP) assay but not in the micronucleated reticulocyte (MNRET) assay. However, the MNHEP assay is not as frequently used as the MNRET assay for evaluating in vivo genotoxicity. The present study evaluated MN formation in the liver of Big Blue transgenic rats exposed to four small-molecule nitrosamines, NDMA, N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisoporpylamine (NEIPA), and N-nitrosomethylphenylamine (NMPA), using a repeat-dose protocol typically used for in vivo mutagenicity studies. NDMA is a potent liver carcinogen, while NDIPA and NEIPA are relatively weak liver carcinogens, and NMPA primarily produces esophageal tumors. Seven-week-old rats were treated with the nitrosamines for 28 consecutive days; liver was harvested three days after the last dose and used for conducting the flow-cytometry-based MNHEP assay. All four nitrosamines induced dose-dependent increases in %MNHEP and the magnitude of the responses correlated with their carcinogenicity in rat liver. These results indicate that the flow-cytometry-based MNHEP assay can be successfully integrated into 28-day repeat-dose studies, and that the MNHEP assay may be useful for evaluating the genotoxicity of nitrosamines that have different carcinogenic potencies and different tumor target specificities.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142928281","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}

引用次数: 0

MAD2L1 supports MYC-driven liver carcinogenesis in mice and predicts poor prognosis in human hepatocarcinoma. MAD2L1 支持 MYC 驱动的小鼠肝癌发生，并预测人类肝癌的不良预后。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.1093/toxsci/kfae126

Xinjun Lu, Ya Zhang, Jiahao Xue, Matthias Evert, Diego Calvisi, Xin Chen, Xue Wang

{"title":"MAD2L1 supports MYC-driven liver carcinogenesis in mice and predicts poor prognosis in human hepatocarcinoma.","authors":"Xinjun Lu, Ya Zhang, Jiahao Xue, Matthias Evert, Diego Calvisi, Xin Chen, Xue Wang","doi":"10.1093/toxsci/kfae126","DOIUrl":"10.1093/toxsci/kfae126","url":null,"abstract":"Mitotic arrest-deficient 2 like 1 (MAD2L1) is a component of the mitotic spindle assembly checkpoint implicated in cancer cell proliferation and tumorigenesis. The functional role of MAD2L1 in hepatocellular carcinoma (HCC) has not been adequately investigated, especially in vivo. In the current manuscript, we sought to address the function of MAD2L1 in hepatocarcinogenesis. We found that MAD2L1 expression is upregulated in human HCCs, where its expression is associated with higher aggressive tumor grade, elevated proliferative activity, and poor prognosis. In human HCC cell lines, MAD2L1 knockdown led to decreased cell growth. Moreover, RNA-seq results demonstrated that MAD2L1 silencing induces the expression of genes associated with cell cycle, DNA replication, and various cancer-related pathways, supporting the critical role of MAD2L1 during HCC growth and differentiation. In a c-MYC-induced mouse HCC model, we revealed an increased expression of Mad2l1. Furthermore, Mad2l1 CRIPSR-mediated silencing prevented c-MYC-driven mouse liver development. Altogether, our study suggests that MAD2L1 plays a crucial role in hepatocarcinogenesis, and that its suppression could be a promising therapeutic strategy for treating human HCC. MAD2L1 plays a critical role in liver cancer development, silencing MAD2L1 reduced cell growth in vitro and inhibited c-MYC-driven liver cancer development in vivo. MAD2L1 suppression might be a promising therapeutic approach for treating human liver cancer.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"41-51"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664104/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308626","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Defining VOC signatures of airway epithelial cells with PM2.5 exposure. 通过 PM2.5 暴露确定气道上皮细胞的挥发性有机化合物特征。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.1093/toxsci/kfae141

Angela L Linderholm, Eva Borras, Katyayini Aribindi, Leilani L Jones, Dante E Rojas, Keith Bein, Mitchell M McCartney, Cristina E Davis, Richart W Harper, Nicholas J Kenyon

{"title":"Defining VOC signatures of airway epithelial cells with PM2.5 exposure.","authors":"Angela L Linderholm, Eva Borras, Katyayini Aribindi, Leilani L Jones, Dante E Rojas, Keith Bein, Mitchell M McCartney, Cristina E Davis, Richart W Harper, Nicholas J Kenyon","doi":"10.1093/toxsci/kfae141","DOIUrl":"10.1093/toxsci/kfae141","url":null,"abstract":"Volatile organic compounds (VOCs) produced by the lung in response to exposure to environmental pollutants can be utilized to study their impact on lung health and function. Previously, we developed a method to measure VOCs emitted from well-differentiated tracheobronchial epithelial cells in vitro. Using this method, we exposed well-differentiated proximal (PECs) and distal airway epithelial cells (DECs) to varying doses of traffic-related air pollutants (TRAP) and wildfire particulates to determine specific VOC signatures after exposure. We utilized PM2.5 TRAP collected from the Caldecott tunnel in Oakland, CA and the 2018 Camp Fire to model \"real-life\" exposures. The VOCs were collected and extracted from Twisters and analyzed using gas chromatography-mass spectrometry. Exposure to both types of particulate matter (PM) resulted in specific VOC responses grouped by individual subjects with little overlap. Interestingly the VOCs produced by the PECs and DECs were also differentiated from each other. Our studies suggest that PM exposure induces a specific compartmentalized cellular response that can be exploited for future studies. This response is cell-type specific and potentially related to a phenotype we have yet to uncover.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"88-95"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664101/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142547643","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Limitations of acetaminophen as a reference hepatotoxin for the evaluation of in vitro liver models. 对乙酰氨基酚作为评估体外肝脏模型的参考肝毒素的局限性。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.1093/toxsci/kfae133

Lucia A Livoti, Rowena Sison-Young, Dennis Reddyhoff, Ciarán P Fisher, Iain Gardner, Rafael Diaz-Nieto, Christopher E Goldring, Ian M Copple

引用次数: 0

Tolvaptan safety in autosomal-dominant polycystic kidney disease; a focus on idiosyncratic drug-induced liver injury liabilities. 托伐普坦在常染色体显性多囊肾病中的安全性；关注药物诱发的肝损伤责任。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.1093/toxsci/kfae142

Sean Hammond, Xiaoli Meng, Jane Barber, Merrie Mosedale, Amy Chadwick, Paul B Watkins, Dean J Naisbitt

引用次数: 0

An in vitro and machine learning framework for quantifying serum albumin binding of per- and polyfluoroalkyl substances. 用于量化全氟和多氟烷基物质血清白蛋白结合的体外和机器学习框架。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.1093/toxsci/kfae124

Hannah M Starnes, Adrian J Green, David M Reif, Scott M Belcher

{"title":"An in vitro and machine learning framework for quantifying serum albumin binding of per- and polyfluoroalkyl substances.","authors":"Hannah M Starnes, Adrian J Green, David M Reif, Scott M Belcher","doi":"10.1093/toxsci/kfae124","DOIUrl":"10.1093/toxsci/kfae124","url":null,"abstract":"Per- and polyfluoroalkyl substances (PFAS) are a diverse class of anthropogenic chemicals; many are persistent, bioaccumulative, and mobile in the environment. Worldwide, PFAS bioaccumulation causes serious adverse health impacts, yet the physiochemical determinants of bioaccumulation and toxicity for most PFAS are not well understood, largely due to experimental data deficiencies. As most PFAS are proteinophilic, protein binding is a critical parameter for predicting PFAS bioaccumulation and toxicity. Among these proteins, human serum albumin (HSA) is the predominant blood transport protein for many PFAS. We previously demonstrated the utility of an in vitro differential scanning fluorimetry assay for determining relative HSA binding affinities for 24 PFAS. Here, we report HSA affinities for 65 structurally diverse PFAS from 20 chemical classes. We leverage these experimental data, and chemical/molecular descriptors of PFAS, to build 7 machine learning classifier algorithms and 9 regression algorithms, and evaluate their performance to identify the best predictive binding models. Evaluation of model accuracy revealed that the top-performing classifier model, logistic regression, had an AUROC (area under the receiver operating characteristic curve) statistic of 0.936. The top-performing regression model, support vector regression, had an R2 of 0.854. These top-performing models were then used to predict HSA-PFAS binding for chemicals in the EPAPFASINV list of 430 PFAS. These developed in vitro and in silico methodologies represent a high-throughput framework for predicting protein-PFAS binding based on empirical data, and generate directly comparable binding data of potential use in predictive modeling of PFAS bioaccumulation and other toxicokinetic endpoints.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"67-78"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664106/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142296181","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0

Physiological liver microtissue 384-well microplate system for preclinical hepatotoxicity assessment of therapeutic small molecule drugs. 用于小分子治疗药物临床前肝脏毒性评估的生理性肝脏微组织 384 孔微孔板系统。

IF 3.4 3区医学

Toxicological Sciences Pub Date : 2025-01-01 DOI: 10.1093/toxsci/kfae123

Lola Fäs, Minjun Chen, Weida Tong, Friederike Wenz, Nicola J Hewitt, Monika Tu, Katarzyna Sanchez, Natalia Zapiórkowska-Blumer, Hajnalka Varga, Karolina Kaczmarska, Maria Vittoria Colombo, Bruno G H Filippi

{"title":"Physiological liver microtissue 384-well microplate system for preclinical hepatotoxicity assessment of therapeutic small molecule drugs.","authors":"Lola Fäs, Minjun Chen, Weida Tong, Friederike Wenz, Nicola J Hewitt, Monika Tu, Katarzyna Sanchez, Natalia Zapiórkowska-Blumer, Hajnalka Varga, Karolina Kaczmarska, Maria Vittoria Colombo, Bruno G H Filippi","doi":"10.1093/toxsci/kfae123","DOIUrl":"10.1093/toxsci/kfae123","url":null,"abstract":"Hepatotoxicity can lead to the discontinuation of approved or investigational drugs. The evaluation of the potential hepatoxicity of drugs in development is challenging because current models assessing this adverse effect are not always predictive of the outcome in human beings. Cell lines are routinely used for early hepatotoxicity screening, but to improve the detection of potential hepatotoxicity, in vitro models that better reflect liver morphology and function are needed. One such promising model is human liver microtissues. These are spheroids made of primary human parenchymal and nonparenchymal liver cells, which are amenable to high throughput screening. To test the predictivity of this model, the cytotoxicity of 152 FDA (US Food & Drug Administration)-approved small molecule drugs was measured as per changes in ATP content in human liver microtissues incubated in 384-well microplates. The results were analyzed with respect to drug label information, drug-induced liver injury (DILI) concern class, and drug class. The threshold IC50ATP-to-Cmax ratio of 176 was used to discriminate between safe and hepatotoxic drugs. \"vMost-DILI-concern\" drugs were detected with a sensitivity of 72% and a specificity of 89%, and \"vMost-DILI-concern\" drugs affecting the nervous system were detected with a sensitivity of 92% and a specificity of 91%. The robustness and relevance of this evaluation were assessed using a 5-fold cross-validation. The good predictivity, together with the in vivo-like morphology of the liver microtissues and scalability to a 384-well microplate, makes this method a promising and practical in vitro alternative to 2D cell line cultures for the early hepatotoxicity screening of drug candidates.","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"79-87"},"PeriodicalIF":3.4,"publicationDate":"2025-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11664105/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142475445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

引用次数: 0