Toxicological Sciences最新文献

{"title":"Lessons learned from evaluating defined chemical mixtures in a high throughput estrogen receptor assay system.","authors":"Fred Parham, Kristin M Eccles, Cynthia V Rider, Srilatha Sakamuru, Menghang Xia, Ruili Huang, Raymond R Tice, Gregg E Dinse, Michael J Devito","doi":"10.1093/toxsci/kfaf020","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf020","url":null,"abstract":"<p><p>In this paper, we provide a proof of concept evaluating the utility of the U.S. Tox21 high-throughput screening approach to assess the hazard of chemical mixtures using two estrogen receptor assays. A subset of chemicals identified in Phase I of the Tox21 program as active in the estrogen receptor (ER) agonist assay were used to design mixtures for testing in Phase II. Individual chemicals and mixtures were evaluated in two cell-based estrogen receptor alpha (ERα) activation assays: One incorporating a transfected ligand-binding domain in an ERα β-lactamase reporter cell line (ER-bla) and the full-length endogenous receptor in the MCF7 cell line with a luciferase reporter gene (ER-luc). Concentration-response data from individual chemicals were used to predict the joint effect based on mixtures modeling methods and were compared to observed mixtures data to assess model fit. The models tended to overpredict mixture responses in the ER-bla assay, while predictions were closer to observed responses in the ER-luc assay, indicating that a full-length endogenous estrogen receptor is a preferred model for high-throughput mixture analysis. Lessons learned from this research include the importance of analyzing the individual chemicals used for predictions and the mixtures in the same experimental paradigm to minimize variation, developing methods for imputing missing values from incomplete concentration-response curves, and establishing criteria to determine when inactive chemicals should be omitted from mixture predictions.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143459410","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":"Integration of New Approach Methods for the Assessment of Data Poor Chemicals.","authors":"Katie Paul Friedman, Russell S Thomas, John F Wambaugh, Joshua A Harrill, Richard S Judson, Timothy J Shafer, Antony J Williams, Jia-Ying Joey Lee, Lit-Hsin Loo, Matthew Gagné, Alexandra S Long, Tara S Barton-Maclaren, Maurice Whelan, Mounir Bouhifd, Mike Rasenberg, Ulla Simanainen, Tomasz Sobanski","doi":"10.1093/toxsci/kfaf019","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf019","url":null,"abstract":"<p><p>Use of new approach methods (NAMs), including high-throughput, in vitro bioactivity data, in setting a point-of-departure (POD) will accelerate the pace of human health hazard assessments. Combining hazard and exposure predictions into a bioactivity: Exposure ratio (BER) for use in risk-based prioritization and utilizing NAM-based bioactivity flags to indicate potential hazards of interest for further prediction or mechanism-based screening together comprise a prospective approach for management of substances with limited traditional toxicity testing data. In this work we demonstrate a NAM-based assessment case study conducted via the Accelerating the Pace of Chemical Risk Assessment (APCRA) initiative, a consortium of international research and regulatory scientists. The primary objective was to develop a reusable and adaptable approach for addressing chemicals with limited traditional toxicity data using a NAM-based POD, BER, and bioactivity-based flags for indication of putative endocrine, developmental, neurological, and immunosuppressive effects via data generation and interpretation for 200 substances. Multiple data streams, including in silico and in vitro NAMs, were used. High-throughput transcriptomics and phenotypic profiling data, as well as targeted biochemical and cell-based assays, were combined with generic high-throughput toxicokinetic models parameterized with chemical-specific data to estimate dose for comparison to exposure predictions. This case study further enables regulatory scientists from different international purviews to utilize efficient approaches for prospective chemical management, addressing hazard and risk-based data needs, while reducing the need for animal studies. This work demonstrates the feasibility of using a battery of toxicodynamic and toxicokinetic NAMs to provide a NAM-based POD for screening-level assessment.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143450271","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":"Transcriptomic analysis identifies muscle-specific mitochondrial and vesicular transport genes as methylmercury toxicity targets in a Drosophila model of Congenital Minamata Disease.","authors":"Catherine R Beamish, Jennifer Becker, Lok Ming Tam, Tanzy Love, Matthew D Rand","doi":"10.1093/toxsci/kfaf018","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf018","url":null,"abstract":"<p><p>Prenatal methylmercury (MeHg) exposure presents a heightened concern in early human development, as has been exemplified in historic cases of Congenital Minimata Disease (CMD). Children that experience CMD characteristically present with various degrees of cognitive and motor symptoms and signs, much like cerebral palsy. MeHg has thus been characterized as a neurotoxicant, where motor deficits are ascribed to central nervous system targets. Skeletal muscle as a post-synaptic MeHg target and contributor to the etiology of CMD has garnered far less attention. Prior studies using Drosophila to model CMD revealed that developmental exposure of MeHg in the larval/pupal stages can elicit graded and latent dose responses affecting adult flight behavior at lower doses (0.4-2.5 ppm in food) and eclosion (emergence from the pupa case) at higher doses (>2.5 ppm in food). The latter phenotype is accompanied by dysmorphogenesis of skeletal muscles. Here, we investigate respective roles for muscle and neural targets in MeHg toxicity. Using RNA-seq analysis, we find that developmental MeHg exposure produces 10-times as many differentially expressed transcripts in indirect flight muscle (IFM) compared to the ventral nerve cord (VNC). Among known MeHg response genes, Nrf2 antioxidant response pathway genes showed muscle-specific MeHg-induced expression changes. Within the muscle transcriptome, the most enriched and significant Gene Ontology terms identified genes required for mitochondrial ribosomal translation at the pupa stage and mitochondrial function (respiratory chain complex I) and vesicle trafficking (ESCRT III) pathways in adults, all showing decreased expression with MeHg exposure. By using an intact, whole-animal developmental model, we identify preferential candidates to evaluate a novel role for muscle-specific mitochondria and intercellular vesicular communication mechanisms as targets in MeHg toxicity and the etiology of CMD.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143415295","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":"Comparisons of PK-Sim® and R Program for Physiologically Based Pharmacokinetic Model Development for Broiler Chickens and Laying Hens: Meloxicam as a Case Study.","authors":"Zhicheng Zhang, Lisa A Tell, Zhoumeng Lin","doi":"10.1093/toxsci/kfaf016","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf016","url":null,"abstract":"<p><p>Physiologically based pharmacokinetic (PBPK) models play a critical role in evaluating drug residue concentrations and estimating withdrawal intervals (WDIs) for food-producing animals. These models are facilitated by various programming software (e.g., R program) and predefined PBPK platforms, such as Open Systems Pharmacology (OSP) suite integrated by PK-Sim® and Mobi, which offers a user-friendly graphical interface. Both R and OSP are open-source software. However, there is a lack of comparative analyses of both platforms and their potential impact on PBPK models. This study aims to evaluate the influence of different platforms on PBPK workflow, parameters selection, and output results, which is exemplified via a case study for meloxicam in chickens in both platforms. Our findings indicate that while the choice of PBPK platforms affected the workflow and input parameters, the predictive performance of established models remained consistent across both platforms. Both platforms predicted meloxicam pharmacokinetics in plasma and tissues accurately across different exposure scenarios. The PBPK-estimated WDIs under various dosing regimens from both platforms were quite similar. Notable differences between OSP suite and R were primarily observed during sensitivity analysis and parameter identification processes, especially the time consumption. This study offers insight into software variances and their implications for translating PBPK modeling knowledge between users of two platforms. Also, it provides a PBPK model structure template implemented in both software platforms for food safety and risk assessment in poultry and a detailed tutorial on expanding the model structure in PK-Sim® and Mobi.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400002","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":"DNA adducts form in mouse lung and liver after oral naphthalene exposure.","authors":"Morgan C Domanico, Nicole M Collette, Esther Ubick, Xinxin Ding, Bruce A Buchholz, Laura S Van Winkle","doi":"10.1093/toxsci/kfaf017","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf017","url":null,"abstract":"<p><p>Naphthalene is a ubiquitous combustion product and environmental contaminant with known human exposure. Chronic exposure to naphthalene vapor leads to respiratory tumor formation in rodents. Naphthalene forms DNA adducts (precursors to genotoxicity) in tissue explants but it is unclear if this occurs in vivo. Wild-type C57BL/6 mice were orally exposed to 50 mg/kg 14C-naphthalene. Naphthalene-DNA adducts were detected by accelerator mass spectrometry at 2-72 hours post-exposure in both lung and liver, with decreasing abundance over time. Adducts persisted even at 72 hours after exposure, which indicates possible evasion of DNA repair and potential to contribute to mutagenesis.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374573","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":"Evaluation of phenotypic and behavioural toxicity of micro- and nano-plastic polystyrene particles in larval zebrafish (Danio rerio).","authors":"Bailey Levesque, Sabahudin Hrapovic, Fabrice Berrué, Anja Vogt, Lee D Ellis, Ludovic Hermabessiere","doi":"10.1093/toxsci/kfaf015","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf015","url":null,"abstract":"<p><p>Plastic particles have been found in all environments and it is necessary to understand the risks these particles pose in, and to, the environment. The objectives of this work were to understand the toxic effects of varying size and concentration of polystyrene (PS) micro- and nano-plastics in zebrafish embryos and their fate within the larvae. In this work, larval zebrafish (Danio rerio) were exposed to six sizes (0.05, 0.25, 0.53, 2.1, 6.02, and 10.2 µm diameter) and concentrations (0.0005-0.2 µg/µL) of PS micro/nanoplastics particles. The Zebrafish Embryo Toxicity (ZET) and the General and Behavioral Toxicity (GBT) assays were used to determine particle toxicity in embryos. Behavioural analysis was performed and micro/nanoplastics uptake and organ distribution were assessed. Phenotypic and behavioural toxicity was observed in all exposures with the exception of 0.25 µm particle-exposed larvae. Significant phenotypic toxicity was seen at the highest tested exposure concentration, with some sizes showing potential recovery as time increased in the assay. Behavioural analysis demonstrated a decrease in baseline activity across all micro- and nano-plastic sizes. Significant increases in light- dark responses were recorded in ZET assays of smaller sized particles and no significant effects were observed at larger sizes. Significant decreases in this response were reported in the GBT assays of all tested sizes with the exception of the 0.05 µm particles. These assays demonstrate the general, developmental, and neurotoxicity of micro/nanoplastics to a model organism, which can be used to infer individual and population level effects of exposure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143374580","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":"Diet-induced obesity alters the ovarian chemical biotransformation and oxidative stress response proteins both basally and in response to 7,12-dimethylbenz[a]anthracene exposure.","authors":"Kelsey Timme, Imaobong Inyang, Hunter E White, Aileen F Keating","doi":"10.1093/toxsci/kfae150","DOIUrl":"https://doi.org/10.1093/toxsci/kfae150","url":null,"abstract":"<p><p>7,12-dimethylbenz[a]anthracene (DMBA) is a polycyclic aromatic hydrocarbon (PAH) that causes female infertility via DNA damage, and the ovary has the capacity to mitigate DMBA exposure via the action of proteins including the glutathione S-transferase (GST) family. Due to previous findings of DNA damage and a reduced ovarian chemical biotransformation response to DMBA exposure in hyperphagia-induced obese mice, this study investigated the hypothesis that diet-induced obesity would hamper the ovarian biotransformative response to DMBA exposure. Six-week-old C57BL6/J mice were fed either a normal rodent diet (L) or a high fat high sucrose diet (O) until the O group was ∼30% heavier than the L. Both L and O mice were exposed to either corn oil (C) or DMBA (1 mg/kg) for 7 d. Liver weight was increased (P < 0.05) in obese mice exposed to DMBA but no effect on spleen weight, uterine weight, ovary weight, estrous cyclicity, or circulating 17β-estradiol and progesterone were observed. Primordial and preantral follicle numbers were higher (P < 0.05) in the obese mice and there was a tendency (P = 0.055) for higher antral follicles in DMBA-exposed obese mice. The ovarian proteome was identified by LC-MS/MS analysis to be altered both by diet-induced obesity and by DMBA exposure with changes observed in levels of proteins involved in oocyte development and chemical biotransformation, including GST isoform pi. Fewer proteins were affected by the combined exposure of diet and DMBA than by a single treatment, indicating that physiological status impacts the response to DMBA exposure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256822","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":"Developmental Immunotoxicity Study of Tris(chloropropyl) phosphate (TCPP) in Hsd:Sprague Dawley® SD® Rats Exposed Through Dosed Feed.","authors":"Victor J Johnson, Kristen Ryan, Michael I Luster, Arun Pandiri, Kristen Hobbie, Michelle Cora, Keith R Shockley, Gary R Burleson, Guanhua Xie, Dori R Germolec","doi":"10.1093/toxsci/kfaf006","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf006","url":null,"abstract":"<p><p>Tris(Chloropropyl) phosphate (TCPP) is a member of organophosphate flame retardants (OPFRs) used commonly as a replacement for polybrominated diphenyl ethers in consumer and commercial products. Flame retardants have been shown to modulate immune function in vivo and in vitro and there is evidence that at least some related compounds such as organophosphate pesticides can cause developmental immunotoxicity. Developmental immunotoxicology studies were conducted by administering 0, 2500, 5000 or 10000 ppm TCPP in feed to pregnant Hsd: Sprague Dawley® SD® rats from gestation day (GD) 6 through weaning on postnatal day (PND) 28. Feed exposure to TCPP was continued in the F1 offspring until terminal euthanasia at approximately 16-21 weeks of age when assessments for developmental immunotoxicity were conducted. Innate, humoral, and cell mediated immune function were assessed in the F1 adults. The antibody forming cells (AFC) response to sheep red blood cells (SRBC) was reduced in male and female F1 rats in the 10000 ppm treatment group but coincided with reduced bodyweights. The AFC response was also significantly reduced in male rats exposed to 5000 ppm where only moderate effects on bodyweights occurred. TCPP exposure affected baseline T-cell proliferation without stimulation; however, the relevance of this change for immunotoxicity risk is unknown. TCPP exposure did not affect cytotoxic T-lymphocyte activity. Only minor and inconsistent treatment related effects on hematology, innate NK cell function, and immune cell population distributions in the spleen were observed. Taken together, these data indicate that TCPP has the potential to impact humoral immune responses following developmental exposure.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143256821","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":"Distribution of perfluorooctanoic acid in exposed female post-pubertal pigs in thermal neutral or heat stressed conditions.","authors":"Samantha L Good, Collins Antwi-Boasiako, M Estefanía González-Alvarez, Bridget M Buol, Lance H Baumgard, Aileen F Keating, Joseph A Charbonnet","doi":"10.1093/toxsci/kfaf013","DOIUrl":"https://doi.org/10.1093/toxsci/kfaf013","url":null,"abstract":"<p><p>Perfluorooctanoic acid (PFOA), a legacy perfluoroalkyl substance with immuno- and repro-toxicant effects, has poorly characterized bioaccumulation and distribution patterns in female pigs. The potential for heat stress to influence PFOA partitioning, potentially through intestinal hyperpermeability and alterations in systemic blood flow, also warrants investigation. This study investigated PFOA uptake, accumulation, and distribution in thermal neutral and heat-stressed gilts. Pigs (n = 48) were estrus synchronized and experienced thermal neutral (TN; 20 °C) or heat stress (HS; 26.6 to 32.2 °C) conditions during which they consumed 70 ng/kg bodyweight PFOA via cookie dough as vehicle control daily. Plasma was collected on d 1, 15, and 20. Liver, ovary, and follicular fluid were collected at euthanasia (d 20). Post-exposure, PFOA was detected in serum, liver, ovary, and follicular fluid. Heat stress increased (P < 0.05) plasma PFOA compared to TN pigs on d 15, but on d 20, plasma PFOA levels in TN and HS pigs were similar. Liver PFOA concentrations were similar between TN and HS pigs. Ovarian PFOA levels tended (P = 0.06) to be higher in TN relative to HS pigs, with an opposing pattern in follicular fluid, in which PFOA concentrations were greater (P < 0.05) in HS pigs. These findings suggest that PFOA apportions to plasma, liver, ovary, and follicular fluid of exposed pigs and that heat stress alters PFOA distribution, which could negatively impact reproductive health. This study underscores the need to consider the interaction of heat stress and toxicant exposure in environmental health risk assessments.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":""},"PeriodicalIF":3.4,"publicationDate":"2025-02-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143122679","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":"A twin transition in regulatory toxicology: moving toward Chemicals 2.0 and phasing out animal testing.","authors":"Andrew P Worth, Elisabet Berggren","doi":"10.1093/toxsci/kfae130","DOIUrl":"10.1093/toxsci/kfae130","url":null,"abstract":"<p><p>The European regulatory framework on chemicals is at a crossroads. There are calls for the framework to be more effective, by better protecting people and the environment. There is also room for it to be more efficient and cost-effective, by harmonizing assessment practices across sectors and avoiding the need for unnecessary testing. At the same time, there is a political commitment to phase out animal testing in chemical safety assessments. In this commentary, we argue that these needs are not at odds with each other. On the contrary, the European Commission's roadmap to phase out animal testing could also be the transition pathway to a more efficient, effective, and sustainable regulatory ecosystem. Central to our proposal is a framework based on biological reasoning in which biological questions can be answered by a choice of methods, with non-animal methods progressively becoming the only choice. Within this framework, a tiered approach to testing and assessment allows for greater efficiency and effectiveness, while also introducing considerations of proportionality and cost-effectiveness. Testing strategies, and their component methods, should be developed in tandem and judged in terms of their outcomes, and the protection levels they inform, rather than their ability to predict the outputs of animal tests.</p>","PeriodicalId":23178,"journal":{"name":"Toxicological Sciences","volume":" ","pages":"160-165"},"PeriodicalIF":3.4,"publicationDate":"2025-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11775417/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142372951","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}