TOX3 (TNRC9) overexpression in bladder cancer cells decreases cellular proliferation and triggers an interferon-like response

DEFF Research Database (Denmark)

Birkenkamp-Demtröder, Karin; Mansilla, Francisco; Andersen, Lars Dyrskjøt

2013-01-01

Background Human TOX3 (TOX high mobility group box family member 3) regulates Ca2+-dependent transcription in neurons and has been associated with breast cancer susceptibility. Aim of the study was to investigate the expression of TOX3 in bladder cancer tissue samples and to identify genes...... urothelium. Microarray expression profiling of human bladder cancer cells overexpressing TOX3 followed by Pathway analysis showed that TOX3 overexpression mainly affected the Interferon Signaling Pathway. TOX3 upregulation induced the expression of several genes with a gamma interferon activation site (GAS......), e.g. STAT1. In vitro functional studies showed that TOX3 was able to bind to the GAS-sequence located at the STAT1 promoter. siRNA mediated knockdown of TOX3 in RT4 bladder cancer cells decreased STAT1 expression suggesting a direct impact of TOX3 on STAT1. Immunoprecipitation of TOX3 overexpressing...

ToxCast Profiling in a Human Stem Cell Assay for ...

Science.gov (United States)

Standard practice for assessing disruptions in embryogenesis involves testing pregnant animals of two species, typically rats and rabbits, exposed during major organogenesis and evaluated just prior to term. Under this design the major manifestations of developmental toxicity are observed as one or more apical endpoints including intrauterine death, fetal growth retardation, structural malformations and variations. Alternative approaches to traditional developmental toxicity testing have been proposed in the form of in vitro data (e.g., embryonic stem cells, zebrafish embryos, HTS assays) and in silico models (e.g., computational toxicology). To increase the diversity of assays used to assess developmental toxicity in EPA’s ToxCast program, we tested the chemicals in Stemina’s metabolomics-based platform that utilizes the commecrially available H9 human embryonic stem cell line. The devTOXqP dataset for ToxCast of high-quality based on replicate samples and model performance (82% balanced accuracy, 0.71 sensitivity and 1.00 specificity). To date, 136 ToxCast chemicals (12.8% of 1065 tested) were positive in this platform; 48 triggered the biomarker signal without any change in hESC viability and 88 triggered activity concurrent with effects on cell viability. Work is in progress to complete the STM dataset entry into the TCPL, compare data with results from zFish and mESC platforms, profile bioactivity (ToxCastDB), endpoints (ToxRefDB), chemotypes (DSSTox)

TOX3 (TNRC9) Over Expression in Bladder Cancer Cells Decreases Cellular Proliferation and Triggers an Interferon-Like Response

DEFF Research Database (Denmark)

Birkenkamp-Demtroder, Karin; Mansilla Castaño, Francisco; Dyrskjøt, Lars

2013-01-01

Background: Human TOX3 (TOX high mobility group box family member 3) regulates Ca2+ dependent transcription in neurons and has been associated with breast cancer susceptibility. Aim of the study was to investigate the expression of TOX3 in bladder cancer tissue samples and to identify genes...... urothelium. Microarray expression profiling of human bladder cancer cells over expressing TOX3 followed by Pathway analysis showed that TOX3 Overexpression mainly affected the Interferon Signaling Pathway. TOX3 up regulation induced the expression of several genes with a gamma interferon activation site (GAS......), e.g. STAT1. In vitro functional studies showed that TOX3 was able to bind to the GAS-sequence located at the STAT1 promoter. siRNA mediated knockdown of TOX3 in RT4 bladder cancer cells decreased STAT1 expression suggesting a direct impact of TOX3 on STAT1. Immunoprecipitation of TOX3 over...

CompTox Chemistry Dashboard webinar

Science.gov (United States)

The CompTox Chemistry Dashboard is part of a suite of dashboards developed by EPA to help evaluate the safety of chemicals. The dashboard provides access to a variety of information on over 700,000 chemicals currently in use. Within the application, users

Chemical and HTS Profiling of 63 Cleft Palate Teratogens from ToxCast (FutureTox III)

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Cleft palate is a common human birth defect that has been linked to both genetic and environmental factors. To characterize the potential molecular targets and biological processes across mechanistically diverse teratogens that cause cleft palate, we mined the ToxCast high-throug...

20180416 - Understanding the Biology and Technology of ToxCast and Tox21 Assays (SETAC Durham NC)

Science.gov (United States)

The ToxCast high-throughput toxicity (HTT) testing methods have been developed to evaluate the hazard potential of diverse environmental, industrial and consumer product chemicals. The main goal is prioritizing the compounds of greatest concern for more detailed toxicological stu...

Total Petroleum Hydrocarbons (TPH): ToxFAQs

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... a state: This map displays locations where Total Petroleum Hydrocarbons (TPH) is known to be present. On ... I get more information? ToxFAQs TM for Total Petroleum Hydrocarbons (TPH) ( Hidrocarburos Totales de Petróleo (TPH) ) August ...

The Tox21 robotic platform for the assessment of environmental chemicals--from vision to reality.

Science.gov (United States)

Attene-Ramos, Matias S; Miller, Nicole; Huang, Ruili; Michael, Sam; Itkin, Misha; Kavlock, Robert J; Austin, Christopher P; Shinn, Paul; Simeonov, Anton; Tice, Raymond R; Xia, Menghang

2013-08-01

Since its establishment in 2008, the US Tox21 inter-agency collaboration has made great progress in developing and evaluating cellular models for the evaluation of environmental chemicals as a proof of principle. Currently, the program has entered its production phase (Tox21 Phase II) focusing initially on the areas of modulation of nuclear receptors and stress response pathways. During Tox21 Phase II, the set of chemicals to be tested has been expanded to nearly 10,000 (10K) compounds and a fully automated screening platform has been implemented. The Tox21 robotic system combined with informatics efforts is capable of screening and profiling the collection of 10K environmental chemicals in triplicate in a week. In this article, we describe the Tox21 screening process, compound library preparation, data processing, and robotic system validation. Published by Elsevier Ltd.

Chemical Function Predictions for Tox21 Chemicals

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U.S. Environmental Protection Agency — Random forest chemical function predictions for Tox21 chemicals in personal care products uses and "other" uses. This dataset is associated with the following...

In silico ADME-Tox modeling: progress and prospects.

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Alqahtani, Saeed

2017-11-01

Although significant progress has been made in high-throughput screening of absorption, distribution, metabolism and excretion, and toxicity (ADME-Tox) properties in drug discovery and development, in silico ADME-Tox prediction continues to play an important role in facilitating the appropriate selection of candidate drugs by pharmaceutical companies prior to expensive clinical trials. Areas covered: This review provides an overview of the available in silico models that have been used to predict the ADME-Tox properties of compounds. It also provides a comprehensive overview and summarization of the latest modeling methods and algorithms available for the prediction of physicochemical characteristics, ADME properties, and drug toxicity issues. Expert opinion: The in silico models currently available have greatly contributed to the knowledge of screening approaches in the early stages of drug discovery and the development process. As the definitive goal of in silico molding is to predict the pharmacokinetics and disposition of compounds in vivo by assembling all kinetic processes within one global model, PBPK models can serve this purpose. However, much work remains to be done in this area to generate more data and input parameters to build more reliable and accurate prediction models.

ToxCast Workflow: High-throughput screening assay data processing, analysis and management (SOT)

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US EPA’s ToxCast program is generating data in high-throughput screening (HTS) and high-content screening (HCS) assays for thousands of environmental chemicals, for use in developing predictive toxicity models. Currently the ToxCast screening program includes over 1800 unique c...

The cysteine rich necrotrophic effector SnTox1 produced by Stagonospora nodorum triggers susceptibility of wheat lines harboring Snn1.

Directory of Open Access Journals (Sweden)

Zhaohui Liu

2012-01-01

Full Text Available The wheat pathogen Stagonospora nodorum produces multiple necrotrophic effectors (also called host-selective toxins that promote disease by interacting with corresponding host sensitivity gene products. SnTox1 was the first necrotrophic effector identified in S. nodorum, and was shown to induce necrosis on wheat lines carrying Snn1. Here, we report the molecular cloning and validation of SnTox1 as well as the preliminary characterization of the mechanism underlying the SnTox1-Snn1 interaction which leads to susceptibility. SnTox1 was identified using bioinformatics tools and verified by heterologous expression in Pichia pastoris. SnTox1 encodes a 117 amino acid protein with the first 17 amino acids predicted as a signal peptide, and strikingly, the mature protein contains 16 cysteine residues, a common feature for some avirulence effectors. The transformation of SnTox1 into an avirulent S. nodorum isolate was sufficient to make the strain pathogenic. Additionally, the deletion of SnTox1 in virulent isolates rendered the SnTox1 mutated strains avirulent on the Snn1 differential wheat line. SnTox1 was present in 85% of a global collection of S. nodorum isolates. We identified a total of 11 protein isoforms and found evidence for strong diversifying selection operating on SnTox1. The SnTox1-Snn1 interaction results in an oxidative burst, DNA laddering, and pathogenesis related (PR gene expression, all hallmarks of a defense response. In the absence of light, the development of SnTox1-induced necrosis and disease symptoms were completely blocked. By comparing the infection processes of a GFP-tagged avirulent isolate and the same isolate transformed with SnTox1, we conclude that SnTox1 may play a critical role during fungal penetration. This research further demonstrates that necrotrophic fungal pathogens utilize small effector proteins to exploit plant resistance pathways for their colonization, which provides important insights into the molecular

20180312 - Profiling the ToxCast library with a pluripotent human (H9) embryonic stem cell assay (SOT)

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The Stemina devTOX quickPredict platform (STM) is a human pluripotent H9 stem cell-based assay that predicts developmental toxicants. Using the STM model, we screened 1065 ToxCast chemicals and entered the data into the ToxCast data analysis pipeline. Model performance was 83.3% ...

FutureTox III: Bridges for Translation

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The present document describes key discussion points and outcomes of a Society of Toxicology (SOT) Contemporary Concepts in Toxicology (CCT) Workshop, entitled FutureTox III1,2 that was held in Crystal City, Virginia, November 19-20, 2015. The workshop built on the many lessons l...

“httk”: EPA’s Tool for High Throughput Toxicokinetics (CompTox CoP)

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Thousands of chemicals have been pro?led by high-throughput screening programs such as ToxCast and Tox21; these chemicals are tested in part because most of them have limited or no data on hazard, exposure, or toxicokinetics. Toxicokinetic models aid in predicting tissue concentr...

Intracranial contrast transit times on digital subtraction angiography decrease more in patients with delayed intraparenchymal hemorrhage after Pipeline.

Science.gov (United States)

Brunozzi, Denise; Shakur, Sophia F; Charbel, Fady T; Alaraj, Ali

2018-04-01

Background Pipeline embolization devices (PEDs) are used for endovascular treatment of cerebral aneurysms but can be associated with delayed ipsilateral intraparenchymal hemorrhage (DIPH). Changes in intracranial hemodynamics after PED are poorly understood. Objective Here, we assess hemodynamic changes after PED in patients and compare these changes in patients with and without DIPH (DIPH+ and DIPH-). Methods Records of patients with distal internal carotid artery (ICA) aneurysms treated with PED at our institution between 2012 and 2017 were retrospectively reviewed. Regions of interest were selected proximally to PED over the cavernous ICA and distally over the middle cerebral artery (MCA), and then transit times were determined using syngo iFlow software (Siemens). Ratio of MCA to ICA transit time was compared before, after treatment, and at follow-up. Ratios were also compared between DIPH+ and DIPH- subgroups. Correlations between aneurysm size, age, and ratios were investigated. Results Fifty-three patients were included. The ratio of MCA to ICA transit time decreased significantly after PED deployment (1.13 vs. 1.22, p transit time decreases following PED treatment and decreases more in patients with DIPH. These contrast transit time changes can be detected in real time immediately after PED deployment.

ToxPi Graphical User Interface 2.0: Dynamic exploration, visualization, and sharing of integrated data models.

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Marvel, Skylar W; To, Kimberly; Grimm, Fabian A; Wright, Fred A; Rusyn, Ivan; Reif, David M

2018-03-05

Drawing integrated conclusions from diverse source data requires synthesis across multiple types of information. The ToxPi (Toxicological Prioritization Index) is an analytical framework that was developed to enable integration of multiple sources of evidence by transforming data into integrated, visual profiles. Methodological improvements have advanced ToxPi and expanded its applicability, necessitating a new, consolidated software platform to provide functionality, while preserving flexibility for future updates. We detail the implementation of a new graphical user interface for ToxPi (Toxicological Prioritization Index) that provides interactive visualization, analysis, reporting, and portability. The interface is deployed as a stand-alone, platform-independent Java application, with a modular design to accommodate inclusion of future analytics. The new ToxPi interface introduces several features, from flexible data import formats (including legacy formats that permit backward compatibility) to similarity-based clustering to options for high-resolution graphical output. We present the new ToxPi interface for dynamic exploration, visualization, and sharing of integrated data models. The ToxPi interface is freely-available as a single compressed download that includes the main Java executable, all libraries, example data files, and a complete user manual from http://toxpi.org .

Effect of toxin-g from Tityus serrulatus scorpion venom on gastric emptying in rats

Directory of Open Access Journals (Sweden)

F. Bucaretchi

1999-04-01

Full Text Available The effect of toxin-g from Tityus serrulatus scorpion venom on the gastric emptying of liquids was studied in 176 young adult male Wistar rats (2-3 months of age divided into subgroups of 8 animals each. Toxin-g was injected iv at doses of 25, 37.5, 50 or 100 µg/kg and the effect on gastric emptying was assessed 30 min and 8 h later. A time-course study was also performed by injecting 50 µg of toxin-g /kg and measuring the effect on gastric emptying at times 0.25, 0.5, 1, 2, 4, 8, 24 and 48 h post-venom. Each envenomed animal was paired with its saline control and all received a saline test meal solution containing phenol red (60 µg/ml as a marker. Ten minutes after administering the test meal by gavage the animals were sacrificed and gastric retention was determined by measuring the residual marker concentration of the test meal. A significant delay in gastric emptying, at 30 min and 8 h post-venom, was observed only after 50 and 100 µg of toxin-g /kg compared to control values. The responses to these two doses were significantly different after 8 h post-venom. Toxin-g (50 µg/kg significantly delayed the gastric emptying of liquids at all times studied, with a peak response at 4 h after toxin administration compared to control values. These results indicate that the iv injection of toxin-g may induce a rapid, intense and sustained inhibition of gastric emptying 0.25 to 48 h after envenomation.

CBirTox is a selective antigen-specific agonist of the Treg-IgA-microbiota homeostatic pathway.

Directory of Open Access Journals (Sweden)

Katie L Alexander

Full Text Available Cultivating an environment of mutualism between host cells and the microbiota is vital, and dysregulation of this relationship is associated with multiple immune disorders including metabolic and skin diseases, asthma, allergy, and Inflammatory Bowel Disease (IBD. One prominent mechanism for maintaining homeostasis is the protective regulatory T cell (Treg- Immunoglobulin A (IgA pathway toward microbiota antigens, in which Tregs maintain homeostasis and provide critical survival factors to IgA+ B cells. In order to amplify the Treg-IgA pathway, we have generated a fusion protein, CBirTox, comprised of a portion of the carboxy terminus of CBir1, a microbiota flagellin, genetically coupled to Cholera Toxin B subunit (CTB via the A2 linker of CT. Both dendritic cells (DCs and B cells pulsed with CBirTox selectively induced functional CD4+Foxp3+ Tregs in vitro, and CBirTox augmented CD4+Foxp3+ cell numbers in vivo. The induced Foxp3 expression was independent of retinoic acid (RA signaling but was inhibited by neutralization of TGF-β. CBirTox treatment of B cells downregulated mammalian target of rapamycin (mTOR signaling. Furthermore, CBirTox-pulsed DCs induced substantial production of IgA from naïve B cells. Collectively these data demonstrate that CBirTox represents a novel approach to bolstering the Treg-IgA pathway at the host-microbiota interface.

ProTox: a web server for the in silico prediction of rodent oral toxicity.

Science.gov (United States)

Drwal, Malgorzata N; Banerjee, Priyanka; Dunkel, Mathias; Wettig, Martin R; Preissner, Robert

2014-07-01

Animal trials are currently the major method for determining the possible toxic effects of drug candidates and cosmetics. In silico prediction methods represent an alternative approach and aim to rationalize the preclinical drug development, thus enabling the reduction of the associated time, costs and animal experiments. Here, we present ProTox, a web server for the prediction of rodent oral toxicity. The prediction method is based on the analysis of the similarity of compounds with known median lethal doses (LD50) and incorporates the identification of toxic fragments, therefore representing a novel approach in toxicity prediction. In addition, the web server includes an indication of possible toxicity targets which is based on an in-house collection of protein-ligand-based pharmacophore models ('toxicophores') for targets associated with adverse drug reactions. The ProTox web server is open to all users and can be accessed without registration at: http://tox.charite.de/tox. The only requirement for the prediction is the two-dimensional structure of the input compounds. All ProTox methods have been evaluated based on a diverse external validation set and displayed strong performance (sensitivity, specificity and precision of 76, 95 and 75%, respectively) and superiority over other toxicity prediction tools, indicating their possible applicability for other compound classes. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

TOX sets the stage for innate lymphoid cells

NARCIS (Netherlands)

Spits, Hergen

2015-01-01

Like T cells and B cells, innate lymphoid cells (ILCs) develop from common lymphoid progenitors, but how commitment to the ILC lineage is regulated has remained unclear. The transcriptional regulator TOX is important in this process

Toxicology in the 21st Century (Tox21)

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Tox21 researchers aim to develop better toxicity assessment methods to quickly and efficiently test whether certain chemical compounds have the potential to disrupt processes in the human body that may lead to negative health effects.

Cheminformatics Analysis of EPA ToxCast Chemical Libraries ...

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An important goal of toxicology research is the development of robust methods that use in vitro and chemical structure information to predict in vivo toxicity endpoints. The US EPA ToxCast program is addressing this goal using ~600 in vitro assays to create bioactivity profiles on a set of 320 compounds, mostly pesticide actives, that have well characterized in vivo toxicity. These 320 compounds (EPA-320 set evaluated in Phase I of ToxCast) are a subset of a much larger set of ~10,000 candidates that are of interest to the EPA (called here EPA-10K). Predictive models of in vivo toxicity are being constructed from the in vitro assay data on the EPA-320 chemical set. These models require validation on additional chemicals prior to wide acceptance, and this will be carried out by evaluating compounds from EPA-10K in Phase II of ToxCast. We have used cheminformatics approaches including clustering, data visualization, and QSAR to develop models for EPA-320 that could help prioritizing EPA-10K validation chemicals. Both chemical descriptors, as well as calculated physicochemical properties have been used. Compounds from EPA-10K are prioritized based on their similarity to EPA-320 using different similarity metrics, with similarity thresholds defining the domain of applicability for the predictive models built for EPA-320 set. In addition, prioritized lists of compounds of increasing dissimilarity from the EPA-320 have been produced, to test the ability of the EPA-320

TOXsIgN: a cross-species repository for toxicogenomic signatures.

Science.gov (United States)

Darde, Thomas A; Gaudriault, Pierre; Beranger, Rémi; Lancien, Clément; Caillarec-Joly, Annaëlle; Sallou, Olivier; Bonvallot, Nathalie; Chevrier, Cécile; Mazaud-Guittot, Séverine; Jégou, Bernard; Collin, Olivier; Becker, Emmanuelle; Rolland, Antoine D; Chalmel, Frédéric

2018-01-27

At the same time that toxicologists express increasing concern about reproducibility in this field, the development of dedicated databases has already smoothed the path toward improving the storage and exchange of raw toxicogenomic data. Nevertheless, none provides access to analyzed and interpreted data as originally reported in scientific publications. Given the increasing demand for access to this information, we developed TOXsIgN, a repository for TOXicogenomic sIgNatures. The TOXsIgN repository provides a flexible environment that facilitates online submission, storage, and retrieval of toxicogenomic signatures by the scientific community. It currently hosts 754 projects that describe more than 450 distinct chemicals and their 8491 associated signatures. It also provides users with a working environment containing a powerful search engine as well as bioinformatics/biostatistics modules that enable signature comparisons or enrichment analyses. The TOXsIgN repository is freely accessible at http://toxsign.genouest.org. Website implemented in Python, JavaScript, and MongoDB, with all major browsers supported. frederic.chalmel@inserm.fr. Supplementary data are available at Bioinformatics online. © The Author (2018). Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com

Tutorial Video Series: Using Stakeholder Outreach to Increase Usage of ToxCast Data (SETAC EU)

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The limited amount of toxicity data on thousands of chemicals found in consumer products has led to the development of research endeavors such as the U.S. EPA’s Toxicity Forecaster (ToxCast). ToxCast uses high-throughput screening technology to evaluate thousands of chemicals for...

Intersection of toxicogenomics and high throughput screening in the Tox21 program: an NIEHS perspective.

Science.gov (United States)

Merrick, B Alex; Paules, Richard S; Tice, Raymond R

Humans are exposed to thousands of chemicals with inadequate toxicological data. Advances in computational toxicology, robotic high throughput screening (HTS), and genome-wide expression have been integrated into the Tox21 program to better predict the toxicological effects of chemicals. Tox21 is a collaboration among US government agencies initiated in 2008 that aims to shift chemical hazard assessment from traditional animal toxicology to target-specific, mechanism-based, biological observations using in vitro assays and lower organism models. HTS uses biocomputational methods for probing thousands of chemicals in in vitro assays for gene-pathway response patterns predictive of adverse human health outcomes. In 1999, NIEHS began exploring the application of toxicogenomics to toxicology and recent advances in NextGen sequencing should greatly enhance the biological content obtained from HTS platforms. We foresee an intersection of new technologies in toxicogenomics and HTS as an innovative development in Tox21. Tox21 goals, priorities, progress, and challenges will be reviewed.

Predicting Developmental Toxicity of ToxCast Phase I Chemicals Using Human Embryonic Stem Cells and Metabolomics

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EPA’s ToxRefDB contains prenatal guideline study data from rats and rabbits for over 240 chemicals that overlap with the ToxCast in vitro high throughput screening project. A subset of these compounds were tested in Stemina Biomarker Discovery's developmental toxicity platform, a...

Metabolism Retrofit Strategies for ToxCast Assays (BOSC)

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The EPA’s ToxCast program utilizes a wide variety of high-throughput screening assays (HTS) to assess chemical perturbations of molecular and cellular endpoints. A limitation of many HTS assays used for toxicity assessment is the lack of xenobiotic metabolism (XM) which precludes...

Proteolysis of virulence regulator ToxR is associated with entry of Vibrio cholerae into a dormant state.

Directory of Open Access Journals (Sweden)

Salvador Almagro-Moreno

2015-04-01

Full Text Available Vibrio cholerae O1 is a natural inhabitant of aquatic environments and causes the diarrheal disease, cholera. Two of its primary virulence regulators, TcpP and ToxR, are localized in the inner membrane. TcpP is encoded on the Vibrio Pathogenicity Island (VPI, a horizontally acquired mobile genetic element, and functions primarily in virulence gene regulation. TcpP has been shown to undergo regulated intramembrane proteolysis (RIP in response to environmental conditions that are unfavorable for virulence gene expression. ToxR is encoded in the ancestral genome and is present in non-pathogenic strains of V. cholerae, indicating it has roles outside of the human host. In this study, we show that ToxR undergoes RIP in V. cholerae in response to nutrient limitation at alkaline pH, a condition that occurs during the stationary phase of growth. This process involves the site-2 protease RseP (YaeL, and is dependent upon the RpoE-mediated periplasmic stress response, as deletion mutants for the genes encoding these two proteins cannot proteolyze ToxR under nutrient limitation at alkaline pH. We determined that the loss of ToxR, genetically or by proteolysis, is associated with entry of V. cholerae into a dormant state in which the bacterium is normally found in the aquatic environment called viable but nonculturable (VBNC. Strains that can proteolyze ToxR, or do not encode it, lose culturability, experience a change in morphology associated with cells in VBNC, yet remain viable under nutrient limitation at alkaline pH. On the other hand, mutant strains that cannot proteolyze ToxR remain culturable and maintain the morphology of cells in an active state of growth. Overall, our findings provide a link between the proteolysis of a virulence regulator and the entry of a pathogen into an environmentally persistent state.

Highlight report: Launch of a large integrated European in vitro toxicology project: EU-ToxRisk.

Science.gov (United States)

Daneshian, Mardas; Kamp, Hennicke; Hengstler, Jan; Leist, Marcel; van de Water, Bob

2016-05-01

The integrated European project, EU-ToxRisk, proudly sees itself as "flagship" exploring new alternative-to-animal approaches to chemical safety evaluation. It promotes mechanism-based toxicity testing and risk assessment according to the principles laid down for toxicology for the twenty-first century. The project was officially launched in January 2016 with a kickoff meeting in Egmond aan Zee, the Netherlands. Over 100 scientists representing academia and industry as well as regulatory authorities attended the inaugural meeting. The project will integrate advances in in vitro and in silico toxicology, read-across methods, and adverse outcome pathways. EU-ToxRisk will continue to make use of the case study strategy deployed in SEURAT-1, a FP7 initiative ended in December 2015. Even though the development of new non-animal methods is one target of EU-ToxRisk, the project puts special emphasis on their acceptance and implementation in regulatory contexts. This €30 million Horizon 2020 project involves 38 European partners and one from the USA. EU-ToxRisk aims at the "development of a new way of risk assessment."

Molecular cloning and characterization of a ToxA-like gene from the maize pathogen Cochliobolus heterostrophus

Science.gov (United States)

ToxA, the first discovered fungal proteinaceous host-selective toxin, was originally identified from the tan spot fungus Pyrenophora tritici-repentis (Ptr). Homologues of the PtrToxA gene have not been identified from any other ascomycetes except the leaf/glume blotch fungus Stagonospora nodorum, w...

Toxicology Testing in the 21st Century (Tox21)

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Tox21 researchers aim to develop better toxicity assessment methods to quickly and efficiently test whether certain chemical compounds have the potential to disrupt processes in the human body that may lead to negative health effects.

An Evaluation of ToxCast Angiogenic Disruptors for Effects on Mitochondrial Bioactivity Profiles (Teratology Society Annual Meeting)

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Angiogenesis is a critical developmental process and a potential target for chemical teratogenesis. Over one-tenth of the Tox21 library of 10,000 compounds have been shown to disrupt mitochondrial function [Attene-Ramos et al., 2015]. Previous studies utilizing ToxCast chemicals ...

Deiodinase 1 Screening of ToxCast Phase 1 Chemical Library

Data.gov (United States)

U.S. Environmental Protection Agency — This excel spreadsheet contains the resultant data for over from inhibition assays with human Deiodinase 1 screened against the ToxCast Phase 1 chemical library and...

Structure Identification Using High Resolution Mass Spectrometry Data and the EPA’s CompTox Chemistry Dashboard (EAS)

Science.gov (United States)

The iCSS CompTox Dashboard is a publicly accessible dashboard provided by the National Center for Computation Toxicology at the US-EPA. It serves a number of purposes, including providing a chemistry database underpinning many of our public-facing projects (e.g. ToxCast and ExpoC...

Extending the Derek-Meteor Workflow to Predict Chemical-Toxicity Space Impacted by Metabolism: Application to ToxCast and Tox21 Chemical Inventories

Science.gov (United States)

A central aim of EPA’s ToxCast project is to use in vitro high-throughput screening (HTS) profiles to build predictive models of in vivo toxicity. Where assays lack metabolic capability, such efforts may need to anticipate the role of metabolic activation (or deactivation). A wo...

Development of a toxR-based loop-mediated isothermal amplification assay for detecting Vibrio parahaemolyticus

Directory of Open Access Journals (Sweden)

Ge Beilei

2010-02-01

Full Text Available Abstract Background Vibrio parahaemolyticus is a leading cause of seafood-related bacterial gastroenteritis and outbreaks worldwide. Sensitive and specific detection methods are needed to better control V. parahaemolyticus infections. This study aimed at developing a highly specific and sensitive loop-mediated isothermal amplification (LAMP assay for detecting V. parahaemolyticus in oysters. A set of five LAMP primers, two outer, two inner, and one loop were designed based on the published V. parahaemolyticus toxR sequence. Specificity of the assay was evaluated using a panel of 36 V. parahaemolyticus and 39 other strains. The assay sensitivity was determined using serial dilutions of V. parahaemolyticus ATCC 27969 culture ranging from 108 CFU/ml to extinction. The assay was also tested in experimentally inoculated oyster samples. Results The toxR-based LAMP assay was able to specifically detect all of the 36 V. parahaemolyticus strains without amplification from 39 other strains. The detection limit was 47-470 cells per reaction in pure culture, up to 100-fold more sensitive than that of toxR-PCR. When applied in spiked oysters, the assay was able to detect 1.1 × 105 V. parahaemolyticus cells per gram of oyster without enrichment, up to 100-fold more sensitive than that of toxR-PCR. Standard curves generated for detecting V. parahaemolyticus in both pure culture and spiked oyster samples showed good linear relationship between cell numbers and the fluorescence or turbidity signals. Conclusions The toxR-based LAMP assay developed in this study was sensitive, specific, and quantitative, holding great potential for future field detection of V. parahaemolyticus in raw oysters.

Value of shared preclinical safety studies - The eTOX database.

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Briggs, Katharine; Barber, Chris; Cases, Montserrat; Marc, Philippe; Steger-Hartmann, Thomas

2015-01-01

A first analysis of a database of shared preclinical safety data for 1214 small molecule drugs and drug candidates extracted from 3970 reports donated by thirteen pharmaceutical companies for the eTOX project (www.etoxproject.eu) is presented. Species, duration of exposure and administration route data were analysed to assess if large enough subsets of homogenous data are available for building in silico predictive models. Prevalence of treatment related effects for the different types of findings recorded were analysed. The eTOX ontology was used to determine the most common treatment-related clinical chemistry and histopathology findings reported in the database. The data were then mined to evaluate sensitivity of established in vivo biomarkers for liver toxicity risk assessment. The value of the database to inform other drug development projects during early drug development is illustrated by a case study.

ToxCast Data Expands Universe of Chemical-Gene Interactions (SOT)

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Characterizing the effects of chemicals in biological systems is often summarized by chemical-gene interactions, which have sparse coverage in literature. The ToxCast chemical screening program has produced bioactivity data for nearly 2000 chemicals and over 450 gene targets. Thi...

A Data Analysis Pipeline Accounting for Artifacts in Tox21 Quantitative High-Throughput Screening Assays.

Science.gov (United States)

Hsieh, Jui-Hua; Sedykh, Alexander; Huang, Ruili; Xia, Menghang; Tice, Raymond R

2015-08-01

A main goal of the U.S. Tox21 program is to profile a 10K-compound library for activity against a panel of stress-related and nuclear receptor signaling pathway assays using a quantitative high-throughput screening (qHTS) approach. However, assay artifacts, including nonreproducible signals and assay interference (e.g., autofluorescence), complicate compound activity interpretation. To address these issues, we have developed a data analysis pipeline that includes an updated signal noise-filtering/curation protocol and an assay interference flagging system. To better characterize various types of signals, we adopted a weighted version of the area under the curve (wAUC) to quantify the amount of activity across the tested concentration range in combination with the assay-dependent point-of-departure (POD) concentration. Based on the 32 Tox21 qHTS assays analyzed, we demonstrate that signal profiling using wAUC affords the best reproducibility (Pearson's r = 0.91) in comparison with the POD (0.82) only or the AC(50) (i.e., half-maximal activity concentration, 0.81). Among the activity artifacts characterized, cytotoxicity is the major confounding factor; on average, about 8% of Tox21 compounds are affected, whereas autofluorescence affects less than 0.5%. To facilitate data evaluation, we implemented two graphical user interface applications, allowing users to rapidly evaluate the in vitro activity of Tox21 compounds. © 2015 Society for Laboratory Automation and Screening.

Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

Energy Technology Data Exchange (ETDEWEB)

Kleinstreuer, N.C., E-mail: kleinstreuer.nicole@epa.gov [NCCT, US EPA, RTP, NC 27711 (United States); Smith, A.M.; West, P.R.; Conard, K.R.; Fontaine, B.R. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); Weir-Hauptman, A.M. [Covance, Inc., Madison, WI 53704 (United States); Palmer, J.A. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); Knudsen, T.B.; Dix, D.J. [NCCT, US EPA, RTP, NC 27711 (United States); Donley, E.L.R. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); Cezar, G.G. [Stemina Biomarker Discovery, Inc., Madison, WI 53719 (United States); University of Wisconsin-Madison, Madison, WI 53706 (United States)

2011-11-15

Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast Trade-Mark-Sign chemical screening and prioritization research project. Metabolites from hES cultures were evaluated for known and novel signatures that may be indicative of developmental toxicity. Significant fold changes in endogenous metabolites were detected for 83 putatively annotated mass features in response to the subset of ToxCast chemicals. The annotations were mapped to specific human metabolic pathways. This revealed strong effects on pathways for nicotinate and nicotinamide metabolism, pantothenate and CoA biosynthesis, glutathione metabolism, and arginine and proline metabolism pathways. Predictivity for adverse outcomes in mammalian prenatal developmental toxicity studies used ToxRefDB and other sources of information, including Stemina Biomarker Discovery's predictive DevTox Registered-Sign model trained on 23 pharmaceutical agents of known developmental toxicity and differing potency. The model initially predicted developmental toxicity from the blinded ToxCast compounds in concordance with animal data with 73% accuracy. Retraining the model with data from the unblinded test compounds at one concentration level increased the predictive accuracy for the remaining concentrations to 83%. These preliminary results on a 11-chemical subset of the ToxCast chemical library indicate that metabolomics analysis of the hES secretome provides information valuable for predictive modeling and mechanistic understanding of mammalian developmental toxicity. -- Highlights: Black-Right-Pointing-Pointer We tested 11 environmental compounds in a hESC metabolomics platform. Black-Right-Pointing-Pointer Significant changes in secreted small molecule metabolites were observed. Black-Right-Pointing-Pointer Perturbed mass features map to pathways critical for normal

Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

International Nuclear Information System (INIS)

Kleinstreuer, N.C.; Smith, A.M.; West, P.R.; Conard, K.R.; Fontaine, B.R.; Weir-Hauptman, A.M.; Palmer, J.A.; Knudsen, T.B.; Dix, D.J.; Donley, E.L.R.; Cezar, G.G.

2011-01-01

Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast™ chemical screening and prioritization research project. Metabolites from hES cultures were evaluated for known and novel signatures that may be indicative of developmental toxicity. Significant fold changes in endogenous metabolites were detected for 83 putatively annotated mass features in response to the subset of ToxCast chemicals. The annotations were mapped to specific human metabolic pathways. This revealed strong effects on pathways for nicotinate and nicotinamide metabolism, pantothenate and CoA biosynthesis, glutathione metabolism, and arginine and proline metabolism pathways. Predictivity for adverse outcomes in mammalian prenatal developmental toxicity studies used ToxRefDB and other sources of information, including Stemina Biomarker Discovery's predictive DevTox® model trained on 23 pharmaceutical agents of known developmental toxicity and differing potency. The model initially predicted developmental toxicity from the blinded ToxCast compounds in concordance with animal data with 73% accuracy. Retraining the model with data from the unblinded test compounds at one concentration level increased the predictive accuracy for the remaining concentrations to 83%. These preliminary results on a 11-chemical subset of the ToxCast chemical library indicate that metabolomics analysis of the hES secretome provides information valuable for predictive modeling and mechanistic understanding of mammalian developmental toxicity. -- Highlights: ► We tested 11 environmental compounds in a hESC metabolomics platform. ► Significant changes in secreted small molecule metabolites were observed. ► Perturbed mass features map to pathways critical for normal development and pregnancy. ► Arginine, proline, nicotinate, nicotinamide and glutathione pathways were affected.

Structure of Vibrio cholerae ToxT reveals a mechanism for fatty acid regulation of virulence genes

Energy Technology Data Exchange (ETDEWEB)

Lowden, Michael J.; Skorupski, Karen; Pellegrini, Maria; Chiorazzo, Michael G.; Taylor, Ronald K.; Kull, F. Jon (Dartmouth)

2010-03-04

Cholera is an acute intestinal infection caused by the bacterium Vibrio cholerae. In order for V. cholerae to cause disease, it must produce two virulence factors, the toxin-coregulated pilus (TCP) and cholera toxin (CT), whose expression is controlled by a transcriptional cascade culminating with the expression of the AraC-family regulator, ToxT. We have solved the 1.9 {angstrom} resolution crystal structure of ToxT, which reveals folds in the N- and C-terminal domains that share a number of features in common with AraC, MarA, and Rob as well as the unexpected presence of a buried 16-carbon fatty acid, cis-palmitoleate. The finding that cis-palmitoleic acid reduces TCP and CT expression in V. cholerae and prevents ToxT from binding to DNA in vitro provides a direct link between the host environment of V. cholerae and regulation of virulence gene expression.

CAirTOX, An inter-media transfer model for assessing indirect exposures to hazardous air contaminants

International Nuclear Information System (INIS)

McKone, T.E.

1994-01-01

Risk assessment is a quantitative evaluation of information on potential health hazards of environmental contaminants and the extent of human exposure to these contaminants. As applied to toxic chemical emissions to air, risk assessment involves four interrelated steps. These are (1) determination of source concentrations or emission characteristics, (2) exposure assessment, (3) toxicity assessment, and (4) risk characterization. These steps can be carried out with assistance from analytical models in order to estimate the potential risk associated with existing and future releases. CAirTOX has been developed as a spreadsheet model to assist in making these types of calculations. CAirTOX follows an approach that has been incorporated into the CalTOX model, which was developed for the California Department of Toxic Substances Control, With CAirTOX, we can address how contaminants released to an air basin can lead to contamination of soil, food, surface water, and sediments. The modeling effort includes a multimedia transport and transformation model, exposure scenario models, and efforts to quantify uncertainty in multimedia, multiple-pathway exposure assessments. The capacity to explicitly address uncertainty has been incorporated into the model in two ways. First, the spreadsheet form of the model makes it compatible with Monte-Carlo add-on programs that are available for uncertainty analysis. Second, all model inputs are specified in terms of an arithmetic mean and coefficient of variation so that uncertainty analyses can be carried out

Analysis of ToxCast data for food-relevant compounds by comparison with in vivo data using the RISK21 approach

Science.gov (United States)

The ToxCast program has generated a wealth of in vitro high throughput screening data, and best approaches for the interpretation and use of these data remain undetermined. We present case studies comparing the ToxCast and in vivo toxicity data for two food contact substances us...

Causal Inferences from Mining ToxCast Data and the Biomedical Literature for Molecular Pathways and Cellular Processes in Cleft Palate (SOT)

Science.gov (United States)

Sixty-five chemicals in the ToxCast high-throughput screening (HTS) dataset have been linked to cleft palate based on data from ToxRefDB (rat or rabbit prenatal developmental toxicity studies) or from literature reports. These compounds are structurally diverse and thus likely to...

LimTox: a web tool for applied text mining of adverse event and toxicity associations of compounds, drugs and genes.

Science.gov (United States)

Cañada, Andres; Capella-Gutierrez, Salvador; Rabal, Obdulia; Oyarzabal, Julen; Valencia, Alfonso; Krallinger, Martin

2017-07-03

A considerable effort has been devoted to retrieve systematically information for genes and proteins as well as relationships between them. Despite the importance of chemical compounds and drugs as a central bio-entity in pharmacological and biological research, only a limited number of freely available chemical text-mining/search engine technologies are currently accessible. Here we present LimTox (Literature Mining for Toxicology), a web-based online biomedical search tool with special focus on adverse hepatobiliary reactions. It integrates a range of text mining, named entity recognition and information extraction components. LimTox relies on machine-learning, rule-based, pattern-based and term lookup strategies. This system processes scientific abstracts, a set of full text articles and medical agency assessment reports. Although the main focus of LimTox is on adverse liver events, it enables also basic searches for other organ level toxicity associations (nephrotoxicity, cardiotoxicity, thyrotoxicity and phospholipidosis). This tool supports specialized search queries for: chemical compounds/drugs, genes (with additional emphasis on key enzymes in drug metabolism, namely P450 cytochromes-CYPs) and biochemical liver markers. The LimTox website is free and open to all users and there is no login requirement. LimTox can be accessed at: http://limtox.bioinfo.cnio.es. © The Author(s) 2017. Published by Oxford University Press on behalf of Nucleic Acids Research.

Prediction of metabolites of epoxidation reaction in MetaTox.

Science.gov (United States)

Rudik, A V; Dmitriev, A V; Bezhentsev, V M; Lagunin, A A; Filimonov, D A; Poroikov, V V

2017-10-01

Biotransformation is a process of the chemical modifications which may lead to the reactive metabolites, in particular the epoxides. Epoxide reactive metabolites may cause the toxic effects. The prediction of such metabolites is important for drug development and ecotoxicology studies. Epoxides are formed by some oxidation reactions, usually catalysed by cytochromes P450, and represent a large class of three-membered cyclic ethers. Identification of molecules, which may be epoxidized, and indication of the specific location of epoxide functional group (which is called SOE - site of epoxidation) are important for prediction of epoxide metabolites. Datasets from 355 molecules and 615 reactions were created for training and validation. The prediction of SOE is based on a combination of LMNA (Labelled Multilevel Neighbourhood of Atom) descriptors and Bayesian-like algorithm implemented in PASS software and MetaTox web-service. The average invariant accuracy of prediction (AUC) calculated in leave-one-out and 20-fold cross-validation procedures is 0.9. Prediction of epoxide formation based on the created SAR model is included as the component of MetaTox web-service ( http://www.way2drug.com/mg ).

Mass-Spectrometry Based Structure Identification of "Known-Unknowns" Using the EPA's CompTox Dashboard (ACS Spring National Meeting) 4 of 7

Science.gov (United States)

The CompTox Dashboard is a publicly accessible database provided by the National Center for Computational Toxicology at the US-EPA. The dashboard provides access to a database containing ~720,000 chemicals and integrates a number of our public-facing projects (e.g. ToxCast and Ex...

Developmental status of bioassays in genetic toxicology: a report of Phase II of the US Environmental Protection Agency Gene-Tox program

Energy Technology Data Exchange (ETDEWEB)

Brusick, D; Auletta, A

1985-01-01

The Gene-Tox Program was structured around two phases of genetic test data evaluation. The first phase consisted of 36 Work Group reports, each evaluating the results and performance of a specific bioassay. The second phase consisted of a plan to summarize the information provided by the Work Groups. The Gene-Tox Coordinating Committee was to be responsible for Phase II, and several subgroups were assigned specific goals in implementing this analysis. This report deals with Goal I which is to identify the developmental status of the individual bioassays reviewed by the Gene-Tox Work Groups in the first phase of the Program. 5 references, 6 tables.

CalTOX, a multimedia total exposure model for hazardous-waste sites

International Nuclear Information System (INIS)

McKone, T.E.

1993-06-01

CalTOX has been developed as a spreadsheet model to assist in health-risk assessments that address contaminated soils and the contamination of adjacent air, surface water, sediments, and ground water. The modeling effort includes a multimedia transport and transformation model, exposure scenario models, and efforts to quantify and reduce uncertainty in multimedia, multiple-pathway exposure models. This report provides an overview of the CalTOX model components, lists the objectives of the model, describes the philosophy under which the model was developed, identifies the chemical classes for which the model can be used, and describes critical sensitivities and uncertainties. The multimedia transport and transformation model is a dynamic model that can be used to assess time-varying concentrations of contaminants introduced initially to soil layers or for contaminants released continuously to air or water. This model assists the user in examining how chemical and landscape properties impact both the ultimate route and quantity of human contact. Multimedia, multiple pathway exposure models are used in the CalTOX model to estimate average daily potential doses within a human population in the vicinity of a hazardous substances release site. The exposure models encompass twenty-three exposure pathways. The exposure assessment process consists of relating contaminant concentrations in the multimedia model compartments to contaminant concentrations in the media with which a human population has contact (personal air, tap water, foods, household dusts soils, etc.). The average daily dose is the product of the exposure concentrations in these contact media and an intake or uptake factor that relates the concentrations to the distributions of potential dose within the population

ToxR regulates the production of lipoproteins and the expression of serum resistance in Vibrio cholerae

International Nuclear Information System (INIS)

Parsot, C.; Taxman, E.; Mekalanos, J.J.

1991-01-01

The genes encoding three lipoproteins of Vibrio cholerae were identified by a combination of DNA sequence analysis and [ 3 H]palmitate labeling of hybrid proteins encoded by TnphoA gene fusions. The expression of these three lipoproteins, TagA, AcfD, and TcpC, was controlled by ToxR, the cholera toxin transcriptional activator. The involvement of other bacterial lipoproteins in conferring resistance ot the bactericidal effects of complement prompted us to examine this possibility in V. cholerae. Remarkably, mutations in toxR and tcp genes (including tcpC), involved in the biogenesis of the toxin coregulated pili, rendered V. cholerae about 10 4 - 10 6 times more sensitive to the vibriocidal activity of antibody and complement. Since V. cholerae is a noninvasive organism and toxR and tcp mutants are highly defective in intestinal colonization in animals and humans, these results raise the possibility that resistance to a gut-associated, complement-like bactericidal activity may be a major virulence determinant of V. cholerae and other enterobacterial species

NanoE-Tox: New and in-depth database concerning ecotoxicity of nanomaterials

Directory of Open Access Journals (Sweden)

Katre Juganson

2015-08-01

Full Text Available The increasing production and use of engineered nanomaterials (ENMs inevitably results in their higher concentrations in the environment. This may lead to undesirable environmental effects and thus warrants risk assessment. The ecotoxicity testing of a wide variety of ENMs rapidly evolving in the market is costly but also ethically questionable when bioassays with vertebrates are conducted. Therefore, alternative methods, e.g., models for predicting toxicity mechanisms of ENMs based on their physico-chemical properties (e.g., quantitative (nanostructure-activity relationships, QSARs/QNARs, should be developed. While the development of such models relies on good-quality experimental toxicity data, most of the available data in the literature even for the same test species are highly variable. In order to map and analyse the state of the art of the existing nanoecotoxicological information suitable for QNARs, we created a database NanoE-Tox that is available as . The database is based on existing literature on ecotoxicology of eight ENMs with different chemical composition: carbon nanotubes (CNTs, fullerenes, silver (Ag, titanium dioxide (TiO2, zinc oxide (ZnO, cerium dioxide (CeO2, copper oxide (CuO, and iron oxide (FeOx; Fe2O3, Fe3O4. Altogether, NanoE-Tox database consolidates data from 224 articles and lists altogether 1,518 toxicity values (EC50/LC50/NOEC with corresponding test conditions and physico-chemical parameters of the ENMs as well as reported toxicity mechanisms and uptake of ENMs in the organisms. 35% of the data in NanoE-Tox concerns ecotoxicity of Ag NPs, followed by TiO2 (22%, CeO2 (13%, and ZnO (10%. Most of the data originates from studies with crustaceans (26%, bacteria (17%, fish (13%, and algae (11%. Based on the median toxicity values of the most sensitive organism (data derived from three or more articles the toxicity order was as follows: Ag > ZnO > CuO > CeO2 > CNTs > TiO2 > FeOx. We believe NanoE-Tox database contains

Legacy data sharing to improve drug safety assessment: the eTOX project

DEFF Research Database (Denmark)

Sanz, Ferran; Pognan, François; Steger-Hartmann, Thomas

2017-01-01

The sharing of legacy preclinical safety data among pharmaceutical companies and its integration with other information sources offers unprecedented opportunities to improve the early assessment of drug safety. Here, we discuss the experience of the eTOX project, which was established through...

Extracorporeal Membrane Oxygenation (ECMO) for Severe Toxicological Exposures: Review of the Toxicology Investigators Consortium (ToxIC).

Science.gov (United States)

Wang, G S; Levitan, R; Wiegand, T J; Lowry, J; Schult, R F; Yin, S

2016-03-01

Although there have been many developments related to specific strategies for treating patients after poisoning exposures, the mainstay of therapy remains symptomatic and supportive care. One of the most aggressive supportive modalities is extracorporeal membrane oxygenation (ECMO). Our goal was to describe the use of ECMO for toxicological exposures reported to the American College of Medical Toxicology (ACMT) Toxicology Investigators Consortium (ToxIC). We performed a retrospective review of the ACMT ToxIC Registry from January 1, 2010 to December 31, 2013. Inclusion criteria included patients aged 0 to 89 years, evaluated between January 2010 through December 2013, and received ECMO for toxicological exposure. There were 26,271 exposures (60 % female) reported to the ToxIC Registry, 10 (0.0004 %) received ECMO: 4 pediatric (18 years). Time of initiation of ECMO ranged from 4 h to 4 days, with duration from 15 h to 12 days. Exposures included carbon monoxide/smoke inhalation (2), bitter almonds, methanol, and several medications including antihistamines (2), antipsychotic/antidepressant (2), cardiovascular drugs (2), analgesics (2), sedative/hypnotics (2), and antidiabetics (2). Four ECMO patients received cardiopulmonary resuscitation (CPR) during their hospital course, and the overall survival rate was 80 %. ECMO was rarely used for poisoning exposures in the ACMT ToxIC Registry. ECMO was utilized for a variety of ages and for pharmaceutical and non-pharmaceutical exposures. In most cases, ECMO was administered prior to cardiovascular failure, and survival rate was high. If available, ECMO may be a valid treatment modality.

CAirTOX: A compartment model for assessing the fate of and human exposure to toxic-chemical emissions to air

Energy Technology Data Exchange (ETDEWEB)

McKone, T.E.

1993-10-01

CAirTOX has been developed as a spreadsheet model to assist in making a risk assessment of toxic air emissions. With CAirTOX, one can address how contaminants released to an air basin can lead to contamination of soil, food, surface water, and sediments. The modeling effort includes a multimedia transport and transformation model, exposure scenario models, and efforts to quantify uncertainty in multimedia, multiple-pathway exposure assessments. The multimedia transport and transformation model is a steady-state, but non-equilibrium model that can be used to assess concentrations of contaminants released continuously to air. In Part 1, the authors describe the multimedia transport and transformation model used to determine the fate of air emissions. In Part 2, they describe inputs and data needs for CAirTOX and the development of a set of landscape factors, which can be used to represent regional air basin/water-shed systems in California. In Part 3, they describe the multiple-pathway exposure scenarios and exposure algorithms. In Part 4, they compare the HRA approach and results and the CAirTOX exposure equations. In Part 5, they consider model sensitivity and uncertainty to determine how variability and uncertainty in model inputs affects the precision, accuracy, and credibility of the model output.

Evaluation of the on-site immunoassay drug-screening device Triage-TOX in routine forensic autopsy.

Science.gov (United States)

Tominaga, Mariko; Michiue, Tomomi; Maeda, Hitoshi

2015-11-01

Instrumental identification of drugs with quantification is essential in forensic toxicology, while on-site immunoassay urinalysis drug-screening devices conveniently provide preliminary information when adequately used. However, suitable or sufficient urine specimens are not always available. The present study evaluated the efficacy of a new on-site immunoassay drug-screening device Triage-TOX (Alere Inc., San Diego, CA, USA), which has recently been developed to provide objective data on the one-step automated processor, using 51 urine and 19 pericardial fluid samples from 66 forensic autopsy cases, compared with Triage-Drug of Abuse (DOA) and Monitect-9. For benzodiazepines, the positive predictive value and specificity of Triage-TOX were higher than those of Triage-DOA; however, sensitivity was higher with Monitect-9, despite frequent false-positives. The results for the other drugs with the three devices also included a few false-negatives and false-positives. These observations indicate the applicability of Triage-TOX in preliminary drug screening using urine or alternative materials in routine forensic autopsy, when a possible false-negative is considered, especially for benzodiazepines, providing objective information; however, the combined use of another device such as Monitect-9 can help minimize misinterpretation prior to instrumental analysis. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Using the US EPA's CompTox Dashboard to support identification and screening of emerging organic contaminants in the environment (ACS Spring National meeting) 2 of 7

Science.gov (United States)

The US EPA’s iCSS CompTox Dashboard is a curated, publicly accessible resource provided by the National Center for Computational Toxicology (https://comptox.epa.gov). The Dashboard provides support for toxicology and risk assessment within and external to the EPA (including ToxC...

AMBIT RESTful web services: an implementation of the OpenTox application programming interface

Directory of Open Access Journals (Sweden)

Jeliazkova Nina

2011-05-01

Full Text Available Abstract The AMBIT web services package is one of the several existing independent implementations of the OpenTox Application Programming Interface and is built according to the principles of the Representational State Transfer (REST architecture. The Open Source Predictive Toxicology Framework, developed by the partners in the EC FP7 OpenTox project, aims at providing a unified access to toxicity data and predictive models, as well as validation procedures. This is achieved by i an information model, based on a common OWL-DL ontology ii links to related ontologies; iii data and algorithms, available through a standardized REST web services interface, where every compound, data set or predictive method has a unique web address, used to retrieve its Resource Description Framework (RDF representation, or initiate the associated calculations. The AMBIT web services package has been developed as an extension of AMBIT modules, adding the ability to create (Quantitative Structure-Activity Relationship (QSAR models and providing an OpenTox API compliant interface. The representation of data and processing resources in W3C Resource Description Framework facilitates integrating the resources as Linked Data. By uploading datasets with chemical structures and arbitrary set of properties, they become automatically available online in several formats. The services provide unified interfaces to several descriptor calculation, machine learning and similarity searching algorithms, as well as to applicability domain and toxicity prediction models. All Toxtree modules for predicting the toxicological hazard of chemical compounds are also integrated within this package. The complexity and diversity of the processing is reduced to the simple paradigm "read data from a web address, perform processing, write to a web address". The online service allows to easily run predictions, without installing any software, as well to share online datasets and models. The

AMBIT RESTful web services: an implementation of the OpenTox application programming interface.

Science.gov (United States)

Jeliazkova, Nina; Jeliazkov, Vedrin

2011-05-16

The AMBIT web services package is one of the several existing independent implementations of the OpenTox Application Programming Interface and is built according to the principles of the Representational State Transfer (REST) architecture. The Open Source Predictive Toxicology Framework, developed by the partners in the EC FP7 OpenTox project, aims at providing a unified access to toxicity data and predictive models, as well as validation procedures. This is achieved by i) an information model, based on a common OWL-DL ontology ii) links to related ontologies; iii) data and algorithms, available through a standardized REST web services interface, where every compound, data set or predictive method has a unique web address, used to retrieve its Resource Description Framework (RDF) representation, or initiate the associated calculations.The AMBIT web services package has been developed as an extension of AMBIT modules, adding the ability to create (Quantitative) Structure-Activity Relationship (QSAR) models and providing an OpenTox API compliant interface. The representation of data and processing resources in W3C Resource Description Framework facilitates integrating the resources as Linked Data. By uploading datasets with chemical structures and arbitrary set of properties, they become automatically available online in several formats. The services provide unified interfaces to several descriptor calculation, machine learning and similarity searching algorithms, as well as to applicability domain and toxicity prediction models. All Toxtree modules for predicting the toxicological hazard of chemical compounds are also integrated within this package. The complexity and diversity of the processing is reduced to the simple paradigm "read data from a web address, perform processing, write to a web address". The online service allows to easily run predictions, without installing any software, as well to share online datasets and models. The downloadable web application

75 FR 43162 - Tetrahedron, Inc., with Subcontractors: Syracuse Research Corporation; Tox Path, Inc; and...

Science.gov (United States)

2010-07-23

... obligations of the contract. DATES: Tetrahedron, Inc., and its subcontractors: Syracuse Research Corporation... contract to perform work for OPP, and access to this information will enable Tetrahedron, Inc., and its... Contract No. EP-W-10-013, Tetrahedron, Inc., and its subcontractors: Syracuse Research Corporation, Tox...

ToxPlorerTM: A Comprehensive Knowledgebase of Toxicity Pathways Using Ontology-driven Information Extraction

Science.gov (United States)

Realizing the potential of pathway-based toxicity testing requires a fresh look at how we describe phenomena leading to adverse effects in vivo, how we assess them in vitro and how we extrapolate them in silico across chemicals, doses and species. We developed the ToxPlorer™ fram...

Neurospora crassa tox-1 Gene Encodes a pH- and Temperature-Tolerant Mini-Cellulase.

Science.gov (United States)

Xiao, Yue; Zhang, Qiongsi; Luo, Yiquan; Zhang, Ying; Luo, Xi; Wang, Yuchuan; Cao, Weiguo; Pinto, Vito De; Liu, Qiuyun; Li, Gang

2016-06-15

Cellulases that endure extreme conditions are essential in various industrial sectors. This study reports a mini-cellulase gene tox-1 from Neurospora crassa. The gene tox-1 was cloned in Escherichia coli after chimerization with the YebF gene and substitutions of certain isoleucine and valine with leucine residues. The yeast transformants could grow on rice straw-agar medium. The 44-amino acid peptide and its two mutant variants displayed potent cellulase activities in Congo Red assay and enzymatic assays. Conservative replacements with leucine have substantially increased the stabilities and half-lives of the peptides at alkaline pH and low and high temperatures and also the tolerance to organic solvents and surfactants, on the basis of activities toward cellose. The small size of the mini-cellulase would allow for commercially viable automatic chemical peptide synthesis. This work suggests that conservative leucine replacements may serve as a general strategy in the engineering of more robust enzymes with special features with little loss of activities.

FORUM - FutureTox II: In vitro Data and In Silico Models for Predictive Toxicology

Science.gov (United States)

FutureTox II, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in January, 2014. The meeting goals were to review and discuss the state of the science in toxicology in the context of implementing the NRC 21st century vision of predicting in vivo resp...

Quantitative Structure-Use Relationship Model Predictions to evaluate Tox21 Chemicals as Functional Substitutes and Candidate Alternatives

Data.gov (United States)

U.S. Environmental Protection Agency — This dataset provides a prediction for all Tox21 chemicals with available QSUR descriptors across all 41 valid QSUR models developed with FUse. This dataset is...

A genetic polymorphism in TOX3 is associated with survival of gastric cancer in a Chinese population.

Directory of Open Access Journals (Sweden)

Xiaojing Zhang

Full Text Available PURPOSE: Recently, genetic polymorphism (rs3803662C>T in TOX3 was reported to induce the risk of breast cancer. In this study, we hypothesized that rs3803662 could influence gastric cancer survival outcomes. METHODS: With multiplex SNaPshot method, we genotyped TOX3 rs3803662 in 880 gastric patients with surgical resection. The association between genotype and survival outcomes was performed by the Kaplan-Meier method, Cox regression analysis models and the log-rank test. RESULTS: There was no association in the analyses of rs3803662 and survival of gastric cancer. However, the stratified analysis by histology showed that rs3803662 CT/TT genotype was associated with a significantly better survival for diffuse-type gastric cancer (log-rank p = 0.030, hazard ratio [HR]  = 0.67, 95% confidence interval [CI]  = 0.46-0.96, than the CC genotype. In addition, this favorable effect was especially obvious among gastric cancer patients with tumor size >5 cm, T3 and T4 depth of invasion, lymph node metastasis, no drinking, no distant metastasis, no chemotherapy and gastric cardia cancer. CONCLUSIONS: TOX3 rs3803662 might play an important role in the prognostic outcome and treatment of gastric cancer, especially perhaps further help in explaining the reduced risk of death associated with diffuse-type gastric cancer.

Metal mixture toxicity to aquatic biota in laboratory experiments: Application of the WHAM-F{sub TOX} model

Energy Technology Data Exchange (ETDEWEB)

Tipping, E., E-mail: et@ceh.ac.uk; Lofts, S.

2013-10-15

Highlights: •Metal accumulation by living organisms is successfully simulated with WHAM. •Modelled organism-bound metal provides a measure of toxic exposure. •The toxic potency of individual bound metals is quantified by fitting toxicity data. •Eleven laboratory mixture toxicity data sets were parameterised. •Relatively little variability amongst individual test organisms is indicated. -- Abstract: The WHAM-F{sub TOX} model describes the combined toxic effects of protons and metal cations towards aquatic organisms through the toxicity function (F{sub TOX}), a linear combination of the products of organism-bound cation and a toxic potency coefficient (α{sub i}) for each cation. Organism-bound, metabolically-active, cation is quantified by the proxy variable, amount bound by humic acid (HA), as predicted by the WHAM chemical speciation model. We compared published measured accumulations of metals by living organisms (bacteria, algae, invertebrates) in different solutions, with WHAM predictions of metal binding to humic acid in the same solutions. After adjustment for differences in binding site density, the predictions were in reasonable line with observations (for logarithmic variables, r{sup 2} = 0.89, root mean squared deviation = 0.44), supporting the use of HA binding as a proxy. Calculated loadings of H{sup +}, Al, Cu, Zn, Cd, Pb and UO{sub 2} were used to fit observed toxic effects in 11 published mixture toxicity experiments involving bacteria, macrophytes, invertebrates and fish. Overall, WHAM-F{sub TOX} gave slightly better fits than a conventional additive model based on solution concentrations. From the derived values of α{sub i}, the toxicity of bound cations can tentatively be ranked in the order: H < Al < (Zn–Cu–Pb–UO{sub 2}) < Cd. The WHAM-F{sub TOX} analysis indicates much narrower ranges of differences amongst individual organisms in metal toxicity tests than was previously thought. The model potentially provides a means to

Developing predictions of in vivo developmental toxicity of ToxCast chemicals using mouse embryonic stem cells.

Science.gov (United States)

Developing predictions of in vivo developmental toxicity of ToxCast chemicals using mouse embryonic stem cells S. Hunter, M. Rosen, M. Hoopes, H. Nichols, S. Jeffay, K. Chandler1, Integrated Systems Toxicology Division, National Health and Environmental Effects Research Labor...

Chemical-Gene Interactions from ToxCast Bioactivity Data Expands Universe of Literature Network-Based Associations (SOT)

Science.gov (United States)

Characterizing the effects of chemicals in biological systems is often summarized by chemical-gene interactions, which have sparse coverage in the literature. The ToxCast chemical screening program has produced bioactivity data for nearly 2000 chemicals and over 450 gene targets....

CalTOX, a multimedia total exposure model for hazardous-waste sites; Part 1, Executive summary

Energy Technology Data Exchange (ETDEWEB)

McKone, T.E.

1993-06-01

CalTOX has been developed as a spreadsheet model to assist in health-risk assessments that address contaminated soils and the contamination of adjacent air, surface water, sediments, and ground water. The modeling effort includes a multimedia transport and transformation model, exposure scenario models, and efforts to quantify and reduce uncertainty in multimedia, multiple-pathway exposure models. This report provides an overview of the CalTOX model components, lists the objectives of the model, describes the philosophy under which the model was developed, identifies the chemical classes for which the model can be used, and describes critical sensitivities and uncertainties. The multimedia transport and transformation model is a dynamic model that can be used to assess time-varying concentrations of contaminants introduced initially to soil layers or for contaminants released continuously to air or water. This model assists the user in examining how chemical and landscape properties impact both the ultimate route and quantity of human contact. Multimedia, multiple pathway exposure models are used in the CalTOX model to estimate average daily potential doses within a human population in the vicinity of a hazardous substances release site. The exposure models encompass twenty-three exposure pathways. The exposure assessment process consists of relating contaminant concentrations in the multimedia model compartments to contaminant concentrations in the media with which a human population has contact (personal air, tap water, foods, household dusts soils, etc.). The average daily dose is the product of the exposure concentrations in these contact media and an intake or uptake factor that relates the concentrations to the distributions of potential dose within the population.

A comparison of temporal, spatial and parallel phase shifting algorithms for digital image plane holography

International Nuclear Information System (INIS)

Arroyo, M P; Lobera, J

2008-01-01

This paper investigates the performance of several phase shifting (PS) techniques when using digital image plane holography (DIPH) as a fluid velocimetry technique. The main focus is on increasing the recording system aperture in order to overcome the limitation on the little light available in fluid applications. Some experiments with small rotations of a fluid-like solid object have been used to test the ability of PS-DIPH to faithfully reconstruct the object complex amplitude. Holograms for several apertures and for different defocusing distances have been recorded using spatial phase shifting (SPS) or temporal phase shifting (TPS) techniques. The parallel phase shifted holograms (H PPS ) have been generated from the TPS holograms (H TPS ). The data obtained from TPS-DIPH have been taken as the true object complex amplitude, which is used to benchmark that recovered using the other techniques. The findings of this work show that SPS and PPS are very similar indeed, and suggest that both can work for bigger apertures yet retain phase information

Extrapolation of mammalian-based ToxCast assay results to non-mammalian species to evaluate endocrine disruption

Science.gov (United States)

In vitro high-throughput screening (HTS) and in silico technologies have emerged as 21st century tools for chemical hazard identification. In 2007 the U.S. Environmental Protection Agency (EPA) launched the ToxCast Program, which has screened thousands of chemicals in hundreds of...

Tox21: Putting a Lens on the Vision of Toxicity Testing in the 21st Century

Science.gov (United States)

In response to the release of the NRC report on "Toxicity Testing in the 21st Century, a Vision and Strategy" (NRC, 2007), two NIH institutes and EPA formed a collaboration (Tox21) to 1) identify mechanisms of chemically induced biological activity, 2) prioritize chemicals for mo...

Human Pluripotent Stem Cell-Based Assay Predicts Developmental Toxicity Potential of ToxCast Chemicals (ACT meeting)

Science.gov (United States)

Worldwide initiatives to screen for toxicity potential among the thousands of chemicals currently in use require inexpensive and high-throughput in vitro models to meet their goals. The devTOX quickPredict platform is an in vitro human pluripotent stem cell-based assay used to as...

Toxicokinetiek van benzo(a)pyreen bij de Riv:TOX rat na herhaalde orale toediening

NARCIS (Netherlands)

Olling M; Lusthof KJ; Kroese ED; Beenen J; Klaassen R; BFT

1995-01-01

Benzo(a)pyrene was administered once daily (30 mg/kg) by gavage to 12 male and 12 female Riv:TOX rats, for 15 days on five successive days per week, in the form of a solution in soy oil. Blood samples were taken over a period of 12 hours on the first day of administration (day 1) and on day 12 from

Identifying developmental toxicity pathways for a subset of ToxCast chemicals using human embryonic stem cells and metabolomics

Science.gov (United States)

Metabolomics analysis was performed on the supernatant of human embryonic stem (hES) cell cultures exposed to a blinded subset of 11 chemicals selected from the chemical library of EPA's ToxCast™ chemical screening and prioritization research project. Metabolites from hES cultur...

(ENVIRONMENTAL SCIENCE and TECHNOLOGY) An Intuitive Approach for Predicting Human Risk with the Tox21 10k Library

Science.gov (United States)

In vitro to in vivo extrapolation (IVIVE) analyses translating high-throughput screening (HTS) data to human relevance have been limited. This is the first time IVIVE approaches and exposure comparisons have explored the entire Tox21 federal collaboration’s 10,000 chemi...

Development and Evaluation of a Hyperbaric Toxic Gas Monitor (SubTox) for Disabled Submarines

Science.gov (United States)

2013-08-01

air near the CO2 scrubbers was sampled, the common amine/ ammonia smell was present. And while no NH3 sensor was installed in the SubTox, no monitored...under pressure, the eight gases — ammonia , carbon monoxide, chlorine, hydrogen chloride, hydrogen cyanide, hydrogen sulfide, nitrogen dioxide, and...gases for which SEALs have been defined: ammonia (NH3), carbon monoxide (CO), chlorine (Cl2), hydrogen chloride (HCl), hydrogen cyanide (HCN

E-SovTox: An online database of the main publicly-available sources of toxicity data concerning REACH-relevant chemicals published in the Russian language.

Science.gov (United States)

Sihtmäe, Mariliis; Blinova, Irina; Aruoja, Villem; Dubourguier, Henri-Charles; Legrand, Nicolas; Kahru, Anne

2010-08-01

A new open-access online database, E-SovTox, is presented. E-SovTox provides toxicological data for substances relevant to the EU Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) system, from publicly-available Russian language data sources. The database contains information selected mainly from scientific journals published during the Soviet Union era. The main information source for this database - the journal, Gigiena Truda i Professional'nye Zabolevania [Industrial Hygiene and Occupational Diseases], published between 1957 and 1992 - features acute, but also chronic, toxicity data for numerous industrial chemicals, e.g. for rats, mice, guinea-pigs and rabbits. The main goal of the abovementioned toxicity studies was to derive the maximum allowable concentration limits for industrial chemicals in the occupational health settings of the former Soviet Union. Thus, articles featured in the database include mostly data on LD50 values, skin and eye irritation, skin sensitisation and cumulative properties. Currently, the E-SovTox database contains toxicity data selected from more than 500 papers covering more than 600 chemicals. The user is provided with the main toxicity information, as well as abstracts of these papers in Russian and in English (given as provided in the original publication). The search engine allows cross-searching of the database by the name or CAS number of the compound, and the author of the paper. The E-SovTox database can be used as a decision-support tool by researchers and regulators for the hazard assessment of chemical substances. 2010 FRAME.

Variability of Pasteurella multocida isolated from Icelandic sheep and detection of the toxA gene.

Science.gov (United States)

Einarsdottir, Thorbjorg; Gunnarsson, Eggert; Sigurdardottir, Olof G; Jorundsson, Einar; Fridriksdottir, Vala; Thorarinsdottir, Gudridur E; Hjartardottir, Sigridur

2016-09-01

Pasteurella multocida can be part of the upper respiratory flora of animals, but under conditions of stress or immunocompromisation, the bacteria can cause severe respiratory symptoms. In this study, we compared 10 P. multocida isolates from Icelandic sheep with respiratory symptoms and 19 isolates from apparently healthy abattoir sheep. We examined capsule type, genetic variability and the presence of the toxA gene in the two groups. Surprisingly, we found that all ovine P. multocida isolates examined in this study carried the toxA gene, which markedly differs from what has been published from other studies. Interestingly, all isolates from abattoir animals were capsule type D, whilst bacteria isolated from animals with clinical respiratory symptoms had capsule type A, D or F. Examination of seven housekeeping genes indicated that the clinical respiratory isolates were significantly more heterogeneous than the abattoir isolates (P<0.05, two-tailed Mann-Whitney U test). The results suggest that there may be at least two groups of P. multocida in sheep - a genetically homogeneous group that resides in the respiratory tract and a genetically heterogeneous group that is the predominant cause of disease.

Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships (MCBIOS)

Science.gov (United States)

Comparative Analysis of Predictive Models for Liver Toxicity Using ToxCast Assays and Quantitative Structure-Activity Relationships Jie Liu1,2, Richard Judson1, Matthew T. Martin1, Huixiao Hong3, Imran Shah1 1National Center for Computational Toxicology (NCCT), US EPA, RTP, NC...

Virtual Liver: Estimating Proliferation and Apoptosis of Hepatocytes Exposed to Environmental Chemicals Using ToxCastTM Data

Science.gov (United States)

The U.S. EPA’s ToxCastTM program has screened over a thousand chemicals for potential toxicity using hundreds of high-throughput, in vitro assays. The U.S. EPA’s Virtual Liver (v-Liver™) is a cellular systems model of hepatic tissues that enables the estimation of in vivo effects...

In Vitro Screening of Environmental Chemicals for Targeted Testing Prioritization: The ToxCast Project

OpenAIRE

Judson, Richard S.; Houck, Keith A.; Kavlock, Robert J.; Knudsen, Thomas B.; Martin, Matthew T.; Mortensen, Holly M.; Reif, David M.; Rotroff, Daniel M.; Shah, Imran; Richard, Ann M.; Dix, David J.

2009-01-01

Background Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use, and the thousands of environmental chemicals lacking toxicity data. The U.S. Environmental Protection Agency?s ToxCast program aims to address these concerns by screening and prioritizing chemicals for potential human toxicity using in vitro assays and in silico approaches. Objectives This project aims to evaluate the use of in vitro assays for understanding the ty...

Overview of Provisional Peer-Reviewed Toxicity Values (PPRTVs), Alternative Methods in Human Health Risk Assessment, and the RapidTox Dashboard

Science.gov (United States)

This poster provides an overview of three key lines of ongoing work at EPA/ORD/NCEA-CIN: Provisional Peer-Reviewed Toxicity Values (PPRTVs), Alternative Methods in Human Health Risk Assessment, and the RapidTox Dashboard collaboration.

Probing the ToxCastTM Chemical Library for Predictive Signatures of Developmental Toxicity - Poster at Teratology Society Annual Meeting

Science.gov (United States)

EPA’s ToxCast™ project is profiling the in vitro bioactivity of chemical compounds to assess pathway-level and cell-based signatures that correlate with observed in vivo toxicity. We hypothesize that cell signaling pathways are primary targets for diverse environmental chemicals ...

VirtualToxLab — A platform for estimating the toxic potential of drugs, chemicals and natural products

International Nuclear Information System (INIS)

Vedani, Angelo; Dobler, Max; Smieško, Martin

2012-01-01

The VirtualToxLab is an in silico technology for estimating the toxic potential (endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity) of drugs, chemicals and natural products. The technology is based on an automated protocol that simulates and quantifies the binding of small molecules towards a series of proteins, known or suspected to trigger adverse effects. The toxic potential, a non-linear function ranging from 0.0 (none) to 1.0 (extreme), is derived from the individual binding affinities of a compound towards currently 16 target proteins: 10 nuclear receptors (androgen, estrogen α, estrogen β, glucocorticoid, liver X, mineralocorticoid, peroxisome proliferator-activated receptor γ, progesterone, thyroid α, and thyroid β), four members of the cytochrome P450 enzyme family (1A2, 2C9, 2D6, and 3A4), a cytosolic transcription factor (aryl hydrocarbon receptor) and a potassium ion channel (hERG). The interface to the technology allows building and uploading molecular structures, viewing and downloading results and, most importantly, rationalizing any prediction at the atomic level by interactively analyzing the binding mode of a compound with its target protein(s) in real-time 3D. The VirtualToxLab has been used to predict the toxic potential for over 2500 compounds: the results are posted on (http://www.virtualtoxlab.org). The free platform — the OpenVirtualToxLab — is accessible (in client–server mode) over the Internet. It is free of charge for universities, governmental agencies, regulatory bodies and non-profit organizations. -- Highlights: ► In silico technology for estimating the toxic potential of drugs and chemicals. ► Simulation of binding towards 16 proteins suspected to trigger adverse effects. ► Mechanistic interpretation and real-time 3D visualization. ► Accessible over the Internet. ► Free of charge for universities, governmental agencies, regulatory bodies and NPOs.

VirtualToxLab — A platform for estimating the toxic potential of drugs, chemicals and natural products

Energy Technology Data Exchange (ETDEWEB)

Vedani, Angelo, E-mail: angelo.vedani@unibas.ch [Biographics Laboratory 3R, Klingelbergstrasse 50, 4056 Basel (Switzerland); Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel (Switzerland); Dobler, Max [Biographics Laboratory 3R, Klingelbergstrasse 50, 4056 Basel (Switzerland); Smieško, Martin [Department of Pharmaceutical Sciences, University of Basel, Klingelbergstrasse 50, 4056 Basel (Switzerland)

2012-06-01

The VirtualToxLab is an in silico technology for estimating the toxic potential (endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity) of drugs, chemicals and natural products. The technology is based on an automated protocol that simulates and quantifies the binding of small molecules towards a series of proteins, known or suspected to trigger adverse effects. The toxic potential, a non-linear function ranging from 0.0 (none) to 1.0 (extreme), is derived from the individual binding affinities of a compound towards currently 16 target proteins: 10 nuclear receptors (androgen, estrogen α, estrogen β, glucocorticoid, liver X, mineralocorticoid, peroxisome proliferator-activated receptor γ, progesterone, thyroid α, and thyroid β), four members of the cytochrome P450 enzyme family (1A2, 2C9, 2D6, and 3A4), a cytosolic transcription factor (aryl hydrocarbon receptor) and a potassium ion channel (hERG). The interface to the technology allows building and uploading molecular structures, viewing and downloading results and, most importantly, rationalizing any prediction at the atomic level by interactively analyzing the binding mode of a compound with its target protein(s) in real-time 3D. The VirtualToxLab has been used to predict the toxic potential for over 2500 compounds: the results are posted on (http://www.virtualtoxlab.org). The free platform — the OpenVirtualToxLab — is accessible (in client–server mode) over the Internet. It is free of charge for universities, governmental agencies, regulatory bodies and non-profit organizations. -- Highlights: ► In silico technology for estimating the toxic potential of drugs and chemicals. ► Simulation of binding towards 16 proteins suspected to trigger adverse effects. ► Mechanistic interpretation and real-time 3D visualization. ► Accessible over the Internet. ► Free of charge for universities, governmental agencies, regulatory bodies and NPOs.

Cross-species extrapolation of mammalian-based ToxCast Data using Sequence Alignment to Predict Across Species Susceptibility (SeqAPASS)

Science.gov (United States)

In vitro high-throughput screening (HTS) and in silico technologies have emerged as 21st century tools for chemical hazard identification. In 2007 the U.S. Environmental Protection Agency (EPA) launched the ToxCast Program, which has screened thousands of chemicals in hundreds of...

CompNanoTox2015: novel perspectives from a European conference on computational nanotoxicology on predictive nanotoxicology

Energy Technology Data Exchange (ETDEWEB)

Bañares, Miguel A. [Instituto de Catalisis y Petroleoquimica, ICP, CSIC, Madrid, Spain,; Haase, Andrea [German Federal Institute for Risk Assessment (BfR), Department of Chemical and Product Safety, Berlin, Germany,; Tran, Lang [Statistics and Toxicology Section, Institute of Occupational Medicine, Edinburgh, UK,; Lobaskin, Vladimir [School of Physics, University College Dublin, Dublin, Ireland,; Oberdörster, Günter [Department of Environmental Medicine, University of Rochester, Rochester, NY, USA,; Rallo, Robert [Departament d’Enginyeria Informatica i Matematiques, Universitat Rovira i Virgili, Tarragona, Spain,; Advanced Computing, Mathematics, and Data Division, Pacific Northwest National Laboratory, Richland, WA, USA,; Leszczynski, Jerzy [Interdisciplinary Nanotoxicity Center, Jackson State University, Jackson, MS, USA,; Hoet, Peter [Public Health, Unit Lung Toxicology, K. U. Leuven, Leuven, Belgium,; Korenstein, Rafi [Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel,; Hardy, Barry [Technology Park Basel, Douglas Connect GmbH, Basel, Switzerland,; Puzyn, Tomasz [Laboratory of Environmental Chemometrics, Faculty of Chemistry, University of Gdansk, Gdansk, Poland

2017-08-09

A first European Conference on Computational Nanotoxicology, CompNanoTox, was held in November 2015 in Benahavís, Spain with the objectives to disseminate and integrate results from the European modeling and database projects (NanoPUZZLES, ModENPTox, PreNanoTox, MembraneNanoPart, MODERN, eNanoMapper and EU COST TD1204 MODENA) as well as to create synergies within the European NanoSafety Cluster. This conference was supported by the COST Action TD1204 MODENA on developing computational methods for toxicological risk assessment of engineered nanoparticles and provided a unique opportunity for crossfertilization among complementary disciplines. The efforts to develop and validate computational models crucially depend on high quality experimental data and relevant assays which will be the basis to identify relevant descriptors. The ambitious overarching goal of this conference was to promote predictive nanotoxicology, which can only be achieved by a close collaboration between the computational scientists (e.g. database experts, modeling experts for structure, (eco) toxicological effects, performance and interaction of nanomaterials) and experimentalists from different areas (in particular toxicologists, biologists, chemists and material scientists, among others). The main outcome and new perspectives of this conference are summarized here.

Cheminformatics and Data Mining Approaches for Exploring the Alternatives Testing Landscsape: Case Studies in ToxCast and Skin Sensitization (BOSC CSS)

Science.gov (United States)

Cheminformatics approaches and structure-based rules are being used to evaluate and explore the ToxCast chemical landscape and associated high-throughput screening (HTS) data. We have shown that the library provides comprehensive coverage of the knowledge domains and target inven...

Evaluation of the Neuroactivity of ToxCast Compounds Using Multi-well Microelectrode Array Recordings in Primary Cortical Neurons

Science.gov (United States)

Evaluation of the Neuroactivity of ToxCast Compounds Using Multi-well Microelectrode Array Recordings in Primary Cortical Neurons P Valdivia1, M Martin2, WR LeFew3, D Hall3, J Ross1, K Houck2 and TJ Shafer3 1Axion Biosystems, Atlanta GA and 2NCCT, 3ISTD, NHEERL, ORD, US EPA, RT...

OpenVirtualToxLab--a platform for generating and exchanging in silico toxicity data.

Science.gov (United States)

Vedani, Angelo; Dobler, Max; Hu, Zhenquan; Smieško, Martin

2015-01-22

The VirtualToxLab is an in silico technology for estimating the toxic potential--endocrine and metabolic disruption, some aspects of carcinogenicity and cardiotoxicity--of drugs, chemicals and natural products. The technology is based on an automated protocol that simulates and quantifies the binding of small molecules towards a series of currently 16 proteins, known or suspected to trigger adverse effects: 10 nuclear receptors (androgen, estrogen α, estrogen β, glucocorticoid, liver X, mineralocorticoid, peroxisome proliferator-activated receptor γ, progesterone, thyroid α, thyroid β), four members of the cytochrome P450 enzyme family (1A2, 2C9, 2D6, 3A4), a cytosolic transcription factor (aryl hydrocarbon receptor) and a potassium ion channel (hERG). The toxic potential of a compound--its ability to trigger adverse effects--is derived from its computed binding affinities toward these very proteins: the computationally demanding simulations are executed in client-server model on a Linux cluster of the University of Basel. The graphical-user interface supports all computer platforms, allows building and uploading molecular structures, inspecting and downloading the results and, most important, rationalizing any prediction at the atomic level by interactively analyzing the binding mode of a compound with its target protein(s) in real-time 3D. Access to the VirtualToxLab is available free of charge for universities, governmental agencies, regulatory bodies and non-profit organizations. Copyright © 2014 The Authors. Published by Elsevier Ireland Ltd.. All rights reserved.

Predicting dermal penetration for ToxCast chemicals using in silico estimates for diffusion in combination with physiologically based pharmacokinetic (PBPK) modeling.

Science.gov (United States)

Predicting dermal penetration for ToxCast chemicals using in silico estimates for diffusion in combination with physiologically based pharmacokinetic (PBPK) modeling.Evans, M.V., Sawyer, M.E., Isaacs, K.K, and Wambaugh, J.With the development of efficient high-throughput (HT) in ...

The US EPA CompTox Chemistry Dashboard as a source of data to fill data gaps for chemical sources of risk

Science.gov (United States)

Chemical risk assessment is both time-consuming and difficult because it requires the assembly of data for chemicals generally distributed across multiple sources. The US EPA CompTox Chemistry Dashboard is a publicly accessible web-based application providing access to various da...

Real-time prediction of Physicochemical and Toxicological Endpoints Using the Web-based CompTox Chemistry Dashboard (ACS Fall meeting) 10 of 12

Science.gov (United States)

The EPA CompTox Chemistry Dashboard developed by the National Center for Computational Toxicology (NCCT) provides access to data for ~750,000 chemical substances. The data include experimental and predicted data for physicochemical, environmental fate and transport and toxicologi...

Diisopropylammonium methanesulfonate

Directory of Open Access Journals (Sweden)

Guido J. Reiss

2011-08-01

Full Text Available The title molecular salt, C6H16N+·CH3SO3−, has been determined at 150 K. Two diisopropylammonium cations (dipH and two anions form N—H...O hydrogen-bonded cyclic dimers lying around centers of symmetry. Only two of the three O atoms of the methanesulfonate anion are involved in hydrogen bonding, resulting in slightly longer S—O bond lengths. The title structure represents an example of a sulfonate anion that is part of a hydrogen-bonding R44(12 graph-set motif, which is well known for related dipH acetates. Additionally, the Raman and the IR spectroscopic data for the title compound are presented.

Modulation of Xenobiotic Metabolizing Enzyme and Transporter Gene Expression in Primary Cultures of Human Hepatocytes by ToxCast Chemicals

Science.gov (United States)

ToxCast chemicals were assessed for induction or suppression of xenobiotic metabolizing enzyme and transporter gene expression using primary human hepatocytes. The mRNA levels of 14 target and 2 control genes were measured: ABCB1, ABCB11, ABCG2, SLCO1B1, CYP1A1, CYP1A2, CYP2B6, C...

LuminoTox : a tool for the rapid detection of PAH, BPC and chlorobenzenes in waste water and sediments

Energy Technology Data Exchange (ETDEWEB)

Bellemare, F.; Boucher, N.; Lorrain, L.; Rouette, M.E.; Perron, E. [Lab-bell Inc., Shawnigan, PQ (Canada)

2005-07-01

The LuminoTox is a portable fluorimetric detection device capable of assessing water toxicity in 10 to 15 minutes. The toxicity of a water sample is indicated by the modification of fluorescence parameters within isolated both isolated photosynthetic complexes (PECs) and photosynthetic algae (SAPs). An array of 4 LEDs and photodetectors is used to determine fluorescence emissions from PEPs and SAPs. Fluorescence data is then transferred to a computer for analysis. A kinetic detection mode is currently being developed for the tool. This paper provided details of a test conducted to demonstrate the kinetic detection capabilities of the new design. Sediment containing polycyclic aromatic hydrocarbons (PAH), polychlorinated biphenyls, and chlorobenzene were used in the analysis. Results showed that the fluorescence kinetic mode yielded improved sensitivity with molecules acting on the electron transport chain downstream from the tool's photosystem. The test demonstrated that the LuminoTox technology is capable of accurately monitoring the presence of PAHs, PCBs, and chlorobenzenes. It was concluded that the tool is sensitive to a wide range of pollutants and can be used to analyze complex waste water and slurries. 15 refs., 2 tabs., 1 fig.

Evaluation of Computational Docking to Identify Pregnane X Receptor Agonists in the ToxCast Database

OpenAIRE

Kortagere, Sandhya; Krasowski, Matthew D.; Reschly, Erica J.; Venkatesh, Madhukumar; Mani, Sridhar; Ekins, Sean

2010-01-01

Background The pregnane X receptor (PXR) is a key transcriptional regulator of many genes [e.g., cytochrome P450s (CYP2C9, CYP3A4, CYP2B6), MDR1] involved in xenobiotic metabolism and excretion. Objectives As part of an evaluation of different approaches to predict compound affinity for nuclear hormone receptors, we used the molecular docking program GOLD and a hybrid scoring scheme based on similarity weighted GoldScores to predict potential PXR agonists in the ToxCast database of pesticides...

The ToxBank Data Warehouse: Supporting the Replacement of In Vivo Repeated Dose Systemic Toxicity Testing.

Science.gov (United States)

Kohonen, Pekka; Benfenati, Emilio; Bower, David; Ceder, Rebecca; Crump, Michael; Cross, Kevin; Grafström, Roland C; Healy, Lyn; Helma, Christoph; Jeliazkova, Nina; Jeliazkov, Vedrin; Maggioni, Silvia; Miller, Scott; Myatt, Glenn; Rautenberg, Michael; Stacey, Glyn; Willighagen, Egon; Wiseman, Jeff; Hardy, Barry

2013-01-01

The aim of the SEURAT-1 (Safety Evaluation Ultimately Replacing Animal Testing-1) research cluster, comprised of seven EU FP7 Health projects co-financed by Cosmetics Europe, is to generate a proof-of-concept to show how the latest technologies, systems toxicology and toxicogenomics can be combined to deliver a test replacement for repeated dose systemic toxicity testing on animals. The SEURAT-1 strategy is to adopt a mode-of-action framework to describe repeated dose toxicity, combining in vitro and in silico methods to derive predictions of in vivo toxicity responses. ToxBank is the cross-cluster infrastructure project whose activities include the development of a data warehouse to provide a web-accessible shared repository of research data and protocols, a physical compounds repository, reference or "gold compounds" for use across the cluster (available via wiki.toxbank.net), and a reference resource for biomaterials. Core technologies used in the data warehouse include the ISA-Tab universal data exchange format, REpresentational State Transfer (REST) web services, the W3C Resource Description Framework (RDF) and the OpenTox standards. We describe the design of the data warehouse based on cluster requirements, the implementation based on open standards, and finally the underlying concepts and initial results of a data analysis utilizing public data related to the gold compounds. Copyright © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Small-molecule inhibitors of toxT expression in Vibrio cholerae.

Science.gov (United States)

Anthouard, Rebecca; DiRita, Victor J

2013-08-06

Vibrio cholerae, a Gram-negative bacterium, infects humans and causes cholera, a severe disease characterized by vomiting and diarrhea. These symptoms are primarily caused by cholera toxin (CT), whose production by V. cholerae is tightly regulated by the virulence cascade. In this study, we designed and carried out a high-throughput chemical genetic screen to identify inhibitors of the virulence cascade. We identified three compounds, which we named toxtazin A and toxtazin B and B', representing two novel classes of toxT transcription inhibitors. All three compounds reduce production of both CT and the toxin-coregulated pilus (TCP), an important colonization factor. We present evidence that toxtazin A works at the level of the toxT promoter and that toxtazins B and B' work at the level of the tcpP promoter. Treatment with toxtazin B results in a 100-fold reduction in colonization in an infant mouse model of infection, though toxtazin A did not reduce colonization at the concentrations tested. These results add to the growing body of literature indicating that small-molecule inhibitors of virulence genes could be developed to treat infections, as alternatives to antibiotics become increasingly needed. V. cholerae caused more than 580,000 infections worldwide in 2011 alone (WHO, Wkly. Epidemiol. Rec. 87:289-304, 2012). Cholera is treated with an oral rehydration therapy consisting of water, glucose, and electrolytes. However, as V. cholerae is transmitted via contaminated water, treatment can be difficult for communities whose water source is contaminated. In this study, we address the need for new therapeutic approaches by targeting the production of the main virulence factor, cholera toxin (CT). The high-throughput screen presented here led to the identification of two novel classes of inhibitors of the virulence cascade in V. cholerae, toxtazin A and toxtazins B and B'. We demonstrate that (i) small-molecule inhibitors of virulence gene production can be

Conjugated Linoleic Acid Reduces Cholera Toxin Production In Vitro and In Vivo by Inhibiting Vibrio cholerae ToxT Activity.

Science.gov (United States)

Withey, Jeffrey H; Nag, Drubhajyoti; Plecha, Sarah C; Sinha, Ritam; Koley, Hemanta

2015-12-01

The severe diarrheal disease cholera is endemic in over 50 countries. Current therapies for cholera patients involve oral and/or intravenous rehydration, often combined with the use of antibiotics to shorten the duration and intensity of the disease. However, as antibiotic resistance increases, treatment options will become limited. Linoleic acid has been shown to be a potent negative effector of V. cholerae virulence that acts on the major virulence transcription regulator protein, ToxT, to inhibit virulence gene expression. ToxT activates transcription of the two major virulence factors required for disease, cholera toxin (CT) and toxin-coregulated pilus (TCP). A conjugated form of linoleic acid (CLA) is currently sold over the counter as a dietary supplement and is generally recognized as safe by the U.S. Food and Drug Administration. This study examined whether CLA could be used as a new therapy to reduce CT production, which, in turn, would decrease disease duration and intensity in cholera patients. CLA could be used in place of traditional antibiotics and would be very unlikely to generate resistance, as it affects only virulence factor production and not bacterial growth or survival. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

The eTOX Data-Sharing Project to Advance in Silico Drug-Induced Toxicity Prediction

Directory of Open Access Journals (Sweden)

Montserrat Cases

2014-11-01

Full Text Available The high-quality in vivo preclinical safety data produced by the pharmaceutical industry during drug development, which follows numerous strict guidelines, are mostly not available in the public domain. These safety data are sometimes published as a condensed summary for the few compounds that reach the market, but the majority of studies are never made public and are often difficult to access in an automated way, even sometimes within the owning company itself. It is evident from many academic and industrial examples, that useful data mining and model development requires large and representative data sets and careful curation of the collected data. In 2010, under the auspices of the Innovative Medicines Initiative, the eTOX project started with the objective of extracting and sharing preclinical study data from paper or pdf archives of toxicology departments of the 13 participating pharmaceutical companies and using such data for establishing a detailed, well-curated database, which could then serve as source for read-across approaches (early assessment of the potential toxicity of a drug candidate by comparison of similar structure and/or effects and training of predictive models. The paper describes the efforts undertaken to allow effective data sharing intellectual property (IP protection and set up of adequate controlled vocabularies and to establish the database (currently with over 4000 studies contributed by the pharma companies corresponding to more than 1400 compounds. In addition, the status of predictive models building and some specific features of the eTOX predictive system (eTOXsys are presented as decision support knowledge-based tools for drug development process at an early stage.

Computation Modeling of Limb-bud Dysmorphogenesis: Predicting Cellular Dynamics and Key Events in Developmental Toxicity with a Multicellular Systems Model (FutureToxII)

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Congenital limb malformations are among the most frequent malformation occurs in humans, with a frequency of about 1 in 500 to 1 in 1000 human live births. ToxCast is profiling the bioactivity of thousands of chemicals based on high-throughput (HTS) and computational methods that...

Distribution of the ompA-types among ruminant and swine pneumonic strains of Pasteurella multocida exhibiting various cap-locus and toxA patterns.

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Vougidou, C; Sandalakis, V; Psaroulaki, A; Siarkou, V; Petridou, E; Ekateriniadou, L

2015-05-01

Pasteurella multocida is an important pathogen in food-producing animals and numerous virulence genes have been identified in an attempt to elucidate the pathogenesis of pasteurellosis. Currently, some of these genes including the capsule biosynthesis genes, the toxA and the OMPs-encoding genes have been suggested as epidemiological markers. However, the number of studies concerning ruminant isolates is limited, while, no attempt has ever been made to investigate the existence of ompA sequence diversity among P. multocida isolates. The aim of the present study was the comparative analysis of 144 P. multocida pneumonic isolates obtained from sheep, goats, cattle and pigs by determining the distribution of the ompA-types in conjunction with the cap-locus and toxA patterns. The ompA genotypes of the isolates were determined using both a PCR-RFLP method and DNA sequence analysis. The most prevalent capsule biosynthesis gene among the isolates was capA (86.1%); a noticeable, however, rate of capD-positive isolates (38.6%) was found among the ovine isolates that had been associated primarily with the capsule type A in the past. Moreover, an unexpectedly high percentage of toxA-positive pneumonic isolates was noticed among small ruminants (93.2% and 85.7% in sheep and goats, respectively), indicating an important epidemiological role of toxigenic P. multocida for these species. Despite their great heterogeneity, certain ompA-genotypes were associated with specific host species, showing evidence of a host preference. The OmpA-based PCR-RFLP method developed proved to be a valuable tool in typing P. multocida strains. Copyright © 2015 Elsevier GmbH. All rights reserved.

The EPA CompTox Dashboard and Underpinning Software Architecture – a platform for data integration for environmental chemistry data (ACS Fall Meeting 7 of 12)

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The CompTox Dashboard was developed by the Environmental Protection Agency’s National Center for Computational Toxicology. This dashboard has been architected in a manner that allows for the deployment of multiple “applications”, both as publicly available databases, and for dep...

Using semi-automated curation workflows to collect, organize, and curate the data and models necessary to support the EPA CompTox chemical dashboard (ACS Spring meeting)

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With the increasing need to leverage data and models to perform cutting edge analyses within the environmental science community, collection and organization of that data into a readily accessible format for consumption is a pressing need. The EPA CompTox chemical dashboard is i...

ADME-Tox profiling of some low molecular weight water soluble chitosan derivatives

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Adriana Isvoran

2017-09-01

Full Text Available Within this study we use a few computational tools for predicting absorption, distribution, metabolism, excretion and toxicity (ADME-Tox, pharmacokinetics profiles, toxic/adverse effects, carcinogenicity, cardiotoxicity and endocrine disruption of some of low molecular weight water soluble derivatives of chitosan that are used in wound healing. Investigated compounds do not possess drug-like properties, their pharmacokinetics profiles reveal poor gastrointestinal absorption and low skin penetration. Chitosan derivatives cannot pass the blood-brain barrier and they are not able to inhibit the enzymes of the cytochrome P450 that are involved in the metabolism of xenobiotics. They do not reflect carcinogenicity and cardiotoxicity and reveal only a low probability to be endocrine disruptors. The main side effects in humans of the investigated compounds are: weight loss, acidosis, gastrointestinal toxicity, respiratory failure. This information is especially important for professional exposure and accidental contamination with these compounds.

Cell-Based High-Throughput Screening for Aromatase Inhibitors in the Tox21 10K Library.

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Chen, Shiuan; Hsieh, Jui-Hua; Huang, Ruili; Sakamuru, Srilatha; Hsin, Li-Yu; Xia, Menghang; Shockley, Keith R; Auerbach, Scott; Kanaya, Noriko; Lu, Hannah; Svoboda, Daniel; Witt, Kristine L; Merrick, B Alex; Teng, Christina T; Tice, Raymond R

2015-10-01

Multiple mechanisms exist for endocrine disruption; one nonreceptor-mediated mechanism is via effects on aromatase, an enzyme critical for maintaining the normal in vivo balance of androgens and estrogens. We adapted the AroER tri-screen 96-well assay to 1536-well format to identify potential aromatase inhibitors (AIs) in the U.S. Tox21 10K compound library. In this assay, screening with compound alone identifies estrogen receptor alpha (ERα) agonists, screening in the presence of testosterone (T) identifies AIs and/or ERα antagonists, and screening in the presence of 17β-estradiol (E2) identifies ERα antagonists. Screening the Tox-21 library in the presence of T resulted in finding 302 potential AIs. These compounds, along with 31 known AI actives and inactives, were rescreened using all 3 assay formats. Of the 333 compounds tested, 113 (34%; 63 actives, 50 marginal actives) were considered to be potential AIs independent of cytotoxicity and ER antagonism activity. Structure-activity analysis suggested the presence of both conventional (eg, 1, 2, 4, - triazole class) and novel AI structures. Due to their novel structures, 14 of the 63 potential AI actives, including both drugs and fungicides, were selected for confirmation in the biochemical tritiated water-release aromatase assay. Ten compounds were active in the assay; the remaining 4 were only active in high-throughput screen assay, but with low efficacy. To further characterize these 10 novel AIs, we investigated their binding characteristics. The AroER tri-screen, in high-throughput format, accurately and efficiently identified chemicals in a large and diverse chemical library that selectively interact with aromatase. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

[Ideas and methods on efficient screening of traditional medicines for anti-osteoporosis activity based on M-Act/Tox integrated evaluation using zebrafish].

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Wang, Mo; Ling, Jie; Chen, Ying; Song, Jie; Sun, E; Shi, Zi-Qi; Feng, Liang; Jia, Xiao-Bin; Wei, Ying-Jie

2017-11-01

The increasingly apparent liver injury problems of bone strengthening Chinese medicines have brought challenges for clinical application, and it is necessary to consider both effectiveness and safety in screening anti-osteoporosis Chinese medicines. Metabolic transformation is closely related to drug efficacy and toxicity, so it is significant to comprehensively consider metabolism-action/toxicity(M-Act/Tox) for screening anti-osteoporosis Chinese medicines. The current evaluation models and the number of compounds(including metabolites) severely restrict efficient screening in vivo. By referring to previous relevant research and domestic and abroad literature, zebrafish M-Act/Tox integrative method was put forward for efficiently screening anti-osteoporosis herb medicines, which has organically integrated zebrafish metabolism model, osteoporosis model and toxicity evaluation method. This method can break through the bottleneck and blind spots that trace compositions can't achieve efficient and integrated in vivo evaluation, and realize both efficient and comprehensive screening on anti-osteoporosis traditional medicines based on in vivo process taking both safety and effectiveness into account, which is significant to accelerate discovery of effective and safe innovative traditional Chinese medicines for osteoporosis. Copyright© by the Chinese Pharmaceutical Association.

Risk-Association of Five SNPs in TOX3/LOC643714 with Breast Cancer in Southern China

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Xuanqiu He

2014-01-01

Full Text Available The specific mechanism by which low-risk genetic variants confer breast cancer risk is currently unclear, with contradictory evidence on the role of single nucleotide polymorphisms (SNPs in TOX3/LOC643714 as a breast cancer susceptibility locus. Investigations of this locus using a Chinese population may indicate whether the findings initially identified in a European population are generalizable to other populations, and may provide new insight into the role of genetic variants in the etiology of breast cancer. In this case-control study, 623 Chinese female breast cancer patients and 620 cancer-free controls were recruited to investigate the role of five SNPs in TOX3/LOC643714 (rs8051542, rs12443621, rs3803662, rs4784227, and rs3112612; Linkage disequilibrium (LD pattern analysis was performed. Additionally, we evaluated how these common SNPs influence the risk of specific types of breast cancer, as defined by estrogen receptor (ER status, progesterone receptor (PR status and human epidermal growth factor receptor 2 (HER2 status. Significant associations with breast cancer risk were observed for rs4784227 and rs8051542 with odds ratios (OR of 1.31 ((95% confidence intervals (CI, 1.10–1.57 and 1.26 (95% CI, 1.02–1.56, respectively, per T allele. The T-rs8051542 allele was significantly associated with ER-positive and HER2-negative carriers. No significant association existed between rs12443621, rs3803662, and rs3112612 polymorphisms and risk of breast cancer. Our results support the hypothesis that the applicability of a common susceptibility locus must be confirmed among genetically different populations, which may together explain an appreciable fraction of the genetic etiology of breast cancer.

Profiling of the Tox21 Chemical Collection for Mitochondrial Function to Identify Compounds that Acutely Decrease Mitochondrial Membrane Potential

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Attene-Ramos, Matias S.; Huang, Ruili; Michael, Sam; Witt, Kristine L.; Richard, Ann; Tice, Raymond R.; Simeonov, Anton; Austin, Christopher P.

2014-01-01

Background: Mitochondrial dysfunction has been implicated in the pathogenesis of a variety of disorders including cancer, diabetes, and neurodegenerative and cardiovascular diseases. Understanding whether different environmental chemicals and druglike molecules impact mitochondrial function represents an initial step in predicting exposure-related toxicity and defining a possible role for such compounds in the onset of various diseases. Objectives: We sought to identify individual chemicals and general structural features associated with changes in mitochondrial membrane potential (MMP). Methods: We used a multiplexed [two end points in one screen; MMP and adenosine triphosphate (ATP) content] quantitative high throughput screening (qHTS) approach combined with informatics tools to screen the Tox21 library of 10,000 compounds (~ 8,300 unique chemicals) at 15 concentrations each in triplicate to identify chemicals and structural features that are associated with changes in MMP in HepG2 cells. Results: Approximately 11% of the compounds (913 unique compounds) decreased MMP after 1 hr of treatment without affecting cell viability (ATP content). In addition, 309 compounds decreased MMP over a concentration range that also produced measurable cytotoxicity [half maximal inhibitory concentration (IC50) in MMP assay/IC50 in viability assay ≤ 3; p Tice RR, Simeonov A, Austin CP, Xia M. 2015. Profiling of the Tox21 chemical collection for mitochondrial function to identify compounds that acutely decrease mitochondrial membrane potential. Environ Health Perspect 123:49–56; http://dx.doi.org/10.1289/ehp.1408642 PMID:25302578

Computer simulations and modeling-assisted ToxR screening in deciphering 3D structures of transmembrane α-helical dimers: ephrin receptor A1

International Nuclear Information System (INIS)

Volynsky, P E; Mineeva, E A; Goncharuk, M V; Ermolyuk, Ya S; Arseniev, A S; Efremov, R G

2010-01-01

Membrane-spanning segments of numerous proteins (e.g. receptor tyrosine kinases) represent a novel class of pharmacologically important targets, whose activity can be modulated by specially designed artificial peptides, the so-called interceptors. Rational construction of such peptides requires understanding of the main factors driving peptide–peptide association in lipid membranes. Here we present a new method for rapid prediction of the spatial structure of transmembrane (TM) helix–helix complexes. It is based on computer simulations in membrane-like media and subsequent refinement/validation of the results using experimental studies of TM helix dimerization in a bacterial membrane by means of the ToxR system. The approach was applied to TM fragments of the ephrin receptor A1 (EphA1). A set of spatial structures of the dimer was proposed based on Monte Carlo simulations in an implicit membrane followed by molecular dynamics relaxation in an explicit lipid bilayer. The resulting models were employed for rational design of wild-type and mutant genetic constructions for ToxR assays. The computational and the experimental data are self-consistent and provide an unambiguous spatial model of the TM dimer of EphA1. The results of this work can be further used to develop new biologically active 'peptide interceptors' specifically targeting membrane domains of proteins

Characterization of ToxCast Phase II compounds disruption of ...

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The development of multi-well microelectrode array (mwMEA) systems has increased in vitro screening throughput making them an effective method to screen and prioritize large sets of compounds for potential neurotoxicity. In the present experiments, a multiplexed approach was used to determine compound effects on both neural function and cell health in primary cortical networks grown on mwMEA plates following exposure to ~1100 compounds from EPA’s Phase II ToxCast libraries. On DIV 13, baseline activity (40 min) was recorded prior to exposure to each compound at 40 µM. DMSO and the GABAA antagonist bicuculline (BIC) were included as controls on each mwMEA plate. Changes in spontaneous network activity (mean firing rate; MFR) and cell viability (lactate dehydrogenase; LDH and CellTiter Blue; CTB) were assessed within the same well following compound exposure. Activity calls (“hits”) were established using the 90th and 20th percentiles of the compound-induced change in MFR (medians of triplicates) across all tested compounds; compounds above (top 10% of compounds increasing MFR), and below (bottom 20% of compounds decreasing MFR) these thresholds, respectively were considered hits. MFR was altered beyond one of these thresholds by 322 compounds. Four compound categories accounted for 66% of the hits, including: insecticides (e.g. abamectin, lindane, prallethrin), pharmaceuticals (e.g. haloperidol, reserpine), fungicides (e.g. hexaconazole, fenamidone), and h

Developmental Effects of the ToxCast™ Phase I and Phase II Chemicals in Caenorhabditis elegans and Corresponding Responses in Zebrafish, Rats, and Rabbits

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Boyd, Windy A.; Smith, Marjolein V.; Co, Caroll A.; Pirone, Jason R.; Rice, Julie R.; Shockley, Keith R.; Freedman, Jonathan H.

2015-01-01

Background: Modern toxicology is shifting from an observational to a mechanistic science. As part of this shift, high-throughput toxicity assays are being developed using alternative, nonmammalian species to prioritize chemicals and develop prediction models of human toxicity. Methods: The nematode Caenorhabditis elegans (C. elegans) was used to screen the U.S. Environmental Protection Agency’s (EPA’s) ToxCast™ Phase I and Phase II libraries, which contain 292 and 676 chemicals, respectively, for chemicals leading to decreased larval development and growth. Chemical toxicity was evaluated using three parameters: a biologically defined effect size threshold, half-maximal activity concentration (AC50), and lowest effective concentration (LEC). Results: Across both the Phase I and Phase II libraries, 62% of the chemicals were classified as active ≤ 200 μM in the C. elegans assay. Chemical activities and potencies in C. elegans were compared with those from two zebrafish embryonic development toxicity studies and developmental toxicity data for rats and rabbits. Concordance of chemical activity was higher between C. elegans and one zebrafish assay across Phase I chemicals (79%) than with a second zebrafish assay (59%). Using C. elegans or zebrafish to predict rat or rabbit developmental toxicity resulted in balanced accuracies (the average value of the sensitivity and specificity for an assay) ranging from 45% to 53%, slightly lower than the concordance between rat and rabbit (58%). Conclusions: Here, we present an assay that quantitatively and reliably describes the effects of chemical toxicants on C. elegans growth and development. We found significant overlap in the activity of chemicals in the ToxCast™ libraries between C. elegans and zebrafish developmental screens. Incorporating C. elegans toxicological assays as part of a battery of in vitro and in vivo assays provides additional information for the development of models to predict a chemical�

O período toxêmico da esquistossomose

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J. Leocádio

1969-06-01

Full Text Available O A. apresenta seis casos de pacientes observados durante o período toxêmico da esquistosomose mansônica. Dêstes, um foi de mulher cuja sintomatologia datava de um ano. Concebeu e deu à luz durante a enfermidade. Apresentava sinais de fibrose hepática quando do primeiro exame, ainda na vigência de sintomas do período agudo da enfermidade. Todos êstes pacientes apresentavam febre, dores abdominais, hepatoesplenomegalia e outras manifestações que têm sido descritas neste período da parasitose. Como notas dominantes no hemograma, leucocitose com eosinofilia, como ocorre nas infecções por helmintos com ciclo textrino, e anemia. Esta, nem todos apresentavam. Além de alterações do equilíbrio proteico e de resultados da exploração funcional do fígado, o A. chamou a atenção para a hípoglicemia e hipocolesterolemia encontradas em alguns dos observados. Foi digno de registro, também, a positividade tardia da intradermorreação para diagnóstico da esquistosomose. Todos os pacientes foram submetidos a tratamento antimonial, com bom resultado. Como reação colateral devemos mencionar a exacerbação da febre forçando, por vêzes à interrupção do mesmo. O A. faz referências a outros recursos terapêuticos empregados no Oriente: o F30.066, um nitrofurano de uso oral, e as sementes de Cucurbita moshata. Sugere a investigação em animais e no homem com sementes de abóbora outrora empregadas como tenifugo

Real-time cell toxicity profiling of Tox21 10K compounds reveals cytotoxicity dependent toxicity pathway linkage.

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Jui-Hua Hsieh

Full Text Available Cytotoxicity is a commonly used in vitro endpoint for evaluating chemical toxicity. In support of the U.S. Tox21 screening program, the cytotoxicity of ~10K chemicals was interrogated at 0, 8, 16, 24, 32, & 40 hours of exposure in a concentration dependent fashion in two cell lines (HEK293, HepG2 using two multiplexed, real-time assay technologies. One technology measures the metabolic activity of cells (i.e., cell viability, glo while the other evaluates cell membrane integrity (i.e., cell death, flor. Using glo technology, more actives and greater temporal variations were seen in HEK293 cells, while results for the flor technology were more similar across the two cell types. Chemicals were grouped into classes based on their cytotoxicity kinetics profiles and these classes were evaluated for their associations with activity in the Tox21 nuclear receptor and stress response pathway assays. Some pathways, such as the activation of H2AX, were associated with the fast-responding cytotoxicity classes, while others, such as activation of TP53, were associated with the slow-responding cytotoxicity classes. By clustering pathways based on their degree of association to the different cytotoxicity kinetics labels, we identified clusters of pathways where active chemicals presented similar kinetics of cytotoxicity. Such linkages could be due to shared underlying biological processes between pathways, for example, activation of H2AX and heat shock factor. Others involving nuclear receptor activity are likely due to shared chemical structures rather than pathway level interactions. Based on the linkage between androgen receptor antagonism and Nrf2 activity, we surmise that a subclass of androgen receptor antagonists cause cytotoxicity via oxidative stress that is associated with Nrf2 activation. In summary, the real-time cytotoxicity screen provides informative chemical cytotoxicity kinetics data related to their cytotoxicity mechanisms, and with our

Applying physical science techniques and CERN technology to an unsolved problem in radiation treatment for cancer: the multidisciplinary 'VoxTox' research programme.

Science.gov (United States)

Burnet, Neil G; Scaife, Jessica E; Romanchikova, Marina; Thomas, Simon J; Bates, Amy M; Wong, Emma; Noble, David J; Shelley, Leila Ea; Bond, Simon J; Forman, Julia R; Hoole, Andrew Cf; Barnett, Gillian C; Brochu, Frederic M; Simmons, Michael Pd; Jena, Raj; Harrison, Karl; Yeap, Ping Lin; Drew, Amelia; Silvester, Emma; Elwood, Patrick; Pullen, Hannah; Sultana, Andrew; Seah, Shannon Yk; Wilson, Megan Z; Russell, Simon G; Benson, Richard J; Rimmer, Yvonne L; Jefferies, Sarah J; Taku, Nicolette; Gurnell, Mark; Powlson, Andrew S; Schönlieb, Carola-Bibiane; Cai, Xiaohao; Sutcliffe, Michael Pf; Parker, Michael A

2017-06-01

The VoxTox research programme has applied expertise from the physical sciences to the problem of radiotherapy toxicity, bringing together expertise from engineering, mathematics, high energy physics (including the Large Hadron Collider), medical physics and radiation oncology. In our initial cohort of 109 men treated with curative radiotherapy for prostate cancer, daily image guidance computed tomography (CT) scans have been used to calculate delivered dose to the rectum, as distinct from planned dose, using an automated approach. Clinical toxicity data have been collected, allowing us to address the hypothesis that delivered dose provides a better predictor of toxicity than planned dose.

Bruno Latour: Philosopher of togetherness in action

DEFF Research Database (Denmark)

Bajde, Domen

2018-01-01

Latourian thought has been seeping into consumer research for decades (Kavanagh 1994). Recently, the seepage has grown into a torrent of research carried out under banners such as actor-network theory (ANT) and assemblage theory (Canniford and Bajde 2015). Similar to the slippery crossbreeds conj...

2333-IJBCS-Article-Ulrich Maloueki

African Journals Online (AJOL)

hp

Activité antioxydante par le radical 1,1- diphényl-2-picrylhydrazyle (DPPH). Un composé à activité antioxydante mis en présence du radical libre DPPH. (couleur violet), vire en jaune en donnant un proton au radical. Evaluation qualitative par chromatographie sur couche mince (CCM). La réalisation de la CCM a été.

FRAMING Linguistics: ``SEANCES"(!!!) Martin-Bradshaw-Siegel ``Buzzwordism, Bandwagonism, Sloganeering For:Fun, Profit, Survival, Ego": Rampant UNethics Sociological-DYSfunctionality!!!

Science.gov (United States)

Bradshaw, John; Siegel, E.

2010-03-01

``Sciences''/SEANCES(!!!) rampant UNethics!!! WITNESS: Yau v Perelman Poincare-conj.-pf. [Naser, NewYorker(8/06)]; digits log- law Siegel[AMS Nat.Mtg.(02)-Abs.973-60-124] inversion to ONLY BEQS: Newcomb(1881)theory method[Doyle-Snell, Random-Walks/Electric-Nets (81)]: 1881Ethics? SHMETHICS!!!

Demonstration that Australian Pasteurella multocida isolates from sporadic outbreaks of porcine pneumonia are non-toxigenic (toxA-) and display heterogeneous DNA restriction endonuclease profiles compared with toxigenic isolates from herds with progressive atrophic rhinitis.

Science.gov (United States)

Djordjevic, S P; Eamens, G J; Ha, H; Walker, M J; Chin, J C

1998-08-01

Capsular types A and D of Pasteurella multocida cause economic losses in swine because of their association with progressive atrophic rhinitis (PAR) and enzootic pneumonia. There have been no studies comparing whole-cell DNA profiles of isolates associated with these two porcine respiratory diseases. Twenty-two isolates of P. multocida from diseased pigs in different geographic localities within Australia were characterised genotypically by restriction endonuclease analysis (REA) with the enzyme CfoI. Seven of 12 P. multocida isolates from nasal swabs from pigs in herds where PAR was either present or suspected displayed a capsular type D phenotype. These were shown to possess the toxA gene by polymerase chain reaction (PCR) and Southern hybridisation, and further substantiated by production of cytotoxin in vitro. The CfoI profile of one of these seven isolates, which was from the initial outbreak of PAR in Australia (in Western Australia, WA), was identical with profiles of all six other toxigenic isolates from sporadic episodes in New South Wales (NSW). The evidence suggests that the strain involved in the initial outbreak was responsible for the spread of PAR to the eastern states of Australia. Another 10 isolates, representing both capsular types A and D, were isolated exclusively from porcine lung lesions after sporadic outbreaks of enzootic pneumonia in NSW and WA. CfoI restriction endonuclease profiles of these isolates revealed considerable genomic heterogeneity. Furthermore, none of these possessed the toxA gene. This suggests that P. multocida strains with the toxA gene do not have a competitive survival advantage in the lower respiratory tract or that toxin production does not play a role in the pathology of pneumonic lesions, or both. REA with polyacrylamide gel electrophoresis and silver staining was found to be a practical and discriminatory tool for epidemiological tracing of P. multocida outbreaks associated with PAR or pneumonia in pigs.

FutureTox II: in vitro data and in silico models for predictive toxicology.

Science.gov (United States)

Knudsen, Thomas B; Keller, Douglas A; Sander, Miriam; Carney, Edward W; Doerrer, Nancy G; Eaton, David L; Fitzpatrick, Suzanne Compton; Hastings, Kenneth L; Mendrick, Donna L; Tice, Raymond R; Watkins, Paul B; Whelan, Maurice

2015-02-01

FutureTox II, a Society of Toxicology Contemporary Concepts in Toxicology workshop, was held in January, 2014. The meeting goals were to review and discuss the state of the science in toxicology in the context of implementing the NRC 21st century vision of predicting in vivo responses from in vitro and in silico data, and to define the goals for the future. Presentations and discussions were held on priority concerns such as predicting and modeling of metabolism, cell growth and differentiation, effects on sensitive subpopulations, and integrating data into risk assessment. Emerging trends in technologies such as stem cell-derived human cells, 3D organotypic culture models, mathematical modeling of cellular processes and morphogenesis, adverse outcome pathway development, and high-content imaging of in vivo systems were discussed. Although advances in moving towards an in vitro/in silico based risk assessment paradigm were apparent, knowledge gaps in these areas and limitations of technologies were identified. Specific recommendations were made for future directions and research needs in the areas of hepatotoxicity, cancer prediction, developmental toxicity, and regulatory toxicology. © The Author 2015. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

EU Framework 6 Project: Predictive Toxicology (PredTox)-overview and outcome

International Nuclear Information System (INIS)

Suter, Laura; Schroeder, Susanne; Meyer, Kirstin; Gautier, Jean-Charles; Amberg, Alexander; Wendt, Maria; Gmuender, Hans; Mally, Angela; Boitier, Eric; Ellinger-Ziegelbauer, Heidrun; Matheis, Katja; Pfannkuch, Friedlieb

2011-01-01

In this publication, we report the outcome of the integrated EU Framework 6 Project: Predictive Toxicology (PredTox), including methodological aspects and overall conclusions. Specific details including data analysis and interpretation are reported in separate articles in this issue. The project, partly funded by the EU, was carried out by a consortium of 15 pharmaceutical companies, 2 SMEs, and 3 universities. The effects of 16 test compounds were characterized using conventional toxicological parameters and 'omics' technologies. The three major observed toxicities, liver hypertrophy, bile duct necrosis and/or cholestasis, and kidney proximal tubular damage were analyzed in detail. The combined approach of 'omics' and conventional toxicology proved a useful tool for mechanistic investigations and the identification of putative biomarkers. In our hands and in combination with histopathological assessment, target organ transcriptomics was the most prolific approach for the generation of mechanistic hypotheses. Proteomics approaches were relatively time-consuming and required careful standardization. NMR-based metabolomics detected metabolite changes accompanying histopathological findings, providing limited additional mechanistic information. Conversely, targeted metabolite profiling with LC/GC-MS was very useful for the investigation of bile duct necrosis/cholestasis. In general, both proteomics and metabolomics were supportive of other findings. Thus, the outcome of this program indicates that 'omics' technologies can help toxicologists to make better informed decisions during exploratory toxicological studies. The data support that hypothesis on mode of action and discovery of putative biomarkers are tangible outcomes of integrated 'omics' analysis. Qualification of biomarkers remains challenging, in particular in terms of identification, mechanistic anchoring, appropriate specificity, and sensitivity.

Genes for carbon metabolism and the ToxA virulence factor in Pseudomonas aeruginosa are regulated through molecular interactions of PtxR and PtxS.

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Abdelali Daddaoua

Full Text Available Homologs of the transcriptional regulator PtxS are omnipresent in Pseudomonas, whereas PtxR homologues are exclusively found in human pathogenic Pseudomonas species. In all Pseudomonas sp., PtxS with 2-ketogluconate is the regulator of the gluconate degradation pathway and controls expression from its own promoter and also from the P(gad and P(kgu for the catabolic operons. There is evidence that PtxS and PtxR play a central role in the regulation of exotoxin A expression, a relevant primary virulence factor of Pseudomonas aeruginosa. We show using DNaseI-footprint analysis that in P. aeruginosa PtxR binds to the -35 region of the P(toxA promoter in front of the exotoxin A gene, whereas PtxS does not bind to this promoter. Bioinformatic and DNaseI-footprint analysis identified a PtxR binding site in the P(kgu and P(gad promoters that overlaps the -35 region, while the PtxS operator site is located 50 bp downstream from the PtxR site. In vitro, PtxS recognises PtxR with nanomolar affinity, but this interaction does not occur in the presence of 2-ketogluconate, the specific effector of PtxS. DNAaseI footprint assays of P(kgu and P(gad promoters with PtxS and PtxR showed a strong region of hyper-reactivity between both regulator binding sites, indicative of DNA distortion when both proteins are bound; however in the presence of 2-ketogluconate no protection was observed. We conclude that PtxS modulates PtxR activity in response to 2-ketogluconate by complex formation in solution in the case of the P(toxA promoter, or via the formation of a DNA loop as in the regulation of gluconate catabolic genes. Data suggest two different mechanisms of control exerted by the same regulator.

tant sorghum grain as energy source in fattening diets for beef steers

African Journals Online (AJOL)

FORD, J.E., 1977. Availability of methionine and lysine in sorghum grain in relation to the tannin content. Proc. Nutr. Soc. 36, 124A. HALE, W.H. & PROUTY, F.L., 1980.Current status of grain process- ing: Efficiency of processing systems. Proc. 8th Annual Texas Beef. Conj., Amarillo, Texas. HALE, W.H., TAYLOR, B., SABA, ...

Activity profiles of 309 ToxCastTM chemicals evaluated across 292 biochemical targets

International Nuclear Information System (INIS)

Knudsen, Thomas B.; Houck, Keith A.; Sipes, Nisha S.; Singh, Amar V.; Judson, Richard S.; Martin, Matthew T.; Weissman, Arthur; Kleinstreuer, Nicole C.; Mortensen, Holly M.; Reif, David M.; Rabinowitz, James R.; Setzer, R. Woodrow; Richard, Ann M.; Dix, David J.; Kavlock, Robert J.

2011-01-01

Understanding the potential health risks posed by environmental chemicals is a significant challenge elevated by the large number of diverse chemicals with generally uncharacterized exposures, mechanisms, and toxicities. The present study is a performance evaluation and critical analysis of assay results for an array of 292 high-throughput cell-free assays aimed at preliminary toxicity evaluation of 320 environmental chemicals in EPA's ToxCast TM project (Phase I). The chemicals (309 unique, 11 replicates) were mainly precursors or the active agent of commercial pesticides, for which a wealth of in vivo toxicity data is available. Biochemical HTS (high-throughput screening) profiled cell and tissue extracts using semi-automated biochemical and pharmacological methodologies to evaluate a subset of G-protein coupled receptors (GPCRs), CYP450 enzymes (CYPs), kinases, phosphatases, proteases, HDACs, nuclear receptors, ion channels, and transporters. The primary screen tested all chemicals at a relatively high concentration 25 μM concentration (or 10 μM for CYP assays), and a secondary screen re-tested 9132 chemical-assay pairs in 8-point concentration series from 0.023 to 50 μM (or 0.009-20 μM for CYPs). Mapping relationships across 93,440 chemical-assay pairs based on half-maximal activity concentration (AC50) revealed both known and novel targets in signaling and metabolic pathways. The primary dataset, summary data and details on quality control checks are available for download at (http://www.epa.gov/ncct/toxcast/).

The combined SPE:ToxY-PAM phytotoxicity assay; application and appraisal of a novel biomonitoring tool for the aquatic environment.

Science.gov (United States)

Bengtson Nash, S M; Schreiber, U; Ralph, P J; Müller, J F

2005-01-15

Mounting concerns regarding the environmental impact of herbicides has meant a growing requirement for accurate, timely information regarding herbicide residue contamination of, in particular, aquatic systems. Conventional methods of detection remain limited in terms of practicality due to high costs of operation and the specialised information that analysis provides. A new phytotoxicity bioassay was trialled for the detection of herbicide residues in filter-purified (Milli-Q) as well as natural waters. The performance of the system, which combines solid-phase extraction (SPE) with the ToxY-PAM dual-channel yield analyser (Heinz Walz GmbH), was tested alongside the traditional method of liquid chromatography-mass spectrometry (LC-MS). The assay methodology was found to be highly sensitive (LOD 0.1 ng L(-1) diuron) with good reproducibility. The study showed that the assay protocol is time effective and can be employed for the aquatic screening of herbicide residues in purified as well as natural waters.

Clinical significance of combined detection of multiple serum antibodies (AsAb, EmAb, AcAb, AoAb, ToxAb) in infertile women

International Nuclear Information System (INIS)

Chen Jing; Jiang Li; Lu Ya

2005-01-01

Objective: To determine the clinical significance of combined detection of multiple serum antibodies in infertile women. Methods; Serum multiple antibodies were examined in 120 infertile women, including 88 failed to get pregnancy and 32 with repeated spontaneous abortion. The antibodies tested were: (1) anti-sperm antibody (AsAb) (2) endometrial antibody (EmAb) (3) anti-cardiophospholipid antibody (AcAb) (4) Anti-ovarian antibody (AoAb) and Toxoplasmosis antibody (ToxAb). Results: In 48 of the infertile women, none of the five antibodies were positive (40% of 120). The rest were: one antibody positive--38/120 or 31.6%; two antibodies positive--31/120 or 25.83%, three and four antibodies positive--4/120 or 3.33%. None of the women were positive with all five antibodies. Conclusion: Immune factor was the chief cause of infertility in women. (authors)

Testing of chemicals for genetic activity with Saccharomyces cerevisiae: a report of the U. S. Environmental Protection Agency Gene-Tox Program

Energy Technology Data Exchange (ETDEWEB)

Zimmermann, F.K.; von Borstel, R.C.; von Halle, E.S.; Parry, J.M.; Siebert, D.; Zetterberg, G.; Barale, R.; Loprieno, N.

1984-01-01

This review article with over 200 references summarizes the results of mutation screening tests with 492 chemicals using saccharomyces cerevisiae as the test organism. In addition, an extensive description of S. cerevisiae as a test organism is given. Yeast can be used to study genetic effects both in mitotic and in meiotic cells because it can be cultured as a stable haploid or a stable diploid. The most commonly used genetic endpoint has been mitotic recombination either as mitotic crossing-over or mitotic gene conversion. Data were available on tests with 492 chemicals, of which 249 were positive, as reported in 173 articles or reports. The genetic test/carcinogenicity accuracy was 0.74, based on the carcinogen listing established in the gene-tox program. The yeast tests supplement the bacterial tests for detecting agents that act via radical formation, antibacterial drugs, and other chemicals interfering with chromosome segregation and recombination processes.

An efficient targeted drug delivery through apotransferrin loaded nanoparticles.

Directory of Open Access Journals (Sweden)

Athuluri Divakar Sai Krishna

Full Text Available BACKGROUND: Cancerous state is a highly stimulated environment of metabolically active cells. The cells under these conditions over express selective receptors for assimilation of factors essential for growth and transformation. Such receptors would serve as potential targets for the specific ligand mediated transport of pharmaceutically active molecules. The present study demonstrates the specificity and efficacy of protein nanoparticle of apotransferrin for targeted delivery of doxorubicin. METHODOLOGY/PRINCIPAL FINDINGS: Apotransferrin nanoparticles were developed by sol-oil chemistry. A comparative analysis of efficiency of drug delivery in conjugated and non-conjugated forms of doxorubicin to apotransferrin nanoparticle is presented. The spherical shaped apotransferrin nanoparticles (nano have diameters of 25-50 etam, which increase to 60-80 etam upon direct loading of drug (direct-nano, and showed further increase in dimension (75-95 etam in conjugated nanoparticles (conj-nano. The competitive experiments with the transferrin receptor specific antibody showed the entry of both conj-nano and direct-nano into the cells through transferrin receptor mediated endocytosis. Results of various studies conducted clearly establish the superiority of the direct-nano over conj-nano viz. (a localization studies showed complete release of drug very early, even as early as 30 min after treatment, with the drug localizing in the target organelle (nucleus (b pharmacokinetic studies showed enhanced drug concentrations, in circulation with sustainable half-life (c the studies also demonstrated efficient drug delivery, and an enhanced inhibition of proliferation in cancer cells. Tissue distribution analysis showed intravenous administration of direct nano lead to higher drug localization in liver, and blood as compared to relatively lesser localization in heart, kidney and spleen. Experiments using rat cancer model confirmed the efficacy of the formulation in

The Vitotox and ToxTracker assays: A two-test combination for quick and reliable assessment of genotoxic hazards.

Science.gov (United States)

Ates, Gamze; Favyts, Dorien; Hendriks, Giel; Derr, Remco; Mertens, Birgit; Verschaeve, Luc; Rogiers, Vera; Y Doktorova, Tatyana

2016-11-01

To ensure safety for humans, it is essential to characterize the genotoxic potential of new chemical entities, such as pharmaceutical and cosmetic substances. In a first tier, a battery of in vitro tests is recommended by international regulatory agencies. However, these tests suffer from inadequate specificity: compounds may be wrongly categorized as genotoxic, resulting in unnecessary, time-consuming, and expensive in vivo follow-up testing. In the last decade, novel assays (notably, reporter-based assays) have been developed in an attempt to overcome these drawbacks. Here, we have investigated the performance of two in vitro reporter-based assays, Vitotox and ToxTracker. A set of reference compounds was selected to span a variety of mechanisms of genotoxic action and applicability domains (e.g., pharmaceutical and cosmetic ingredients). Combining the performance of the two assays, we achieved 93% sensitivity and 79% specificity for prediction of gentoxicity for this set of compounds. Both assays permit quick high-throughput analysis of drug candidates, while requiring only small quantities of the test substances. Our study shows that these two assays, when combined, can be a reliable method for assessment of genotoxicity hazard. Copyright © 2016 Elsevier B.V. All rights reserved.

LiverTox: Advanced QSAR and Toxicogeomic Software for Hepatotoxicity Prediction

Energy Technology Data Exchange (ETDEWEB)

Lu, P-Y.; Yuracko, K. (YAHSGS, LLC)

2011-02-25

YAHSGS LLC and Oak Ridge National Laboratory (ORNL) established a CRADA in an attempt to develop a predictive system using a pre-existing ORNL computational neural network and wavelets format. This was in the interest of addressing national needs for toxicity prediction system to help overcome the significant drain of resources (money and time) being directed toward developing chemical agents for commerce. The research project has been supported through an STTR mechanism and funded by the National Institute of Environmental Health Sciences beginning Phase I in 2004 (CRADA No. ORNL-04-0688) and extending Phase II through 2007 (ORNL NFE-06-00020). To attempt the research objectives and aims outlined under this CRADA, state-of-the-art computational neural network and wavelet methods were used in an effort to design a predictive toxicity system that used two independent areas on which to base the system’s predictions. These two areas were quantitative structure-activity relationships and gene-expression data obtained from microarrays. A third area, using the new Massively Parallel Signature Sequencing (MPSS) technology to assess gene expression, also was attempted but had to be dropped because the company holding the rights to this promising MPSS technology went out of business. A research-scale predictive toxicity database system called Multi-Intelligent System for Toxicogenomic Applications (MISTA) was developed and its feasibility for use as a predictor of toxicological activity was tested. The fundamental focus of the CRADA was an attempt and effort to operate the MISTA database using the ORNL neural network. This effort indicated the potential that such a fully developed system might be used to assist in predicting such biological endpoints as hepatotoxcity and neurotoxicity. The MISTA/LiverTox approach if eventually fully developed might also be useful for automatic processing of microarray data to predict modes of action. A technical paper describing the

In vitro screening of environmental chemicals for targeted testing prioritization: the ToxCast project.

Science.gov (United States)

Judson, Richard S; Houck, Keith A; Kavlock, Robert J; Knudsen, Thomas B; Martin, Matthew T; Mortensen, Holly M; Reif, David M; Rotroff, Daniel M; Shah, Imran; Richard, Ann M; Dix, David J

2010-04-01

Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use, and the thousands of environmental chemicals lacking toxicity data. The U.S. Environmental Protection Agency's ToxCast program aims to address these concerns by screening and prioritizing chemicals for potential human toxicity using in vitro assays and in silico approaches. This project aims to evaluate the use of in vitro assays for understanding the types of molecular and pathway perturbations caused by environmental chemicals and to build initial prioritization models of in vivo toxicity. We tested 309 mostly pesticide active chemicals in 467 assays across nine technologies, including high-throughput cell-free assays and cell-based assays, in multiple human primary cells and cell lines plus rat primary hepatocytes. Both individual and composite scores for effects on genes and pathways were analyzed. Chemicals displayed a broad spectrum of activity at the molecular and pathway levels. We saw many expected interactions, including endocrine and xenobiotic metabolism enzyme activity. Chemicals ranged in promiscuity across pathways, from no activity to affecting dozens of pathways. We found a statistically significant inverse association between the number of pathways perturbed by a chemical at low in vitro concentrations and the lowest in vivo dose at which a chemical causes toxicity. We also found associations between a small set of in vitro assays and rodent liver lesion formation. This approach promises to provide meaningful data on the thousands of untested environmental chemicals and to guide targeted testing of environmental contaminants.

Targeted Nanodiamonds for Identification of Subcellular Protein Assemblies in Mammalian Cells

OpenAIRE

Lake, Michael P.; Bouchard, Louis-S.

2017-01-01

Transmission electron microscopy (TEM) can be used to successfully determine the structures of proteins. However, such studies are typically done ex situ after extraction of the protein from the cellular environment. Here we describe an application for nanodiamonds as targeted intensity contrast labels in biological TEM, using the nuclear pore complex (NPC) as a model macroassembly. We demonstrate that delivery of antibody-conjugated nanodiamonds to live mammalian cells using maltotriose-conj...

Design of a testing strategy using non-animal based test methods: lessons learnt from the ACuteTox project.

Science.gov (United States)

Kopp-Schneider, Annette; Prieto, Pilar; Kinsner-Ovaskainen, Agnieszka; Stanzel, Sven

2013-06-01

In the framework of toxicology, a testing strategy can be viewed as a series of steps which are taken to come to a final prediction about a characteristic of a compound under study. The testing strategy is performed as a single-step procedure, usually called a test battery, using simultaneously all information collected on different endpoints, or as tiered approach in which a decision tree is followed. Design of a testing strategy involves statistical considerations, such as the development of a statistical prediction model. During the EU FP6 ACuteTox project, several prediction models were proposed on the basis of statistical classification algorithms which we illustrate here. The final choice of testing strategies was not based on statistical considerations alone. However, without thorough statistical evaluations a testing strategy cannot be identified. We present here a number of observations made from the statistical viewpoint which relate to the development of testing strategies. The points we make were derived from problems we had to deal with during the evaluation of this large research project. A central issue during the development of a prediction model is the danger of overfitting. Procedures are presented to deal with this challenge. Copyright © 2012 Elsevier Ltd. All rights reserved.

TIC-Tox: A preliminary discussion on identifying the forcing agents of DBP-mediated toxicity of disinfected water.

Science.gov (United States)

Plewa, Michael J; Wagner, Elizabeth D; Richardson, Susan D

2017-08-01

The disinfection of drinking water is a major public health achievement; however, an unintended consequence of disinfection is the generation of disinfection by-products (DBPs). Many of the identified DBPs exhibit in vitro and in vivo toxicity, generate a diversity of adverse biological effects, and may be hazards to the public health and the environment. Only a few DBPs are regulated by several national and international agencies and it is not clear if these regulated DBPs are the forcing agents that drive the observed toxicity and their associated health effects. In this study, we combine analytical chemical and biological data to resolve the forcing agents associated with mammalian cell cytotoxicity of drinking water samples from three cities. These data suggest that the trihalomethanes (THMs) and haloacetic acids may be a small component of the overall cytotoxicity of the organic material isolated from disinfected drinking water. Chemical classes of nitrogen-containing DBPs, such as the haloacetonitriles and haloacetamides, appear to be the major forcing agents of toxicity in these samples. These findings may have important implications for the design of epidemiological studies that primarily rely on the levels of THMs to define DBP exposure among populations. The TIC-Tox approach constitutes a beginning step in the process of identifying the forcing agents of toxicity in disinfected water. Copyright © 2017. Published by Elsevier B.V.

Organs-on-a-chip: Current applications and consideration points for in vitro ADME-Tox studies.

Science.gov (United States)

Ishida, Seiichi

2018-02-01

Assay systems using in vitro cultured cells are increasingly applied for evaluation of the efficacy, safety, and toxicity of drug candidates. In vitro cell-based assays have two main applications in the drug discovery process: searching for a compound that is effective against the target disease (seed investigation) and confirmation of safety during use of the identified compounds (safety assessment). Currently available in vitro cell-based assays have been designed to evaluate the efficacy and toxicity in single organs, but the in vivo pharmacokinetics and pharmacodynamics of the administered drug candidates have not been considered. Thus, an evaluation system that interconnects cell culture units, one of which has appropriate drug metabolism activities and the other assesses the efficacy and toxicity of compounds, is needed. Accordingly, the in vitro ADME-Tox culture system known as organs-on-a-chip has been proposed. In this review, after introducing the organs-on-a-chip system, the evaluation of enterohepatic circulation and the gut-liver axis relationship will be presented as an example of the application of the organs-on-a-chip system for ADME studies based on inter-organ network. Additionally, the functions required for the organs-on-a-chip system and the necessity of standardization of cells mounted on the chip system will be discussed. Copyright © 2018 The Japanese Society for the Study of Xenobiotics. Published by Elsevier Ltd. All rights reserved.

Ensemble-based ADME-Tox profiling and virtual screening for the discovery of new inhibitors of the Leishmania mexicana cysteine protease CPB2.8ΔCTE.

Science.gov (United States)

Scala, Angela; Rescifina, Antonio; Micale, Nicola; Piperno, Anna; Schirmeister, Tanja; Maes, Louis; Grassi, Giovanni

2018-02-01

In an effort to identify novel molecular warheads able to inhibit Leishmania mexicana cysteine protease CPB2.8ΔCTE, fused benzo[b]thiophenes and β,β'-triketones emerged as covalent inhibitors binding the active site cysteine residue. Enzymatic screening showed a moderate-to-excellent activity (12%-90% inhibition of the target enzyme at 20 μm). The most promising compounds were selected for further profiling including in vitro cell-based assays and docking studies. Computational data suggest that benzo[b]thiophenes act immediately as non-covalent inhibitors and then as irreversible covalent inhibitors, whereas a reversible covalent mechanism emerged for the 1,3,3'-triketones with a Y-topology. Based on the predicted physicochemical and ADME-Tox properties, compound 2b has been identified as a new drug-like, non-mutagen, non-carcinogen, and non-neurotoxic lead candidate. © 2017 John Wiley & Sons A/S.

Genetic mapping of the regulator gene determining enterotoxin synthesis in Vibrio cholerae

International Nuclear Information System (INIS)

Smirnova, N.I.; Livanova, L.F.; Shaginyan, I.A.; Motin, V.L.

1986-01-01

Data on the genetic mapping of mutation tox-7 (the mutation affecting the synthesis of the cholera toxin) were obtained by conjugation crosses between the atoxigenic donor strain Vibrio cholerae Eltor and the toxigenic recipient strain V. cholera classica. The molecular and genetic analysis of the Tox - recombinants indicated that, when the synthesis of the cholera toxin is disrupted in these strains, the tox-7 mutation (which impairs the regulator gene tox) is gained. Close linkage between the tox-7 and pur-63 mutations was established (during the selection procedure there was 81.1% combined transfer with respect to marker pur-63 situated in the donor strain chromosome more proximal than mutation tox-7). The markers were localized in the following order in the region under investigation: asp-cys-nal-pur-61-trp-his-pur-63-tox-7-ile

Host-selective toxins of Pyrenophora tritici-repentis induce common responses associated with host susceptibility.

Directory of Open Access Journals (Sweden)

Iovanna Pandelova

Full Text Available Pyrenophora tritici-repentis (Ptr, a necrotrophic fungus and the causal agent of tan spot of wheat, produces one or a combination of host-selective toxins (HSTs necessary for disease development. The two most studied toxins produced by Ptr, Ptr ToxA (ToxA and Ptr ToxB (ToxB, are proteins that cause necrotic or chlorotic symptoms respectively. Investigation of host responses induced by HSTs provides better insight into the nature of the host susceptibility. Microarray analysis of ToxA has provided evidence that it can elicit responses similar to those associated with defense. In order to evaluate whether there are consistent host responses associated with susceptibility, a similar analysis of ToxB-induced changes in the same sensitive cultivar was conducted. Comparative analysis of ToxA- and ToxB-induced transcriptional changes showed that similar groups of genes encoding WRKY transcription factors, RLKs, PRs, components of the phenylpropanoid and jasmonic acid pathways are activated. ROS accumulation and photosystem dysfunction proved to be common mechanism-of-action for these toxins. Despite similarities in defense responses, transcriptional and biochemical responses as well as symptom development occur more rapidly for ToxA compared to ToxB, which could be explained by differences in perception as well as by differences in activation of a specific process, for example, ethylene biosynthesis in ToxA treatment. Results of this study suggest that perception of HSTs will result in activation of defense responses as part of a susceptible interaction and further supports the hypothesis that necrotrophic fungi exploit defense responses in order to induce cell death.

No risk to health from DEET residues in chanterelle mushrooms from Eastern Europe

OpenAIRE

German Federal Institute for Risk Assessment

2009-01-01

Up to 1 milligram DEET (N,N-diethyl-3-methylbenzamide) per kilogram mushrooms was de-tected in fresh chanterelles from Lithuania, Russia and Belarus. DEET is used in biocide products for instance to offer protection against mosquitoes and ticks. The Federal Institute for Risk Assessment (BfR) examined whether the contaminated mushrooms constitute a health risk for consumers. The toxicological assessment of DEET is based on the evaluation of this substance by the Member State Sweden in conj...

The CompTox Chemistry Dashboard: a community data resource for environmental chemistry.

Science.gov (United States)

Williams, Antony J; Grulke, Christopher M; Edwards, Jeff; McEachran, Andrew D; Mansouri, Kamel; Baker, Nancy C; Patlewicz, Grace; Shah, Imran; Wambaugh, John F; Judson, Richard S; Richard, Ann M

2017-11-28

Despite an abundance of online databases providing access to chemical data, there is increasing demand for high-quality, structure-curated, open data to meet the various needs of the environmental sciences and computational toxicology communities. The U.S. Environmental Protection Agency's (EPA) web-based CompTox Chemistry Dashboard is addressing these needs by integrating diverse types of relevant domain data through a cheminformatics layer, built upon a database of curated substances linked to chemical structures. These data include physicochemical, environmental fate and transport, exposure, usage, in vivo toxicity, and in vitro bioassay data, surfaced through an integration hub with link-outs to additional EPA data and public domain online resources. Batch searching allows for direct chemical identifier (ID) mapping and downloading of multiple data streams in several different formats. This facilitates fast access to available structure, property, toxicity, and bioassay data for collections of chemicals (hundreds to thousands at a time). Advanced search capabilities are available to support, for example, non-targeted analysis and identification of chemicals using mass spectrometry. The contents of the chemistry database, presently containing ~ 760,000 substances, are available as public domain data for download. The chemistry content underpinning the Dashboard has been aggregated over the past 15 years by both manual and auto-curation techniques within EPA's DSSTox project. DSSTox chemical content is subject to strict quality controls to enforce consistency among chemical substance-structure identifiers, as well as list curation review to ensure accurate linkages of DSSTox substances to chemical lists and associated data. The Dashboard, publicly launched in April 2016, has expanded considerably in content and user traffic over the past year. It is continuously evolving with the growth of DSSTox into high-interest or data-rich domains of interest to EPA, such

INVESTIGATION OF THE TOTAL ORGANIC HALOGEN ANALYTICAL METHOD AT THE WASTE SAMPLING AND CHARACTERIZATION FACILITY

International Nuclear Information System (INIS)

Douglas, J.G.; Meznarich, H.K.; Olsen, J.R.; Ross, G.A.; Stauffer, M.

2009-01-01

Total organic halogen (TOX) is used as a parameter to screen groundwater samples at the Hanford Site. Trending is done for each groundwater well, and changes in TOX and other screening parameters can lead to costly changes in the monitoring protocol. The Waste Sampling and Characterization Facility (WSCF) analyzes groundwater samples for TOX using the United States Environmental Protection Agency (EPA) SW-S46 method 9020B (EPA 1996a). Samples from the Soil and Groundwater Remediation Project (SGRP) are submitted to the WSCF for analysis without information regarding the source of the sample; each sample is in essence a ''blind'' sample to the laboratory. Feedback from the SGRP indicated that some of the WSCF-generated TOX data from groundwater wells had a number of outlier values based on the historical trends (Anastos 200Sa). Additionally, analysts at WSCF observed inconsistent TOX results among field sample replicates. Therefore, the WSCF lab performed an investigation of the TOX analysis to determine the cause of the outlier data points. Two causes were found that contributed to generating out-of-trend TOX data: (1) The presence of inorganic chloride in the groundwater samples: at inorganic chloride concentrations greater than about 10 parts per million (ppm), apparent TOX values increase with increasing chloride concentration. A parallel observation is the increase in apparent breakthrough of TOX from the first to the second activated-carbon adsorption tubes with increasing inorganic chloride concentration. (2) During the sample preparation step, excessive purging of the adsorption tubes with oxygen pressurization gas after sample loading may cause channeling in the activated carbon bed. This channeling leads to poor removal of inorganic chloride during the subsequent wash step with aqueous potassium nitrate. The presence of this residual inorganic chloride then produces erroneously high TOX values. Changes in sample preparation were studied to more effectively

High-Throughput Screening and Quantitative Chemical Ranking for Sodium-Iodide Symporter Inhibitors in ToxCast Phase I Chemical Library.

Science.gov (United States)

Wang, Jun; Hallinger, Daniel R; Murr, Ashley S; Buckalew, Angela R; Simmons, Steven O; Laws, Susan C; Stoker, Tammy E

2018-05-01

Thyroid uptake of iodide via the sodium-iodide symporter (NIS) is the first step in the biosynthesis of thyroid hormones that are critical for health and development in humans and wildlife. Despite having long been a known target of endocrine disrupting chemicals such as perchlorate, information regarding NIS inhibition activity is still unavailable for the vast majority of environmental chemicals. This study applied a previously validated high-throughput approach to screen for NIS inhibitors in the ToxCast phase I library, representing 293 important environmental chemicals. Here 310 blinded samples were screened in a tiered-approach using an initial single-concentration (100 μM) radioactive-iodide uptake (RAIU) assay, followed by 169 samples further evaluated in multi-concentration (0.001 μM-100 μM) testing in parallel RAIU and cell viability assays. A novel chemical ranking system that incorporates multi-concentration RAIU and cytotoxicity responses was also developed as a standardized method for chemical prioritization in current and future screenings. Representative chemical responses and thyroid effects of high-ranking chemicals are further discussed. This study significantly expands current knowledge of NIS inhibition potential in environmental chemicals and provides critical support to U.S. EPA's Endocrine Disruptor Screening Program (EDSP) initiative to expand coverage of thyroid molecular targets, as well as the development of thyroid adverse outcome pathways (AOPs).

Host translational inhibition by Pseudomonas aeruginosa Exotoxin A Triggers an immune response in Caenorhabditis elegans.

Science.gov (United States)

McEwan, Deborah L; Kirienko, Natalia V; Ausubel, Frederick M

2012-04-19

Intestinal epithelial cells are exposed to both innocuous and pathogenic microbes, which need to be distinguished to mount an effective immune response. To understand the mechanisms underlying pathogen recognition, we investigated how Pseudomonas aeruginosa triggers intestinal innate immunity in Caenorhabditis elegans, a process independent of Toll-like pattern recognition receptors. We show that the P. aeruginosa translational inhibitor Exotoxin A (ToxA), which ribosylates elongation factor 2 (EF2), upregulates a significant subset of genes normally induced by P. aeruginosa. Moreover, immune pathways involving the ATF-7 and ZIP-2 transcription factors, which protect C. elegans from P. aeruginosa, are required for preventing ToxA-mediated lethality. ToxA-responsive genes are not induced by enzymatically inactive ToxA protein but can be upregulated independently of ToxA by disruption of host protein translation. Thus, C. elegans has a surveillance mechanism to recognize ToxA through its effect on protein translation rather than by direct recognition of either ToxA or ribosylated EF2. Copyright © 2012 Elsevier Inc. All rights reserved.

Collaborative development of predictive toxicology applications.

Science.gov (United States)

Hardy, Barry; Douglas, Nicki; Helma, Christoph; Rautenberg, Micha; Jeliazkova, Nina; Jeliazkov, Vedrin; Nikolova, Ivelina; Benigni, Romualdo; Tcheremenskaia, Olga; Kramer, Stefan; Girschick, Tobias; Buchwald, Fabian; Wicker, Joerg; Karwath, Andreas; Gütlein, Martin; Maunz, Andreas; Sarimveis, Haralambos; Melagraki, Georgia; Afantitis, Antreas; Sopasakis, Pantelis; Gallagher, David; Poroikov, Vladimir; Filimonov, Dmitry; Zakharov, Alexey; Lagunin, Alexey; Gloriozova, Tatyana; Novikov, Sergey; Skvortsova, Natalia; Druzhilovsky, Dmitry; Chawla, Sunil; Ghosh, Indira; Ray, Surajit; Patel, Hitesh; Escher, Sylvia

2010-08-31

OpenTox provides an interoperable, standards-based Framework for the support of predictive toxicology data management, algorithms, modelling, validation and reporting. It is relevant to satisfying the chemical safety assessment requirements of the REACH legislation as it supports access to experimental data, (Quantitative) Structure-Activity Relationship models, and toxicological information through an integrating platform that adheres to regulatory requirements and OECD validation principles. Initial research defined the essential components of the Framework including the approach to data access, schema and management, use of controlled vocabularies and ontologies, architecture, web service and communications protocols, and selection and integration of algorithms for predictive modelling. OpenTox provides end-user oriented tools to non-computational specialists, risk assessors, and toxicological experts in addition to Application Programming Interfaces (APIs) for developers of new applications. OpenTox actively supports public standards for data representation, interfaces, vocabularies and ontologies, Open Source approaches to core platform components, and community-based collaboration approaches, so as to progress system interoperability goals.The OpenTox Framework includes APIs and services for compounds, datasets, features, algorithms, models, ontologies, tasks, validation, and reporting which may be combined into multiple applications satisfying a variety of different user needs. OpenTox applications are based on a set of distributed, interoperable OpenTox API-compliant REST web services. The OpenTox approach to ontology allows for efficient mapping of complementary data coming from different datasets into a unifying structure having a shared terminology and representation.Two initial OpenTox applications are presented as an illustration of the potential impact of OpenTox for high-quality and consistent structure-activity relationship modelling of REACH

Environmental T4-Family Bacteriophages Evolve to Escape Abortive Infection via Multiple Routes in a Bacterial Host Employing "Altruistic Suicide" through Type III Toxin-Antitoxin Systems.

Science.gov (United States)

Chen, Bihe; Akusobi, Chidiebere; Fang, Xinzhe; Salmond, George P C

2017-01-01

Abortive infection is an anti-phage mechanism employed by a bacterium to initiate its own death upon phage infection. This reduces, or eliminates, production of viral progeny and protects clonal siblings in the bacterial population by an act akin to an "altruistic suicide." Abortive infection can be mediated by a Type III toxin-antitoxin system called ToxIN Pa consisting of an endoribonuclease toxin and RNA antitoxin. ToxIN Pa is a heterohexameric quaternary complex in which pseudoknotted RNA inhibits the toxicity of the toxin until infection by certain phages causes destabilization of ToxIN Pa , leading to bacteriostasis and, eventually, lethality. However, it is still unknown why only certain phages are able to activate ToxIN Pa . To try to address this issue we first introduced ToxIN Pa into the Gram-negative enterobacterium, Serratia sp. ATCC 39006 ( S 39006) and then isolated new environmental S 39006 phages that were scored for activation of ToxIN Pa and abortive infection capacity. We isolated three T4-like phages from a sewage treatment outflow point into the River Cam, each phage being isolated at least a year apart. These phages were susceptible to ToxIN Pa -mediated abortive infection but produced spontaneous "escape" mutants that were insensitive to ToxIN Pa . Analysis of these resistant mutants revealed three different routes of escaping ToxIN Pa , namely by mutating asiA (the product of which is a phage transcriptional co-activator); by mutating a conserved, yet functionally unknown, orf84 ; or by deleting a 6.5-10 kb region of the phage genome. Analysis of these evolved escape mutants may help uncover the nature of the corresponding phage product(s) involved in activation of ToxIN Pa .

El enriquecimiento trabajo-familia y la satisfacción docente

OpenAIRE

Jijena Michel, Robert Daniel; Martínez Sánchez, Ángel; Pérez Pérez, Manuela

2012-01-01

INTRODUCCIÓN Psicólogos y asesores industriales/organizacionales han estado durante mucho tiempo preocupados por comprender los factores responsables de la satisfacción en el trabajo, que puede definirse como el grado en que a la gente le gusta su trabajo, ya sea en su totalidad o con respecto a condiciones o recompensas particulares (Spector, 1997). Una serie de modelos teóricos han sido desarrollados para explicar la satisfacción en el trabajo. Cada uno de estos modelos cuenta con un conj...

Pugna por el libre comercio en las postrimerías del virreinato: la Nueva Galicia y las Provincias Internas frente a los comerciantes de la ciudad de México, 1811-1818

OpenAIRE

Trejo Barajas, Dení

2014-01-01

A partir del estudio de caso respecto de cómo se adoptaron medidas coyunturales de libre comercio, tanto en el puerto de San Blas como en otras zonas costeras del noroeste de Nueva España, durante el periodo de la guerra de Independencia, hemos podido dar seguimiento al conflicto desatado entre los comerciantes de los poderosos consulados de México y Veracruz y las autoridades y corporaciones de las regiones noroccidentales de Nueva España. By developing a case study that analyzes how conj...

Hidroterapia en el embarazo. Dolor lumbar

OpenAIRE

Martínez Manzano, Eva S.; Martínez Payá, Jacinto Javier

2002-01-01

Con este trabajo hemos estudiado las ventajas que tiene la hidroterapia en el embarazo y la presencia de dolor lumbar, tan frecuente, sobre todo en los últimos meses de gestación. Creemos conveniente hacer referencia a la evolución que sufre la columna vertebral de la cuadrupedia a la bipedestación. Dicho paso contribuye al desarrollo de la inteligencia humana, pero es un importante inconveniente para su columna vertebral, que sigue pagando tributo a la posición erguida, y al conj...

Adaptation of the ToxRTool to Assess the Reliability of Toxicology Studies Conducted with Genetically Modified Crops and Implications for Future Safety Testing.

Science.gov (United States)

Koch, Michael S; DeSesso, John M; Williams, Amy Lavin; Michalek, Suzanne; Hammond, Bruce

2016-01-01

To determine the reliability of food safety studies carried out in rodents with genetically modified (GM) crops, a Food Safety Study Reliability Tool (FSSRTool) was adapted from the European Centre for the Validation of Alternative Methods' (ECVAM) ToxRTool. Reliability was defined as the inherent quality of the study with regard to use of standardized testing methodology, full documentation of experimental procedures and results, and the plausibility of the findings. Codex guidelines for GM crop safety evaluations indicate toxicology studies are not needed when comparability of the GM crop to its conventional counterpart has been demonstrated. This guidance notwithstanding, animal feeding studies have routinely been conducted with GM crops, but their conclusions on safety are not always consistent. To accurately evaluate potential risks from GM crops, risk assessors need clearly interpretable results from reliable studies. The development of the FSSRTool, which provides the user with a means of assessing the reliability of a toxicology study to inform risk assessment, is discussed. Its application to the body of literature on GM crop food safety studies demonstrates that reliable studies report no toxicologically relevant differences between rodents fed GM crops or their non-GM comparators.

ToxGen: an improved reference database for the identification of type B-trichothecene genotypes in Fusarium

Directory of Open Access Journals (Sweden)

Tomasz Kulik

2017-02-01

Full Text Available Type B trichothecenes, which pose a serious hazard to consumer health, occur worldwide in grains. These mycotoxins are produced mainly by three different trichothecene genotypes/chemotypes: 3ADON (3-acetyldeoxynivalenol, 15ADON (15-acetyldeoxynivalenol and NIV (nivalenol, named after these three major mycotoxin compounds. Correct identification of these genotypes is elementary for all studies relating to population surveys, fungal ecology and mycotoxicology. Trichothecene producers exhibit enormous strain-dependent chemical diversity, which may result in variation in levels of the genotype’s determining toxin and in the production of low to high amounts of atypical compounds. New high-throughput DNA-sequencing technologies promise to boost the diagnostics of mycotoxin genotypes. However, this requires a reference database containing a satisfactory taxonomic sampling of sequences showing high correlation to actually produced chemotypes. We believe that one of the most pressing current challenges of such a database is the linking of molecular identification with chemical diversity of the strains, as well as other metadata. In this study, we use the Tri12 gene involved in mycotoxin biosynthesis for identification of Tri genotypes through sequence comparison. Tri12 sequences from a range of geographically diverse fungal strains comprising 22 Fusarium species were stored in the ToxGen database, which covers descriptive and up-to-date annotations such as indication on Tri genotype and chemotype of the strains, chemical diversity, information on trichothecene-inducing host, substrate or media, geographical locality, and most recent taxonomic affiliations. The present initiative bridges the gap between the demands of comprehensive studies on trichothecene producers and the existing nucleotide sequence databases, which lack toxicological and other auxiliary data. We invite researchers working in the fields of fungal taxonomy, epidemiology and

ToxGen: an improved reference database for the identification of type B-trichothecene genotypes in Fusarium.

Science.gov (United States)

Kulik, Tomasz; Abarenkov, Kessy; Buśko, Maciej; Bilska, Katarzyna; van Diepeningen, Anne D; Ostrowska-Kołodziejczak, Anna; Krawczyk, Katarzyna; Brankovics, Balázs; Stenglein, Sebastian; Sawicki, Jakub; Perkowski, Juliusz

2017-01-01

Type B trichothecenes, which pose a serious hazard to consumer health, occur worldwide in grains. These mycotoxins are produced mainly by three different trichothecene genotypes/chemotypes: 3ADON (3-acetyldeoxynivalenol), 15ADON (15-acetyldeoxynivalenol) and NIV (nivalenol), named after these three major mycotoxin compounds. Correct identification of these genotypes is elementary for all studies relating to population surveys, fungal ecology and mycotoxicology. Trichothecene producers exhibit enormous strain-dependent chemical diversity, which may result in variation in levels of the genotype's determining toxin and in the production of low to high amounts of atypical compounds. New high-throughput DNA-sequencing technologies promise to boost the diagnostics of mycotoxin genotypes. However, this requires a reference database containing a satisfactory taxonomic sampling of sequences showing high correlation to actually produced chemotypes. We believe that one of the most pressing current challenges of such a database is the linking of molecular identification with chemical diversity of the strains, as well as other metadata. In this study, we use the Tri12 gene involved in mycotoxin biosynthesis for identification of Tri genotypes through sequence comparison. Tri12 sequences from a range of geographically diverse fungal strains comprising 22 Fusarium species were stored in the ToxGen database, which covers descriptive and up-to-date annotations such as indication on Tri genotype and chemotype of the strains, chemical diversity, information on trichothecene-inducing host, substrate or media, geographical locality, and most recent taxonomic affiliations. The present initiative bridges the gap between the demands of comprehensive studies on trichothecene producers and the existing nucleotide sequence databases, which lack toxicological and other auxiliary data. We invite researchers working in the fields of fungal taxonomy, epidemiology and mycotoxicology to join the

INVESTIGATION OF THE TOTAL ORGANIC HALOGEN ANALYTICAL METHOD AT THE WASTE SAMPLING CHARACTERIZATION FACILITY (WSCF)

International Nuclear Information System (INIS)

DOUGLAS JG; MEZNARICH HD, PHD; OLSEN JR; ROSS GA; STAUFFER M

2008-01-01

Total organic halogen (TOX) is used as a parameter to screen groundwater samples at the Hanford Site. Trending is done for each groundwater well, and changes in TOX and other screening parameters can lead to costly changes in the monitoring protocol. The Waste Sampling and Characterization Facility (WSCF) analyzes groundwater samples for TOX using the United States Environmental Protection Agency (EPA) SW-846 method 9020B (EPA 1996a). Samples from the Soil and Groundwater Remediation Project (S and GRP) are submitted to the WSCF for analysis without information regarding the source of the sample; each sample is in essence a 'blind' sample to the laboratory. Feedback from the S and GRP indicated that some of the WSCF-generated TOX data from groundwater wells had a number of outlier values based on the historical trends (Anastos 2008a). Additionally, analysts at WSCF observed inconsistent TOX results among field sample replicates. Therefore, the WSCF lab performed an investigation of the TOX analysis to determine the cause of the outlier data points. Two causes were found that contributed to generating out-of-trend TOX data: (1) The presence of inorganic chloride in the groundwater samples: at inorganic chloride concentrations greater than about 10 parts per million (ppm), apparent TOX values increase with increasing chloride concentration. A parallel observation is the increase in apparent breakthrough of TOX from the first to the second activated-carbon adsorption tubes with increasing inorganic chloride concentration. (2) During the sample preparation step, excessive purging of the adsorption tubes with oxygen pressurization gas after sample loading may cause channeling in the activated-carbon bed. This channeling leads to poor removal of inorganic chloride during the subsequent wash step with aqueous potassium nitrate. The presence of this residual inorganic chloride then produces erroneously high TOX values. Changes in sample preparation were studied to more

Collaborative development of predictive toxicology applications

Directory of Open Access Journals (Sweden)

Hardy Barry

2010-08-01

Full Text Available Abstract OpenTox provides an interoperable, standards-based Framework for the support of predictive toxicology data management, algorithms, modelling, validation and reporting. It is relevant to satisfying the chemical safety assessment requirements of the REACH legislation as it supports access to experimental data, (Quantitative Structure-Activity Relationship models, and toxicological information through an integrating platform that adheres to regulatory requirements and OECD validation principles. Initial research defined the essential components of the Framework including the approach to data access, schema and management, use of controlled vocabularies and ontologies, architecture, web service and communications protocols, and selection and integration of algorithms for predictive modelling. OpenTox provides end-user oriented tools to non-computational specialists, risk assessors, and toxicological experts in addition to Application Programming Interfaces (APIs for developers of new applications. OpenTox actively supports public standards for data representation, interfaces, vocabularies and ontologies, Open Source approaches to core platform components, and community-based collaboration approaches, so as to progress system interoperability goals. The OpenTox Framework includes APIs and services for compounds, datasets, features, algorithms, models, ontologies, tasks, validation, and reporting which may be combined into multiple applications satisfying a variety of different user needs. OpenTox applications are based on a set of distributed, interoperable OpenTox API-compliant REST web services. The OpenTox approach to ontology allows for efficient mapping of complementary data coming from different datasets into a unifying structure having a shared terminology and representation. Two initial OpenTox applications are presented as an illustration of the potential impact of OpenTox for high-quality and consistent structure

The three-body problem

CERN Document Server

Marchal, Christian

1990-01-01

Recent research on the theory of perturbations, the analytical approach and the quantitative analysis of the three-body problem have reached a high degree of perfection. The use of electronics has aided developments in quantitative analysis and has helped to disclose the extreme complexity of the set of solutions. This accelerated progress has given new orientation and impetus to the qualitative analysis that is so complementary to the quantitative analysis. The book begins with the various formulations of the three-body problem, the main classical results and the important questions and conje

ToxAlerts: a Web server of structural alerts for toxic chemicals and compounds with potential adverse reactions.

Science.gov (United States)

Sushko, Iurii; Salmina, Elena; Potemkin, Vladimir A; Poda, Gennadiy; Tetko, Igor V

2012-08-27

The article presents a Web-based platform for collecting and storing toxicological structural alerts from literature and for virtual screening of chemical libraries to flag potentially toxic chemicals and compounds that can cause adverse side effects. An alert is uniquely identified by a SMARTS template, a toxicological endpoint, and a publication where the alert was described. Additionally, the system allows storing complementary information such as name, comments, and mechanism of action, as well as other data. Most importantly, the platform can be easily used for fast virtual screening of large chemical datasets, focused libraries, or newly designed compounds against the toxicological alerts, providing a detailed profile of the chemicals grouped by structural alerts and endpoints. Such a facility can be used for decision making regarding whether a compound should be tested experimentally, validated with available QSAR models, or eliminated from consideration altogether. The alert-based screening can also be helpful for an easier interpretation of more complex QSAR models. The system is publicly accessible and tightly integrated with the Online Chemical Modeling Environment (OCHEM, http://ochem.eu). The system is open and expandable: any registered OCHEM user can introduce new alerts, browse, edit alerts introduced by other users, and virtually screen his/her data sets against all or selected alerts. The user sets being passed through the structural alerts can be used at OCHEM for other typical tasks: exporting in a wide variety of formats, development of QSAR models, additional filtering by other criteria, etc. The database already contains almost 600 structural alerts for such endpoints as mutagenicity, carcinogenicity, skin sensitization, compounds that undergo metabolic activation, and compounds that form reactive metabolites and, thus, can cause adverse reactions. The ToxAlerts platform is accessible on the Web at http://ochem.eu/alerts, and it is constantly

Use of High Throughput Screening Data in IARC Monograph ...

Science.gov (United States)

Purpose: Evaluation of carcinogenic mechanisms serves a critical role in IARC monograph evaluations, and can lead to “upgrade” or “downgrade” of the carcinogenicity conclusions based on human and animal evidence alone. Three recent IARC monograph Working Groups (110, 112, and 113) pioneered analysis of high throughput in vitro screening data from the U.S. Environmental Protection Agency’s ToxCast program in evaluations of carcinogenic mechanisms. Methods: For monograph 110, ToxCast assay data across multiple nuclear receptors were used to test the hypothesis that PFOA acts exclusively through the PPAR family of receptors, with activity profiles compared to several prototypical nuclear receptor-activating compounds. For monographs 112 and 113, ToxCast assays were systematically evaluated and used as an additional data stream in the overall evaluation of the mechanistic evidence. Specifically, ToxCast assays were mapped to 10 “key characteristics of carcinogens” recently identified by an IARC expert group, and chemicals’ bioactivity profiles were evaluated both in absolute terms (number of relevant assays positive for bioactivity) and relative terms (ranking with respect to other compounds evaluated by IARC, using the ToxPi methodology). Results: PFOA activates multiple nuclear receptors in addition to the PPAR family in the ToxCast assays. ToxCast assays offered substantial coverage for 5 of the 10 “key characteristics,” with the greates

Molecular analysis of exotoxin A associated with antimicrobial resistance of Pseudomonas aeruginosa strains isolated from patients in Tehran hospitals

Directory of Open Access Journals (Sweden)

Nour Amirmozafari

2014-12-01

Full Text Available Background and Aim:  Pseudomonas aeruginosa is a unique bacteria that in order to survive in different environments by complex adaptation process can make changes in his virulence genes expression and drug resistance. The aim of this research is the investigation of existence of a logical association between toxA gene and antibiotic resistance in strains possess the gene. Materials and Methods: Antibiogram test by disk diffusion method (Kirby Bauer was performed according to CLSI protocols. In this study, the existence of toxA gene with the help of polymerase chain reaction (PCR in 102 clinical isolates from blood samples, wound, urine and trachea was examined. Chi-square test was used to investigate the relationship between exotoxin A and antibiotic resistance. Results: The 81 strains (79.4% had toxA gene. Frequency of toxA genes in isolated strains from different infections were wound (91.4%, blood (85.7%, trachea (72.7%, and urine (42.1%. Multiple resistance index in strains possess the toxA gene was calculated 75%. Chi 2 test to determine the relationship between drug resistance and gene toxA was significant (P<0.05. Conclusions: The significant chi-square test and an increase in multi-resistant strains possessing the toxA gene, can represent a considerable genetic switch between exotoxin A activity and resistance to antibiotics in the blood, urine, tracheal, wound infections Respectively, which lead to turn genes on of drug resistance regulating in bacteria. The results of this study will be verified by southern blot, analysis of the expression of toxA gene and determine the mechanism of resistance in resistant strains Methods.

TOXPERT: An Expert System for Risk Assessment

Science.gov (United States)

Soto, R. J.; Osimitz, T. G.; Oleson, A.

1988-01-01

TOXPERT is an artificial intelligence based system used to model product safety, toxicology (TOX) and regulatory (REG) decision processes. An expert system shell uses backward chaining rule control to link “marketing approval” goals to the type of product, REG agency, exposure conditions and TOX. Marketing risks are primarily a function of the TOX, hazards and exposure potential. The method employed differentiates between REG requirements in goal seeking control for various types of products. This is accomplished by controlling rule execution by defining frames for each REG agency. In addition, TOXPERT produces classifications of TOX ratings and suggested product labeling. This production rule system uses principles of TOX, REGs, corporate guidelines and internal “rules of thumb.” TOXPERT acts as an advisor for this narrow domain. Advantages are that it can make routine decisions freeing professional's time for more complex problem solving, provide backup and training.

Toxicology ontology perspectives.

Science.gov (United States)

Hardy, Barry; Apic, Gordana; Carthew, Philip; Clark, Dominic; Cook, David; Dix, Ian; Escher, Sylvia; Hastings, Janna; Heard, David J; Jeliazkova, Nina; Judson, Philip; Matis-Mitchell, Sherri; Mitic, Dragana; Myatt, Glenn; Shah, Imran; Spjuth, Ola; Tcheremenskaia, Olga; Toldo, Luca; Watson, David; White, Andrew; Yang, Chihae

2012-01-01

The field of predictive toxicology requires the development of open, public, computable, standardized toxicology vocabularies and ontologies to support the applications required by in silico, in vitro, and in vivo toxicology methods and related analysis and reporting activities. In this article we review ontology developments based on a set of perspectives showing how ontologies are being used in predictive toxicology initiatives and applications. Perspectives on resources and initiatives reviewed include OpenTox, eTOX, Pistoia Alliance, ToxWiz, Virtual Liver, EU-ADR, BEL, ToxML, and Bioclipse. We also review existing ontology developments in neighboring fields that can contribute to establishing an ontological framework for predictive toxicology. A significant set of resources is already available to provide a foundation for an ontological framework for 21st century mechanistic-based toxicology research. Ontologies such as ToxWiz provide a basis for application to toxicology investigations, whereas other ontologies under development in the biological, chemical, and biomedical communities could be incorporated in an extended future framework. OpenTox has provided a semantic web framework for the implementation of such ontologies into software applications and linked data resources. Bioclipse developers have shown the benefit of interoperability obtained through ontology by being able to link their workbench application with remote OpenTox web services. Although these developments are promising, an increased international coordination of efforts is greatly needed to develop a more unified, standardized, and open toxicology ontology framework.

Self-protection of Pseudomonas syringae pv. tabaci from its toxin, tabtoxinine-β-lactam

International Nuclear Information System (INIS)

Knight, T.J.; Durbin, R.D.; Langston-Unkefer, P.J.

1987-01-01

An extracellular toxin, tabtoxinine-β-lactam (TβL), is produced by Pseudomonas syringae pv. tabaci. This toxin irreversibly inhibits its target, glutamine synthetase; yet P. syringae pv. tabaci retains significant amounts of glutamine synthetase activity during toxin production in culture. As part of our investigation of the self-protection of P. syringae pv. tabaci, the authors compared the effects of TβL on Tox + (TβL-producing, insensitive to TβL) and Tox - (TβL nonproducing, sensitive to TΛ) strains. The extent of protection afforded to the Tox - strain when induced to adenylylate glutamine synthetase was tested. It was concluded that an additional protection mechanism was required. A detoxification activity was found in the Tox + strain which opens the ε-lactam ring to TβL to produce the inactive, open-chain form, tabtoxinine. Whole cells of the Tox + strain incubated for 24 h with [ 14 C]TβL (0.276 μmol/3 x 10 10 cells) contained [ 14 C]tabtoxinine (0.056 μmol), and the medium contained TβL (0.226 μmol). Extracts of spheroplasts of the Tox + stain also converted TβL to tabtoxinine, whereas extracts of the Tox - strain did not alter TβL. The conversion was time dependent and stoichiometric and was destroyed by boiling for 30 min or by the addition of 5mM EDTA. Penicillin, a possible substrate and competitive inhibitor of this lactamase activity, inhibited the conversion of TΛ to tabtoxinine. Periplasmic fluid did not catalyze the conversion of TβL

Effect of temperature and pH on dehalogenation of total organic chlorine, bromine and iodine in drinking water.

Science.gov (United States)

Abusallout, Ibrahim; Rahman, Shamimur; Hua, Guanghui

2017-11-01

Disinfection byproduct (DBP) concentrations in drinking water distribution systems and indoor water uses depend on competitive formation and degradation reactions. This study investigated the dehalogenation kinetics of total organic chlorine (TOCl), bromine (TOBr) and iodine (TOI) produced by fulvic acid under different pH and temperature conditions, and total organic halogen (TOX) variations in a treated drinking water under simulated distribution system and heating scenarios. TOX dehalogenation rates were generally in the order of TOI ≅ TOCl(NH 2 Cl) > TOBr > TOCl(Cl 2 ). The half-lives of different groups of TOX compounds formed by fulvic acid varied between 27 and 139 days during incubation at 20 °C and 0.98-2.17 days during heating at 55 °C. Base-catalyzed reactions played a major role in TOX degradation as evidenced by enhanced dehalogenation under high pH conditions. The results of heating of a treated water in the presence of residuals showed that TOX concentrations of chlorinated samples increased rapidly when chlorine residuals were present and then gradually decreased after chlorine residuals were exhausted. The final TOX concentrations of chlorinated samples after heating showed moderate decreases with increasing ambient water ages. Chloraminated samples with different ambient water ages exhibited similar final TOX concentrations during simulated distribution system and heating experiments. This study reinforces the importance of understanding DBP variations in indoor water uses as wells as in distribution systems to provide more accurate DBP information for exposure assessment and regulatory determination. Published by Elsevier Ltd.

Machine learning can differentiate venom toxins from other proteins having non-toxic physiological functions

Directory of Open Access Journals (Sweden)

Ranko Gacesa

2016-10-01

Full Text Available Ascribing function to sequence in the absence of biological data is an ongoing challenge in bioinformatics. Differentiating the toxins of venomous animals from homologues having other physiological functions is particularly problematic as there are no universally accepted methods by which to attribute toxin function using sequence data alone. Bioinformatics tools that do exist are difficult to implement for researchers with little bioinformatics training. Here we announce a machine learning tool called ‘ToxClassifier’ that enables simple and consistent discrimination of toxins from non-toxin sequences with >99% accuracy and compare it to commonly used toxin annotation methods. ‘ToxClassifer’ also reports the best-hit annotation allowing placement of a toxin into the most appropriate toxin protein family, or relates it to a non-toxic protein having the closest homology, giving enhanced curation of existing biological databases and new venomics projects. ‘ToxClassifier’ is available for free, either to download (https://github.com/rgacesa/ToxClassifier or to use on a web-based server (http://bioserv7.bioinfo.pbf.hr/ToxClassifier/.

Toxicity Reference Database

Data.gov (United States)

U.S. Environmental Protection Agency — The Toxicity Reference Database (ToxRefDB) contains approximately 30 years and $2 billion worth of animal studies. ToxRefDB allows scientists and the interested...

Pu recycling in a full Th-MOX PWR core. Part I: Steady state analysis

International Nuclear Information System (INIS)

Fridman, E.; Kliem, S.

2011-01-01

Research highlights: → Detailed 3D 100% Th-MOX PWR core design is developed. → Pu incineration increased by a factor of 2 as compared to a full MOX PWR core. → The core controllability under steady state conditions is demonstrated. - Abstract: Current practice of Pu recycling in existing Light Water Reactors (LWRs) in the form of U-Pu mixed oxide fuel (MOX) is not efficient due to continuous Pu production from U-238. The use of Th-Pu mixed oxide (TOX) fuel will considerably improve Pu consumption rates because virtually no new Pu is generated from thorium. In this study, the feasibility of Pu recycling in a typical pressurized water reactor (PWR) fully loaded with TOX fuel is investigated. Detailed 3-dimensional 100% TOX and 100% MOX PWR core designs are developed. The full MOX core is considered for comparison purposes. The design stages included determination of Pu loading required to achieve 18-month fuel cycle assuming three-batch fuel management scheme, selection of poison materials, development of the core loading pattern, optimization of burnable poison loadings, evaluation of critical boron concentration requirements, estimation of reactivity coefficients, core kinetic parameters, and shutdown margin. The performance of the MOX and TOX cores under steady-state condition and during selected reactivity initiated accidents (RIAs) is compared with that of the actual uranium oxide (UOX) PWR core. Part I of this paper describes the full TOX and MOX PWR core designs and reports the results of steady state analysis. The TOX core requires a slightly higher initial Pu loading than the MOX core to achieve the target fuel cycle length. However, the TOX core exhibits superior Pu incineration capabilities. The significantly degraded worth of control materials in Pu cores is partially addressed by the use of enriched soluble boron and B 4 C as a control rod absorbing material. Wet annular burnable absorber (WABA) rods are used to flatten radial power distribution

Application of a bacterial whole cell biosensor for the rapid detection of cytotoxicity in heavy metal contaminated seawater.

Science.gov (United States)

Cui, Zhisong; Luan, Xiao; Jiang, Huichao; Li, Qian; Xu, Guangfei; Sun, Chengjun; Zheng, Li; Song, Yizhi; Davison, Paul A; Huang, Wei E

2018-06-01

A toxicity biosensor Acinetobacter baylyi Tox2 was constructed with the host strain A. baylyi ADP1 harboring a new and medium-copy-number plasmid pWH1274_lux, and was applied to detect the cytotoxicity of heavy metal contaminated seawater. The gene cassette luxCDABE was controlled by constitutively expressed promoter P tet on pWH1274_lux and the bioluminescence intensity of the biosensor reduces in proportional to the concentrations of toxic compounds. A. baylyi Tox2 exhibits tolerance to salinity, hence it is applicable to seawater samples. A. baylyi Tox2 and Mugilogobius chulae were exposed to different concentrations of heavy metals (Hg 2+ , Zn 2+ , Cu 2+ , and Cd 2+ ) in artificial seawater for performance comparison and Pearson correlation analysis showed a significant correlation (p heavy metal contaminated seawater. Furthermore, A. baylyi Tox2 was used to evaluate cytotoxicity of field-collected seawater samples. The results indicate that there was a significant correlation between the luminescence inhibition ratio (IR) of A. baylyi Tox2 and heavy metal concentrations detected by ICP-MS in the samples. Two seawater samples, which contained a high concentration of total heavy metals, exhibited stronger cytotoxicity than the samples containing low concentrations of heavy metals. In conclusion, A. baylyi Tox2 can be used as an alternative tool to aquatic animals for the evaluation of the cytotoxicity of heavy metal contamination in the marine environment. Copyright © 2018 Elsevier Ltd. All rights reserved.

Metal and proton toxicity to lake zooplankton: A chemical speciation based modelling approach

International Nuclear Information System (INIS)

Stockdale, Anthony; Tipping, Edward; Lofts, Stephen; Fott, Jan; Garmo, Øyvind A.; Hruska, Jakub; Keller, Bill; Löfgren, Stefan; Maberly, Stephen C.; Majer, Vladimir; Nierzwicki-Bauer, Sandra A.; Persson, Gunnar; Schartau, Ann-Kristin; Thackeray, Stephen J.

2014-01-01

The WHAM-F TOX model quantifies the combined toxic effects of protons and metal cations towards aquatic organisms through the toxicity function (F TOX ), a linear combination of the products of organism-bound cation and a toxic potency coefficient for each cation. We describe the application of the model to predict an observable ecological field variable, species richness of pelagic lake crustacean zooplankton, studied with respect to either acidification or the impacts of metals from smelters. The fitted results give toxic potencies increasing in the order H + TOX to relate combined toxic effects of protons and metal cations towards lake crustacean zooplankton. • The fitted results give toxic potencies increasing in the order H + TOX model has been applied to field data for pelagic lake crustacean zooplankton. The fitted results give metal toxic potencies increasing in the order H + < Al < Cu < Zn < Ni

In vitro sensitivity of granulo-monocytic progenitors as a new toxicological cell system and endpoint in the ACuteTox Project

International Nuclear Information System (INIS)

Cerrato, Laura; Valeri, Antonio; Bueren, Juan A.; Albella, Beatriz

2009-01-01

The ACuteTox Project (part of the EU 6th Framework Programme) was started up in January 2005. The aim of this project is to develop a simple and robust in vitro strategy for prediction of human acute systemic toxicity, which could replace animal tests used for regulatory purposes. Our group is responsible for the characterization of the effect of the reference chemicals on the hematopoietic tissue. CFU-GM assay based on the culture of human mononuclear cord blood cells has been used to characterize the effects of the selected compounds on the myeloid progenitors. Previous results have shown the relevance of the CFU-GM assay for the prediction of human acute neutropenia after treatment of antitumoral compounds, and this assay has been recently approved by the ECVAM's Scientific Advisory Committee. Among the compounds included in the study there were pharmaceuticals, environmental pollutants and industrial chemicals. Eleven out of 55 chemicals did not show any cytotoxic effect at the maximum concentration tested. The correlation coefficients of CFU-GM IC50, IC70 and IC90 values with human LC50 values (50% lethal concentration calculated from time-related sublethal and lethal human blood concentrations) were 0.4965, 0.5106 and 0.5142 respectively. Although this correlation is not improve respect to classical in vitro basal cytotoxicity tests such as 3T3 Neutral Red Uptake, chemicals which deviate substantially in the correlation with these assays (colchicine, digoxin, 5-Fluorouracil and thallium sulfate) fitted very well in the linear regression analysis of the CFU-GM progenitors. The results shown in the present study indicate that the sensitivity of CFU-GM progenitors correlates better than the sensitivity of HL-60 cells with human LC50 values and could help to refine the predictability for human acute systemic toxicity when a given chemical may affect to the hematopoietic myeloid system.

Organic halogens in landfill leachates

DEFF Research Database (Denmark)

Grøn, C.; Christensen, J. B.; Jensen, Dorthe Lærke

2000-01-01

Using a group parameter, total organic halogens (TOX), high TOX concentrations were found in leachates and leachate contaminated groundwaters at two Danish mixed sanitary and hazardous waste sites. With commonly used screening procedures for organic contaminants, the individual halogenated organi...

Defining the taxonomic domain of applicability for mammalian-based high-throughput screening assays

Science.gov (United States)

Cell-based high throughput screening (HTS) technologies are becoming mainstream in chemical safety evaluations. The US Environmental Protection Agency (EPA) Toxicity Forecaster (ToxCastTM) and the multi-agency Tox21 Programs have been at the forefront in advancing this science, m...

Estimating Likelihood of Fetal In Vivo Interactions Using In Vitro HTS Data (Teratology meeting)

Science.gov (United States)

Tox21/ToxCast efforts provide in vitro concentration-response data for thousands of compounds. Predicting whether chemical-biological interactions observed in vitro will occur in vivo is challenging. We hypothesize that using a modified model from the FDA guidance for drug intera...

Double-Track Electrochemical Green Approach for Simultaneous Dissolution Profiling of Naproxen Sodium and Diphenhydramine Hydrochloride.

Science.gov (United States)

Shehata, Mostafa A; Fawaz, Esraa M; El-Rahman, Mohamed K Abd; Abdel-Moety, Ezzat M

2017-11-30

Acquisition of the dissolution profiles of more than single active ingredient in a multi-analyte pharmaceutical formulation is a mandatory manufacturing practice that is dominated by utilization of the off-line separation-based chromatographic methods. This contribution adopts a new "Double-Track" approach with the ultimate goal of advancing the in-line potentiometric sensors to their most effective applicability for simultaneous acquisition of the dissolution profiles of two active ingredients in a binary pharmaceutical formulation. The unique abilities of these sensors for real-time measurements is the key driver for adoption of "green analytical chemistry" (GAC) principles aiming to expand the application of eco-friendly analytical methods With the aim of performing a side-by-side comparison, this work investigates the degree of adherence of ISEs to the 12 principles of GAC in multicomponent dissolution profiling with respect to the HPLC. For the proof of concept, a binary mixture of naproxen sodium (NAPR) and diphenhydramine hydrochloride (DIPH) marketed as Aleve pm ® tablets was selected as a model for which dissolution profiles were attained by two techniques. The first "Double-Track" in-line strategy depends on dipping two highly integrated membrane sensors for continuous monitoring of the dissolution of each active pharmaceutical ingredient (API) by tracing the e.m.f change over the time scale. For the determination of NAPR, sensor I was developed using tridodecyl methyl ammonium chloride as an anion exchanger, while sensor II was developed for the determination of DIPH using potassium tetrakis (4-chlorophenyl) borate as a cation exchanger. The second off-line strategy utilizes a separation-based HPLC method via off-line tracking the increase of peak area by UV detection at 220nm over time using a mobile phase of acetonitrile: water (90:10) pH 3. The advantages of the newly introduced "Double-Track" approach regarding GAC principles are highlighted, and

Residual oxygen time model for oxygen partial pressure near 130 kPa (1.3 atm).

Science.gov (United States)

Shykoff, Barbara E

2015-01-01

A two-part residual oxygen time model predicts the probability of detectible pulmonary oxygen toxicity P(P[O2tox]) after dives with oxygen partial pressure (PO2) approximately 130 kPa, and provides a tool to plan dive series with selected risk of P[O2tox]. Data suggest that pulmonary oxygen injury at this PO2 is additive between dives. Recovery begins after a delay and continues during any following dive. A logistic relation expresses P(P[O2tox]) as a function of dive duration (T(dur)) [hours]: P(P[O2tox]) = 100/[1+exp (3.586-0.49 x T(dur))] This expression maps T(dur) to P(P[O2tox]) or, in the linear mid-portion of the curve, P(P[O2tox]) usefully to T(dur). For multiple dives or during recovery, it maps to an equivalent dive duration, T(eq). T(eq) was found after second dives of duration T(dur 2). Residual time from the first dive t(r) = T(eq) - T(dur2). With known t(r), t and T(dur) a recovery model was fitted. t(r) = T(dur) x exp [-k x((t-5)/T(dur)2], where t = t - 5 hours, k = 0.149 for resting, and 0.047 for exercising divers, and t represents time after surfacing. The fits were assessed for 1,352 man-dives. Standard deviations of the residuals were 8.5% and 18.3% probability for resting or exercise dives, respectively.

In Silico Prediction of Physicochemical Properties of Environmental Chemicals Using Molecular Fingerprints and Machine Learning

Science.gov (United States)

There are little available toxicity data on the vast majority of chemicals in commerce. High-throughput screening (HTS) studies, such as those being carried out by the U.S. Environmental Protection Agency (EPA) ToxCast program in partnership with the federal Tox21 research progra...

Measuring Impact of EPAs Computational Toxicology Research (BOSC)

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Computational Toxicology (CompTox) research at the EPA was initiated in 2005. Since 2005, CompTox research efforts have made tremendous advances in developing new approaches to evaluate thousands of chemicals for potential health effects. The purpose of this case study is to trac...

HTTK: R Package for High-Throughput Toxicokinetics

Science.gov (United States)

Thousands of chemicals have been profiled by high-throughput screening programs such as ToxCast and Tox21; these chemicals are tested in part because most of them have limited or no data on hazard, exposure, or toxicokinetics. Toxicokinetic models aid in predicting tissue concent...

Fun with High Throughput Toxicokinetics (CalEPA webinar)

Science.gov (United States)

Thousands of chemicals have been profiled by high-throughput screening (HTS) programs such as ToxCast and Tox21. These chemicals are tested in part because there are limited or no data on hazard, exposure, or toxicokinetics (TK). TK models aid in predicting tissue concentrations ...

Precision-cut intestinal slices: alternative model for drug transport, metabolism, and toxicology research.

Science.gov (United States)

Li, Ming; de Graaf, Inge A M; Groothuis, Geny M M

2016-01-01

The absorption, distribution, metabolism, excretion and toxicity (ADME-tox) processes of drugs are of importance and require preclinical investigation intestine in addition to the liver. Various models have been developed for prediction of ADME-tox in the intestine. In this review, precision-cut intestinal slices (PCIS) are discussed and highlighted as model for ADME-tox studies. This review provides an overview of the applications and an update of the most recent research on PCIS as an ex vivo model to study the transport, metabolism and toxicology of drugs and other xenobiotics. The unique features of PCIS and the differences with other models as well as the translational aspects are also discussed. PCIS are a simple, fast, and reliable ex vivo model for drug ADME-tox research. Therefore, PCIS are expected to become an indispensable link in the in vitro-ex vivo-in vivo extrapolation, and a bridge in translation of animal data to the human situation. In the future, this model may be helpful to study the effects of interorgan interactions, intestinal bacteria, excipients and drug formulations on the ADME-tox properties of drugs. The optimization of culture medium and the development of a (cryo)preservation technique require more research.

High Throughput PBTK: Evaluating EPA’s Open-Source Data and Tools for Dosimetry and Exposure Reconstruction

Science.gov (United States)

Thousands of chemicals have been profiled by high-throughput screening (HTS) programs such as ToxCast and Tox21; these chemicals are tested in part because most of them have limited or no data on hazard, exposure, or toxicokinetics (TK). While HTS generates in vitro bioactivity d...

In-silico structure activity relationship study of toxicity endpoints by QSAR modeling (SOT)

Science.gov (United States)

Several thousand chemicals were tested in 700 toxicity-related in-vitro HTS bioassays through the EPA’s ToxCast and Tox21 projects. This chemical set only covers a portion of the chemical space of interest for environmental exposure, leading to a need to fill data gaps with alter...

Suppression of Virulence of Toxigenic Vibrio cholerae by Anethole through the Cyclic AMP (cAMP-cAMP Receptor Protein Signaling System.

Directory of Open Access Journals (Sweden)

M Shamim Hasan Zahid

Full Text Available Use of natural compounds as antivirulence drugs could be an alternative therapeutic approach to modify the outcome of bacterial infections, particularly in view of growing resistance to available antimicrobials. Here, we show that sub-bactericidal concentration of anethole, a component of sweet fennel seed, could suppress virulence potential in O1 El Tor biotype strains of toxigenic Vibrio cholerae, the causative agent of the ongoing 7th cholera pandemic. The expression of cholera toxin (CT and toxin coregulated pilus (TCP, the major virulence factors of V. cholerae, is controlled through a regulatory cascade involving activation of ToxT with synergistic coupling interaction of ToxR/ToxS with TcpP/TcpH. We present evidence that anethole inhibits in vitro expression of CT and TCP in a toxT-dependent but toxR/toxS-independent manner and through repression of tcpP/tcpH, by using bead-ELISA, western blotting and quantitative real-time RT-PCR assays. The cyclic AMP (cAMP-cAMP receptor protein (CRP is a well-studied global signaling system in bacterial pathogens, and this complex is known to suppress expression of tcpP/tcpH in V. cholerae. We find that anethole influences the virulence regulatory cascade by over-expressing cyaA and crp genes. Moreover, suppression of toxigenic V. cholerae-mediated fluid accumulation in ligated ileum of rabbit by anethole demonstrates its potentiality as an antivirulence drug candidate against the diseases caused by toxigenic V. cholerae. Taken altogether, these results revealing a mechanism of virulence inhibition in V. cholerae by the natural compound anethole, may have relevance in designing antivirulence compounds, particularly against multiple antibiotic resistant bacterial pathogens.

Suppression of Virulence of Toxigenic Vibrio cholerae by Anethole through the Cyclic AMP (cAMP)-cAMP Receptor Protein Signaling System.

Science.gov (United States)

Zahid, M Shamim Hasan; Awasthi, Sharda Prasad; Asakura, Masahiro; Chatterjee, Shruti; Hinenoya, Atsushi; Faruque, Shah M; Yamasaki, Shinji

2015-01-01

Use of natural compounds as antivirulence drugs could be an alternative therapeutic approach to modify the outcome of bacterial infections, particularly in view of growing resistance to available antimicrobials. Here, we show that sub-bactericidal concentration of anethole, a component of sweet fennel seed, could suppress virulence potential in O1 El Tor biotype strains of toxigenic Vibrio cholerae, the causative agent of the ongoing 7th cholera pandemic. The expression of cholera toxin (CT) and toxin coregulated pilus (TCP), the major virulence factors of V. cholerae, is controlled through a regulatory cascade involving activation of ToxT with synergistic coupling interaction of ToxR/ToxS with TcpP/TcpH. We present evidence that anethole inhibits in vitro expression of CT and TCP in a toxT-dependent but toxR/toxS-independent manner and through repression of tcpP/tcpH, by using bead-ELISA, western blotting and quantitative real-time RT-PCR assays. The cyclic AMP (cAMP)-cAMP receptor protein (CRP) is a well-studied global signaling system in bacterial pathogens, and this complex is known to suppress expression of tcpP/tcpH in V. cholerae. We find that anethole influences the virulence regulatory cascade by over-expressing cyaA and crp genes. Moreover, suppression of toxigenic V. cholerae-mediated fluid accumulation in ligated ileum of rabbit by anethole demonstrates its potentiality as an antivirulence drug candidate against the diseases caused by toxigenic V. cholerae. Taken altogether, these results revealing a mechanism of virulence inhibition in V. cholerae by the natural compound anethole, may have relevance in designing antivirulence compounds, particularly against multiple antibiotic resistant bacterial pathogens.

Evaluation and comparison of bisphenol A analog activity ...

Science.gov (United States)

Bisphenol A (BPA) is used in consumer products and industrial applications, primarily in plastics, and has been detected in the environment, human urine, blood, and breast milk. Mainly studied as an endocrine disruptor, other toxicities, including obesity, metabolic conditions such as diabetes, and neurodevelopmental effects have also been associated with exposure to BPA, indicating that its effects may not be limited to estrogenicity. In addition, a number of BPA analogs are in use and may exhibit other additional toxicities. To address these unknowns, we examined the bioactivity of 21 BPA analogs across a selection of ToxCast/Tox21 assays grouped by 7 gene sets including estrogen receptor (ER), androgen receptor (AR), thyroid receptor (TR), peroxisome proliferator-activated receptor (PPAR), pregnane x receptor (PXR), aromatase (AROM), and aryl hydrocarbon receptor (AHR). The most active compounds were bisphenol AF (BPAF) (ER, AR, AROM, AHR), bisphenol A glycidyl methacrylate (TR), 3,3’,5,5’-tetrabromobisphenol A (PPAR) and bisphenol B (BPB) (PXR). We used these data to produce toxicological prioritization index (ToxPi) scores and images to integrate and visually compare the toxicity profiles across all gene sets. The compounds with highest ToxPi scores were BPAF, BPA and BPB. We also mapped the intended gene targets for all ToxCast assays to their associated KEGG BRITE protein families in order to characterize their toxicity profiles on a broader spectr

In Vivo and In Vitro Activities and ADME-Tox Profile of a Quinolizidine-Modified 4-Aminoquinoline: A Potent Anti-P. falciparum and Anti-P. vivax Blood-Stage Antimalarial

Directory of Open Access Journals (Sweden)

Nicoletta Basilico

2017-12-01

Full Text Available Natural products are a prolific source for the identification of new biologically active compounds. In the present work, we studied the in vitro and in vivo antimalarial efficacy and ADME-Tox profile of a molecular hybrid (AM1 between 4-aminoquinoline and a quinolizidine moiety derived from lupinine (Lupinus luteus. The aim was to find a compound endowed with the target product profile-1 (TCP-1: molecules that clear asexual blood-stage parasitaemia, proposed by the Medicine for Malaria Venture to accomplish the goal of malaria elimination/eradication. AM1 displayed a very attractive profile in terms of both in vitro and in vivo activity. By using standard in vitro antimalarial assays, AM1 showed low nanomolar inhibitory activity against chloroquine-sensitive and resistant P. falciparum strains (range IC50 16–53 nM, matched with a high potency against P. vivax field isolates (Mean IC50 29 nM. Low toxicity and additivity with artemisinin derivatives were also demonstrated in vitro. High in vivo oral efficacy was observed in both P. berghei and P. yoelii mouse models with IC50 values comparable or better than those of chloroquine. The metabolic stability in different species and the pharmacokinetic profile in the mouse model makes AM1 a compound worth further investigation as a potential novel schizonticidal agent.

ToxFAQs

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... hidrógeno y flúor Formaldehyde | Formaldehido Fuel Oils / Kerosene | Aceites combustibles G Gasoline, Automotive | Gasolina de automóvil Glutaraldehyde * ... Uranium * Other Languages... Used Mineral-based Crankcase Oil | Aceite Usado de Cárter V Vanadium * Other Languages... ...

Inverse gene-for-gene interactions contribute additively to tan spot susceptibility in wheat.

Science.gov (United States)

Liu, Zhaohui; Zurn, Jason D; Kariyawasam, Gayan; Faris, Justin D; Shi, Gongjun; Hansen, Jana; Rasmussen, Jack B; Acevedo, Maricelis

2017-06-01

Tan spot susceptibility is conferred by multiple interactions of necrotrophic effector and host sensitivity genes. Tan spot of wheat, caused by Pyrenophora tritici-repentis, is an important disease in almost all wheat-growing areas of the world. The disease system is known to involve at least three fungal-produced necrotrophic effectors (NEs) that interact with the corresponding host sensitivity (S) genes in an inverse gene-for-gene manner to induce disease. However, it is unknown if the effects of these NE-S gene interactions contribute additively to the development of tan spot. In this work, we conducted disease evaluations using different races and quantitative trait loci (QTL) analysis in a wheat recombinant inbred line (RIL) population derived from a cross between two susceptible genotypes, LMPG-6 and PI 626573. The two parental lines each harbored a single known NE sensitivity gene with LMPG-6 having the Ptr ToxC sensitivity gene Tsc1 and PI 626573 having the Ptr ToxA sensitivity gene Tsn1. Transgressive segregation was observed in the population for all races. QTL mapping revealed that both loci (Tsn1 and Tsc1) were significantly associated with susceptibility to race 1 isolates, which produce both Ptr ToxA and Ptr ToxC, and the two genes contributed additively to tan spot susceptibility. For isolates of races 2 and 3, which produce only Ptr ToxA and Ptr ToxC, only Tsn1 and Tsc1 were associated with tan spot susceptibility, respectively. This work clearly demonstrates that tan spot susceptibility in this population is due primarily to two NE-S interactions. Breeders should remove both sensitivity genes from wheat lines to obtain high levels of tan spot resistance.

[Serological survey on Toxoplasma gondii infection in pregnant women with history of adverse pregnancy in Bazhou area, Hebei Province].

Science.gov (United States)

Ming-Hui, Zhu; Li-Juan, Xu; Zhen-Wei, Xue

2016-06-22

To investigate the Toxoplasma gondii infection status in pregnant women with history of adverse pregnancy and risk factors in Bazhou area, Hebei Province. A total of 302 pregnant women with the history of adverse pregnancy were chosen as respondents (an experimental group) in the hospital from March 2012 to December 2015, and 197 pregnant women without the history of adverse pregnancy as a control group. TOX-IgG and TOX-IgM were detected by using ELISA in two groups. The risk factors of Toxoplasma infection were surveyed by questionnaires. The total positive rate of Toxoplasma antibodies was 28.15% (85/302) in the experimental group, which was significantly higher than that [9.64%(19/197)] in the control group, and the difference was statistically significant ( χ 2 = 24.76, P ＜0.05). The positive rates of TOX-IgM, TOX-IgG and TOX-IgM + TOX-IgG were 6.95% (21/302), 18.54% (56/302), and 2.65% (8/302) respectively in the experimental group, which were higher than 2.03% (4/197), 7.61% (15/197), and 0% (0/197) respectively in the control group ( χ 2 = 6.07, 11.67, 3.76, all P ＜0.05). The questionnaire survey showed that the proportions of keeping pets, cutting board regardless, liking to eat hot pot or barbecue, eating raw meat, often eating in the restaurant in the pregnant women with Toxoplasma infection were higher than those in the pregnant women without Toxoplasma infection, and the differences were statistically significant ( χ 2 = 22.57, 3.96, 5.87, 7.40, 4.86, all P ＜0.05), and therefore, the above unhealthy habits may be important risk factors. Toxoplasma infection could lead to adverse pregnancy outcomes. Therefore, the above-mentioned unhealthy habits should be avoided, especially during pregnancy period.

Overdiagnosis of Clostridium difficile Infection in the Molecular Test Era.

Science.gov (United States)

Polage, Christopher R; Gyorke, Clare E; Kennedy, Michael A; Leslie, Jhansi L; Chin, David L; Wang, Susan; Nguyen, Hien H; Huang, Bin; Tang, Yi-Wei; Lee, Lenora W; Kim, Kyoungmi; Taylor, Sandra; Romano, Patrick S; Panacek, Edward A; Goodell, Parker B; Solnick, Jay V; Cohen, Stuart H

2015-11-01

Clostridium difficile is a major cause of health care-associated infection, but disagreement between diagnostic tests is an ongoing barrier to clinical decision making and public health reporting. Molecular tests are increasingly used to diagnose C difficile infection (CDI), but many molecular test-positive patients lack toxins that historically defined disease, making it unclear if they need treatment. To determine the natural history and need for treatment of patients who are toxin immunoassay negative and polymerase chain reaction (PCR) positive (Tox-/PCR+) for CDI. Prospective observational cohort study at a single academic medical center among 1416 hospitalized adults tested for C difficile toxins 72 hours or longer after admission between December 1, 2010, and October 20, 2012. The analysis was conducted in stages with revisions from April 27, 2013, to January 13, 2015. Patients undergoing C difficile testing were grouped by US Food and Drug Administration-approved toxin and PCR tests as Tox+/PCR+, Tox-/PCR+, or Tox-/PCR-. Toxin results were reported clinically. Polymerase chain reaction results were not reported. The main study outcomes were duration of diarrhea during up to 14 days of treatment, rate of CDI-related complications (ie, colectomy, megacolon, or intensive care unit care) and CDI-related death within 30 days. Twenty-one percent (293 of 1416) of hospitalized adults tested for C difficile were positive by PCR, but 44.7% (131 of 293) had toxins detected by the clinical toxin test. At baseline, Tox-/PCR+ patients had lower C difficile bacterial load and less antibiotic exposure, fecal inflammation, and diarrhea than Tox+/PCR+ patients (P difficile by either method. Exclusive reliance on molecular tests for CDI diagnosis without tests for toxins or host response is likely to result in overdiagnosis, overtreatment, and increased health care costs.

Biochemical Characterization and Structural Basis of Reactivity and Regioselectivity Differences between Burkholderia thailandensis and Burkholderia glumae 1,6-Didesmethyltoxoflavin N-Methyltransferase.

Science.gov (United States)

Fenwick, Michael K; Almabruk, Khaled H; Ealick, Steven E; Begley, Tadhg P; Philmus, Benjamin

2017-08-01

Burkholderia glumae converts the guanine base of guanosine triphosphate into an azapteridine and methylates both the pyrimidine and triazine rings to make toxoflavin. Strains of Burkholderia thailandensis and Burkholderia pseudomallei have a gene cluster encoding seven putative biosynthetic enzymes that resembles the toxoflavin gene cluster. Four of the enzymes are similar in sequence to BgToxBCDE, which have been proposed to make 1,6-didesmethyltoxoflavin (1,6-DDMT). One of the remaining enzymes, BthII1283 in B. thailandensis E264, is a predicted S-adenosylmethionine (SAM)-dependent N-methyltransferase that shows a low level of sequence identity to BgToxA, which sequentially methylates N6 and N1 of 1,6-DDMT to form toxoflavin. Here we show that, unlike BgToxA, BthII1283 catalyzes a single methyl transfer to N1 of 1,6-DDMT in vitro. In addition, we investigated the differences in reactivity and regioselectivity by determining crystal structures of BthII1283 with bound S-adenosylhomocysteine (SAH) or 1,6-DDMT and SAH. BthII1283 contains a class I methyltransferase fold and three unique extensions used for 1,6-DDMT recognition. The active site structure suggests that 1,6-DDMT is bound in a reduced form. The plane of the azapteridine ring system is orthogonal to its orientation in BgToxA. In BthII1283, the modeled SAM methyl group is directed toward the p orbital of N1, whereas in BgToxA, it is first directed toward an sp 2 orbital of N6 and then toward an sp 2 orbital of N1 after planar rotation of the azapteridine ring system. Furthermore, in BthII1283, N1 is hydrogen bonded to a histidine residue whereas BgToxA does not supply an obvious basic residue for either N6 or N1 methylation.

Re-evaluation of solid-phase adsorption and desorption techniques for isolation of trace organic pollutants from chlorinated water.

Science.gov (United States)

Onodera, S; Nagatsuka, A; Rokuhara, T; Asakura, T; Hirayama, N; Suzuki, S

1993-07-16

Amberlite XAD resin and activated carbon columns were tested for their abilities to concentrate trace organic pollutants in chlorinated water. Both XAD-2 and XAD-7 resin columns (20 ml) were capable of adsorbing about 30% of total organic halogen (TOX) present in 20 l of drinking water (pH 7) containing about 100 micrograms/l of TOX, whereas the carbon column (10 ml) adsorbed over 90% of TOX. The adsorption capacity of XAD-7 resin was found to be strongly dependent on the solution pH, as compared with those of XAD-2 and carbon adsorbents. Soxhlet and sonication extractions were also evaluated for their abilities to recover the adsorbed organics from the adsorbents, by measurements of TOX, chromatographable compounds and mutagenicity in the eluates. Soxhlet extraction gave higher recoveries than sonication, as measured with the above indices, but these differences were generally small (ca. 20%), with exception of the carbon extracts. The XAD-2 and XAD-7 extracts of drinking water also showed about 3-4 times higher mutagenic activity than the carbon extracts.

Tutorial Video Series: Using Stakeholder Outreach to Increase ...

Science.gov (United States)

The limited amount of toxicity data on thousands of chemicals found in consumer products has led to the development of research endeavors such as the U.S. EPA’s Toxicity Forecaster (ToxCast). ToxCast uses high-throughput screening technology to evaluate thousands of chemicals for potential toxicity. At the end of 2013, U.S. EPA released ToxCast chemical data on almost 2,000 chemicals through the interactive Chemical Safety for Sustainability (iCSS) Dashboard. The iCSS Dashboard provides public access to the high-throughput screening data that can be used to inform the evaluation of the safety of chemicals. U.S. EPA recognized early in the development of ToxCast that stakeholder outreach was needed in order to translate the complex scientific information featured in the iCSS Dashboard and data, with the goal of educating the diverse user community through targeted efforts to increase data usage and analysis. Through survey feedback and the request of stakeholders, a series of tutorial videos to demonstrate how to access and use the data has been planned, and the first video of the series has been released to guide data usage. This presentation will describe the video tutorial strategy including an overview of: 1) Stakeholder outreach goals and approach; 2) Planning, production, and dissemination of tutorial videos; 3) Overview of Survey Feedback; 4) Overview of tutorial video usage statistics and usage of the ToxCast data. This stakeholder-outreach approach

Hollow nanogold microsphere-signalized lateral flow immuno dipstick for the sensitive determination of the neurotoxin brevetoxin B

International Nuclear Information System (INIS)

Zhang, Kangyao; Wu, Jiachang; Li, Yineng; Wu, Yarong; Huang, Tianfu; Tang, Dianping

2014-01-01

We report on a new membrane-based lateral-flow assay for the rapid determination of the algal biotoxin brevetoxin B (BrevTox) that can be found in fish. Hollow nanogold microspheres (HGMS) with an average size of 45 nm were synthesized by using the reverse micelle method, followed by functionalization with monoclonal mouse anti-BrevTox antibody (mAb-HGMS). They served as the signalling reagent. Bovine serum albumin-BrevTox conjugate and rabbit anti-mouse IgG antibody were manually spotted on the nitrocellulose membrane and served as reagents for the test line and control line, respectively. Both spherical gold nanoparticle-labeled anti-BrevTox antibody (mAb-AuNP) and mAb-HGMS conjugate were investigated with respect to their suitability as signal-transduction tags, and the latter was found to give improved analytical features. The HGMS-based labeling method was then also studied in terms of performance in the immuno dipstick assay. Under optimal conditions, the visual detection limit (cut-off value) of the mAb-AuNP based assay is 1.5 ng mL −1 , while the sensitivity of the mAb-HGMS based assay is as low as 0.1 ng mL −1 . Yes/no decisions can be made within 10 min without the need for expensive instrumentation. The results for the analysis of target BrevTox in spiked fish samples showed a good correlation with data obtained with the commercial ELISA. Importantly, the assay gave no false negative results. (author)

Reaction of Global Collection of Rye (Secale cereale L. to Tan Spot and Pyrenophora tritici-repentis Races in South Dakota

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Sidrat Abdullah

2017-06-01

Full Text Available Rye (Secale cereale L. serves as an alternative host of Pyrenophora tritici-repentis (PTR the cause of tan spot on wheat. Rye is cultivated as a forage or cover crop and overlaps with a significant portion of wheat acreage in the U.S. northern Great Plains; however, it is not known whether the rye crop influences the evolution of PTR races. We evaluated a global collection of 211 rye accessions against tan spot and assessed the diversity in PTR population on rye in South Dakota. All the rye genotypes were inoculated with PTR races 1 and 5, and infiltrated with Ptr ToxA and Ptr ToxB, at seedling stage. We observed 21% of the genotypes exhibited susceptibility to race 1, whereas, 39% were susceptible to race 5. All 211 accessions were insensitive to both the Ptr toxins. It indicates that though rye exhibits diversity in reaction to tan spot, it lacks Ptr ToxA and ToxB sensitivity genes. This suggests that unknown toxins or other factors can lead to PTR establishment in rye. We characterized the race structure of 103 PTR isolates recovered from rye in South Dakota. Only 22% of the isolates amplified Ptr ToxA gene and were identified as race 1 based on their phenotypic reaction on the differential set. The remaining 80 isolates were noted to be race 4. Our results show that races 1 and 4 are prevalent on rye in South Dakota with a higher frequency of race 4, suggesting a minimal role of rye in the disease epidemiology.

Reaction of Global Collection of Rye (Secale cereale L.) to Tan Spot and Pyrenophora tritici-repentis Races in South Dakota.

Science.gov (United States)

Abdullah, Sidrat; Sehgal, Sunish K; Glover, Karl D; Ali, Shaukat

2017-06-01

Rye ( Secale cereale L.) serves as an alternative host of Pyrenophora tritici-repentis ( PTR ) the cause of tan spot on wheat. Rye is cultivated as a forage or cover crop and overlaps with a significant portion of wheat acreage in the U.S. northern Great Plains; however, it is not known whether the rye crop influences the evolution of PTR races. We evaluated a global collection of 211 rye accessions against tan spot and assessed the diversity in PTR population on rye in South Dakota. All the rye genotypes were inoculated with PTR races 1 and 5, and infiltrated with Ptr ToxA and Ptr ToxB, at seedling stage. We observed 21% of the genotypes exhibited susceptibility to race 1, whereas, 39% were susceptible to race 5. All 211 accessions were insensitive to both the Ptr toxins. It indicates that though rye exhibits diversity in reaction to tan spot, it lacks Ptr ToxA and ToxB sensitivity genes. This suggests that unknown toxins or other factors can lead to PTR establishment in rye. We characterized the race structure of 103 PTR isolates recovered from rye in South Dakota. Only 22% of the isolates amplified Ptr ToxA gene and were identified as race 1 based on their phenotypic reaction on the differential set. The remaining 80 isolates were noted to be race 4. Our results show that races 1 and 4 are prevalent on rye in South Dakota with a higher frequency of race 4, suggesting a minimal role of rye in the disease epidemiology.

EL ESTUDIO DE LAS ETAPAS DEL APRENDIZAJE LÉXICO BASADO EN EL CATE-CIC. EL ESTUDIO DE LAS ETAPAS DEL APRENDIZAJE LÉXICO BASADO EN EL CATE-CIC

Directory of Open Access Journals (Sweden)

Hui-Chuan Lu

2008-07-01

Full Text Available Taking the base of the Corpus of Taiwanese Learners of Spanish, created by Lu, and applying as special analytical instruments, we've tried to study the lexical development of the students learning Spanish as second foreign language. We've focused on the comparison of the combination of words used in different levels of learning in which we proposed a continuum for the degree of learnablity form the easiest to the most difficult as follows VPrep- V/N-Prep-N, V-Conj, V-Adv/V-N, N-Adj, V-Adj, Adj-N, N-V, Det-N. Moreover, we not only derived, in the developmental stages of learning, an order from early stage to late stage exists that comes from the orthographic type to the grammatical and then to lexical types; but we also identified that the semantic meaning appears in a stage later than the vocabulary with regard to the lexical type of the combinative wordsTaking the base of the Corpus of Taiwanese Learners of Spanish, created by Lu, and applying as special analytical instruments, we've tried to study the lexical development of the students learning Spanish as second foreign language. We've focused on the comparison of the combination of words used in different levels of learning in which we proposed a continuum for the degree of learnablity form the easiest to the most difficult as follows VPrep- V/N-Prep-N, V-Conj, V-Adv/V-N, N-Adj, V-Adj, Adj-N, N-V, Det-N. Moreover, we not only derived, in the developmental stages of learning, an order from early stage to late stage exists that comes from the orthographic type to the grammatical and then to lexical types; but we also identified that the semantic meaning appears in a stage later than the vocabulary with regard to the lexical type of the combinative words

Prediction of Clinically Relevant Safety Signals of Nephrotoxicity through Plasma Metabolite Profiling

Directory of Open Access Journals (Sweden)

W. B. Mattes

2013-01-01

Full Text Available Addressing safety concerns such as drug-induced kidney injury (DIKI early in the drug pharmaceutical development process ensures both patient safety and efficient clinical development. We describe a unique adjunct to standard safety assessment wherein the metabolite profile of treated animals is compared with the MetaMap Tox metabolomics database in order to predict the potential for a wide variety of adverse events, including DIKI. To examine this approach, a study of five compounds (phenytoin, cyclosporin A, doxorubicin, captopril, and lisinopril was initiated by the Technology Evaluation Consortium under the auspices of the Drug Safety Executive Council (DSEC. The metabolite profiles for rats treated with these compounds matched established reference patterns in the MetaMap Tox metabolomics database indicative of each compound’s well-described clinical toxicities. For example, the DIKI associated with cyclosporine A and doxorubicin was correctly predicted by metabolite profiling, while no evidence for DIKI was found for phenytoin, consistent with its clinical picture. In some cases the clinical toxicity (hepatotoxicity, not generally seen in animal studies, was detected with MetaMap Tox. Thus metabolite profiling coupled with the MetaMap Tox metabolomics database offers a unique and powerful approach for augmenting safety assessment and avoiding clinical adverse events such as DIKI.

Use of high-throughput in vitro toxicity screening data in cancer hazard evaluations by IARC Monograph Working Groups.

Science.gov (United States)

Chiu, Weihsueh A; Guyton, Kathryn Z; Martin, Matthew T; Reif, David M; Rusyn, Ivan

2018-01-01

Evidence regarding carcinogenic mechanisms serves a critical role in International Agency for Research on Cancer (IARC) Monograph evaluations. Three recent IARC Working Groups pioneered inclusion of the US Environmental Protection Agency (EPA) ToxCast program high-throughput screening (HTS) data to supplement other mechanistic evidence. In Monograph V110, HTS profiles were compared between perfluorooctanoic acid (PFOA) and prototypical activators across multiple nuclear receptors. For Monograph V112-113, HTS assays were mapped to 10 key characteristics of carcinogens identified by an IARC expert group, and systematically considered as an additional mechanistic data stream. Both individual assay results and ToxPi-based rankings informed mechanistic evaluations. Activation of multiple nuclear receptors in HTS assays showed that PFOA targets not only peroxisome proliferator activated receptors, but also other receptors. ToxCast assays substantially covered 5 of 10 key characteristics, corroborating literature evidence of "induces oxidative stress" and "alters cell proliferation, cell death or nutrient supply" and filling gaps for "modulates receptor-mediated effects." Thus, ToxCast HTS data were useful both in evaluating specific mechanistic hypotheses and in contributing to the overall evaluation of mechanistic evidence. However, additional HTS assays are needed to provide more comprehensive coverage of the 10 key characteristics of carcinogens that form the basis of current IARC mechanistic evaluations.

SURVEY ON V. CHOLERAE, V. VULNIFICUS AND V. PARAHAEMOLYTICUS IN BIVALVE MOLLUSCS OF THE ADRIATIC SEA AND PROPOSAL OF AN ANALYTICAL PROTOCOL

Directory of Open Access Journals (Sweden)

M.L. Valeri

2009-06-01

Full Text Available Bivalve molluscs from Adriatic sea were analyzed for V. parahaemolyticus, V. cholerae e V. vulnificus presence. The isolates on TCBS Agar and m-CPC Agar were selected on the basis of a new biochemical screening, that showed a good performance, because among 2344 strains from primary culture only 237 (10% were presumptively assigned to the species of interest. The PCR analyses was performed for the target genes toxR hlyA, ctxA, tcpI (V. cholerae, toxR, tl, tdh, trh (V. parahaemolyticus, vvhA and viuB (V. vulnificus. Among the 9 strains confirmed to belong to V. parahaemolyticus specie, 6 were sucrose positive. On 215 samples of molluscs only 5 resulted positive for V. parahaemolyticus being toxR+, tl+, although non pathogenic (tdh-, trh-, and none for V. cholerae e V. vulnificus.

Quorum-sensing regulators control virulence gene expression in Vibrio cholerae

OpenAIRE

Zhu, Jun; Miller, Melissa B.; Vance, Russell E.; Dziejman, Michelle; Bassler, Bonnie L.; Mekalanos, John J.

2002-01-01

The production of virulence factors including cholera toxin and the toxin-coregulated pilus in the human pathogen Vibrio cholerae is strongly influenced by environmental conditions. The well-characterized ToxR signal transduction cascade is responsible for sensing and integrating the environmental information and controlling the virulence regulon. We show here that, in addition to the known components of the ToxR signaling circuit, quorum-sensing regulators are involved in regulation of V. ch...

LC and LD50 values of Bacillus thuringiensis Serovar japonensis strain buibui toxin to Oriental beetle and northern masked chafer larvae (Coleoptera: Scarabaeidae).

Science.gov (United States)

Mashtoly, Tamer A; El-Zemaity, Mohamed El-Said; Hussien, Mohamed I; Alm, Steven R

2009-10-01

Bacillus thuringiensis serovar japonensis strain Buibui has the potential to be an important control agent for pest scarabs. Bioassays were designed to test B. t. japonensis against two of the major turf and ornamental scarab pests infesting turfgrasses and ornamentals and to serve as a basis for further tests against other scarab pests. LC and LD50 values of B. t. serovarjaponensis strain Buibui toxin and spores were determined by four different bioassays for the oriental beetle, Anomala orientalis (Waterhouse), and northern masked chafer, Cyclocephala borealis Arrow. Oriental beetle larvae were bioassayed in autoclaved and nonautoclaved soil from where they were collected (Kingston, RI [native]), in nonautoclaved soil from where the northern masked chafer larvae were collected (Groton, CT [foreign]), and per os. Northern masked chafer larvae were bioassayed in autoclaved and nonautoclaved soil from where they were collected (Groton, CT [native]), in nonautoclaved soil from where the oriental beetle larvae were collected (Kingston, RI [foreign]) and per os. LC50 values of 3.93 microg toxin/g autoclaved native soil, 1.80 microg toxin/g nonautoclaved native soil, and 0.42 microg toxin/g nonautoclaved foreign soil and an LD50 value of 0.41 microg per os were determined at 14 d forA. orientalis. LC50 values of 588.28 microg toxin/g autoclaved native soil, 155.10 microg toxin/g nonautoclaved native soil, 265.32 microg toxin/g nonautoclaved foreign soil, and LD50 of 5.21 microg per os were determined at 14 d (soils) and 10 d (per os) for C. borealis. There were significant differences in LC50 values for oriental beetles in autoclaved, nonautoclaved native soil and nonautoclaved foreign soil. There were significant differences in LCo values for northern masked chafers in autoclaved and nonautoclaved native soil. B. t. japonensis can be applied now for control of oriental beetles at rates that are economically competitive with synthetic chemicals. If we can determine the

Tox_esterase_2016

Data.gov (United States)

U.S. Environmental Protection Agency — individual values for liver detoxification for each human sample and for each chemical. This dataset is associated with the following publication: Moser, G., and S....

Role of biomarkers of nephrotoxic acute kidney injury in deliberate poisoning and envenomation in less developed countries.

Science.gov (United States)

Mohamed, Fahim; Endre, Zoltan H; Buckley, Nicholas A

2015-07-01

Acute kidney injury (AKI) has diverse causes and is associated with increased mortality and morbidity. In less developed countries (LDC), nephrotoxic AKI (ToxAKI) is common and mainly due to deliberate ingestion of nephrotoxic pesticides, toxic plants or to snake envenomation. ToxAKI shares some pathophysiological pathways with the much more intensively studied ischaemic AKI, but in contrast to ischaemic AKI, most victims are young, previously healthy adults. Diagnosis of AKI is currently based on a rise in serum creatinine. However this may delay diagnosis because of the kinetics of creatinine. Baseline creatinine values are also rarely available in LDC. Novel renal injury biomarkers offer a way forward because they usually increase more rapidly in AKI and are normally regarded as absent or very low in concentration, thereby reducing the need for a baseline estimate. This should increase sensitivity and speed of diagnosis. Specificity should also be increased for urine biomarkers since many originate from the renal tubular epithelium. Earlier diagnosis of ToxAKI should allow earlier initiation of appropriate therapy. However, translation of novel biomarkers of ToxAKI into clinical practice requires better understanding of non-renal factors in poisoning that alter biomarkers and the influence of dose of nephrotoxin on biomarker performance. Further issues are establishing LDC population-based normal ranges and assessing sampling and analytical parameters for low resource settings. The potential role of renal biomarkers in exploring ToxAKI aetiologies for chronic kidney disease of unknown origin (CKDu) is a high research priority in LDC. Therefore, developing more sensitive biomarkers for early diagnosis of nephrotoxicity is a critical step to making progress against AKI and CKDu in the developing world. © 2015 The British Pharmacological Society.

Toxicity of proton-metal mixtures in the field: Linking stream macroinvertebrate species diversity to chemical speciation and bioavailability

Energy Technology Data Exchange (ETDEWEB)

Stockdale, Anthony [Centre for Ecology and Hydrology, Lancaster Environment Centre, Library Avenue, Bailrigg, Lancaster LA1 4AP (United Kingdom); Tipping, Edward, E-mail: et@ceh.ac.uk [Centre for Ecology and Hydrology, Lancaster Environment Centre, Library Avenue, Bailrigg, Lancaster LA1 4AP (United Kingdom); Lofts, Stephen [Centre for Ecology and Hydrology, Lancaster Environment Centre, Library Avenue, Bailrigg, Lancaster LA1 4AP (United Kingdom); Ormerod, Stephen J. [Catchment Research Group, Cardiff School of Biosciences, Cardiff University, Cardiff CF10 3US (United Kingdom); Clements, William H. [Department of Fish, Wildlife, and Conservation Biology, Colorado State University, Fort Collins, CO 80523 (United States); Blust, Ronny [Ecophysiology, Biochemistry and Toxicology Group, Department of Biology, University of Antwerp, Groenenborgerlaan 171, 2020 Antwerp (Belgium)

2010-10-01

Understanding metal and proton toxicity under field conditions requires consideration of the complex nature of chemicals in mixtures. Here, we demonstrate a novel method that relates streamwater concentrations of cationic metallic species and protons to a field ecological index of biodiversity. The model WHAM-F{sub TOX} postulates that cation binding sites of aquatic macroinvertebrates can be represented by the functional groups of natural organic matter (humic acid), as described by the Windermere Humic Aqueous Model (WHAM6), and supporting field evidence is presented. We define a toxicity function (F{sub TOX}) by summing the products: (amount of invertebrate-bound cation) x (cation-specific toxicity coefficient, {alpha}{sub i}). Species richness data for Ephemeroptera, Plecoptera and Trichoptera (EPT), are then described with a lower threshold of F{sub TOX}, below which all organisms are present and toxic effects are absent, and an upper threshold above which organisms are absent. Between the thresholds the number of species declines linearly with F{sub TOX}. We parameterised the model with chemistry and EPT data for low-order streamwaters affected by acid deposition and/or abandoned mines, representing a total of 412 sites across three continents. The fitting made use of quantile regression, to take into account reduced species richness caused by (unknown) factors other than cation toxicity. Parameters were derived for the four most common or abundant cations, with values of {alpha}{sub i} following the sequence (increasing toxicity) H{sup +} < Al < Zn < Cu. For waters affected mainly by H{sup +} and Al, F{sub TOX} shows a steady decline with increasing pH, crossing the lower threshold near to pH 7. Competition effects among cations mean that toxicity due to Cu and Zn is rare at lower pH values, and occurs mostly between pH 6 and 8.

5th Bionanotox and Applications International Research Conference, Peabody, Little Rock, Arkansas, USA

Science.gov (United States)

Sabb, Taneicie; Chowdhury, Parimal

2011-06-01

"BioNanoTox and Toxicity: using Technology to Advance Discovery" was this year's theme at the 5th BioNanoTox and Applications International Research Conference held at the Peabody Hotel, Little Rock, Arkansas on November 4-5th, 2010. This year, the international participation in this conference increased to 25 countries spanning the globe. The conference began with opening remarks by Paul Howard, Associate Director of the National Center for Toxicological Research, Food and Drug Administration, Jefferson, Arkansas, United States. Two keynote speakers, Dr. Ananth V. Annapragada and Dr. Merle G. Paule presented lectures on "Toxicity of Novel Nanoparticles for CT imaging" and "The Biology of Neurotoxicity: using Technology to Advance Discovery", respectively. Teachers, students, faculty, and scientists presented oral and poster presentations on fundamental and translational research related to BioNanoTox and related fields of science. Six presentation sessions were held over the two-day conference. There were 31 presentations and 39 posters from disciplines ranging from biology to chemistry, toxicology, nanotechnology, computational sciences, mathematics, engineering, plant science, and biotechnology. Poster presentation awards were presented to three high school students, three high school teachers, and three college students. In addition to poster awards a memorial, travel, and BioNanoTox award were presented. This year's meeting paved the way for a more outstanding meeting for the future.

Characterization of Vibrio parahaemolyticus isolated from oysters in Korea: Resistance to various antibiotics and prevalence of virulence genes.

Science.gov (United States)

Kang, Chang-Ho; Shin, YuJin; Jang, SeokCheol; Yu, HongSik; Kim, SuKyung; An, Sera; Park, Kunbawui; So, Jae-Seong

2017-05-15

Vibrio parahaemolyticus, found frequently in oysters, is the most prevalent gastroenteritis-causing pathogen in Korea and in several other Asian countries. This study monitored changes in the environmental parameters and occurrence of V. parahaemolyticus in oyster aquaculture sites. Of the 44 presumed V. parahaemolyticus isolates obtained, when tested against 16 antibiotics, 90.9, 86.4, and 75.0% of the 44 isolates exhibited resistance to vancomycin, ampicillin, and streptomycin, respectively. PCR analysis for the presence of the toxR gene confirmed 31 of the 44 isolates as being positive V. parahaemolyticus strains. The toxR positive isolates were tested for the presence of thermostable direct hemolysin (tdh) and tdh-related hemolysin (trh) virulence genes. Only 9.1% toxR positive isolate exhibit the trh gene and none of the isolates were tested positive for tdh. The occurrence of multi drug resistance strains in the environment could be an indication of excessive usage of antibiotics in agriculture and aquaculture fields. Copyright © 2017 Elsevier Ltd. All rights reserved.

Evaluation of trace organic contaminants in ultra-pure water production processes by measuring total organic halogen formation potential

International Nuclear Information System (INIS)

Urano, Kohei; Iwase, Yoko

1984-01-01

A new procedure for the determination of organic substances in water with high accuracy and high sensitivity was proposed, in which a hypochlorite is added to water, and the resultant total amount of organic halogen compounds (TOX formation potential) was measured, and it was applied to the evaluation of trace organic contaminants in ultra-pure water production process. In this investigation, the TOX formation potential of the raw water which was to be used for the ultra-pure water production process, intermediately treated water and ultra-pure water was measured to clarify the behavior of organic substances in the ultra-pure water production process and to demonstrate the usefulness of this procedure to evaluate trace organic contaminants in water. The measurement of TOX formation potential requires no specific technical skill, and only a short time, and gives accurate results, therefore, it is expected that the water quality control in the ultra-pure water production process can be performed more exactly by applying this procedure. (Yoshitake, I.)

A High-Content Live-Cell Viability Assay and Its Validation on a Diverse 12K Compound Screen.

Science.gov (United States)

Chiaravalli, Jeanne; Glickman, J Fraser

2017-08-01

We have developed a new high-content cytotoxicity assay using live cells, called "ImageTOX." We used a high-throughput fluorescence microscope system, image segmentation software, and the combination of Hoechst 33342 and SYTO 17 to simultaneously score the relative size and the intensity of the nuclei, the nuclear membrane permeability, and the cell number in a 384-well microplate format. We then performed a screen of 12,668 diverse compounds and compared the results to a standard cytotoxicity assay. The ImageTOX assay identified similar sets of compounds to the standard cytotoxicity assay, while identifying more compounds having adverse effects on cell structure, earlier in treatment time. The ImageTOX assay uses inexpensive commercially available reagents and facilitates the use of live cells in toxicity screens. Furthermore, we show that we can measure the kinetic profile of compound toxicity in a high-content, high-throughput format, following the same set of cells over an extended period of time.

Results of RCRA groundwater quality assessment at the 216-B-3 Pond Facility

International Nuclear Information System (INIS)

Barnett, D.B.; Teel, S.S.

1997-06-01

This document describes a groundwater quality assessment of the 216-B-3 pond system, a Resources Conservation and Recovery act of 1976 (RCRA) waste facility. In 1990, sampling and chemical analysis of groundwater underlying the facility indicated that the contamination indicator parameters, total organic halogens (TOX), and total organic carbon (TOC) had exceeded established limits in two wells. This discovery placed the facility into RCRA groundwater assessment status and subsequently led to a more detailed hydrochemical analysis of groundwater underlying the facility. Comprehensive chemical analyses of groundwater samples from 1994 through 1996 revealed one compound, tris (2-chloroethyl) phosphate (TRIS2CH), that may have contributed to elevated TOX concentrations. No compound was identified as a contributor to TOC. Detailed evaluations of TOX, TOC, and TRIS2CH and comparison of occurrences of these parameters led to conclusions that (1) with few exceptions, these constituents occur at low concentrations below or near limits of quantitation; (2) it is problematic whether the low concentrations of TRIS2CH represent a contaminant originating from the facility or if it is a product of well construction; and (3) given the low and diminishing concentration of TOX, TOC, and TRIS2CH, no further investigation into the occurrent of these constituents is justified. Continued groundwater monitoring should include an immediate recalculation of background critical means of upgradient/downgradient comparisons and a return to seminannual groundwater monitoring under a RCRA indicator parameter evaluation program

The effectiveness of removing precursors of chlorinated organic substances in pilot water treatment plant

Science.gov (United States)

Wolska, Małgorzata; Szerzyna, Sławomir; Machi, Justyna; Mołczan, Marek; Adamski, Wojciech; Wiśniewski, Jacek

2017-11-01

The presence of organic substances in the water intaken for consumption could be hazardous to human health due to the potential formation of disinfection by-products (TOX). The study were carried out in the pilot surface water treatment system consisting of coagulation, sedimentation, filtration, ozonation, adsorption and disinfection. Due to continuous operation of the system and interference with the parameters of the processes it was possible not only assess the effectiveness of individual water treatment processes in removing TOX, but also on factors participating on the course of unit processes.

Delivery, Effect on Cell Viability, and Plasticity of Modified Aptamer Constructs

DEFF Research Database (Denmark)

Gissberg, Olof; Zaghloul, Eman M; Lundin, Karin E

2016-01-01

AS1411 is a g-quadruplex-forming aptamer capable of selectively entering cancer cells by nucleolin receptor-mediated uptake. In this study, we investigated the cell internalization properties and plasticity of AS1411 carrying different locked nucleic acid-containing cargo oligonucleotides (ONs......) for delivery into A549 and U2OS cells. We found that internalization efficiency is highly governed by ON cargo chemistry and composition since the inherent antitumor properties of AS1411 were lost when attached to a nontoxic ON, noTox. However, a toxic ON, Tox, demonstrated potent cytotoxicity after aptamer...

Characterization and PCR Detection Of Binary, Pir-Like Toxins from Vibrio parahaemolyticus Isolates that Cause Acute Hepatopancreatic Necrosis Disease (AHPND in Shrimp.

Directory of Open Access Journals (Sweden)

Ratchanok Sirikharin

Full Text Available Unique isolates of Vibrio parahaemolyticus (VPAHPND have previously been identified as the causative agent of acute hepatopancreatic necrosis disease (AHPND in shrimp. AHPND is characterized by massive sloughing of tubule epithelial cells of the hepatopancreas (HP, proposed to be induced by soluble toxins released from VPAHPND that colonize the shrimp stomach. Since these toxins (produced in broth culture have been reported to cause AHPND pathology in reverse gavage bioassays with shrimp, we used ammonium sulfate precipitation to prepare protein fractions from broth cultures of VPAHPND isolates for screening by reverse gavage assays. The dialyzed 60% ammonium sulfate fraction caused high mortality within 24-48 hours post-administration, and histological analysis of the moribund shrimp showed typical massive sloughing of hepatopancreatic tubule epithelial cells characteristic of AHPND. Analysis of the active fraction by SDS-PAGE revealed two major bands at marker levels of approximately 16 kDa (ToxA and 50 kDa (ToxB. Mass spectrometry analysis followed by MASCOT analysis revealed that both proteins had similarity to hypothetical proteins of V. parahaemolyticus M0605 (contig034 GenBank accession no. JALL01000066.1 and similarity to known binary insecticidal toxins called 'Photorhabdus insect related' proteins A and B (Pir-A and Pir-B, respectively, produced by the symbiotic, nematode bacterium Photorhabdus luminescens. In in vivo tests, it was shown that recombinant ToxA and ToxB were both required in a dose dependent manner to cause AHPND pathology, indicating further similarity to Pir-A and -B. A single-step PCR method was designed for detection of the ToxA gene and was validated using 104 bacterial isolates consisting of 51 VPAHPND isolates, 34 non-AHPND VP isolates and 19 other isolates of bacteria commonly found in shrimp ponds (including other species of Vibrio and Photobacterium. The results showed 100% specificity and sensitivity for

Application of first order rate kinetics to explain changes in bloom toxicity—the importance of understanding cell toxin quotas

Science.gov (United States)

Orr, Philip T.; Willis, Anusuya; Burford, Michele A.

2018-04-01

Cyanobacteria are oxygenic photosynthetic Gram-negative bacteria that can form potentially toxic blooms in eutrophic and slow flowing aquatic ecosystems. Bloom toxicity varies spatially and temporally, but understanding the mechanisms that drive these changes remains largely a mystery. Changes in bloom toxicity may result from changes in intracellular toxin pool sizes of cyanotoxins with differing molecular toxicities, and/or from changes in the cell concentrations of toxic and non-toxic cyanobacterial species or strains within bloom populations. We show here how first-order rate kinetics at the cellular level can be used to explain how environmental conditions drive changes in bloom toxicity at the ecological level. First order rate constants can be calculated for changes in cell concentration (μ c: specific cell division rate) or the volumetric biomass concentration (μ g: specific growth rate) between short time intervals throughout the cell cycle. Similar first order rate constants can be calculated for changes in nett volumetric cyanotoxin concentration (μ tox: specific cyanotoxin production rate) over similar time intervals. How μ c (or μ g ) covaries with μ tox over the cell cycle shows conclusively when cyanotoxins are being produced and metabolised, and how the toxicity of cells change in response to environment stressors. When μ tox/μ c>1, cyanotoxin cell quotas increase and individual cells become more toxic because the nett cyanotoxin production rate is higher than the cell division rate. When μ tox/μ c=1, cell cyanotoxin quotas remains fixed because the nett cyanotoxin production rate matches the cell division rate. When μ tox/μ ccyanotoxin cell quota decreases because either the nett cyanotoxin production rate is lower than the cell division rate, or metabolic breakdown and/or secretion of cyanotoxins is occurring. These fundamental equations describe cyanotoxin metabolism dynamics at the cellular level and provide the necessary

R for marketing research and analytics

CERN Document Server

Chapman, Chris

2015-01-01

This book is a complete introduction to the power of R for marketing research practitioners. The text describes statistical models from a conceptual point of view with a minimal amount of mathematics, presuming only an introductory knowledge of statistics. Hands-on chapters accelerate the learning curve by asking readers to interact with R from the beginning. Core topics include the R language, basic statistics, linear modeling, and data visualization, which is presented throughout as an integral part of analysis. Later chapters cover more advanced topics yet are intended to be approachable for all analysts. These sections examine logistic regression, customer segmentation, hierarchical linear modeling, market basket analysis, structural equation modeling, and conjoint analysis in R. The text uniquely presents Bayesian models with a minimally complex approach, demonstrating and explaining Bayesian methods alongside traditional analyses for analysis of variance, linear models, and metric and choice-based conj...

Two enzymes involved in biosynthesis of the host-selective phytotoxin HC-toxin

International Nuclear Information System (INIS)

Walton, J.D.

1987-01-01

Cochliobolus carbonum race 1 produces a cyclic tetrapeptide HC-toxin, which is necessary for its exceptional virulence on certain varieties of maize. Previous genetic analysis of HC-toxin production by the fungus has indicated that a single genetic locus controls HC-toxin production. Enzymes involved in the biosynthesis of HC-toxin have been sought by following the precedents established for the biosynthetic enzymes of cyclic peptide antibiotics. Two enzymatic activities from C. carbonum race 1 were found, a D-alanine- and an L-proline-dependent ATP/PP/sub i/ exchange, which by biochemical and genetic criteria were shown to be involved in the biosynthesis of HC-toxin. These two activities were present in all tested race 1 isolates of C. carbonum, which produce HC-toxin, and in none of the tested race 2 and race 3 isolates, which do not produce the toxin. In a genetic cross between two isolates of C. carbonum differing at the tox locus, all tox + progeny had both activities, and all tox - progeny lacked both activities

Integration of biological responses from a suite of bioassays for the Venice Lagoon (Italy) through sediment toxicity index - part A: development and comparison of two methodological approaches.

Science.gov (United States)

Losso, Chiara; Novelli, Alessandra Arizzi; De Salvador, Davide; Ghetti, Pier Francesco; Ghirardini, Annamaria Volpi

2010-12-01

Marine and coastal quality assessment, based on test batteries involving a wide array of endpoints, organisms and test matrices, needs for setting up toxicity indices that integrate multiple toxicological measures for decision-making processes and that classify the continuous toxicity response into discrete categories according to the European Water Framework Directive. Two toxicity indices were developed for the lagoon environment such as the Venice Lagoon. Stepwise procedure included: the construction of a database that identified test-matrix pairs (indicators); the selection of a minimum number of ecotoxicological indicators, called toxicological core metrics (CMs-tox) on the basis of specific criteria; the development of toxicity scores for each CM-tox; the integration of the CMs-tox into two indices, the Toxicity Effect Index (TEI), based on the transformation of Toxic Unit (TU) data that were integrated as logarithmic sum, and the Weighted Average Toxicity Index (WATI), starting from toxicity classes integrated as weighted mean. Results from the indices are compared; advantages and drawbacks of both approaches are discussed. Copyright © 2010. Published by Elsevier Ltd.

ToxCast Phase I

Data.gov (United States)

U.S. Environmental Protection Agency — Background: Chemical toxicity testing is being transformed by advances in biology and computer modeling, concerns over animal use and the thousands of environmental...

From Classical Toxicology to Tox21: Some Critical Conceptual and Technological Advances in the Molecular Understanding of the Toxic Response Beginning From the Last Quarter of the 20th Century.

Science.gov (United States)

Choudhuri, Supratim; Patton, Geoffrey W; Chanderbhan, Ronald F; Mattia, Antonia; Klaassen, Curtis D

2018-01-01

Toxicology has made steady advances over the last 60+ years in understanding the mechanisms of toxicity at an increasingly finer level of cellular organization. Traditionally, toxicological studies have used animal models. However, the general adoption of the principles of 3R (Replace, Reduce, Refine) provided the impetus for the development of in vitro models in toxicity testing. The present commentary is an attempt to briefly discuss the transformation in toxicology that began around 1980. Many genes important in cellular protection and metabolism of toxicants were cloned and characterized in the 80s, and gene expression studies became feasible, too. The development of transgenic and knockout mice provided valuable animal models to investigate the role of specific genes in producing toxic effects of chemicals or protecting the organism from the toxic effects of chemicals. Further developments in toxicology came from the incorporation of the tools of "omics" (genomics, proteomics, metabolomics, interactomics), epigenetics, systems biology, computational biology, and in vitro biology. Collectively, the advances in toxicology made during the last 30-40 years are expected to provide more innovative and efficient approaches to risk assessment. A goal of experimental toxicology going forward is to reduce animal use and yet be able to conduct appropriate risk assessments and make sound regulatory decisions using alternative methods of toxicity testing. In that respect, Tox21 has provided a big picture framework for the future. Currently, regulatory decisions involving drugs, biologics, food additives, and similar compounds still utilize data from animal testing and human clinical trials. In contrast, the prioritization of environmental chemicals for further study can be made using in vitro screening and computational tools. Published by Oxford University Press on behalf of the Society of Toxicology 2017. This work is written by US Government employees and is in the

High pressure modulated transport and signaling functions of membrane proteins in models and in vivo

International Nuclear Information System (INIS)

Vogel, R F; Linke, K; Teichert, H; Ehrmann, M A

2008-01-01

Cellular membranes serve in the separation of compartments, recognition of the environment, selective transport and signal transduction. Membrane lipids and membrane proteins play distinct roles in these processes, which are affected by environmental chemical (e. g. pH) or physical (e. g. pressure and temperature) changes. High hydrostatic pressure (HHP) affects fluidity and integrity of bacterial membranes instantly during the ramp, resulting in a loss of membrane potential and vital membrane protein functions. We have used the multiple drug transporter LmrA from Lactococcus lactis and ToxR, a membrane protein sensor from Photobacterium profundum, a deep-sea bacterium, and Vibrio cholerae to study membrane protein interaction and functionality in proteolioposomes and by the use of in vivo reporter systems, respectively. Both proteins require dimerization in the phospholipid bilayer for their functionality, which was favoured in the liquid crystalline lipid phase with ToxR and LmrA. Whereas LmrA, which resides in liposomes consisting of DMPC, DMPC/cholesterol or natural lipids, lost its ATPase activity above 20 or 40 MPa, it maintained its active dimeric structure in DOPC/DPPC/cholesterol liposomes up to 120 MPa. By using a specific indicator strain in which the dimerisation of ToxR initiates the transcription of lacZ it was demonstrated, that the amino acid sequence of the transmembrane domain influences HHP stability of ToxR dimerization in vivo. Thus, both the lipid structure and the nature of the protein affect membrane protein interaction. It is suggested that the protein structure determines basic functionality, e.g. principle ability or kinetics to dimerize to a functional complex, while the lipid environment modulates this property

High pressure modulated transport and signaling functions of membrane proteins in models and in vivo

Energy Technology Data Exchange (ETDEWEB)

Vogel, R F; Linke, K; Teichert, H; Ehrmann, M A [Technische Universitaet Muenchen, Technische Mikrobiologie, Weihenstephaner Steig 16, 85350 Freising (Germany)], E-mail: rudi.vogel@wzw.tum.de

2008-07-15

Cellular membranes serve in the separation of compartments, recognition of the environment, selective transport and signal transduction. Membrane lipids and membrane proteins play distinct roles in these processes, which are affected by environmental chemical (e. g. pH) or physical (e. g. pressure and temperature) changes. High hydrostatic pressure (HHP) affects fluidity and integrity of bacterial membranes instantly during the ramp, resulting in a loss of membrane potential and vital membrane protein functions. We have used the multiple drug transporter LmrA from Lactococcus lactis and ToxR, a membrane protein sensor from Photobacterium profundum, a deep-sea bacterium, and Vibrio cholerae to study membrane protein interaction and functionality in proteolioposomes and by the use of in vivo reporter systems, respectively. Both proteins require dimerization in the phospholipid bilayer for their functionality, which was favoured in the liquid crystalline lipid phase with ToxR and LmrA. Whereas LmrA, which resides in liposomes consisting of DMPC, DMPC/cholesterol or natural lipids, lost its ATPase activity above 20 or 40 MPa, it maintained its active dimeric structure in DOPC/DPPC/cholesterol liposomes up to 120 MPa. By using a specific indicator strain in which the dimerisation of ToxR initiates the transcription of lacZ it was demonstrated, that the amino acid sequence of the transmembrane domain influences HHP stability of ToxR dimerization in vivo. Thus, both the lipid structure and the nature of the protein affect membrane protein interaction. It is suggested that the protein structure determines basic functionality, e.g. principle ability or kinetics to dimerize to a functional complex, while the lipid environment modulates this property.

High pressure modulated transport and signaling functions of membrane proteins in models and in vivo

Science.gov (United States)

Vogel, R. F.; Linke, K.; Teichert, H.; Ehrmann, M. A.

2008-07-01

Cellular membranes serve in the separation of compartments, recognition of the environment, selective transport and signal transduction. Membrane lipids and membrane proteins play distinct roles in these processes, which are affected by environmental chemical (e. g. pH) or physical (e. g. pressure and temperature) changes. High hydrostatic pressure (HHP) affects fluidity and integrity of bacterial membranes instantly during the ramp, resulting in a loss of membrane potential and vital membrane protein functions. We have used the multiple drug transporter LmrA from Lactococcus lactis and ToxR, a membrane protein sensor from Photobacterium profundum, a deep-sea bacterium, and Vibrio cholerae to study membrane protein interaction and functionality in proteolioposomes and by the use of in vivo reporter systems, respectively. Both proteins require dimerization in the phospholipid bilayer for their functionality, which was favoured in the liquid crystalline lipid phase with ToxR and LmrA. Whereas LmrA, which resides in liposomes consisting of DMPC, DMPC/cholesterol or natural lipids, lost its ATPase activity above 20 or 40 MPa, it maintained its active dimeric structure in DOPC/DPPC/cholesterol liposomes up to 120 MPa. By using a specific indicator strain in which the dimerisation of ToxR initiates the transcription of lacZ it was demonstrated, that the amino acid sequence of the transmembrane domain influences HHP stability of ToxR dimerization in vivo. Thus, both the lipid structure and the nature of the protein affect membrane protein interaction. It is suggested that the protein structure determines basic functionality, e.g. principle ability or kinetics to dimerize to a functional complex, while the lipid environment modulates this property.

Cholera toxin expression by El Tor Vibrio cholerae in shallow culture growth conditions.

Science.gov (United States)

Cobaxin, Mayra; Martínez, Haydee; Ayala, Guadalupe; Holmgren, Jan; Sjöling, Asa; Sánchez, Joaquín

2014-01-01

Vibrio cholerae O1 classical, El Tor and O139 are the primary biotypes that cause epidemic cholera, and they also express cholera toxin (CT). Although classical V. cholerae produces CT in various settings, the El Tor and O139 strains require specific growth conditions for CT induction, such as the so-called AKI conditions, which consist of growth in static conditions followed by growth under aerobic shaking conditions. However, our group has demonstrated that CT production may also take place in shallow static cultures. How these type of cultures induce CT production has been unclear, but we now report that in shallow culture growth conditions, there is virtual depletion of dissolved oxygen after 2.5 h of growth. Concurrently, during the first three to 4 h, endogenous CO2 accumulates in the media and the pH decreases. These findings may explain CT expression at the molecular level because CT production relies on a regulatory cascade, in which the key regulator AphB may be activated by anaerobiosis and by low pH. AphB activation stimulates TcpP synthesis, which induces ToxT production, and ToxT directly stimulates ctxAB expression, which encodes CT. Importantly, ToxT activity is enhanced by bicarbonate. Therefore, we suggest that in shallow cultures, AphB is activated by initial decreases in oxygen and pH, and subsequently, ToxT is activated by intracellular bicarbonate that has been generated from endogenous CO2. This working model would explain CT production in shallow cultures and, possibly, also in other growth conditions. Copyright © 2013 Elsevier Ltd. All rights reserved.

A Tox21 Approach to Altered Epigenetic Landscapes: Assessing Epigenetic Toxicity Pathways Leading to Altered Gene Expression and Oncogenic Transformation In Vitro

Directory of Open Access Journals (Sweden)

Craig L. Parfett

2017-06-01

A, UHRF1, CTCF, HOTAIR and ANRIL were found to have experimental evidence showing that functional perturbations played “driver” roles in human cellular transformation. Measurement of epigenotoxicants presents challenges for short-term carcinogenicity testing, especially in the high-throughput modes emphasized in the Tox21 chemicals testing approach. There is need to develop and validate in vitro tests to detect both, locus-specific, and genome-wide, epigenetic alterations with causal links to oncogenic cellular phenotypes. Some recent examples of cell-based high throughput chemical screening assays are presented that have been applied or have shown potential for application to epigenetic endpoints.

Integration of biological responses from a suite of bioassays for the Venice Lagoon (Italy) through sediment toxicity index - Part A: Development and comparison of two methodological approaches

International Nuclear Information System (INIS)

Losso, Chiara; Novelli, Alessandra Arizzi; De Salvador, Davide; Ghetti, Pier Francesco; Ghirardini, Annamaria Volpi

2010-01-01

Marine and coastal quality assessment, based on test batteries involving a wide array of endpoints, organisms and test matrices, needs for setting up toxicity indices that integrate multiple toxicological measures for decision-making processes and that classify the continuous toxicity response into discrete categories according to the European Water Framework Directive. Two toxicity indices were developed for the lagoon environment such as the Venice Lagoon. Stepwise procedure included: the construction of a database that identified test-matrix pairs (indicators); the selection of a minimum number of ecotoxicological indicators, called toxicological core metrics (CMs-tox) on the basis of specific criteria; the development of toxicity scores for each CM-tox; the integration of the CMs-tox into two indices, the Toxicity Effect Index (TEI), based on the transformation of Toxic Unit (TU) data that were integrated as logarithmic sum, and the Weighted Average Toxicity Index (WATI), starting from toxicity classes integrated as weighted mean. Results from the indices are compared; advantages and drawbacks of both approaches are discussed. - Two toxicity indices were set up and compared to integrate toxicity data from a battery of bioassays for the Venice lagoon.

Integration of biological responses from a suite of bioassays for the Venice Lagoon (Italy) through sediment toxicity index - Part A: Development and comparison of two methodological approaches

Energy Technology Data Exchange (ETDEWEB)

Losso, Chiara, E-mail: closso@unive.i [Environmental Sciences Department, University Ca' Foscari of Venice, Campo della Celestia 2737/b, I-30122 Venice (Italy); Novelli, Alessandra Arizzi [Environmental Sciences Department, University Ca' Foscari of Venice, Campo della Celestia 2737/b, I-30122 Venice (Italy); De Salvador, Davide [Physics Department, Padova University, via Marzolo 8, 35131 Padova (Italy); Ghetti, Pier Francesco; Ghirardini, Annamaria Volpi [Environmental Sciences Department, University Ca' Foscari of Venice, Campo della Celestia 2737/b, I-30122 Venice (Italy)

2010-12-15

Marine and coastal quality assessment, based on test batteries involving a wide array of endpoints, organisms and test matrices, needs for setting up toxicity indices that integrate multiple toxicological measures for decision-making processes and that classify the continuous toxicity response into discrete categories according to the European Water Framework Directive. Two toxicity indices were developed for the lagoon environment such as the Venice Lagoon. Stepwise procedure included: the construction of a database that identified test-matrix pairs (indicators); the selection of a minimum number of ecotoxicological indicators, called toxicological core metrics (CMs-tox) on the basis of specific criteria; the development of toxicity scores for each CM-tox; the integration of the CMs-tox into two indices, the Toxicity Effect Index (TEI), based on the transformation of Toxic Unit (TU) data that were integrated as logarithmic sum, and the Weighted Average Toxicity Index (WATI), starting from toxicity classes integrated as weighted mean. Results from the indices are compared; advantages and drawbacks of both approaches are discussed. - Two toxicity indices were set up and compared to integrate toxicity data from a battery of bioassays for the Venice lagoon.

OCORRÊNCIA NATURAL DE MICOTOXINAS EM MILHO (Zea mays L.) E SUA INFLUÊNCIA NO DESEMPENHO DE FRANGOS DE CORTE

OpenAIRE

Maurício Schneider Oliveira

2014-01-01

Fungos podem ser encontrados em toda a natureza e são de conhecida ocorrência na cultura do milho. Aqueles que possuem a capacidade de produzir substâncias tóxicas para humanos e animais, a partir de seu metabolismo secundário, denominam-se fungos toxígenos e os metabólitos produzidos são denominados micotoxinas. Devido a presença de diversas espécies fúngicas toxígenas na lavoura de milho, a ocorrência de um grande número de metabólitos é esperada. Além de ocorrerem em sua forma nativa, mico...

Role of the Helicobacter pylori virulence factors vacuolating cytotoxin, CagA, and urease in a mouse model of disease.

Science.gov (United States)

Ghiara, P; Marchetti, M; Blaser, M J; Tummuru, M K; Cover, T L; Segal, E D; Tompkins, L S; Rappuoli, R

1995-10-01

The pathogenic role of Helicobacter pylori virulence factors has been studied with a mouse model of gastric disease. BALB/c mice were treated orally with different amounts of sonic extracts of cytotoxic H. pylori strains (NCTC 11637, 60190, 84-183, and 87A300 [CagA+/Tox+]). The pathological effects on histological sections of gastric mucosae were assessed and were compared with the effects of treatments with extracts from noncytotoxic strains (G21 and G50 [CagA-/Tox-]) and from strains that express either CagA alone (D931 [CagA+/Tox-]) or the cytotoxin alone (G104 [CagA-/Tox+]). The treatment with extracts from cytotoxic strains induced various epithelial lesions (vacuolation, erosions, and ulcerations), recruitment of inflammatory cells in the lamina propria, and a marked reduction of the mucin layer. Extracts of noncytotoxic strains induced mucin depletion but no other significant pathology. Crude extracts of strain D931, expressing CagA alone, caused only mild infiltration of inflammatory cells, whereas extracts of strain G104, expressing cytotoxin alone, induced extensive epithelial damage but little inflammatory reaction. Loss of the mucin layer was not associated with a cytotoxic phenotype, since this loss was observed in mice treated with crude extracts of all strains. The pathogenic roles of CagA, cytotoxin, and urease were further assessed by using extracts of mutant strains of H. pylori defective in the expression of each of these virulence factors. The results obtained suggest that (i) urease activity does not play a significant role in inducing the observed gastric damage, (ii) cytotoxin has an important role in the induction of gastric epithelial cell lesions but not in eliciting inflammation, and (iii) other components present in strains which carry the cagA gene, but distinct from CagA itself, are involved in eliciting the inflammatory response.

Evaluation of the performance of C. DIFF QUIK CHEK COMPLETE and its usefulness in a hospital setting with a high prevalence of Clostridium difficile infection.

Science.gov (United States)

Chung, Hae-Sun; Lee, Miae

2017-01-01

Rapid and accurate diagnosis of Clostridium difficile infection (CDI) is crucial for patient care, infection control, and efficient surveillance. We evaluated C. DIFF QUIK CHEK COMPLETE (QCC; TechLab), which detects glutamate dehydrogenase (GDH) antigen (QCC-Ag) and toxin A/B (QCC-Tox) simultaneously, and compared it to the laboratory diagnostics for CDI currently in use in a tertiary hospital setting with a high prevalence of CDI. QCC, RIDASCREEN C. difficile toxin A/B assay (Toxin EIA; R-Biopharm AG), chromID C. difficile agar (bioMérieux) culture (ChromID culture), and Xpert C. difficile PCR assay (Xpert PCR; Cepheid) were performed according to the manufacturers' instructions. Performances of the assays were compared against that of Xpert PCR as a reference. Of the 231 loose stool specimens, 83 (35.9%) were positive by Xpert PCR. The sensitivity, specificity, and positive and negative predictive values were 97.6%, 93.9%, 90.0%, and 98.6%, respectively, for QCC-Ag and 55.4%, 100%, 100%, and 80.0%, respectively, for QCC-Tox. The median threshold cycle values of the QCC-Tox(+) specimens were lower than those of the QCC-Tox(-) specimens. Results of QCC as an initial screening test were confirmed in 81.0% (187/231) of samples; these specimens did not require further testing. QCC is a rapid, easy, and cost-effective method that would be a useful first-line screening assay for laboratory diagnosis of CDI in a tertiary hospital with a high prevalence of CDI. A two-step algorithm using QCC as an initial screening tool, followed by Xpert PCR as a confirmatory test, is a practical and cost-effective approach. Copyright © 2016 American Federation for Medical Research.

Structure Identification Using the US EPA's CompTox Chemistry Dashboard (CompTox CoP)

Science.gov (United States)

Community of practice webinar presentation on the Identification of unknowns in non-targeted analyses (NTA) requires the integration of complementary data types to generate a confident consensus structure.

Designing a Quantitative Structure-Activity Relationship for the ...

Science.gov (United States)

Toxicokinetic models serve a vital role in risk assessment by bridging the gap between chemical exposure and potentially toxic endpoints. While intrinsic metabolic clearance rates have a strong impact on toxicokinetics, limited data is available for environmentally relevant chemicals including nearly 8000 chemicals tested for in vitro bioactivity in the Tox21 program. To address this gap, a quantitative structure-activity relationship (QSAR) for intrinsic metabolic clearance rate was developed to offer reliable in silico predictions for a diverse array of chemicals. Models were constructed with curated in vitro assay data for both pharmaceutical-like chemicals (ChEMBL database) and environmentally relevant chemicals (ToxCast screening) from human liver microsomes (2176 from ChEMBL) and human hepatocytes (757 from ChEMBL and 332 from ToxCast). Due to variability in the experimental data, a binned approach was utilized to classify metabolic rates. Machine learning algorithms, such as random forest and k-nearest neighbor, were coupled with open source molecular descriptors and fingerprints to provide reasonable estimates of intrinsic metabolic clearance rates. Applicability domains defined the optimal chemical space for predictions, which covered environmental chemicals well. A reduced set of informative descriptors (including relative charge and lipophilicity) and a mixed training set of pharmaceuticals and environmentally relevant chemicals provided the best intr

Prioritizing Environmental Chemicals for Obesity and Diabetes ...

Science.gov (United States)

Background: Diabetes and obesity are major threats to public health in the US and abroad. Understanding the role chemicals in our environment play in the development of these conditions is an emerging issue in environmental health, although identifying and prioritizing chemicals for testing beyond those already implicated in the literature is a challenge. This review is intended to help researchers generate hypotheses about chemicals potentially contributing to diabetes and obesity-related health outcomes by summarizing relevant findings from the US Environmental Protection Agency (EPA) ToxCast high-throughput screening (HTS) program. Objectives: To develop new hypotheses around environmental chemicals of potential interest for diabetes- or obesity-related outcomes using high throughput screening data. Methods: Identify ToxCast assay targets relevant to several biological processes related to diabetes and obesity (insulin sensitivity in peripheral tissue, pancreatic islet and beta cell function, adipocyte dierentiation, and feeding behavior) and present chemical screening data against those assay targets to identify chemicals of potential interest. Discussion: Results of this screening-level analysis suggest that the spectrum of environmental chemicals to consider in research related to diabetes and obesity is much broader than indicated from research papers and reviews published in the peer-reviewed literature. Testing of hypotheses based on ToxCast data will a

Tribbles ortholog NIPI-3 and bZIP transcription factor CEBP-1 regulate a Caenorhabditis elegans intestinal immune surveillance pathway.

Science.gov (United States)

McEwan, Deborah L; Feinbaum, Rhonda L; Stroustrup, Nicholas; Haas, Wilhelm; Conery, Annie L; Anselmo, Anthony; Sadreyev, Ruslan; Ausubel, Frederick M

2016-12-07

Many pathogens secrete toxins that target key host processes resulting in the activation of immune pathways. The secreted Pseudomonas aeruginosa toxin Exotoxin A (ToxA) disrupts intestinal protein synthesis, which triggers the induction of a subset of P. aeruginosa-response genes in the nematode Caenorhabditis elegans. We show here that one ToxA-induced C. elegans gene, the Tribbles pseudokinase ortholog nipi-3, is essential for host survival following exposure to P. aeruginosa or ToxA. We find that NIPI-3 mediates the post-developmental expression of intestinal immune genes and proteins and primarily functions in parallel to known immune pathways, including p38 MAPK signaling. Through mutagenesis screening, we identify mutants of the bZIP C/EBP transcription factor cebp-1 that suppress the hypersusceptibility defects of nipi-3 mutants. NIPI-3 is a negative regulator of CEBP-1, which in turn negatively regulates protective immune mechanisms. This pathway represents a previously unknown innate immune signaling pathway in intestinal epithelial cells that is involved in the surveillance of cellular homeostasis. Because NIPI-3 and CEBP-1 are also essential for C. elegans development, NIPI-3 is analogous to other key innate immune signaling molecules such as the Toll receptors in Drosophila that have an independent role during development.

Morbilidad y mortalidad en neonatos hijos de madres toxémicas Morbidity and mortality related to infants of toxemic mothers

Directory of Open Access Journals (Sweden)

Yanett Sarmiento Portal

2009-09-01

Full Text Available INTRODUCCIÓN. La preeclampsia-eclampsia se caracteriza por edema, hipertensión arterial y proteinuria presente entre la vigésima semana de la gestación hasta 14 días después del parto. La presente investigación se realizó con el objetivo de analizar la morbilidad y mortalidad en neonatos hijos de madres toxémicas, en el Hospital «Abel Santamaría», en Pinar del Río. MÉTODOS. Se realizó un estudio observacional, ambispectivo, longitudinal, descriptivo, en el período entre el 1 de enero de 2006 y el 31 de diciembre de 2007. Se estudiaron 129 neonatos cuyas madres presentaron hipertensión durante el embarazo. Se analizaron las variables: tipo de hipertensión, vía del nacimiento, prematuridad, Apgar, peso, crecimiento intrauterino, morbilidad y mortalidad. RESULTADOS. Predominó la hipertensión arterial (HTA inducida por el embarazo y el nacimiento por cesárea (74,4 %. La HTA crónica y con toxemia sobreañadida se relacionó con mayores porcentajes de prematuridad, crecimiento intrauterino retardado y Apgar bajo. La morbilidad predominante fue la hipoxia al nacer (22,5 %, seguida por la enterocolitis necrosante (12,4 % y el síndrome de dificultad respiratoria (10,8 %. La tasa de mortalidad fue de 1,3 por 1000 nacidos vivos y la de letalidad ascendió a 31 por cada 100 casos. CONCLUSIONES. La hipertensión arterial en el embarazo influye negativamente en una serie de parámetros perinatales, entre los cuales destacan en nuestro medio el incremento de las cesáreas, el bajo peso al nacer, el crecimiento intrauterino retardado y la hipoxia al nacer, entre otras patologías.INTRODUCTION: Pre-eclampsia-eclampsia is characterized by edema, high blood pressure and proteinuria present between the twentieth weeks of pregnancy up to 14 postpartum. Aim of present research was to analyze morbidity and mortality in infants of toxemic mothers at "Abel Santamiría Cuadrado' Hospital, Pinar del Río province. METHODS: A observational

Mercury and Your Health

Science.gov (United States)

... the Risk of Exposure to Mercury Learn About Mercury What is Mercury What is Metallic mercury? Toxicological Profile ToxFAQs Mercury Resources CDC’s National Biomonitoring Program Factsheet on Mercury ...

77 FR 71605 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2012-12-03

... Hersh, Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville... Analytics Inc., NOVAMANN (Ontario), Inc.) MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN...

77 FR 32653 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2012-06-01

... Hersh, Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville... Analytics Inc., NOVAMANN (Ontario), Inc.). MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN...

Modern trends in theoretical radiation chemistry development

International Nuclear Information System (INIS)

Kaplan, I.G.

1983-01-01

Most important trends in the development of radiation chemitry theory are considered. Wide use of electronic computers for modeling different stages of radiolysis in conjUnction with advanced precision experimental methods (picosecond pulse radiolysis, acceptor additions method, magnetic method of detecting interstitial active particles) is noted. Information obtained in photochemistry and molecular spectroscopy, including laser photolysis, is in common use in developing the theory. It is noted that data on the processes occurring within less than 10 -12 s time can be obtained now only on the base of theoretical representations about the mechanism of ionizing irradiation interaction with molecular medium. Therefore, special attention in the review is paid to investigation of primary radiolysis processes. Besides investigation of primary medium excitation processes theoretical investigations into the ways of energy degradation, knocked out electrons and their further state are continued. It is noted that a considerable number of papers deal with the nature and behaviour of radiation-induced excess electrons in non-polar solutions and solid matrices. Works on application of diffusion kinetics in radiolysis have been developed in recent years

Protein secretion and membrane insertion systems in gram-negative bacteria.

Science.gov (United States)

Saier, Milton H

2006-01-01

In contrast to other organisms, gram-negative bacteria have evolved numerous systems for protein export. Eight types are known that mediate export across or insertion into the cytoplasmic membrane, while eight specifically mediate export across or insertion into the outer membrane. Three of the former secretory pathway (SP) systems, type I SP (ISP, ABC), IIISP (Fla/Path) and IVSP (Conj/Vir), can export proteins across both membranes in a single energy-coupled step. A fourth generalized mechanism for exporting proteins across the two-membrane envelope in two distinct steps (which we here refer to as type II secretory pathways [IISP]) utilizes either the general secretory pathway (GSP or Sec) or the twin-arginine targeting translocase for translocation across the inner membrane, and either the main terminal branch or one of several protein-specific export systems for translocation across the outer membrane. We here survey the various well-characterized protein translocation systems found in living organisms and then focus on the systems present in gram-negative bacteria. Comparisons between these systems suggest specific biogenic, mechanistic and evolutionary similarities as well as major differences.

AN ANALYSIS OF STUDENTS’ FREE WRITING

Directory of Open Access Journals (Sweden)

Rahmi Phonna

2014-05-01

Full Text Available Writing contains a compound process to be expressed that entails the writer to pay more attention on linking appropriate words together. Most linguists agree that a writer should attain high level of understanding to pursue the lifelong learning of academic writing pedagogy. This study aimed to analyze the students’ free writing by identifying the category of mistakes that often appear on their writing assignment. 28 free writings were collected, as the main data, from 28 students as the samples for this study. They were then analyzed by using the guidelines of correction symbols from Hogue (1996 and Oshima & Hogue (1999. The results revealed that 11 categories of grammar that often applied incorrectly on the students’ free writing. The misused of verb-agreement (V/A was the most frequent category occurred, followed by word form (Wf and Spelling (Sp. The least category of errors identified on the students’ free writing was conjunction (Conj and wrong word (Ww categories. Overall, 175 errors from different grammatical conventions were repeated in the students’ free writing.

DSSTox: The Open Environmental Chemistry Data underlying the CompTox Chemical Dashboard (OpenTox USA)

Science.gov (United States)

The DSSTox project has long been dedicated to the idea of making chemical information linked to environmental or toxicological data of interest freely available. Since its first posting of data files in 2004, DSSTox database development has consistently focused on enabling data ...

Consensus models to predict endocrine disruption for all ...

Science.gov (United States)

Humans are potentially exposed to tens of thousands of man-made chemicals in the environment. It is well known that some environmental chemicals mimic natural hormones and thus have the potential to be endocrine disruptors. Most of these environmental chemicals have never been tested for their ability to disrupt the endocrine system, in particular, their ability to interact with the estrogen receptor. EPA needs tools to prioritize thousands of chemicals, for instance in the Endocrine Disruptor Screening Program (EDSP). Collaborative Estrogen Receptor Activity Prediction Project (CERAPP) was intended to be a demonstration of the use of predictive computational models on HTS data including ToxCast and Tox21 assays to prioritize a large chemical universe of 32464 unique structures for one specific molecular target – the estrogen receptor. CERAPP combined multiple computational models for prediction of estrogen receptor activity, and used the predicted results to build a unique consensus model. Models were developed in collaboration between 17 groups in the U.S. and Europe and applied to predict the common set of chemicals. Structure-based techniques such as docking and several QSAR modeling approaches were employed, mostly using a common training set of 1677 compounds provided by U.S. EPA, to build a total of 42 classification models and 8 regression models for binding, agonist and antagonist activity. All predictions were evaluated on ToxCast data and on an exte

Accelerating Adverse Outcome Pathway (AOP) development ...

Science.gov (United States)

The Adverse Outcome Pathway (AOP) framework is increasingly being adopted as a tool for organizing and summarizing the mechanistic information connecting molecular perturbations by environmental stressors with adverse outcomes relevant for ecological and human health outcomes. However, the conventional process for assembly of these AOPs is time and resource intensive, and has been a rate limiting step for AOP use and development. Therefore computational approaches to accelerate the process need to be developed. We previously developed a method for generating computationally predicted AOPs (cpAOPs) by association mining and integration of data from publicly available databases. In this work, a cpAOP network of ~21,000 associations was established between 105 phenotypes from TG-GATEs rat liver data from different time points (including microarray, pathological effects and clinical chemistry data), 994 REACTOME pathways, 688 High-throughput assays from ToxCast and 194 chemicals. A second network of 128,536 associations was generated by connecting 255 biological target genes from ToxCast to 4,980 diseases from CTD using either HT screening activity from ToxCast for 286 chemicals or CTD gene expression changes in response to 2,330 chemicals. Both networks were separately evaluated through manual extraction of disease-specific cpAOPs and comparison with expert curation of the relevant literature. By employing data integration strategies that involve the weighting of n

Primary human polarized small intestinal epithelial barriers respond differently to a hazardous and an innocuous protein.

Science.gov (United States)

Eaton, A D; Zimmermann, C; Delaney, B; Hurley, B P

2017-08-01

An experimental platform employing human derived intestinal epithelial cell (IEC) line monolayers grown on permeable Transwell ® filters was previously investigated to differentiate between hazardous and innocuous proteins. This approach was effective at distinguishing these types of proteins and perturbation of monolayer integrity, particularly transepithelial electrical resistance (TEER), was the most sensitive indicator. In the current report, in vitro indicators of monolayer integrity, cytotoxicity, and inflammation were evaluated using primary (non-transformed) human polarized small intestinal epithelial barriers cultured on Transwell ® filters to compare effects of a hazardous protein (Clostridium difficile Toxin A [ToxA]) and an innocuous protein (bovine serum albumin [BSA]). ToxA exerted a reproducible decrease on barrier integrity at doses comparable to those producing effects observed from cell line-derived IEC monolayers, with TEER being the most sensitive indicator. In contrast, BSA, tested at concentrations substantially higher than ToxA, did not cause changes in any of the tested variables. These results demonstrate a similarity in response to certain proteins between cell line-derived polarized IEC models and a primary human polarized small intestinal epithelial barrier model, thereby reinforcing the potential usefulness of cell line-derived polarized IECs as a valid experimental platform to differentiate between hazardous and non-hazardous proteins. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Analysis of Ingredient Lists to Quantitatively Characterize ...

Science.gov (United States)

The EPA’s ExpoCast program is developing high throughput (HT) approaches to generate the needed exposure estimates to compare against HT bioactivity data generated from the US inter-agency Tox21 and the US EPA ToxCast programs. Assessing such exposures for the thousands of chemicals in consumer products requires data on product composition. This is a challenge since quantitative product composition data are rarely available. We developed methods to predict the weight fractions of chemicals in consumer products from weight fraction-ordered chemical ingredient lists, and curated a library of such lists from online manufacturer and retailer sites. The probabilistic model predicts weight fraction as a function of the total number of reported ingredients, the rank of the ingredient in the list, the minimum weight fraction for which ingredients were reported, and the total weight fraction of unreported ingredients. Weight fractions predicted by the model compared very well to available quantitative weight fraction data obtained from Material Safety Data Sheets for products with 3-8 ingredients. Lists were located from the online sources for 5148 products containing 8422 unique ingredient names. A total of 1100 of these names could be located in EPA’s HT chemical database (DSSTox), and linked to 864 unique Chemical Abstract Service Registration Numbers (392 of which were in the Tox21 chemical library). Weight fractions were estimated for these 864 CASRN. Using a

High-throughput literature mining to support read-across ...

Science.gov (United States)

Building scientific confidence in the development and evaluation of read-across remains an ongoing challenge. Approaches include establishing systematic frameworks to identify sources of uncertainty and ways to address them. One source of uncertainty is related to characterizing biological similarity. Many research efforts are underway such as structuring mechanistic data in adverse outcome pathways and investigating the utility of high throughput (HT)/high content (HC) screening data. A largely untapped resource for read-across to date is the biomedical literature. This information has the potential to support read-across by facilitating the identification of valid source analogues with similar biological and toxicological profiles as well as providing the mechanistic understanding for any prediction made. A key challenge in using biomedical literature is to convert and translate its unstructured form into a computable format that can be linked to chemical structure. We developed a novel text-mining strategy to represent literature information for read across. Keywords were used to organize literature into toxicity signatures at the chemical level. These signatures were integrated with HT in vitro data and curated chemical structures. A rule-based algorithm assessed the strength of the literature relationship, providing a mechanism to rank and visualize the signature as literature ToxPIs (LitToxPIs). LitToxPIs were developed for over 6,000 chemicals for a varie

Functional Use Database (FUse)

Data.gov (United States)

U.S. Environmental Protection Agency — There are five different files for this dataset: 1. A dataset listing the reported functional uses of chemicals (FUse) 2. All 729 ToxPrint descriptors obtained from...

Quantitative Structure-Use Relationship (QSUR) Model Descriptors

Data.gov (United States)

U.S. Environmental Protection Agency — This data set contains ToxPrint finger prints for all chemicals in FUse that had QSAR-ready SMILES strings as well as select physicochemical properties from the...

Drug design: structure- and ligand-based approaches

National Research Council Canada - National Science Library

Merz, Kenneth M; Ringe, Dagmar; Reynolds, Charles H

2010-01-01

..., computational ADME-Tox, and drug discovery case studies. A variety of authors from academic and commercial institutions all over the world have contributed to this book, which is illustrated with more than 200 images...

76 FR 40924 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2011-07-12

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857...., NOVAMANN (Ontario), Inc.). MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636...

76 FR 31969 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2011-06-02

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857...., NOVAMANN (Ontario), Inc.). MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636...

76 FR 161 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2011-01-03

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857... certification maintenance program. MedTox Laboratories, Inc., 402 W. County Road D,St. Paul, MN 55112. 651-636...

77 FR 26022 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2012-05-02

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857...., NOVAMANN (Ontario), Inc.). MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636...

77 FR 5037 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2012-02-01

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857...., NOVAMANN (Ontario), Inc.); MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636...

77 FR 20832 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2012-04-06

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857...., NOVAMANN (Ontario), Inc.). MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636...

77 FR 54597 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2012-09-05

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857...., NOVAMANN (Ontario), Inc.). MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636...

Single Nucleotide Polymorphisms in Regulator-Encoding Genes Have an Additive Effect on Virulence Gene Expression in a Vibrio cholerae Clinical Isolate.

Science.gov (United States)

Carignan, Bailey M; Brumfield, Kyle D; Son, Mike S

2016-01-01

Vibrio cholerae is the etiological agent of the infectious disease cholera, which is characterized by vomiting and severe watery diarrhea. Recently, V. cholerae clinical isolates have demonstrated increased virulence capabilities, causing more severe symptoms with a much higher rate of disease progression than previously observed. We have identified single nucleotide polymorphisms (SNPs) in four virulence-regulatory genes (hapR, hns, luxO, and vieA) of a hypervirulent V. cholerae clinical isolate, MQ1795. Herein, all SNPs and SNP combinations of interest were introduced into the prototypical El Tor reference strain N16961, and the effects on the production of numerous virulence-related factors, including cholera toxin (CT), the toxin-coregulated pilus (TCP), and ToxT, were analyzed. Our data show that triple-SNP (hapR hns luxO and hns luxO vieA) and quadruple-SNP combinations produced the greatest increases in CT, TCP, and ToxT production. The hns and hns luxO SNP combinations were sufficient for increased TCP and ToxT production. Notably, the hns luxO vieA triple-SNP combination strain produced TCP and ToxT levels similar to those of MQ1795. Certain SNP combinations (hapR and hapR vieA) had the opposite effect on CT, TCP, and ToxT expression. Interestingly, the hns vieA double-SNP combination strain increased TCP production while decreasing CT production. Our findings suggest that SNPs identified in the four regulatory genes, in various combinations, are associated with increased virulence capabilities observed in V. cholerae clinical isolates. These studies provide insight into the evolution of highly virulent strains. IMPORTANCE Cholera, an infectious disease of the small intestine caused by the aquatic bacterium Vibrio cholerae, often results in vomiting and acute watery diarrhea. If left untreated or if the response is too slow, the symptoms can quickly lead to extreme dehydration and ultimately death of the patient. Recent anecdotal evidence of cholera

76 FR 75889 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2011-12-05

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857... (Ontario), Inc.). MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, (651) 636-7466/(800...

78 FR 14100 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2013-03-04

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857... Laboratory Services, a Division of LabOne, Inc.,) MedTox Laboratories, Inc., 402 W. County Road D, St. Paul...

75 FR 45128 - Current List of Laboratories Which Meet Minimum Standards To Engage in Urine Drug Testing for...

Science.gov (United States)

2010-08-02

.../CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857; 240-276-2600 (voice), 240-276-2610... Analytics Inc., NOVAMANN (Ontario), Inc.) MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN...

77 FR 126 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2012-01-03

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857....). MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, (651) 636-7466/(800) 832-3244...

ECOTOX Knowledgebase: New tools for data visualization and database interoperability (poster)

Science.gov (United States)

The ECOTOXicology knowledgebase (ECOTOX) is a comprehensive, curated database that summarizes toxicology data from single chemical exposure studies to terrestrial and aquatic organisms. The ECOTOX Knowledgebase provides risk assessors and researchers consistent information on tox...

77 FR 69642 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2012-11-20

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857... (Ontario), Inc.) MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636-7466/800-832...

75 FR 5088 - Current List of Laboratories Which Meet Minimum Standards To Engage in Urine Drug Testing for...

Science.gov (United States)

2010-02-01

.../CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857; 240-276-2600 (voice), 240-276-2610...., NOVAMANN (Ontario), Inc.). MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636...

76 FR 24501 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2011-05-02

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857... (Ontario), Inc.) MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636-7466/800-832...

76 FR 6147 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2011-02-03

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857....) MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112. 651-636-7466/800-832-3244. Metro...

78 FR 33429 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2013-06-04

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857....). MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636-7466/800-832-3244. Metro...

76 FR 46309 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2011-08-02

..., Division of Workplace Programs, SAMHSA/CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857... (Ontario), Inc.) MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636-7466/800-832...

78 FR 72684 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2013-12-03

... INFORMATION CONTACT: Giselle Hersh, Division of Workplace Programs, SAMHSA/CSAP, Room 7-1051, One Choke Cherry..., a Division of LabOne, Inc.) MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651...

78 FR 59946 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2013-09-30

... INFORMATION CONTACT: Giselle Hersh, Division of Workplace Programs, SAMHSA/CSAP, Room 7-1051, One Choke Cherry....). MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636-7466/800-832-3244. Metro...

75 FR 75485 - Current List of Laboratories Which Meet Minimum Standards To Engage in Urine Drug Testing for...

Science.gov (United States)

2010-12-03

..., Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857; 240-276-2600 (voice), 240-276-2610 (fax...., NOVAMANN (Ontario), Inc.). MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112. 651-636...

75 FR 62842 - Current List of Laboratories Which Meet Minimum Standards To Engage in Urine Drug Testing for...

Science.gov (United States)

2010-10-13

..., Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857; 240-276-2600 (voice), 240-276-2610 (fax...., NOVAMANN (Ontario), Inc.) MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636-7466...

ToxCast Profiling in a Human Stem Cell Assay for Developmental Toxicity (CompTox CoP)

Science.gov (United States)

Standard practice for assessing disruptions in embryogenesis involves testing pregnant animals of two species, typically rats and rabbits, exposed during major organogenesis and evaluated just prior to term. Under this design the major manifestations of developmental toxicity are...

Association of water-borne diseases morbidity pattern and water ...

African Journals Online (AJOL)

1Department of Env ronmental Management and Tox cology, Un vers ty of Agr culture, PMB 2240,. Abeokuta, Ogun .... and a modern sector) that has implications for ... plastered with cement. ..... residents are at–risk of water-borne diseases.

78 FR 46996 - Current List of Laboratories and Instrumented Initial Testing Facilities Which Meet Minimum...

Science.gov (United States)

2013-08-02

..., Room 7-1051, One Choke Cherry Road, Rockville, Maryland 20857; 240-276-2600 (voice), 240-276-2610 (fax....) MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636-7466/800-832-3244 Metro...

75 FR 9229 - Current List of Laboratories Which Meet Minimum Standards To Engage in Urine Drug Testing for...

Science.gov (United States)

2010-03-01

.../CSAP, Room 2-1042, One Choke Cherry Road, Rockville, Maryland 20857; 240-276-2600 (voice), 240-276-2610... (Ontario), Inc.) MedTox Laboratories, Inc., 402 W. County Road D, St. Paul, MN 55112, 651-636-7466/800-832...

Systems Toxicology of Embryo Development (9th Copenhagen Workshop)

Science.gov (United States)

An important consideration for predictive toxicology is to identify developmental hazards utilizing mechanism-based in vitro assays (e.g., ToxCast) and in silico multiscale models. Steady progress has been made with agent-based models that recapitulate morphogenetic drivers for a...

Toxicity assessment of reference and natural freshwater sediments with the luminotox assay

CSIR Research Space (South Africa)

Dellamatrice, PM

2006-08-01

Full Text Available to exist between LuminoTox-Solid Phase Assay (Lum-SPA) and Microtox Solid Phase Assay (Mic-SPA) indicating that both tests display a similar toxicity response pattern for CRM sediments having differing contaminant profiles. The sediment elutriate Lum...

Differentiating pathway-specific from nonspecific effects in high-throughput toxicity data: A foundation for prioritizing adverse outcome pathway development

Science.gov (United States)

The U.S. Environmental Protection Agency’s ToxCast program has screened thousands of chemicals for biological activity, primarily using high-throughput in vitro bioassays. Adverse outcome pathways (AOPs) offer a means to link pathway-specific biological activities with potential ...

Identification of Chemical Features Linked to Thyroperoxidase Inhibition (SOT)

Science.gov (United States)

Disruption of maternal serum thyroid hormone (TH) adversely affects fetal neurodevelopment. Therefore, assay development within the US EPA ToxCast program is ongoing to enable screening for chemicals that may disrupt TH, in support of the Endocrine Disruption Screening Program (E...

ExpoCast: Exposure Science for Prioritization and Toxicity Testing (S)

Science.gov (United States)

The US EPA is completing the Phase I pilot for a chemical prioritization research program, called ToxCast. Here EPA is developing methods for using computational chemistry, high-throughput screening, and toxicogenomic technologies to predict potential toxicity and prioritize limi...

ExpoCast: Exposure Science for Prioritization and Toxicity Testing

Science.gov (United States)

The US EPA is completing the Phase I pilot for a chemical prioritization research program, called ToxCastTM. Here EPA is developing methods for using computational chemistry, high-throughput screening, and toxicogenomic technologies to predict potential toxicity and prioritize l...

20180311 - High Throughput Transcriptomics: From screening to pathways (SOT 2018)

Science.gov (United States)

The EPA ToxCast effort has screened thousands of chemicals across hundreds of high-throughput in vitro screening assays. The project is now leveraging high-throughput transcriptomic (HTTr) technologies to substantially expand its coverage of biological pathways. The first HTTr sc...

COMMUNITY SCALE STREAM TAXA SENSITIVITIES TO DIFFERENT COMPOSITIONS OF EXCESS TOTAL DISSOLVED SOLIDS

Science.gov (United States)

Model stream chronic dosing studies (42 d) were conducted with three total dissolved solids (TDS) recipes. The recipes differed in composition of major ions. Community scale emergence was compared with single-species responses conducted simultaneously using the whole effluent tox...

Predictive Toxicology and Computer Simulation of Male Reproductive Development (Duke U KURe and PMRC research day)

Science.gov (United States)

The reproductive tract is a complex, integrated organ system with diverse embryology and unique sensitivity to prenatal environmental exposures that disrupt morphoregulatory processes and endocrine signaling. U.S. EPA’s in vitro high-throughput screening (HTS) database (ToxCastDB...

Multiscale Systems Modeling of Male Reproductive Tract Defects: from Genes to Populations (SOT)

Science.gov (United States)

The reproductive tract is a complex, integrated organ system with diverse embryology and unique sensitivity to prenatal environmental exposures that disrupt morphoregulatory processes and endocrine signaling. U.S. EPA’s in vitro high-throughput screening (HTS) database (ToxCastDB...

Genome-Based Comparison of Clostridioides difficile: Average Amino Acid Identity Analysis of Core Genomes.

Science.gov (United States)

Cabal, Adriana; Jun, Se-Ran; Jenjaroenpun, Piroon; Wanchai, Visanu; Nookaew, Intawat; Wongsurawat, Thidathip; Burgess, Mary J; Kothari, Atul; Wassenaar, Trudy M; Ussery, David W

2018-02-14

Infections due to Clostridioides difficile (previously known as Clostridium difficile) are a major problem in hospitals, where cases can be caused by community-acquired strains as well as by nosocomial spread. Whole genome sequences from clinical samples contain a lot of information but that needs to be analyzed and compared in such a way that the outcome is useful for clinicians or epidemiologists. Here, we compare 663 public available complete genome sequences of C. difficile using average amino acid identity (AAI) scores. This analysis revealed that most of these genomes (640, 96.5%) clearly belong to the same species, while the remaining 23 genomes produce four distinct clusters within the Clostridioides genus. The main C. difficile cluster can be further divided into sub-clusters, depending on the chosen cutoff. We demonstrate that MLST, either based on partial or full gene-length, results in biased estimates of genetic differences and does not capture the true degree of similarity or differences of complete genomes. Presence of genes coding for C. difficile toxins A and B (ToxA/B), as well as the binary C. difficile toxin (CDT), was deduced from their unique PfamA domain architectures. Out of the 663 C. difficile genomes, 535 (80.7%) contained at least one copy of ToxA or ToxB, while these genes were missing from 128 genomes. Although some clusters were enriched for toxin presence, these genes are variably present in a given genetic background. The CDT genes were found in 191 genomes, which were restricted to a few clusters only, and only one cluster lacked the toxin A/B genes consistently. A total of 310 genomes contained ToxA/B without CDT (47%). Further, published metagenomic data from stools were used to assess the presence of C. difficile sequences in blinded cases of C. difficile infection (CDI) and controls, to test if metagenomic analysis is sensitive enough to detect the pathogen, and to establish strain relationships between cases from the same

Gene expression profiles of Aspergillus flavus isolates responding to oxidative stress in different culture media

Science.gov (United States)

Aflatoxin contamination of peanut by Aspergillus flavus is exacerbated by drought stress. Drought also stimulates the production of reactive oxygen species (ROS) in plant tissues implying a correlation between ROS and aflatoxin production. Here, we performed gene expression analysis by RNAseq of tox...

REDOX DISRUPTING POTENTIAL OF TOXCAST CHEMICALS RANKED BY ACTIVITY IN MOUSE EMBRYONIC STEM CELLS

Science.gov (United States)

To gain insight regarding the adverse outcome pathways leading to developmental toxicity following exposure to chemicals, we evaluated ToxCast™ Phase I chemicals in an adherent mouse embryonic stem cell (mESC) assay and identified a redox sensitive pathway that correlated with al...

Dicty_cDB: Contig-U06506-1 [Dicty_cDB

Lifescience Database Archive (English)

Full Text Available 3e-08 3 ( DJ019170 ) Molecular Nephrotoxicology Modeling. 54 3e-08 3 ( DJ007525 ) Primary rat hepatocyte tox...icity modeling. 54 3e-08 3 ( DD269914 ) Molecular Hepatotoxicology Modeling. 54 3e-08 3 ( BD301471 ) Identif

Quantitative Nuclease Protection Assays (qNPA) as Windows into Chemical-Induced Adaptive Response in Cultures of Primary Human Hepatocytes (Concentration and Time-Response)

Science.gov (United States)

Cultures of primary human hepatocytes have been shown to be dynamic in vitro model systems that retain liver-like functionality (e.g. metabolism, transport, induction). We have utilized these culture models to interrogate 309 ToxCast chemicals. The study design characterized both...

Meta-analysis of aquatic chronic chemical toxicity data

Science.gov (United States)

Chronic toxicity data from the open literature and from tests submitted for pesticide registration were extracted and assembled into a database, AquaChronTox, with a flexible search interface. Data were captured at a treatment and, when available, replicate level to support conc...

apple juice's clarification process by using cassava and rice starch

African Journals Online (AJOL)

SARAH

2015-11-30

Nov 30, 2015 ... TOX 56-81, NERICA 1, IR 841, and Special rice, were tested for cashew apple ..... the phenolic hydroxyl groups of the tannins and the carbonyl groups of the .... charge on the particles has to be neutralised to near zero charge.

Retrofit Strategies for Incorporating Xenobiotic Metabolism into High Throughput Screening Assays (EMGS)

Science.gov (United States)

The US EPA’s ToxCast program is designed to assess chemical perturbations of molecular and cellular endpoints using a variety of high-throughput screening (HTS) assays. However, existing HTS assays have limited or no xenobiotic metabolism which could lead to a mischaracterization...

Chemical Screening for Bioactivated Electrophilic Metabolites Using Alginate Immobilization of Metabolic Enzymes (AIME) (SOT)

Science.gov (United States)

The US EPA's ToxCast program is designed to assess chemical perturbations of molecular and cellular endpoints using a variety of high-throughput screening (HTS) assays. However, existing HTS assays have limited or no xenobiotic metabolism which could lead to a mischaracterization...

Development of a Systems Computational Model to Investigate Early Biological Events in Hepatic Activation of Constitutive Androstane Receptor (CAR) by Phenobarbital

Science.gov (United States)

Activation of the nuclear receptor CAR (constitutive active/androstane receptor) is implicated in the control several key biological events such as metabolic pathways. Here, we combined data from literature with information obtained from in vitro assays in the US EPA ToxCast dat...

Ageism Discrimination Crowdlynching Shames Physics Pretentions of Intellectual Honesty and Ethics: Extension Throughout Universities Shaming Education By Bankrupting Overdebted Student Defrauding: Caveat Emptor!!!

Science.gov (United States)

Isalie, J.; Codben, Druid; Seidwinder, Gruald; Heiller, Ereich; Young, Muddlekent; Stuntley, Hugene; Siegel, L. E. E.; Deliesie, Charlatan

2014-03-01

Ageism discrimination sociological-dysfunctionality crowdlynching shames physics pretentions of intellectual honesty and ethics! Extension to other departments:philo.,psych.,geo.,maths shames claims of honest education:BU,HU,NEU,UW,SDSU,ICTP/SISSA. Defrauding overdebted students, would be ``sciences'' become alas mere séances! Witness:70 year old Edward Siegel,PhD(70) firsts:multiband Hubbard-model decades pre-``Emery'' with Rosen/Feynman[IBM Conf.Comp./Math.(86)] trendy/ hyped ``Q-computing'' in ANN AI, google search-engine Page-Brin adaption; pre-trendy nanophysics [PSS(a) 11, 45(72);Scripta Met.13,913(79)];decade-earlier GMR discoverer[JMMM 7,312(78)] pre ``Fert''-``Gruenberg'' decade-earlier acoustic-emission F =ma rediscovery in Bak/BNL-hyped SOC; FUZZYICS Aristotle SoO rediscovery eliminating jargonial-obfuscation plaguing physics via implementation of Cohen-Stewart[Collapse of Chaos:Discovering Simplicity in ``Complex'' World] called for compl-icity/ simple-xity both simultaneously automaticallybig-`data'disambiguation via HoT;AMS Joint Mtg.(02) proofs:FLT;P ≠NPBSD conj.,Riemann-hypothesis as BEC; Benford's-law inversion discovering digits = bosons; (87) Majorana-fermion & HDM discoverer in complex-quantum-statistics in fractal-dimensions; ``it's a jack-in-the-box'' universe cosmology.

DETECTION OF HUMAN BLOODSTAINS BY ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA

Directory of Open Access Journals (Sweden)

GHOLAM-HOSSEIN EDRISSIAN

1982-07-01

Full Text Available The microplate method of e nzyme-l i nke d i rnmuno s o r be n t a s s ay (ELISA , usi ng alkaline phosphatase anti-human I gG conj ugate , was modified and appl ied in t he dete c t i on of the human b lood specimens among the blood samples prep a r ed fr om human and laborat or y anima l s i n t he form of small dr ied b loodst a i ns on f ilt e r paper . The modi f i e d ELISA t e chnique wa s compa red wit h t he agar double d i f f us ion me t hod of prec ipitin test ."nThe results of this primary study showed t ha t the ELISA i n compare to gel diffusi o n t e st is sensitive and specific. It is also enough repr oducible and practical t o be consider as a competent technique for i de nt i f i c ation o f human bloodstains in medicolegal laboratories .

Six rapid tests for direct detection of Clostridium difficile and its toxins in fecal samples compared with the fibroblast cytotoxicity assay.

Science.gov (United States)

Turgeon, David K; Novicki, Thomas J; Quick, John; Carlson, LaDonna; Miller, Pat; Ulness, Bruce; Cent, Anne; Ashley, Rhoda; Larson, Ann; Coyle, Marie; Limaye, Ajit P; Cookson, Brad T; Fritsche, Thomas R

2003-02-01

Clostridium difficile is one of the most frequent causes of nosocomial gastrointestinal disease. Risk factors include prior antibiotic therapy, bowel surgery, and the immunocompromised state. Direct fecal analysis for C. difficile toxin B by tissue culture cytotoxin B assay (CBA), while only 60 to 85% sensitive overall, is a common laboratory method. We have used 1,003 consecutive, nonduplicate fecal samples to compare six commercially available immunoassays (IA) for C. difficile detection with CBA: Prima System Clostridium difficile Tox A and VIDAS Clostridium difficile Tox A II, which detect C. difficile toxin A; Premier Cytoclone A/B and Techlab Clostridium difficile Tox A/B, which detect toxins A and B; and ImmunoCard Clostridium difficile and Triage Micro C. difficile panels, which detect toxin A and a species-specific antigen. For all tests, Triage antigen was most sensitive (89.1%; negative predictive value [NPV] = 98.7%) while ImmunoCard was most specific (99.7%; positive predictive value [PPV] = 95.0%). For toxin tests only, Prima System had the highest sensitivity (82.2%; NPV = 98.0%) while ImmunoCard had the highest specificity (99.7%; PPV = 95.0%). Hematopoietic stem cell transplant (HSCT) patients contributed 44.7% of all samples tested, and no significant differences in sensitivity or specificity were noted between HSCT and non-HSCT patients. IAs, while not as sensitive as direct fecal CBA, produce reasonable predictive values, especially when both antigen and toxin are detected. They also offer significant advantages over CBA in terms of turnaround time and ease of use.

In silico study of in vitro GPCR assays by QSAR modeling

Science.gov (United States)

The U.S. EPA is screening thousands of chemicals of environmental interest in hundreds of in vitro high-throughput screening (HTS) assays (the ToxCast program). One goal is to prioritize chemicals for more detailed analyses based on activity in molecular initiating events (MIE) o...

77 FR 22321 - National Toxicology Program (NTP) Interagency Center for the Evaluation of Alternative...

Science.gov (United States)

2012-04-13

... DEPARTMENT OF HEALTH AND HUMAN SERVICES National Toxicology Program (NTP) Interagency Center for... (HTS) Assays for the Tox21 Initiative AGENCY: Division of the National Toxicology Program (DNTP...: April 5, 2012. John R. Bucher, Associate Director, National Toxicology Program. [FR Doc. 2012-8942 Filed...

Drug Testing

Science.gov (United States)

... testing, substance abuse testing, toxicology screen, tox screen, sports doping tests What is it used for? Drug screening is used to find out whether or not a person has taken a certain drug or drugs. It ... Sports organizations. Professional and collegiate athletes usually need to ...

Updates on EPA’s High-Throughput Exposure Forecast (ExpoCast) Research Project (CPCP)

Science.gov (United States)

Recent research advances by the ORD ExpoCast project (CSS Rapid Exposure and Dosimetry) are presented to the computational toxicology community in the context of prioritizing chemicals on a risk-basis using joint ExpoCast and ToxCast predictions. Recent publications by Wambaugh e...

SeqAPASS to evaluate conservation of high-throughput screening targets across non-mammalian species

Science.gov (United States)

Cell-based high-throughput screening (HTS) and computational technologies are being applied as tools for toxicity testing in the 21st century. The U.S. Environmental Protection Agency (EPA) embraced these technologies and created the ToxCast Program in 2007, which has served as a...

A High-Throughput Screening Assay to Detect Thyroperoxidase Inhibitors (Teratology Society)

Science.gov (United States)

In support of the Endocrine Disruption Screening Program (EDSP21), the US EPA ToxCast program is developing assays to enable screening for chemicals that may disrupt thyroid hormone synthesis. Thyroperoxidase (TPO) is critical for TH synthesis and is a known target of thyroid-dis...

Comparison and Analysis of Toxcast Data with In Vivo Data for Food-Relevant Compounds Using The Risk21 Approach

Science.gov (United States)

The ToxCast program has generated a great wealth of in vitro high throughput screening (HTS) data on a large number of compounds, providing a unique resource of information on the bioactivity of these compounds. However, analysis of these data are ongoing, and interpretation and ...

Alginate Immobilization of Metabolic Enzymes (AIME) for High-Throughput Screening Assays (SOT)

Science.gov (United States)

Alginate Immobilization of Metabolic Enzymes (AIME) for High-Throughput Screening Assays DE DeGroot, RS Thomas, and SO SimmonsNational Center for Computational Toxicology, US EPA, Research Triangle Park, NC USAThe EPA’s ToxCast program utilizes a wide variety of high-throughput s...

Fungal bis-Naphthopyrones as Inhibitors of Botulinum Neurotoxin Serotype A

Science.gov (United States)

2012-04-02

compounds that appeared in all three rescored hit lists. The second, the MET-TOX list, consisted of 570 compounds that passed an imposed metabolism ...Delitschia sp. (JS 300) isolated from a sample of kangaroo dung collected in Australia. The talaroderxines were originally described as metabolites of

Toxcast Profiling in a Human Stem Cell Assay for Developmental Toxicity (SOT)

Science.gov (United States)

We correlated the ToxCast library in a metabolic biomarker-based in vitro assay (Stemina devTOXqP) utilizing human embryonic stem (hES) cells (H9 line). This assay identifies the concentration of a chemical that disrupts cellular metabolism in a manner indicative of teratogenic...

Evaluation of In Vitro Biotransformation Using HepaRG Cells to Improve High-Throughput Chemical Hazard Prediction: A Toxicogenomics Analysis (SOT)

Science.gov (United States)

The US EPA’s ToxCast program has generated a wealth of data in >600 in vitro assayson a library of 1060 environmentally relevant chemicals and failed pharmaceuticals to facilitate hazard identification. An inherent criticism of many in vitro-based strategies is the inability of a...

Structure Identification Using High Resolution Mass Spectrometry Data and the EPAs Chemistry Dashboard (ACS Fall meeting)

Science.gov (United States)

The iCSS Chemistry Dashboard is a publicly accessible dashboard provided by the National Center for Computation Toxicology at the US-EPA. It serves a number of purposes, including providing a chemistry database underpinning many of our public-facing projects (e.g. ToxCast and Exp...

Evaluating High Throughput Toxicokinetics and Toxicodynamics for IVIVE (WC10)

Science.gov (United States)

High-throughput screening (HTS) generates in vitro data for characterizing potential chemical hazard. TK models are needed to allow in vitro to in vivo extrapolation (IVIVE) to real world situations. The U.S. EPA has created a public tool (R package “httk” for high throughput tox...

Developing, Applying, and Evaluating Models for Rapid Screening of Chemical Exposures

DEFF Research Database (Denmark)

Arnot, J.; Shin, H.; Ernstoff, Alexi

2015-01-01

provides an introduction to underlying principles of some models used for exposure- and risk-based HTS for chemical prioritization for human health, including tools used in the ExpoDat project (USEtox, RAIDAR, CalTox) and other initiatives (SHEDS-HT). Case study examples of HTS include(i) model...

Optimizing the performance of the amphipod, Hyalella azteca, in chronic toxicity tests: Results of feeding studies with various foods and feeding regimes

Science.gov (United States)

The freshwater amphipod, Hyalella azteca, is a common organism used for sediment toxicity testing. Standard methods for 10-d and 42-d sediment toxicity tests with H. azteca were last revised and published by USEPA/ASTM in 2000. While Hyalella azteca methods exist for sediment tox...

TNO and CBRN defence

NARCIS (Netherlands)

2015-01-01

Within the Defence, Safety & Security branch of TNO a dedicated department focuses on Chemical, Biological, Radiological and Nuclear (CBRN) Protection. This is a world class research department consisting of about 50 people and a High Tox laboratory that is the only facility in The Netherlands that

Experimental investigation of N-MOS inversion layers in the electric quantum limit

NARCIS (Netherlands)

Kalnitsky, A.; Boothroyd, A.R.; Ellul, J.P.; Tarr, N.G.; Weaver, L.; Beerkens, R.G.C.

1992-01-01

The authors report on the exptl. detn. of inversion electron charge d., silicon surface potential, and effective electron mobility vs. oxide elec. field, for NMOSFETs with gate oxide thickness Tox = 2.2 nm operating far beyond the limit of applicability of Boltzmann relations in the inversion layer.

Retrospective Mining of Toxicology Data to Discover Multispecies and Chemical Class Effects: Anemia as a Case Study

Science.gov (United States)

Predictive toxicity models (in vitro to in vivo, QSAR, read-across) rely on large amounts of accurate in vivo data. Here, we analyze the quality of in vivo data from the Toxicity Reference Database (ToxRefDB), using chemical-induced anemia as an example. Considerations include v...

Relationship of the Interaction Between Two Quantitative Trait Loci with γ-Globin Expression in β-Thalassemia Intermedia Patients.

Science.gov (United States)

NickAria, Shiva; Haghpanah, Sezaneh; Ramzi, Mani; Karimi, Mehran

2018-05-10

Globin switching is a significant factor on blood hemoglobin (Hb) level but its molecular mechanisms have not yet been identified, however, several quantitative trait loci (QTL) and polymorphisms involved regions on chromosomes 2p, 6q, 8q and X account for variation in the γ-globin expression level. We studied the effect of interaction between a region on intron six of the TOX gene, chromosome 8q (chr8q) and XmnI locus on the γ-globin promoter, chr11p on γ-globin expression in 150 β-thalassemia intermedia (β-TI) patients, evaluated by statistical interaction analysis. Our results showed a significant interaction between one QTL on intron six of the TOX gene (rs9693712) and XmnI locus that effect γ-globin expression. Interchromosomal interaction mediates through transcriptional machanisms to preserve true genome architectural features, chromosomes localization and DNA bending. This interaction can be a part of the unknown molecular mechanism of globin switching and regulation of gene expression.

Using Machine Learning Models to Predict Functional Use (Interagency Alternatives Assessment Workshop)

Science.gov (United States)

This presentation will outline how data was collected on how chemicals are used in products, models were built using this data to then predict how chemicals can be used in products, and, finally, how combining this information with Tox21 in vitro assays can be use to rapidly scre...

75 FR 76995 - National Toxicology Program (NTP); Center for the Evaluation of Risks to Human Reproduction...

Science.gov (United States)

2010-12-10

... at the workshop. Registration to attend the workshop is closed; however, slides presented during the....O. Box 12233, MD K2-04, Research Triangle Park, NC 27709 (mail), 919-541-5021 (telephone), or thayer... (``Tox21'') high throughput screening initiative. Identify data gaps and areas for future evaluation...

20180416 - Retrofitting an Estrogen Receptor Transactivation Assay with Metabolic Competence Using Alginate Immobilization of Metabolic Enzymes (AIME) (SETAC HTS)

Science.gov (United States)

The VM7Luc4E2 estrogen receptor (ER) transactivation assay is an OECD approved method (TG 457) for the detection of ER agonists and antagonists, and is also part of the Tox21 high-throughput screening (HTS) portfolio. Despite international acceptance as a screening assay, immorta...

20180312 - Retrofitting an Estrogen Receptor Transactivation Assay with Metabolic Competence Using Alginate Immobilization of Metabolic Enzymes (AIME) (SOT)

Science.gov (United States)

The VM7Luc4E2 estrogen receptor (ER) transactivation assay is an OECD approved method (TG 457) for the detection of ER agonists and antagonists, and is also part of the Tox21 high-throughput screening (HTS) portfolio. Despite its international acceptance as a screening assay, imm...

The selection of a model microalgal species as biomaterial for a novel aquatic phytotoxicity assay

Energy Technology Data Exchange (ETDEWEB)

Bengtson Nash, S.M. [National Research Centre for Environmental Toxicology, University of Queensland, Brisbane QLD 4108 (Australia)]. E-mail: s.nash@uq.edu.au; Quayle, P.A. [National Research Centre for Environmental Toxicology, University of Queensland, Brisbane QLD 4108 (Australia); Schreiber, U. [Lehrstuhl Botanik I, Julius-von-Sachs-Institut fuer Biowissenschaften, Universitaet Wuerzburg, D-97082 Wuerzburg (Germany); Mueller, J.F. [National Research Centre for Environmental Toxicology, University of Queensland, Brisbane QLD 4108 (Australia)

2005-05-15

A phytotoxicity assay based on the ToxY-PAM dual-channel yield analyser has been developed and successfully incorporated into field assessments for the detection of phytotoxicants in water. As a means of further exploring the scope of the assay application and of selecting a model biomaterial to complement the instrument design, nine algal species were exposed to four chemical substances deemed of priority for water quality monitoring purposes (chlorpyrifos, copper, diuron and nonylphenol ethoxylate). Inter-species differences in sensitivity to the four toxicants varied by a factor of 1.9-100. Measurements of photosystem-II quantum yield using these nine single-celled microalgae as biomaterial corroborated previous studies which have shown that the ToxY-PAM dual-channel yield analyser is a highly sensitive method for the detection of PS-II impacting herbicides. Besides Phaeodactylum tricornutum, the previously applied biomaterial, three other species consistently performed well (Nitzschia closterium, Chlorella vulgaris and Dunaliella tertiolecta) and will be used in further test optimisation experiments. In addition to sensitivity, response time was evaluated and revealed a high degree of variation between species and toxicants. While most species displayed relatively weak and slow responses to copper, C. vulgaris demonstrated an IC{sub 10} of 51 {mu}g L{sup -1}, with maximum response measured within 25 minutes and inhibition being accompanied by a large decrease in fluorescence yield. The potential for this C. vulgaris-based bioassay to be used for the detection of copper is discussed. There was no evidence that the standard ToxY-PAM protocol, using these unicellular algae species, could be used for the detection of chlorpyrifos or nonylphenol ethoxylate at environmentally relevant levels.

The selection of a model microalgal species as biomaterial for a novel aquatic phytotoxicity assay

International Nuclear Information System (INIS)

Bengtson Nash, S.M.; Quayle, P.A.; Schreiber, U.; Mueller, J.F.

2005-01-01

A phytotoxicity assay based on the ToxY-PAM dual-channel yield analyser has been developed and successfully incorporated into field assessments for the detection of phytotoxicants in water. As a means of further exploring the scope of the assay application and of selecting a model biomaterial to complement the instrument design, nine algal species were exposed to four chemical substances deemed of priority for water quality monitoring purposes (chlorpyrifos, copper, diuron and nonylphenol ethoxylate). Inter-species differences in sensitivity to the four toxicants varied by a factor of 1.9-100. Measurements of photosystem-II quantum yield using these nine single-celled microalgae as biomaterial corroborated previous studies which have shown that the ToxY-PAM dual-channel yield analyser is a highly sensitive method for the detection of PS-II impacting herbicides. Besides Phaeodactylum tricornutum, the previously applied biomaterial, three other species consistently performed well (Nitzschia closterium, Chlorella vulgaris and Dunaliella tertiolecta) and will be used in further test optimisation experiments. In addition to sensitivity, response time was evaluated and revealed a high degree of variation between species and toxicants. While most species displayed relatively weak and slow responses to copper, C. vulgaris demonstrated an IC 10 of 51 μg L -1 , with maximum response measured within 25 minutes and inhibition being accompanied by a large decrease in fluorescence yield. The potential for this C. vulgaris-based bioassay to be used for the detection of copper is discussed. There was no evidence that the standard ToxY-PAM protocol, using these unicellular algae species, could be used for the detection of chlorpyrifos or nonylphenol ethoxylate at environmentally relevant levels

Computational Breakthrough of Natural Lead Hits from the Genus of Arisaema against Human Respiratory Syncytial Virus.

Science.gov (United States)

Kant, Kamal; Lal, Uma Ranjan; Ghosh, Manik

2018-01-01

To date, efforts for the prevention and treatment of human respiratory syncytial virus (RSV) infection have been still vain, and there is no safe and effective clinical accepted vaccine. Arisaema genus has claimed for various traditional bioactivities, but scientific assessments are quite limited. This encouraged us to carry out our present study on around 60 phytoconstituents of different Arisaema species as a natural inhibitor against the human RSV. Selected 60 phytochemical entities were evaluated on the docking behavior of human RSV receptor (PDB: 4UCC) using Maestro 9.3 (Schrödinger, LLC, Cambridge, USA). Furthermore, kinetic properties and toxicity nature of top graded ligands were analyzed through QikProp and ProTox tools. Notably, rutin (glide score: -8.49), schaftoside (glide score: -8.18) and apigenin-6,8-di-C-β-D-galactoside (glide score - 7.29) have resulted in hopeful natural lead hits with an ideal range of kinetic descriptors values. ProTox tool (oral rodent toxicity) has resulted in likely toxicity targets of apex-graded tested ligands. Finally, the whole efforts can be explored further as a model to confirm its anti-human RSV potential with wet laboratory experiments. Rutin, schaftoside, and apigenin-6,8-di-C-β-D-galactoside showed promising top hits docking profile against human respiratory syncytial virusMoreover, absorption, distribution, metabolism, excretion properties (QikProp) of top hits resulted within an ideal range of kinetic descriptorsProTox tool highlighted toxicity class ranges, LD 50 values, and possible toxicity targets of apex-graded tested ligands. Abbreviations used: RSV: Respiratory syncytial virus, PRRSV: Porcine respiratory and reproductive syndrome virus, ADME-T: Absorption, distribution, metabolism, excretion, and toxicity.

Resource Guide to Careers in Toxicology, 3rd Edition.

Science.gov (United States)

Society of Toxicology, Reston, VA.

This resource guide was prepared by the Tox 90's Educational Issues Task Force of the Society of Toxicology. The introduction provides information on the Society of Toxicology and financial support for graduate students in toxicology. Other sections include career opportunities in toxicology, academic and postdoctoral programs in toxicology, and…

Reações locais e níveis de antitoxina circulante decorrentes de administração do toxóide tetânico: estudo comparativo entre Ped-o-Jet e seringa hipodérmica Local reactions and antitoxin levels induced by the administration of tetanus toxoid: a comparative study between Ped-o-Jet and hypodermic syringe

Directory of Open Access Journals (Sweden)

Ana Maria Aratangy Pluciennik

1985-06-01

Full Text Available Com o objetivo de comparar reações locais e conversão sorológica apresentadas por adultos que receberam o toxóide tetânico através de Ped-o-Jet (via subcutânea ou de seringa hipodérmica (via intramuscular, o toxóide foi administrado a 472 recrutas do Exército. Em observações realizadas 4 e 24 horas após a vacinação verificou-se que as reações locais dos indivíduos vacinados com Ped-o-Jet eram significativamente mais freqüentes e mais intensas do que aquelas dos vacinados com seringa hipodérmica, não tendo ocorrido, entretanto, reações graves. A conversão sorológica dos não imunes vacinados com Ped-o-Jet ocorreu numa freqüência maior do que nos indivíduos vacinados com seringa hipodérmica. Conclui-se portanto, que o Ped-o-Jet pode ser utilizado em campanhas de vacinação em massa contra o tétano, embora a via de administração preferencial, até o momento, seja a intramuscular.This paper deals with the administration of tetanus toxoid to 472 army recruits, 50% of which received the vaccine subcutaneously using a Ped-o-Jet pressure injector and the remaining subjects received the vaccine intramuscularly, with hypodermic syringe and needle. The objective was to draw comparative conclusions regarding local reactions and serumconvertion in those young adults. Local reactions were observed four and 24 hours after immunization. Although significantly more frequent and intense in individuals receiving the toxoid by jet injection than in those inoculated with hypodermic syringe, no serious reactions were registered. At the first observation, local reactions occured in 64% of black men vaccinated by Ped-o-Jet and in only 31% of those vaccinated by syringe; 70% of the non-black showed local reactions when vaccinated by Ped-o-Jet and 21% when vaccinated by hypodermic syringe. At the second observation, black men vaccinated by Ped-o-Jet showed local reactions in 78% of the cases and in 3% when vaccinated by syringe; 87% of

Toxicogenomics Investigation Under the eTOX Project

DEFF Research Database (Denmark)

Taboureau, Olivier; Hersey, Anne; Audouze, Karine Marie Laure

2012-01-01

Attrition of drug candidates during pre-clinical development due to toxicity, especially hepatotoxicity and nephrotoxicity, is an important and continuing problem in the pharmaceutical industry. The reasons for this trend may be multifactorial and there is a need to improve toxicity testing parad...

Identification of potential genetic components involved in the deviant quorum-sensing signaling pathways of Burkholderia glumae through a functional genomics approach

Directory of Open Access Journals (Sweden)

Ruoxi eChen

2015-03-01

Full Text Available Burkholderia glumae is the chief causal agent for bacterial panicle blight of rice. The acyl-homoserine lactone (AHL-mediated quorum-sensing (QS system dependent on a pair of luxI and luxR homologs, tofI and tofR, is the primary cell-to-cell signaling mechanism determining the virulence of this bacterium. Production of toxoflavin, a major virulence factor of B. glumae, is known to be dependent on the tofI/tofR QS system. In our previous study, however, it was observed that B. glumae mutants defective in tofI or tofR produced toxoflavin if they grew on the surface of a solid medium, suggesting that alternative signaling pathways independent of tofI or tofR are activated in that growth condition for the production of toxoflavin. In this study, potential genetic components involved in the tofI- and tofR-independent signaling pathways for toxoflavin production were sought through screening random mini-Tn5 mutants of B. glumae to better understand the intercellular signaling pathways of this pathogen. Fifteen and three genes were initially identified as the potential genetic elements of the tofI- and tofR-independent pathways, respectively. Especially, the ORF (bglu_2g06320 divergently transcribed from toxJ, which encodes an orphan LuxR protein and controls toxoflavin biosynthesis, was newly identified in this study as a gene required for the tofR-independent toxoflavin production and named as toxK. Among those genes, flhD, dgcB, and wyzB were further studied to validate their functions in the tofI-independent toxoflavin production, and similar studies were also conducted with qsmR and toxK for their functions in the tofR-independent toxoflavin production. This work provides a foundation for future comprehensive studies of the intercellular signaling systems of B. glumae and other related pathogenic bacteria.

Biocontrol of the Sugarcane Borer Eldana saccharina by Expression of the Bacillus thuringiensis cry1Ac7 and Serratia marcescens chiA Genes in Sugarcane-Associated Bacteria

Science.gov (United States)

Downing, Katrina J.; Leslie, Graeme; Thomson, Jennifer A.

2000-01-01

The cry1Ac7 gene of Bacillus thuringiensis strain 234, showing activity against the sugarcane borer Eldana saccharina, was cloned under the control of the tac promoter. The fusion was introduced into the broad-host-range plasmid pKT240 and the integration vector pJFF350 and without the tac promoter into the broad-host-range plasmids pML122 and pKmM0. These plasmids were introduced into a Pseudomonas fluorescens strain isolated from the phylloplane of sugarcane and the endophytic bacterium Herbaspirillum seropedicae found in sugarcane. The ptac-cry1Ac7 construct was introduced into the chromosome of P. fluorescens using the integration vector pJFF350 carrying the artificial interposon Omegon-Km. Western blot analysis showed that the expression levels of the integrated cry1Ac7 gene were much higher under the control of the tac promoter than under the control of its endogenous promoter. It was also determined that multicopy expression in P. fluorescens and H. seropedicae of ptac-cry1Ac7 carried on pKT240 caused plasmid instability with no detectable protein expression. In H. seropedicae, more Cry1Ac7 toxin was produced when the gene was cloned under the control of the Nmr promoter on pML122 than in the opposite orientation and bioassays showed that the former resulted in higher mortality of E. saccharina larvae than the latter. P. fluorescens 14::ptac-tox resulted in higher mortality of larvae than did P. fluorescens 14::tox. An increased toxic effect was observed when P. fluorescens 14::ptac-tox was combined with P. fluorescens carrying the Serratia marcescens chitinase gene chiA, under the control of the tac promoter, integrated into the chromosome. PMID:10877771

Virulence factors in environmental and clinical Vibrio cholerae from endemic areas in Kenya

Directory of Open Access Journals (Sweden)

Racheal W. Kimani

2014-10-01

Objectives: The objectives of the study were to determine the environmental reservoirs of V. cholerae during an interepidemic period in Kenya and to characterise their virulence factors. Methods: One hundred (50 clinical, 50 environmental samples were tested for V. cholerae isolates using both simplex and multiplex polymerase chain reaction. Results: Both sediments and algae from fishing and landing bays yielded isolates of V. cholerae. Clinical strains were characterised along with the environmental strains for comparison. All clinical strains harboured ctxA, tcpA (El Tor, ompU, zot, ace, toxR, hylA (El Tor and tcpI genes. Prevalence for virulence genes in environmental strains was hylA (El Tor (10%, toxR (24%, zot (22%, ctxA (12%,tcpI (8%, hylA (26% and tcpA (12%. Conclusion: The study sites, including landing bays and beaches, contained environmental V. cholerae, suggesting that these may be reservoirs for frequent epidemics. Improved hygiene and fish-handling techniques will be important in reducing the persistence of reservoirs.

Virulence Genotyping of Pasteurella multocida Isolated from Multiple Hosts from India

Directory of Open Access Journals (Sweden)

Laxmi Narayan Sarangi

2014-01-01

Full Text Available In this study, 108 P. multocida isolates recovered from various host animals such as cattle, buffalo, swine, poultry (chicken, duck, and emu and rabbits were screened for carriage of 8 virulence associated genes. The results revealed some unique information on the prevalence of virulence associated genes among Indian isolates. With the exception of toxA gene, all other virulence associated genes were found to be regularly distributed among host species. Association study between capsule type and virulence genes suggested that pfhA, nanB, and nanH genes were regularly distributed among all serotypes with the exception of CapD, whereas toxA gene was found to be positively associated with CapD and CapA. The frequency of hgbA and nanH genes among swine isolates of Indian origin was found to be less in comparison to its equivalents around the globe. Interestingly, very high prevalence of tbpA gene was observed among poultry, swine, and rabbit isolates. Likewise, very high prevalence of pfhA gene (95.3% was observed among Indian isolates, irrespective of host species origin.

Virulence genotyping of Pasteurella multocida isolated from multiple hosts from India.

Science.gov (United States)

Sarangi, Laxmi Narayan; Priyadarshini, Adyasha; Kumar, Santosh; Thomas, Prasad; Gupta, Santosh Kumar; Nagaleekar, Viswas Konasagara; Singh, Vijendra Pal

2014-01-01

In this study, 108 P. multocida isolates recovered from various host animals such as cattle, buffalo, swine, poultry (chicken, duck, and emu) and rabbits were screened for carriage of 8 virulence associated genes. The results revealed some unique information on the prevalence of virulence associated genes among Indian isolates. With the exception of toxA gene, all other virulence associated genes were found to be regularly distributed among host species. Association study between capsule type and virulence genes suggested that pfhA, nanB, and nanH genes were regularly distributed among all serotypes with the exception of CapD, whereas toxA gene was found to be positively associated with CapD and CapA. The frequency of hgbA and nanH genes among swine isolates of Indian origin was found to be less in comparison to its equivalents around the globe. Interestingly, very high prevalence of tbpA gene was observed among poultry, swine, and rabbit isolates. Likewise, very high prevalence of pfhA gene (95.3%) was observed among Indian isolates, irrespective of host species origin.

An optimized protocol for DNA extraction from wheat seeds and Loop-Mediated Isothermal Amplification (LAMP) to detect Fusarium graminearum contamination of wheat grain.

Science.gov (United States)

Abd-Elsalam, Kamel; Bahkali, Ali; Moslem, Mohamed; Amin, Osama E; Niessen, Ludwig

2011-01-01

A simple, rapid, and efficient method for isolating genomic DNA from germinated seeds of wheat that is free from polysaccharides and polyphenols is reported. DNA was extracted, treated with RNase, measured and tested for completeness using agarose gel electrophoresis. DNA purification from wheat grains yielded abundant, amplifiable DNA with yields typically between 100 and 200 ng DNA/mg. The effectiveness and reliability of the method was tested by assessing quantity and quality of the isolated DNA using three PCR-based markers. Inter-simple sequence repeats (ISSRs) were used to assess the genetic diversity between different wheat varieties. Specific PCR primer pair Tox5-1/Tox5-2 and a loop-mediated isothermal amplification (LAMP) procedure were used to detect genomic DNA of Fusarium graminearum in contaminated wheat seeds. In this method there is no need to use liquid nitrogen for crushing germinated seedlings. The protocol takes approximately one hour to prepare high quality DNA. In combination with the LAMP assay it is a fast and cost-effective alternative to traditional diagnostic methods for the early detection of toxigenic fusaria in cereals.

Case Study: Organotypic human in vitro models of embryonic ...

Science.gov (United States)

Morphogenetic fusion of tissues is a common event in embryonic development and disruption of fusion is associated with birth defects of the eye, heart, neural tube, phallus, palate, and other organ systems. Embryonic tissue fusion requires precise regulation of cell-cell and cell-matrix interactions that drive proliferation, differentiation, and morphogenesis. Chemical low-dose exposures can disrupt morphogenesis across space and time by interfering with key embryonic fusion events. The Morphogenetic Fusion Task uses computer and in vitro models to elucidate consequences of developmental exposures. The Morphogenetic Fusion Task integrates multiple approaches to model responses to chemicals that leaad to birth defects, including integrative mining on ToxCast DB, ToxRefDB, and chemical structures, advanced computer agent-based models, and human cell-based cultures that model disruption of cellular and molecular behaviors including mechanisms predicted from integrative data mining and agent-based models. The purpose of the poster is to indicate progress on the CSS 17.02 Virtual Tissue Models Morphogenesis Task 1 products for the Board of Scientific Counselors meeting on Nov 16-17.

the influence of the dressing procedure on the (mesophilic) bacterial ...

African Journals Online (AJOL)

for 24 hours to determine the mesophilic bacterial count. Point values were transformed to/x + t before analyses of variance were conducted. Least significant difference (L.S.D.) tests were per- formed on all the mean values obtained from the carcass sites and the dressing line positions except in the case of position I of the ...

Common breast cancer susceptibility alleles and the risk of breast cancer for BRCA1 and BRCA2 mutation carriers: implications for risk prediction

DEFF Research Database (Denmark)

Antoniou, Antonis C; Beesley, Jonathan; McGuffog, Lesley

2010-01-01

The known breast cancer susceptibility polymorphisms in FGFR2, TNRC9/TOX3, MAP3K1, LSP1, and 2q35 confer increased risks of breast cancer for BRCA1 or BRCA2 mutation carriers. We evaluated the associations of 3 additional single nucleotide polymorphisms (SNPs), rs4973768 in SLC4A7/NEK10, rs650495...

Relationship between firewood usage and urinary Cr, Cu and As in ...

African Journals Online (AJOL)

All participants answered a questionnaire concerning exposure and were tested for urinary Cr, Cu and As, while the urine of 29 participants was also tested for toxic As (As(tox)). Results. Multivariate analysis showed that the time spent in close proximity to the wood, as well as the quantity of wood used for cooking and for ...

[ADMAdda⁵]-microcystins in Planktothrix agardhii strain PH-123 (cyanobacteria) -  importance for monitoring of microcystins in the environment

DEFF Research Database (Denmark)

Laub, J.; Henriksen, P.; Brittain, S.M.

2002-01-01

Two major and two minor microcystins (MCYST) were isolated from a hepatotoxic Danish strain of Planktothrix agardhii (Gomont) Anagnostidis et Komárek by reversed-phase high-performance liquid chromatography. The microcystins were characterized by UV spectroscopy, amino acid analysis, fast atom bo...... in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/tox.10042...

Genome-Wide Association Study Identifies Novel Restless Legs Syndrome Susceptibility Loci on 2p14 and 16q12.1

Czech Academy of Sciences Publication Activity Database

Winkelmann, J.; Czamara, D.; Schormair, B.; Knauf, F.; Schulte, E. C.; Vodička, Pavel

2011-01-01

Roč. 7, č. 7 (2011), e1002171 ISSN 1553-7390 R&D Projects: GA MZd NR8563 Grant - others:GA MŠk(CZ) MSM0021620849; GA MŠk(CZ) MSM0021620816 Institutional research plan: CEZ:AV0Z50390512 Keywords : TOX3 * transcription * common genetic-variants Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 8.694, year: 2011

A Critical Review of the Drug/Performance Literature. Volume II.

Science.gov (United States)

1979-12-01

Cannabis Drug Tolerance Drugs and Stress Amphetamine Depressants Drug Users Ethanol Behavior Drug Abuse Drug Withdrawal Hallucinogens Cannabinoids Drug...Therapeutics Clin Tox Clinical Toxicology Couw Psychopharm Communications in Psychopharmacology Comp Psychiat Comprehensive Psychiatry Current Ther Res Current...European Journal of Toxicology Exp Neurol Experimental Neurology EEG Clin Neurophys EEG Clinical Neurophysiology EEG J EEG Journal Ger Med German Medicine

Evaluation of quail and chicken embryos for the detection of botulinum toxin serotypes A, B, E and F activity

Science.gov (United States)

Comparison of quail (Coturnix japonica) and chicken (Gallus domesticus) embryos for the detection of BoNT/A activity was conducted using equal dosages of toxin/g of embryo (quail at 7 g and chickens at 48 g). Quail embryos were injected at 0, 0.5 to 50 ng adn chicken embryos at 0, 3.4 to 342 ng and...

Environmental assessment of amine-based carbon capture Scenario modelling with life cycle assessment (LCA)

Energy Technology Data Exchange (ETDEWEB)

Brekke, Andreas; Askham, Cecilia; Modahl, Ingunn Saur; Vold, Bjoern Ivar; Johnsen, Fredrik Moltu

2012-07-01

This report contains a first attempt at introducing the environmental impacts associated with amines and derivatives in a life cycle assessment (LCA) of gas power production with carbon capture and comparing these with other environmental impacts associated with the production system. The report aims to identify data gaps and methodological challenges connected both to modelling toxicity of amines and derivatives and weighting of environmental impacts. A scenario based modelling exercise was performed on a theoretical gas power plant with carbon capture, where emission levels of nitrosamines were varied between zero (gas power without CCS) to a worst case level (outside the probable range of actual carbon capture facilities). Because of extensive research and development in the areas of solvents and emissions from carbon capture facilities in the latter years, data used in the exercise may be outdated and results should therefore not be taken at face value.The results from the exercise showed: According to UseTox, emissions of nitrosamines are less important than emissions of formaldehyde with regard to toxicity related to operation of (i.e. both inputs to and outputs from) a carbon capture facility. If characterisation factors for emissions of metals are included, these outweigh all other toxic emissions in the study. None of the most recent weighting methods in LCA include characterisation factors for nitrosamines, and these are therefore not part of the environmental ranking.These results shows that the EDecIDe project has an important role to play in developing LCA methodology useful for assessing the environmental performance of amine based carbon capture in particular and CCS in general. The EDecIDe project will examine the toxicity models used in LCA in more detail, specifically UseTox. The applicability of the LCA compartment models and site specificity issues for a Norwegian/Arctic situation will be explored. This applies to the environmental compartments

The benthic regeneration of N and P in the Great Brak estuary ...

African Journals Online (AJOL)

The aim of this study was to investigate the flux of inorganic nutrients (NH4 +, TOxN [NO3 - + NO2 -], SRP) as well as total N and P across the sediment–water interface in the estuary. There have been very few studies on nutrient cycling and benthic pelagic coupling in South African estuaries. This study showed that the ...

Analysis of Zolpidem in Postmortem Fluids and Tissues Using Ultra-Performance Liquid Chromatography-Mass Spectrometry

Science.gov (United States)

2014-02-01

in postmortem fluids and tissues. 17. Key Words 18. Distribution Statement Forensic Toxicology , Zolpidem, Ambien, Postmortem Distribution, LC/MS/MS...Institute (CAMI) toxicology database identified 10 fatalities from separate avia- tion accidents that were reported positive for zolpidem and also...Sample Selection and Storage A search of the CAMI toxicology database (ToxFLO, DiscoverSoft Development, LLC; Oklahoma City, OK) identi- fied 10

Effect of quercetin on apoptosis of PANC-1 cells.

Science.gov (United States)

Lee, Joo Hyun; Lee, Han-Beom; Jung, Gum O; Oh, Jung Taek; Park, Dong Eun; Chae, Kwon Mook

2013-12-01

To investigate the chemotherapeutic effect of quercetin against cancer cells, signaling pathway of apoptosis was explored in human pancreatic cells. Various anticancer drugs including adriamycin, cisplatin, 5-fluorouracil (5-FU) and gemcitabine were used. Cell viability was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphe-nyltetra zolium bromide assay. Apoptosis was determined by 4'-6-diamidino-2-phenylindole nuclei staining and flow cytometry in PANC-1 cells treated with 50 µg/mL quercetin for 24 hours. Expression of endoplas mic reticulum (ER) stress mediators including, Grp78/Bip, p-PERK, PERK, ATF4, ATF6 and GADD153/CHOP proteins were measured by Western blot analysis. Mitochondrial membrane potential was measured by fluorescence staining with JC-1, rhodamine 123. Quercetin induced the apoptosis of PANC-1, which was characterized as nucleic acid and genomic DNA fragmentation, chromatin condensation, and sub-G0/G1 fraction of cell cycle increase. But not adriamycin, cisplatin, gemcitabine, and 5-FU. PANC-1 cells were markedly sensitive to quercetin. Treatment with quercetin resulted in the increased accumulation of intracellular Ca(2+) ion. Treatment with quercetin also increased the expression of Grp78/Bip and GADD153/CHOP protein and induced mitochondrial dysfunction. Quercetin exerted cytotoxicity against human pancreatic cancer cells via ER stress-mediated apoptotic signaling including reactive oxygen species production and mitochondrial dysfunction. These data suggest that quercetin may be an important modulator of chemosensitivity of cancer cells against anticancer chemotherapeutic agents.

An Optimized Protocol for DNA Extraction from Wheat Seeds and Loop-Mediated Isothermal Amplification (LAMP to Detect Fusarium graminearum Contamination of Wheat Grain

Directory of Open Access Journals (Sweden)

Mohamed Moslem

2011-06-01

Full Text Available A simple, rapid, and efficient method for isolating genomic DNA from germinated seeds of wheat that is free from polysaccharides and polyphenols is reported. DNA was extracted, treated with RNase, measured and tested for completeness using agarose gel electrophoresis. DNA purification from wheat grains yielded abundant, amplifiable DNA with yields typically between 100 and 200 ng DNA/mg. The effectiveness and reliability of the method was tested by assessing quantity and quality of the isolated DNA using three PCR-based markers. Inter-simple sequence repeats (ISSRs were used to assess the genetic diversity between different wheat varieties. Specific PCR primer pair Tox5-1/Tox5-2 and a loop-mediated isothermal amplification (LAMP procedure were used to detect genomic DNA of Fusarium graminearum in contaminated wheat seeds. In this method there is no need to use liquid nitrogen for crushing germinated seedlings. The protocol takes approximately one hour to prepare high quality DNA. In combination with the LAMP assay it is a fast and cost-effective alternative to traditional diagnostic methods for the early detection of toxigenic fusaria in cereals.

Predicting the carcinogenicity of chemicals with alternative approaches: recent advances.

Science.gov (United States)

Benigni, Romualdo

2014-09-01

Alternative approaches to the rodent bioassay are necessary for early identification of problematic drugs and biocides during the development process, and are the only practicable tool for assessing environmental chemicals with no or adequate safety documentation. This review informs on: i) the traditional prescreening through genotoxicity testing; ii) an integrative approach that assesses DNA-reactivity and ability to disorganize tissues; iii) new applications of omics technologies (ToxCast/Tox21 project); iv) a pragmatic approach aimed at filling data gaps by intrapolating/extrapolating from similar chemicals (read-across, category formation). The review also approaches the issue of the concerns about false-positive and false-negative results that prevents a wider acceptance and use of alternatives. The review addresses strengths and limitations of various proposals, and concludes on the need of differential approaches to the issue of false negatives and false positives. False negatives can be eliminated or reduced below the variability of the animal assay with conservative quantitative structure-activity relationships or in vitro tests; false positives can be cleared with ad hoc mechanistically based follow-ups. This framework can permit a reduction of animal testing and a better protection of human health.

Prediction of post-operative necrosis after mastectomy: A pilot study utilizing optical diffusion imaging spectroscopy

Directory of Open Access Journals (Sweden)

Xie Xian-Jin

2009-11-01

Full Text Available Abstract Introduction Flap necrosis and epidermolysis occurs in 18-30% of all mastectomies. Complications may be prevented by intra-operative detection of ischemia. Currently, no technique enables quantitative valuation of mastectomy skin perfusion. Optical Diffusion Imaging Spectroscopy (ViOptix T.Ox Tissue Oximeter measures the ratio of oxyhemoglobin to deoxyhemoglobin over a 1 × 1 cm area to obtain a non-invasive measurement of perfusion (StO2. Methods This study evaluates the ability of ViOptix T.Ox Tissue Oximeter to predict mastectomy flap necrosis. StO2 measurements were taken at five points before and at completion of dissection in 10 patients. Data collected included: demographics, tumor size, flap length/thickness, co-morbidities, procedure length, and wound complications. Results One patient experienced mastectomy skin flap necrosis. Five patients underwent immediate reconstruction, including the patient with necrosis. Statistically significant factors contributing to necrosis included reduction in medial flap StO2 (p = 0.0189, reduction in inferior flap StO2 (p = 0.003, and flap length (p = 0.009. Conclusion StO2 reductions may be utilized to identify impaired perfusion in mastectomy skin flaps.

Biogas from MSW landfill: Composition and determination of chlorine content with the AOX (adsorbable organically bound halogens) technique

International Nuclear Information System (INIS)

Rey, M.D.; Font, R.; Aracil, I.

2013-01-01

An exhaustive characterization of the biogas from some waste disposal facilities has been carried out. The analysis includes the main components (methane, carbon dioxide, nitrogen and oxygen) as well as trace components such as hydrogen sulphide, ammonia and VOCs (volatile organic compounds) including siloxanes and halogenated compounds. VOCs were measured by GC/MS (Gas Chromatography/Mass Spectrometry) using two different procedures: thermal desorption of the Tenax TA and Carbotrap 349 tubes and SPME (Solid Phase Micro-Extraction). A method has been established to measure the total halogen content of the biogas with the AOX (adsorbable organically bound halogens) technique. The equipment used to analyze the samples was a Total Organic Halogen Analyzer (TOX-100). Similar results were obtained when comparing the TOX (Total Organic Halogen) values with those obtained by GC/MS. The halogen content in all the samples was under 22 mg Cl/Nm 3 which is below the limit of 150 mg/Nm 3 proposed in the Spanish Regulations for any use of the biogas. The low chlorine content in the biogas studied, as well as the low content of other trace compounds, makes it suitable for use as a fuel for electricity generating engines

Continuous Autoregulatory Indices Derived from Multi-modal Monitoring: Each One is Not Like the Other.

OpenAIRE

Zeiler, Frederick; Donnelly, Joseph; Menon, David Krishna; Smieleweski, P; Zweifel, C; Brady, K; Czosnyka, Marek

2017-01-01

We assess the relationships between various continuous measures of autoregulatory capacity in an adult TBI cohort. We assessed relationships between autoregulatory indices derived from intracranial pressure (ICP: PRx, PAx, RAC), Transcranial Doppler (TCD: Mx, Sx, Dx), brain tissue-oxygenation (ORx), and spatially resolved near infrared spectroscopy (NIRS resolved: TOx, THx). Relationships between indices were assessed using Pearson correlation coefficient, Friedman (KW) test, Principle compon...

Phytochemical, Antimicrobial and ToxIicological evaluation of the ...

African Journals Online (AJOL)

Peperomia pellucida is widely used in traditional medicine for the treatment of abscesses, acne, boils, arthritis, wound healing, inflammation and gout. This study was to evaluate the phytochemical composition, antimicrobial activities and toxicological profiles of the chloroform and methanol extracts of P. pellucida. Chemical ...

Application of ToxCast High-Throughput Screening and ...

Science.gov (United States)

Slide presentation at the SETAC annual meeting on High-Throughput Screening and Modeling Approaches to Identify Steroidogenesis Distruptors Slide presentation at the SETAC annual meeting on High-Throughput Screening and Modeling Approaches to Identify Steroidogenssis Distruptors

Predicting_Systemic_Toxicity_Effects_ArchTox_2017_Data

Data.gov (United States)

U.S. Environmental Protection Agency — In an effort to address a major challenge in chemical safety assessment, alternative approaches for characterizing systemic effect levels, a predictive model was...

Death of the TonB shuttle hypothesis

Directory of Open Access Journals (Sweden)

Michael George Gresock

2011-10-01

Full Text Available A complex of ExbB, ExbD, and TonB transduces cytoplasmic membrane (CM proton motive force (pmf to outer membrane (OM transporters so that large, scarce, and important nutrients can be released into the periplasmic space for subsequent transport across the CM. TonB is the component that interacts with the OM transporters and enables ligand transport, and several mechanical models and a shuttle model explain how TonB might work. In the mechanical models, TonB remains attached to the CM during energy transduction, while in the shuttle model the TonB N terminus leaves the CM to deliver conformationally stored potential energy to OM transporters. Previous efforts to test the shuttle model by anchoring TonB to the CM by fusion to a large globular cytoplasmic protein have been hampered by the proteolytic susceptibility of the fusion constructs. Here we confirm that GFP-TonB, tested in a previous study by another laboratory, again gave rise to full-length TonB and slightly larger potentially shuttleable fragments that prevented unambiguous interpretation of the data. Recently, we discovered that a fusion of the Vibrio cholerae ToxR cytoplasmic domain to the N terminus of TonB was proteolytically stable. ToxR-TonB was able to be completely converted into a proteinase K-resistant conformation in response to loss of pmf in spheroplasts and exhibited an ability to form a pmf-dependent formaldehyde crosslink to ExbD, both indicators of its location in the CM. Most importantly, ToxR-TonB had the same relative specific activity as wild-type TonB. Taken together, these results provide the first conclusive evidence that TonB does not shuttle during energy transduction. The interpretations of our previous study, which concluded that TonB shuttled in vivo, were complicated by the fact that the probe used in those studies, Oregon Green® 488 maleimide, was permeant to the CM and could label proteins, including a TonB ∆TMD derivative, confined exclusively to the

Death of the TonB Shuttle Hypothesis.

Science.gov (United States)

Gresock, Michael G; Savenkova, Marina I; Larsen, Ray A; Ollis, Anne A; Postle, Kathleen

2011-01-01

A complex of ExbB, ExbD, and TonB couples cytoplasmic membrane (CM) proton motive force (pmf) to the active transport of large, scarce, or important nutrients across the outer membrane (OM). TonB interacts with OM transporters to enable ligand transport. Several mechanical models and a shuttle model explain how TonB might work. In the mechanical models, TonB remains attached to the CM during energy transduction, while in the shuttle model the TonB N terminus leaves the CM to deliver conformationally stored potential energy to OM transporters. Previous studies suggested that TonB did not shuttle based on the activity of a GFP-TonB fusion that was anchored in the CM by the GFP moiety. When we recreated the GFP-TonB fusion to extend those studies, in our hands it was proteolytically unstable, giving rise to potentially shuttleable degradation products. Recently, we discovered that a fusion of the Vibrio cholerae ToxR cytoplasmic domain to the N terminus of TonB was proteolytically stable. ToxR-TonB was able to be completely converted into a proteinase K-resistant conformation in response to loss of pmf in spheroplasts and exhibited an ability to form a pmf-dependent formaldehyde crosslink to ExbD, both indicators of its location in the CM. Most importantly, ToxR-TonB had the same relative specific activity as wild-type TonB. Taken together, these results provide conclusive evidence that TonB does not shuttle during energy transduction. We had previously concluded that TonB shuttles based on the use of an Oregon Green(®) 488 maleimide probe to assess periplasmic accessibility of N-terminal TonB. Here we show that the probe was permeant to the CM, thus permitting the labeling of the TonB N-terminus. These former results are reinterpreted in the context that TonB does not shuttle, and suggest the existence of a signal transduction pathway from OM to cytoplasm.

Decreased Sensitivity to Changes in the Concentration of Metal Ions as the Basis for the Hyperactivity of DtxR(E175K)

Energy Technology Data Exchange (ETDEWEB)

D’Aquino, J. Alejandro; Denninger, Andrew R.; Moulin, Aaron G.; D’Aquino, Katharine E.; Ringe, Dagmar; (Harvard-Med); (Brandeis)

2010-01-12

The metal-ion-activated diphtheria toxin repressor (DtxR) is responsible for the regulation of virulence and other genes in Corynebacterium diphtheriae. A single point mutation in DtxR, DtxR(E175K), causes this mutant repressor to have a hyperactive phenotype. Mice infected with Mycobacterium tuberculosis transformed with plasmids carrying this mutant gene show reduced signs of the tuberculosis infection. Corynebacterial DtxR is able to complement mycobacterial IdeR and vice versa. To date, an explanation for the hyperactivity of DtxR(E175K) has remained elusive. In an attempt to address this issue, we have solved the first crystal structure of DtxR(E175K) and characterized this mutant using circular dichroism, isothermal titration calorimetry, and other biochemical techniques. The results show that although DtxR(E175K) and the wild type have similar secondary structures, DtxR(E175K) gains additional thermostability upon activation with metal ions, which may lead to this mutant requiring a lower concentration of metal ions to reach the same levels of thermostability as the wild-type protein. The E175K mutation causes binding site 1 to retain metal ion bound at all times, which can only be removed by incubation with an ion chelator. The crystal structure of DtxR(E175K) shows an empty binding site 2 without evidence of oxidation of Cys102. The association constant for this low-affinity binding site of DtxR(E175K) obtained from calorimetric titration with Ni(II) is K{sub a} = 7.6 {+-} 0.5 x 10{sup 4}, which is very similar to the reported value for the wild-type repressor, K{sub a} = 6.3 x 10{sup 4}. Both the wild type and DtxR(E175K) require the same amount of metal ion to produce a shift in the electrophoretic mobility shift assay, but unlike the wild type, DtxR(E175K) binding to its cognate DNA [tox promoter-operator (toxPO)] does not require metal-ion supplementation in the running buffer. In the timescale of these experiments, the Mn(II)-DtxR(E175K)-toxPO complex

Recent advances in fluorination techniques and their anticipated impact on drug metabolism and toxicity

OpenAIRE

Murphy, Cormac D.; Sandford, Graham

2015-01-01

Introduction: Fluorine’s unique physicochemical properties make it a key element for incorporation into pharmacologically active compounds. Its presence in a drug can alter a number of characteristics that affect ADME-Tox, which has prompted efforts at improving synthetic fluorination procedures. Areas covered: This review describes the influence of fluorine on attributes such as potency, lipophilicity, metabolic stability and bioavailablility and how the effects observed are related to the p...

Abiotic stress miRNomes in the Triticeae

OpenAIRE

Alptekin, Burcu; Langridge, Peter; Budak, Hikmet

2016-01-01

The continued growth in world population necessitates increases in both the quantity and quality of agricultural production. Triticeae members, particularly wheat and barley, make an important contribution to world food reserves by providing rich sources of carbohydrate and protein. These crops are grown over diverse production environments that are characterized by a range of environmental or abiotic stresses. Abiotic stresses such as drought, heat, salinity, or nutrient deficiencies and tox...

Comments for the Update to the ATSDR Toxicological Profile for JP-5 and JP-8 Occurring in FY14

Science.gov (United States)

2013-12-30

Exposure Chamber. Made of stainless steel, about the size and shape of an attaché case, this IN-TOX product will hold up to 24 mice, each contained in...hydrocarbon markers (n- octane, n-decane, n-tetradecane, toluene, ethylbenzene , and m-xylene)” is incomplete and therefore incorrect. The model, in...aromatic hydrocarbon markers (n-octane, n-decane, n- tetradecane, toluene, ethylbenzene , and m-xylene), plus three chemical lumped compartments based

New publicly available chemical query language, CSRML, to support chemotype representations for application to data mining and modeling.

Science.gov (United States)

Yang, Chihae; Tarkhov, Aleksey; Marusczyk, Jörg; Bienfait, Bruno; Gasteiger, Johann; Kleinoeder, Thomas; Magdziarz, Tomasz; Sacher, Oliver; Schwab, Christof H; Schwoebel, Johannes; Terfloth, Lothar; Arvidson, Kirk; Richard, Ann; Worth, Andrew; Rathman, James

2015-03-23

Chemotypes are a new approach for representing molecules, chemical substructures and patterns, reaction rules, and reactions. Chemotypes are capable of integrating types of information beyond what is possible using current representation methods (e.g., SMARTS patterns) or reaction transformations (e.g., SMIRKS, reaction SMILES). Chemotypes are expressed in the XML-based Chemical Subgraphs and Reactions Markup Language (CSRML), and can be encoded not only with connectivity and topology but also with properties of atoms, bonds, electronic systems, or molecules. CSRML has been developed in parallel with a public set of chemotypes, i.e., the ToxPrint chemotypes, which are designed to provide excellent coverage of environmental, regulatory, and commercial-use chemical space, as well as to represent chemical patterns and properties especially relevant to various toxicity concerns. A software application, ChemoTyper has also been developed and made publicly available in order to enable chemotype searching and fingerprinting against a target structure set. The public ChemoTyper houses the ToxPrint chemotype CSRML dictionary, as well as reference implementation so that the query specifications may be adopted by other chemical structure knowledge systems. The full specifications of the XML-based CSRML standard used to express chemotypes are publicly available to facilitate and encourage the exchange of structural knowledge.

Genetic toxicology in the 21st century: Reflections and future ...

Science.gov (United States)

A symposium at the 40th anniversary of the Environmental Mutagen Society, held from October 24–28, 2009 in St. Louis, MO, surveyed the current status and future directions of genetic toxicology. This article summarizes the presentations and provides a perspective on the future. An abbreviated history is presented, highlighting the current standard battery of genotoxicity assays and persistent challenges. Application of computational toxicology to safety testing within a regulatory setting is discussed as a means for reducing the need for animal testing and human clinical trials, and current approaches and applications of in silico genotoxicity screening approaches across the pharmaceutical industry were surveyed and are reported here. The expanded use of toxicogenomics to illuminate mechanisms and bridge genotoxicity and carcinogenicity, and new public efforts to use high-throughput screening technologies to address lack of toxicity evaluation for the backlog of thousands of industrial chemicals in the environment are detailed. The Tox21 project involves coordinated efforts of four U.S. Government regulatory/research entities to use new and innovative assays to characterize key steps in toxicity pathways, including genotoxic and nongenotoxic mechanisms for carcinogenesis. Progress to date, highlighting preliminary test results from the National Toxicology Program is summarized. Finally, an overview is presented of ToxCast™, a related research program of the

Computational Assessment of Pharmacokinetics and Biological Effects of Some Anabolic and Androgen Steroids.

Science.gov (United States)

Roman, Marin; Roman, Diana Larisa; Ostafe, Vasile; Ciorsac, Alecu; Isvoran, Adriana

2018-02-05

The aim of this study is to use computational approaches to predict the ADME-Tox profiles, pharmacokinetics, molecular targets, biological activity spectra and side/toxic effects of 31 anabolic and androgen steroids in humans. The following computational tools are used: (i) FAFDrugs4, SwissADME and admetSARfor obtaining the ADME-Tox profiles and for predicting pharmacokinetics;(ii) SwissTargetPrediction and PASS online for predicting the molecular targets and biological activities; (iii) PASS online, Toxtree, admetSAR and Endocrine Disruptomefor envisaging the specific toxicities; (iv) SwissDock to assess the interactions of investigated steroids with cytochromes involved in drugs metabolism. Investigated steroids usually reveal a high gastrointestinal absorption and a good oral bioavailability, may inhibit someof the human cytochromes involved in the metabolism of xenobiotics (CYP2C9 being the most affected) and reflect a good capacity for skin penetration. There are predicted numerous side effects of investigated steroids in humans: genotoxic carcinogenicity, hepatotoxicity, cardiovascular, hematotoxic and genitourinary effects, dermal irritations, endocrine disruption and reproductive dysfunction. These results are important to be known as an occupational exposure to anabolic and androgenic steroids at workplaces may occur and because there also is a deliberate human exposure to steroids for their performance enhancement and anti-aging properties.

An Integrated Chemical Environment to Support 21st-Century Toxicology.

Science.gov (United States)

Bell, Shannon M; Phillips, Jason; Sedykh, Alexander; Tandon, Arpit; Sprankle, Catherine; Morefield, Stephen Q; Shapiro, Andy; Allen, David; Shah, Ruchir; Maull, Elizabeth A; Casey, Warren M; Kleinstreuer, Nicole C

2017-05-25

SUMMARY : Access to high-quality reference data is essential for the development, validation, and implementation of in vitro and in silico approaches that reduce and replace the use of animals in toxicity testing. Currently, these data must often be pooled from a variety of disparate sources to efficiently link a set of assay responses and model predictions to an outcome or hazard classification. To provide a central access point for these purposes, the National Toxicology Program Interagency Center for the Evaluation of Alternative Toxicological Methods developed the Integrated Chemical Environment (ICE) web resource. The ICE data integrator allows users to retrieve and combine data sets and to develop hypotheses through data exploration. Open-source computational workflows and models will be available for download and application to local data. ICE currently includes curated in vivo test data, reference chemical information, in vitro assay data (including Tox21 TM /ToxCast™ high-throughput screening data), and in silico model predictions. Users can query these data collections focusing on end points of interest such as acute systemic toxicity, endocrine disruption, skin sensitization, and many others. ICE is publicly accessible at https://ice.ntp.niehs.nih.gov. https://doi.org/10.1289/EHP1759.

Rchemcpp: a web service for structural analoging in ChEMBL, Drugbank and the Connectivity Map.

Science.gov (United States)

Klambauer, Günter; Wischenbart, Martin; Mahr, Michael; Unterthiner, Thomas; Mayr, Andreas; Hochreiter, Sepp

2015-10-15

We have developed Rchempp, a web service that identifies structurally similar compounds (structural analogs) in large-scale molecule databases. The service allows compounds to be queried in the widely used ChEMBL, DrugBank and the Connectivity Map databases. Rchemcpp utilizes the best performing similarity functions, i.e. molecule kernels, as measures for structural similarity. Molecule kernels have proven superior performance over other similarity measures and are currently excelling at machine learning challenges. To considerably reduce computational time, and thereby make it feasible as a web service, a novel efficient prefiltering strategy has been developed, which maintains the sensitivity of the method. By exploiting information contained in public databases, the web service facilitates many applications crucial for the drug development process, such as prioritizing compounds after screening or reducing adverse side effects during late phases. Rchemcpp was used in the DeepTox pipeline that has won the Tox21 Data Challenge and is frequently used by researchers in pharmaceutical companies. The web service and the R package are freely available via http://shiny.bioinf.jku.at/Analoging/ and via Bioconductor. hochreit@bioinf.jku.at Supplementary data are available at Bioinformatics online. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Systems Toxicology of Male Reproductive Development ...

Science.gov (United States)

Adverse trends in male reproductive health have been reported for increased rates of testicular germ cell tumor, low semen quality, cryptorchidism, and hypospadias. An association with prenatal environmental exposure has been inferred from human and animal studies underlying male reproductive developmental defects. The present study established the links between environmental chemicals, molecular targets, and adverse outcomes using U.S. EPA animal study (ToxRefDB) and high-throughput screening (ToxCast) databases. This systems-based approach revealed a phenotypic hierarchy across 63 chemicals and a pleiotropic in vitro bioactivity profile. Although estrogenic and anti-androgenic activities have been extensively studied in male reproductive developmental toxicity, the present study showed these receptor targets to be only a subset of the potential landscape of molecular targets. A variety of chemical (e.g. phthalates, conazoles, carbamates, and phenol compounds) and bioactivity (e.g. nuclear receptors, vascular remodeling proteins, and cytochrome-P450 reductases) clusters further suggested multiple pathways leading to the adverse outcomes. This points to the need for multi-scale systems models to predict whether the occurrence of one adverse outcome may predict the risk of another. Imbalances in androgen and estrogen signaling have been a general focus in male reproductive toxicology research. While a number of recent studies have demonstrated that both hormonal

Novel transcriptome assembly and comparative toxicity pathway analysis in mahi-mahi (Coryphaena hippurus) embryos and larvae exposed to Deepwater Horizon oil

Science.gov (United States)

Xu, Elvis Genbo; Mager, Edward M.; Grosell, Martin; Hazard, E. Starr; Hardiman, Gary; Schlenk, Daniel

2017-03-01

The impacts of Deepwater Horizon (DWH) oil on morphology and function during embryonic development have been documented for a number of fish species, including the economically and ecologically important pelagic species, mahi-mahi (Coryphaena hippurus). However, further investigations on molecular events and pathways responsible for developmental toxicity have been largely restricted due to the limited molecular data available for this species. We sought to establish the de novo transcriptomic database from the embryos and larvae of mahi-mahi exposed to water accommodated fractions (HEWAFs) of two DWH oil types (weathered and source oil), in an effort to advance our understanding of the molecular aspects involved during specific toxicity responses. By high throughput sequencing (HTS), we obtained the first de novo transcriptome of mahi-mahi, with 60,842 assembled transcripts and 30,518 BLAST hits. Among them, 2,345 genes were significantly regulated in 96hpf larvae after exposure to weathered oil. With comparative analysis to a reference-transcriptome-guided approach on gene ontology and tox-pathways, we confirmed the novel approach effective for exploring tox-pathways in non-model species, and also identified a list of co-expressed genes as potential biomarkers which will provide information for the construction of an Adverse Outcome Pathway which could be useful in Ecological Risk Assessments.

Mutations in the Histone-like Nucleoid Structuring Regulatory Gene (hns) Decrease the Adherence of Shiga Toxin-producing Escherichia coli 091:H21 Strain B2F1 to Human Colonic Epithelial Cells and Increase the Production of Hemolysin

Science.gov (United States)

1999-10-19

osmoregulation of outer membrane proteins and virulence determinants in Vibrio cholerae requires toxR. J. Bacteriol. 170:2575-2583. Mobley, H. L., D. M. Green...produced by ETEC organisms is homologous to the toxin encoded by Y: cholerae . These toxins are the primary cause of the watery diarrhea associated with ETEC...Escherichia coli as a cause ofdiarrhea among children in Mexico . J. Clin. Microbiol. 25:1913-1919. Maurelli, A. T., and P. J. Sansonetti. 1988

Development and validation of an LC?MS/MS method for the determination of biogenic amines in wines and beers

OpenAIRE

Nalazek-Rudnicka, Katarzyna; Wasik, Andrzej

2017-01-01

Abstract Biogenic amines are group of organic, basic, nitrogenous compounds that naturally occur in plant, microorganism, and animal organisms. Biogenic amines are mainly produced through decarboxylation of amino acids. They are formed during manufacturing of some kind of food and beverages such as cheese, wine, or beer. Histamine, cadaverine, agmatine, tyramine, putrescine, and ?-phenylethylamine are the most common biogenic amines found in wines and beers. This group of compounds can be tox...

Predicting in vivo effect levels for repeat-dose systemic toxicity using chemical, biological, kinetic and study covariates.

Science.gov (United States)

Truong, Lisa; Ouedraogo, Gladys; Pham, LyLy; Clouzeau, Jacques; Loisel-Joubert, Sophie; Blanchet, Delphine; Noçairi, Hicham; Setzer, Woodrow; Judson, Richard; Grulke, Chris; Mansouri, Kamel; Martin, Matthew

2018-02-01

In an effort to address a major challenge in chemical safety assessment, alternative approaches for characterizing systemic effect levels, a predictive model was developed. Systemic effect levels were curated from ToxRefDB, HESS-DB and COSMOS-DB from numerous study types totaling 4379 in vivo studies for 1247 chemicals. Observed systemic effects in mammalian models are a complex function of chemical dynamics, kinetics, and inter- and intra-individual variability. To address this complex problem, systemic effect levels were modeled at the study-level by leveraging study covariates (e.g., study type, strain, administration route) in addition to multiple descriptor sets, including chemical (ToxPrint, PaDEL, and Physchem), biological (ToxCast), and kinetic descriptors. Using random forest modeling with cross-validation and external validation procedures, study-level covariates alone accounted for approximately 15% of the variance reducing the root mean squared error (RMSE) from 0.96 log 10 to 0.85 log 10  mg/kg/day, providing a baseline performance metric (lower expectation of model performance). A consensus model developed using a combination of study-level covariates, chemical, biological, and kinetic descriptors explained a total of 43% of the variance with an RMSE of 0.69 log 10  mg/kg/day. A benchmark model (upper expectation of model performance) was also developed with an RMSE of 0.5 log 10  mg/kg/day by incorporating study-level covariates and the mean effect level per chemical. To achieve a representative chemical-level prediction, the minimum study-level predicted and observed effect level per chemical were compared reducing the RMSE from 1.0 to 0.73 log 10  mg/kg/day, equivalent to 87% of predictions falling within an order-of-magnitude of the observed value. Although biological descriptors did not improve model performance, the final model was enriched for biological descriptors that indicated xenobiotic metabolism gene expression, oxidative stress, and

Comparative genomics of koala, cattle and sheep strains of Chlamydia pecorum.

Science.gov (United States)

Bachmann, Nathan L; Fraser, Tamieka A; Bertelli, Claire; Jelocnik, Martina; Gillett, Amber; Funnell, Oliver; Flanagan, Cheyne; Myers, Garry S A; Timms, Peter; Polkinghorne, Adam

2014-08-08

Chlamydia pecorum is an important pathogen of domesticated livestock including sheep, cattle and pigs. This pathogen is also a key factor in the decline of the koala in Australia. We sequenced the genomes of three koala C. pecorum strains, isolated from the urogenital tracts and conjunctiva of diseased koalas. The genome of the C. pecorum VR629 (IPA) strain, isolated from a sheep with polyarthritis, was also sequenced. Comparisons of the draft C. pecorum genomes against the complete genomes of livestock C. pecorum isolates revealed that these strains have a conserved gene content and order, sharing a nucleotide sequence similarity > 98%. Single nucleotide polymorphisms (SNPs) appear to be key factors in understanding the adaptive process. Two regions of the chromosome were found to be accumulating a large number of SNPs within the koala strains. These regions include the Chlamydia plasticity zone, which contains two cytotoxin genes (toxA and toxB), and a 77 kbp region that codes for putative type III effector proteins. In one koala strain (MC/MarsBar), the toxB gene was truncated by a premature stop codon but is full-length in IPTaLE and DBDeUG. Another five pseudogenes were also identified, two unique to the urogenital strains C. pecorum MC/MarsBar and C. pecorum DBDeUG, respectively, while three were unique to the koala C. pecorum conjunctival isolate IPTaLE. An examination of the distribution of these pseudogenes in C. pecorum strains from a variety of koala populations, alongside a number of sheep and cattle C. pecorum positive samples from Australian livestock, confirmed the presence of four predicted pseudogenes in koala C. pecorum clinical samples. Consistent with our genomics analyses, none of these pseudogenes were observed in the livestock C. pecorum samples examined. Interestingly, three SNPs resulting in pseudogenes identified in the IPTaLE isolate were not found in any other C. pecorum strain analysed, raising questions over the origin of these

Potential fluoride toxicity from oral medicaments: A review

OpenAIRE

Rizwan Ullah; Muhammad Sohail Zafar; Nazish Shahani

2017-01-01

The beneficial effects of fluoride on human oral health are well studied. There are numerous studies demonstrating that a small amount of fluoride delivered to the oral cavity decreases the prevalence of dental decay and results in stronger teeth and bones. However, ingestion of fluoride more than the recommended limit leads to toxicity and adverse effects. In order to update our understanding of fluoride and its potential toxicity, we have described the mechanisms of fluoride metabolism, tox...

Determination of Short-Chain Chlorinated Paraffins by Carbon Skeleton Gas Chromatography

OpenAIRE

PELLIZZATO FRANCESCA; RICCI MARINA; HELD ANDREA; EMONS HENDRIK

2008-01-01

Short-Chain Chlorinated Paraffins (SCCPs) are highly complex technical mixtures of polychlorinated n-alkanes with a chlorination degree between 50 and 70 % by mass, and a linear carbon chain length from C10 to C13, constituted by thousands of homologues, diastereomers and enantiomers. They have been used in many different applications, such as extreme pressure additives in lubricants and cutting fluids, plasticizers in PVC, and flame retardants in paints, adhesives and sealants. SCCPs are tox...

The Use of Stimulable Bioluminescence From Dinoflagellates as a Means of Detecting Toxicity in the Marine Environment

Science.gov (United States)

1993-03-01

AND SSTýTL FUNDINCG NUMI)) W, TIHE USE OF STIMt LABILE BIOLUMINESCENCE FROM DI NOIFLAGELLATk. PH: M1E69 AS A MEAN’S OF DETrECTING ToxicITY IN THE...bioluminescence dinoflagellates for asseossmnent of toxic effects when exposed to a single tox~icant or mixture. Successful use of this type of bioassav... tributyltin chloride (TFITCI), Copper (11) Sulfate (CuSO 4 I. zinc sulfate (ZnSO4 ), or storm drain effluent. Stimulable bioluminescence was measured at

Installation Restoration Program. Phase II. Confirmation/Quantification Stage I for Wright-Patterson Air Force Base, Dayton, Ohio.

Science.gov (United States)

1985-09-01

nitrate, chlor- ide, sulfate, boron, iron manga - nese, sodium, TOC, TOX, and phenol. Sample six leachate seeps for specific conductance, chlor- ide...Primary Drinking Water Standard of 10 mg/l for nitrate. No boron, iron or manga - nese were found in MW-17. Sodium was detected at 35 mg/l in the well...Thomas, 1976, "Control Pro- Leis, W., and A. Metry, " Multimedia Pathways of Con- gram for Leachate Affecting a Multiple Aquifer System, taminant

Hematologic and Selected Hepatic Changes Produced by Substituted p-Bensoquinones in the Rat.

Science.gov (United States)

1980-07-01

DIVISION OF NUTRITION TECHNOLOGY *DIVISION OF CUTANEOUS HAZARDS I LEECE D IBAI7 TA EMENl AU I __ b rouleISO, Ca. JULYV 1980 CD, LA. 9=3TIRMAN ARMY...jaundice, anemia, hemoglobinuria, and cachexia (8). In previous studies, we found that benzoquinone tox- icity in rats resulted in respiratory depression...randomly housed in stainless steel wire-bottomed cages, one to a cage, and fed a stock diet (Rodent Laboratory Chow #5001, Ralston Purina Co., St. Louis

An Integrative data mining approach to identifying Adverse ...

Science.gov (United States)

The Adverse Outcome Pathway (AOP) framework is a tool for making biological connections and summarizing key information across different levels of biological organization to connect biological perturbations at the molecular level to adverse outcomes for an individual or population. Computational approaches to explore and determine these connections can accelerate the assembly of AOPs. By leveraging the wealth of publicly available data covering chemical effects on biological systems, computationally-predicted AOPs (cpAOPs) were assembled via data mining of high-throughput screening (HTS) in vitro data, in vivo data and other disease phenotype information. Frequent Itemset Mining (FIM) was used to find associations between the gene targets of ToxCast HTS assays and disease data from Comparative Toxicogenomics Database (CTD) by using the chemicals as the common aggregators between datasets. The method was also used to map gene expression data to disease data from CTD. A cpAOP network was defined by considering genes and diseases as nodes and FIM associations as edges. This network contained 18,283 gene to disease associations for the ToxCast data and 110,253 for CTD gene expression. Two case studies show the value of the cpAOP network by extracting subnetworks focused either on fatty liver disease or the Aryl Hydrocarbon Receptor (AHR). The subnetwork surrounding fatty liver disease included many genes known to play a role in this disease. When querying the cpAOP

Tiered High-Throughput Screening Approach to Identify ...

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High-throughput screening (HTS) for potential thyroid–disrupting chemicals requires a system of assays to capture multiple molecular-initiating events (MIEs) that converge on perturbed thyroid hormone (TH) homeostasis. Screening for MIEs specific to TH-disrupting pathways is limited in the US EPA ToxCast screening assay portfolio. To fill one critical screening gap, the Amplex UltraRed-thyroperoxidase (AUR-TPO) assay was developed to identify chemicals that inhibit TPO, as decreased TPO activity reduces TH synthesis. The ToxCast Phase I and II chemical libraries, comprised of 1,074 unique chemicals, were initially screened using a single, high concentration to identify potential TPO inhibitors. Chemicals positive in the single concentration screen were retested in concentration-response. Due to high false positive rates typically observed with loss-of-signal assays such as AUR-TPO, we also employed two additional assays in parallel to identify possible sources of nonspecific assay signal loss, enabling stratification of roughly 300 putative TPO inhibitors based upon selective AUR-TPO activity. A cell-free luciferase inhibition assay was used to identify nonspecific enzyme inhibition among the putative TPO inhibitors, and a cytotoxicity assay using a human cell line was used to estimate the cellular tolerance limit. Additionally, the TPO inhibition activities of 150 chemicals were compared between the AUR-TPO and an orthogonal peroxidase oxidation assay using

Uncertainty Quantification in High Throughput Screening ...

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Using uncertainty quantification, we aim to improve the quality of modeling data from high throughput screening assays for use in risk assessment. ToxCast is a large-scale screening program that analyzes thousands of chemicals using over 800 assays representing hundreds of biochemical and cellular processes, including endocrine disruption, cytotoxicity, and zebrafish development. Over 2.6 million concentration response curves are fit to models to extract parameters related to potency and efficacy. Models built on ToxCast results are being used to rank and prioritize the toxicological risk of tested chemicals and to predict the toxicity of tens of thousands of chemicals not yet tested in vivo. However, the data size also presents challenges. When fitting the data, the choice of models, model selection strategy, and hit call criteria must reflect the need for computational efficiency and robustness, requiring hard and somewhat arbitrary cutoffs. When coupled with unavoidable noise in the experimental concentration response data, these hard cutoffs cause uncertainty in model parameters and the hit call itself. The uncertainty will then propagate through all of the models built on the data. Left unquantified, this uncertainty makes it difficult to fully interpret the data for risk assessment. We used bootstrap resampling methods to quantify the uncertainty in fitting models to the concentration response data. Bootstrap resampling determines confidence intervals for

ACToR Chemical Structure processing using Open Source ...

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ACToR (Aggregated Computational Toxicology Resource) is a centralized database repository developed by the National Center for Computational Toxicology (NCCT) at the U.S. Environmental Protection Agency (EPA). Free and open source tools were used to compile toxicity data from over 1,950 public sources. ACToR contains chemical structure information and toxicological data for over 558,000 unique chemicals. The database primarily includes data from NCCT research programs, in vivo toxicity data from ToxRef, human exposure data from ExpoCast, high-throughput screening data from ToxCast and high quality chemical structure information from the EPA DSSTox program. The DSSTox database is a chemical structure inventory for the NCCT programs and currently has about 16,000 unique structures. Included are also data from PubChem, ChemSpider, USDA, FDA, NIH and several other public data sources. ACToR has been a resource to various international and national research groups. Most of our recent efforts on ACToR are focused on improving the structural identifiers and Physico-Chemical properties of the chemicals in the database. Organizing this huge collection of data and improving the chemical structure quality of the database has posed some major challenges. Workflows have been developed to process structures, calculate chemical properties and identify relationships between CAS numbers. The Structure processing workflow integrates web services (PubChem and NIH NCI Cactus) to d

Analysis of Chemical Bioactivity through In Vitro Profiling ...

Science.gov (United States)

Safety assessment of drugs and environmental chemicals relies extensively on animal testing. However, the quantity of chemicals needing assessment and challenges of species extrapolation drive the development of alternative approaches. The EPA’s ToxCast and the multiagency Tox21 programs address this through use of an extensive in vitro screening program to generate data on a large library of important environmental chemicals. These in vitro assays encompass both cell-free, biochemical assays targeting proteins that may be potential molecular initiating events and cellular assays that provide coverage of critical signaling pathways and toxicity phenotypes. Effects on model organisms such as the developing zebrafish, are also part of the testing strategy. A variety of computational approaches are used to analyze the resulting complex data sets to gain insight in to inherent biological activity of chemicals and possible mechanisms of toxicity. Several case studies including identification of modulators of estrogen receptor and aromatic hydrocarbon receptor pathways with effects in primary human cell systems will be described. In addition, existing in vivo data from a subset of the chemicals was used to anchor predictive models using in vitro data for a number of adverse endpoints including reproductive and developmental toxicities. The strengths and weaknesses of this approach will be described. This work does not necessarily reflect official Agency policy. Pres

Short Toxin-like Proteins Abound in Cnidaria Genomes

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Michal Linial

2012-11-01

Full Text Available Cnidaria is a rich phylum that includes thousands of marine species. In this study, we focused on Anthozoa and Hydrozoa that are represented by the Nematostella vectensis (Sea anemone and Hydra magnipapillata genomes. We present a method for ranking the toxin-like candidates from complete proteomes of Cnidaria. Toxin-like functions were revealed using ClanTox, a statistical machine-learning predictor trained on ion channel inhibitors from venomous animals. Fundamental features that were emphasized in training ClanTox include cysteines and their spacing along the sequences. Among the 83,000 proteins derived from Cnidaria representatives, we found 170 candidates that fulfill the properties of toxin-like-proteins, the vast majority of which were previously unrecognized as toxins. An additional 394 short proteins exhibit characteristics of toxin-like proteins at a moderate degree of confidence. Remarkably, only 11% of the predicted toxin-like proteins were previously classified as toxins. Based on our prediction methodology and manual annotation, we inferred functions for over 400 of these proteins. Such functions include protease inhibitors, membrane pore formation, ion channel blockers and metal binding proteins. Many of the proteins belong to small families of paralogs. We conclude that the evolutionary expansion of toxin-like proteins in Cnidaria contributes to their fitness in the complex environment of the aquatic ecosystem.

Glucose- but not rice-based oral rehydration therapy enhances the production of virulence determinants in the human pathogen Vibrio cholerae.

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Juliane Kühn

2014-12-01

Full Text Available Despite major attempts to prevent cholera transmission, millions of people worldwide still must address this devastating disease. Cholera research has so far mainly focused on the causative agent, the bacterium Vibrio cholerae, or on disease treatment, but rarely were results from both fields interconnected. Indeed, the treatment of this severe diarrheal disease is mostly accomplished by oral rehydration therapy (ORT, whereby water and electrolytes are replenished. Commonly distributed oral rehydration salts also contain glucose. Here, we analyzed the effects of glucose and alternative carbon sources on the production of virulence determinants in the causative agent of cholera, the bacterium Vibrio cholerae during in vitro experimentation. We demonstrate that virulence gene expression and the production of cholera toxin are enhanced in the presence of glucose or similarly transported sugars in a ToxR-, TcpP- and ToxT-dependent manner. The virulence genes were significantly less expressed if alternative non-PTS carbon sources, including rice-based starch, were utilized. Notably, even though glucose-based ORT is commonly used, field studies indicated that rice-based ORT performs better. We therefore used a spatially explicit epidemiological model to demonstrate that the better performing rice-based ORT could have a significant impact on epidemic progression based on the recent outbreak of cholera in Haiti. Our results strongly support a change of carbon source for the treatment of cholera, especially in epidemic settings.

Dynamics of polycyclic aromatic hydrocarbons (PAHs) in surface sediments of Cochin estuary, India

Digital Repository Service at National Institute of Oceanography (India)

Ramzi, A.;; Rahman, K.H.; Gireeshkumar, T.R.; Balachandran, K.K.; Jacob, C.; Chandramohanakumar, N

- ters, Sediments, and Shrimps of Estero de Urias, an Estuary in Mexico, and Their Tox- icological Effects Scientific World Journal. Joseph, M.L., 2004. Status Report on Periyar River, Centre for Water Resource Develop- Parinos, C., Gogou, A., 2016... to particu- ent (Guzzella and De Marine Pollution Bulletin 114 (2017) 1081–1087 Contents lists available at ScienceDirect Marine Pollut l seincreases for the last four decades; so did concentrations of Cd, Zn, Hg and Pb (Mohan et al., 2012; Ranjitha...

A Reevaluation of X-Irradiation Induced Phocomelia and Proximodistal Limb Patterning

OpenAIRE

Galloway, Jenna L.; Delgado, Irene; Ros, Maria A.; Tabin, Clifford J.

2009-01-01

Phocomelia is a devastating, rare congenital limb malformation in which the long bones are shorter than normal, with the upper portion of the limb being most severely affected. In extreme cases, the hands or fingers are attached directly to the shoulder and the most proximal elements (those closest to the shoulder) are entirely missing. This disorder, previously known in both autosomal recessive and sporadic forms, showed a marked increase in incidence in the early 1960s due to the tragic tox...

Two cases of cutaneous diphtheria associated with occupational pig contact in Germany.

Science.gov (United States)

Berger, A; Boschert, V; Konrad, R; Schmidt-Wieland, T; Hörmansdorfer, S; Eddicks, M; Sing, A

2013-12-01

In 2010, two independent cases of cutaneous diphtheria caused by toxigenic C. ulcerans were identified in Germany. Both patients had intense occupational contact with pigs. Diagnostic work-up comprising biochemical differentiation, rpoB sequencing, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF) analysis, real-time tox PCR and Elek test as well as public health measures including an intensified source tracing involving 83 asymptomatic pigs of an associated pig farm are presented. © 2012 Blackwell Verlag GmbH.

The Toxicity of Inhaled Sulphur Mustard

Science.gov (United States)

2012-10-01

lobes, weighed and then dried in an oven (40 oC). The samples were weighed daily until a stable weight had been achieved (approx. 5 days), to...into account). Lung samples were taken, weighed and then dried in an oven (40o C) until a stable weight had been achieved, to determine lung wet...large porcine model: A 6 hour study. Inhal. Tox. (in press). 16. Garner JP, Watts S, Parry C, Bird J and Kirkman E. 2009. Development of a large

DETEKSI GEN-GEN PENYANDI FAKTOR VIRULENSI PADA BAKTERI VIBRIO

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Ince Ayu Khairani Kadriah

2011-04-01

menggunakan isolat bakteri yang diisolasi dari budidaya udang windu di berbagai daerah di Sulawesi Selatan dan Jawa. Pada penelitian ini digunakan primer spesifik untuk mendeteksi gen-gen virulen toxR gene, hemolysin (vvh gene, dan GyrB gene dengan metode PCR. Dari 35 isolat yang diisolasi, 20 isolat terdeteksi memiliki gen virulensi dan 8 di antaranya memiliki dua gen virulen. Spesies bakteri yang memiliki gen virulen adalah: V.harveyi, V. parahaemolyticus, V. mimicus, dan V. campbelli

Arsenic-transforming microbes and their role in biomining processes

OpenAIRE

Drewniak, L.; Sklodowska, A.

2013-01-01

It is well known that microorganisms can dissolve different minerals and use them as sources of nutrients and energy. The majority of rock minerals are rich in vital elements (e.g., P, Fe, S, Mg and Mo), but some may also contain toxic metals or metalloids, like arsenic. The toxicity of arsenic is disclosed after the dissolution of the mineral, which raises two important questions: (1) why do microorganisms dissolve arsenic-bearing minerals and release this metal into the environment in a tox...

Predictive Toxicology: Modeling Chemical Induced Toxicological Response Combining Circular Fingerprints with Random Forest and Support Vector Machine

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Alexios eKoutsoukas

2016-03-01

Full Text Available Modern drug discovery and toxicological research are under pressure, as the cost of developing and testing new chemicals for potential toxicological risk is rising. Extensive evaluation of chemical products for potential adverse effects is a challenging task, due to the large number of chemicals and the possible hazardous effects on human health. Safety regulatory agencies around the world are dealing with two major challenges. First, the growth of chemicals introduced every year in household products and medicines that need to be tested, and second the need to protect public welfare. Hence, alternative and more efficient toxicological risk assessment methods are in high demand. The Toxicology in the 21st Century (Tox21 consortium a collaborative effort was formed to develop and investigate alternative assessment methods. A collection of 10,000 compounds composed of environmental chemicals and approved drugs were screened for interference in biochemical pathways and released for crowdsourcing data analysis. The physicochemical space covered by Tox21 library was explored, measured by Molecular Weight (MW and the octanol/water partition coefficient (cLogP. It was found that on average chemical structures had MW of 272.6 Daltons. In case of cLogP the average value was 2.476. Next relationships between assays were examined based on compounds activity profiles across the assays utilizing the Pearson correlation coefficient r. A cluster was observed between the Androgen and Estrogen Receptors and their ligand bind domains accordingly indicating presence of cross talks among the receptors. The highest correlations observed were between NR.AR and NR.AR_LBD, where it was r=0.66 and between NR.ER and NR.ER_LBD, where it was r=0.5.Our approach to model the Tox21 data consisted of utilizing circular molecular fingerprints combined with Random Forest and Support Vector Machine by modeling each assay independently. In all of the 12 sub-challenges our modeling

Mechanized toxicological serum tests in screening hospitalized patients.

Science.gov (United States)

Hallbach, J; Guder, W G

1991-09-01

A spectrum of quantitative and qualitative methods was adapted to the RA-1000/RA-XT selective analyser for the purpose of excluding or detecting common types of intoxication in the emergency laboratory of our primary care community hospital. Ethanol and salicylates (measured photometrically) and acetaminophen (measured immunologically by EMIT tox) were quantitatively analysed in serum. immunological group tests (EMIT tox) for barbiturates, benzodiazepines, tricyclic antidepressants and related compounds were used for qualitative analysis. Well established clinical chemical methods (aspartarte aminotransferase, alanine aminotransferase, creatine kinase, pseudocholinesterase, glucose and lactate) were applied to the serum samples using the same selective analyser. Within and between run precision, accuracy, recovery and detection ranges (linearity) fulfilled the recommendations of forefield toxicological analysis for all methods. Ethanol (g/l), measured photometrically with the RA-1000 analyser, agreed with the reference method (headspace gas-chromatography) with a correlation coefficient greater than 0.99 (y = 0.06 + 0.98x). Acetaminophen and salicylates showed correlation coefficients greater than 0.94 and greater than 0.99, when compared with manual colorimetric procedures (acetaminophen (mg/l): y = -3.22 + 0.896x; salicylates (mg/l): y = -2.1 + 1x). Qualitative group tests for barbiturates, benzodiazepines and tricyclic antidepressants measured with the RA-1000 analyser were in good agreement with the EMIT single test procedure. The ranges of the quantitative methods allowed quantification of analytes from therapeutic (non-toxic) to very high levels in undiluted samples (ethanol 0.05 up to 4 g/l; salicylates 32 up to 1200 mg/l and acetaminophen 1.9 up to 200 mg/l). The low detection limits of the qualitative tests allowed the recognition of compounds in plasma that were present in low concentrations and/or displayed only minor reactivity with the antibodies

Compound toxicity screening and structure-activity relationship modeling in Escherichia coli.

Science.gov (United States)

Planson, Anne-Gaëlle; Carbonell, Pablo; Paillard, Elodie; Pollet, Nicolas; Faulon, Jean-Loup

2012-03-01

Synthetic biology and metabolic engineering are used to develop new strategies for producing valuable compounds ranging from therapeutics to biofuels in engineered microorganisms. When developing methods for high-titer production cells, toxicity is an important element to consider. Indeed the production rate can be limited due to toxic intermediates or accumulation of byproducts of the heterologous biosynthetic pathway of interest. Conversely, highly toxic molecules are desired when designing antimicrobials. Compound toxicity in bacteria plays a major role in metabolic engineering as well as in the development of new antibacterial agents. Here, we screened a diversified chemical library of 166 compounds for toxicity in Escherichia coli. The dataset was built using a clustering algorithm maximizing the chemical diversity in the library. The resulting assay data was used to develop a toxicity predictor that we used to assess the toxicity of metabolites throughout the metabolome. This new tool for predicting toxicity can thus be used for fine-tuning heterologous expression and can be integrated in a computational-framework for metabolic pathway design. Many structure-activity relationship tools have been developed for toxicology studies in eukaryotes [Valerio (2009), Toxicol Appl Pharmacol, 241(3): 356-370], however, to the best of our knowledge we present here the first E. coli toxicity prediction web server based on QSAR models (EcoliTox server: http://www.issb.genopole.fr/∼faulon/EcoliTox.php). Copyright © 2011 Wiley Periodicals, Inc.

Diagnosis of Clostridium difficile-associated disease: examination of multiple algorithms using toxin EIA, glutamate dehydrogenase EIA and loop-mediated isothermal amplification.

Science.gov (United States)

Bamber, A I; Fitzsimmons, K; Cunniffe, J G; Beasor, C C; Mackintosh, C A; Hobbs, G

2012-01-01

The laboratory diagnosis of Clostridium difficile infection (CDI) needs to be accurate and timely to ensure optimal patient management, infection control and reliable surveillance. Three methods are evaluated using 810 consecutive stool samples against toxigenic culture: CDT TOX A/B Premier enzyme immunoassay (EIA) kit (Meridian Bioscience, Europe), Premier EIA for C. difficile glutamate dehydrogenase (GDH) (Meridian Bioscience, Europe) and the Illumigene kit (Meridian Bioscience, Europe), both individually and within combined testing algorithms. The study revealed that the CDT TOX A/B Premier EIA gave rise to false-positive and false-negative results and demonstrated poor sensitivity (56.47%), compared to Premier EIA for C. difficile GDH (97.65%), suggesting this GDH EIA can be a useful negative screening method. Results for the Illumigene assay alone showed sensitivity, specificity, negative predictive value (NPV) and positive predictive value (PPV) of 91.57%, 98.07%, 99.03% and 84.44%, respectively. A two-stage algorithm using Premier EIA for C. difficile GDH/Illumigene assay yielded superior results compared with other testing algorithms (91.57%, 98.07%, 99.03% and 84.44%, respectively), mirroring the Illumigene performance. However, Illumigene is approximately half the cost of current polymerase chain reaction (PCR) methods, has a rapid turnaround time and requires no specialised skill base, making it an attractive alternative to assays such as the Xpert C. difficile assay (Cepheid, Sunnyvale, CA). A three-stage algorithm offered no improvement and would hamper workflow.

Comparative analysis of the survival and gene expression of pathogenic strains Vibrio harveyi after starvation.

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Sun, Jingjing; Gao, Xiaojian; Qun, Jiang; Du, Xuedi; Bi, Keran; Zhang, Xiaojun; Lin, Li

2016-11-01

This study aimed to evaluate the survival and gene expression of Vibrio harveyi under starvation conditions. The microcosms V. harveyi were incubated in sterilized seawater for 4 weeks at room temperature. Overall, the cell numeration declined rapidly about 10 3 CFU/ml during starvation, with a tiny rebound at day 21. Scanning electron microscopy revealed that rod-shaped cells became sphere with a rippled cell surface. By polymerase chain reaction (PCR) assay, nine genes, named luxR, toxR, vhhB, flaA, topA, fur, rpoS, mreB and ftsZ, were detected in the non-starved cells. In the starved cells, the expression levels of the detected genes declined substantially ranging from 0.005-fold to 0.028-fold compared to the non-starved cells performed by reverse transcription quantitative real-time PCR with 16S rRNA as the internal control. In the recovering cells, the expression levels of the detected genes, except luxR and mreB, were upregulated dramatically compared to the wild, especially topA (23.720-fold), fur (39.400-fold) and toxR (9.837-fold), validating that the expressions of both the metabolism and virulence genes were important for growth and survival of V. harveyi. The results may shed a new light on understanding of stress adaptation in bacteria. © FEMS 2016. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Development of a Focused Library of Triazole-Linked Privileged-Structure-Based Conjugates Leading to the Discovery of Novel Phenotypic Hits against Protozoan Parasitic Infections.

Science.gov (United States)

Uliassi, Elisa; Piazzi, Lorna; Belluti, Federica; Mazzanti, Andrea; Kaiser, Marcel; Brun, Reto; Moraes, Carolina B; Freitas-Junior, Lucio H; Gul, Sheraz; Kuzikov, Maria; Ellinger, Bernhard; Borsari, Chiara; Costi, Maria Paola; Bolognesi, Maria Laura

2018-04-06

Protozoan infections caused by Plasmodium, Leishmania, and Trypanosoma spp. contribute significantly to the burden of infectious diseases worldwide, causing severe morbidity and mortality. The inadequacy of available treatments calls for cost- and time-effective drug discovery endeavors. To this end, we envisaged the triazole linkage of privileged structures as an effective drug design strategy to generate a focused library of high-quality compounds. The versatility of this approach was combined with the feasibility of a phenotypic assay, integrated with early ADME-tox profiling. Thus, an 18-membered library was efficiently assembled via Huisgen cycloaddition of phenothiazine, biphenyl, and phenylpiperazine scaffolds. The resulting 18 compounds were then tested against seven parasite strains, and counter-screened for selectivity against two mammalian cell lines. In parallel, hERG and cytochrome P450 (CYP) inhibition, and mitochondrial toxicity were assessed. Remarkably, 10-((1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-5-yl)methyl)-10H-phenothiazine (7) and 10-(3-(1-(3-([1,1'-biphenyl]-3-yloxy)propyl)-1H-1,2,3-triazol-4-yl)propyl)-10H-phenothiazine (12) showed respective IC 50 values of 1.8 and 1.9 μg mL -1 against T. cruzi, together with optimal selectivity. In particular, compound 7 showed a promising ADME-tox profile. Thus, hit 7 might be progressed as an antichagasic lead. © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.

Differential modulation of FXR activity by chlorophacinone and ivermectin analogs

Energy Technology Data Exchange (ETDEWEB)

Hsu, Chia-Wen [NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (United States); Hsieh, Jui-Hua [National Toxicology Program, National Institutes of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC (United States); Huang, Ruili [NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (United States); Pijnenburg, Dirk [PamGene International B.V., Wolvenhoek 10, 5211 HH ' s-Hertogenbosch (Netherlands); Khuc, Thai [NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (United States); Hamm, Jon [Integrated Laboratory System, Inc., Morrisville, NC (United States); Zhao, Jinghua; Lynch, Caitlin [NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (United States); Beuningen, Rinie van [PamGene International B.V., Wolvenhoek 10, 5211 HH ' s-Hertogenbosch (Netherlands); Chang, Xiaoqing [Integrated Laboratory System, Inc., Morrisville, NC (United States); Houtman, René [PamGene International B.V., Wolvenhoek 10, 5211 HH ' s-Hertogenbosch (Netherlands); Xia, Menghang, E-mail: mxia@mail.nih.gov [NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, Bethesda, MD (United States)

2016-12-15

Chemicals that alter normal function of farnesoid X receptor (FXR) have been shown to affect the homeostasis of bile acids, glucose, and lipids. Several structural classes of environmental chemicals and drugs that modulated FXR transactivation were previously identified by quantitative high-throughput screening (qHTS) of the Tox21 10 K chemical collection. In the present study, we validated the FXR antagonist activity of selected structural classes, including avermectin anthelmintics, dihydropyridine calcium channel blockers, 1,3-indandione rodenticides, and pyrethroid pesticides, using in vitro assay and quantitative structural-activity relationship (QSAR) analysis approaches. (Z)-Guggulsterone, chlorophacinone, ivermectin, and their analogs were profiled for their ability to alter CDCA-mediated FXR binding using a panel of 154 coregulator motifs and to induce or inhibit transactivation and coactivator recruitment activities of constitutive androstane receptor (CAR), liver X receptor alpha (LXRα), or pregnane X receptor (PXR). Our results showed that chlorophacinone and ivermectin had distinct modes of action (MOA) in modulating FXR-coregulator interactions and compound selectivity against the four aforementioned functionally-relevant nuclear receptors. These findings collectively provide mechanistic insights regarding compound activities against FXR and possible explanations for in vivo toxicological observations of chlorophacinone, ivermectin, and their analogs. - Highlights: • A subset of Tox21 chemicals was investigated for FXR antagonism. • In vitro and computational approaches were used to evaluate FXR antagonists. • Chlorophacinone and ivermectin had distinct patterns in modulating FXR activity.

Chemical stabilization of porous silicon for enhanced biofunctionalization with immunoglobulin

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Nelson Naveas, Vicente Torres Costa, Dario Gallach, Jacobo Hernandez-Montelongo, Raul Jose Martín Palma, Josefa Predenstinacion Garcia-Ruiz and Miguel Manso-Silván

2012-01-01

Full Text Available Porous silicon (PSi is widely used in biological experiments, owing to its biocompatibility and well-established fabrication methods that allow tailoring its surface. Nevertheless, there are some unresolved issues such as deciding whether the stabilization of PSi is necessary for its biological applications and evaluating the effects of PSi stabilization on the surface biofunctionalization with proteins. In this work we demonstrate that non-stabilized PSi is prone to detachment owing to the stress induced upon biomolecular adsorption. Biofunctionalized non-stabilized PSi loses the interference properties characteristic of a thin film, and groove-like structures resulting from a final layer collapse were observed by scanning electron microscopy. Likewise, direct PSi derivatization with 3-aminopropyl-triethoxysilane (APTS does not stabilize PSi against immunoglobulin biofunctionalization. To overcome this problem, we developed a simple chemical process of stabilizing PSi (CoxPSi for biological applications, which has several advantages over thermal stabilization (ToxPSi. The process consists of chemical oxidation in H2O2, surface derivatization with APTS and a curing step at 120 °C. This process offers integral homogeneous PSi morphology, hydrophilic surface termination (contact angle θ = 26° and highly efficient derivatized and biofunctionalized PSi surfaces (six times more efficient than ToxPSi. All these features are highly desirable for biological applications, such as biosensing, where our results can be used for the design and optimization of the biomolecular immobilization cascade on PSi surfaces.

Heavy Metals in ToxCast: Relevance to Food Safety (SOT)

Science.gov (United States)

Human exposure to heavy metals occurs through food contamination due to industrial processes, vehicle emissions and farming methods. Specific toxicity endpoints have been associated with metal exposures, e.g. lead and neurotoxicity; however, numerous varieties of heavy metals hav...

tcpl: The ToxCast Pipeline for High-Throughput Screening Data

Science.gov (United States)

Motivation: The large and diverse high-throughput chemical screening efforts carried out by the US EPAToxCast program requires an efficient, transparent, and reproducible data pipeline.Summary: The tcpl R package and its associated MySQL database provide a generalized platform fo...

A proposal for a test method for assessment of hazard property HP 12 (“Release of an acute toxic gas”) in hazardous waste classification - Experience from 49 waste

OpenAIRE

Hennebert , Pierre; Samaali , Ismahen; Molina , Pauline

2016-01-01

International audience; A stepwise method for assessment of the HP 12 is proposed and tested with 49 waste samples. The hazard property HP 12 is defined as “Release of an acute toxic gas”: waste which releases acute toxic gases (Acute Tox. 1, 2 or 3) in contact with water or an acid. When a waste contains a substance assigned to one of the following supplemental hazards EUH029, EUH031 and EUH032, it shall be classified as hazardous by HP 12 according to test methods or guidelines (EC, 2014a, ...

Tumor Immunotherapy by Gene-circuit Recruited Immunomodulatory Systems (TIGRIS) for Prostate Cancer

Science.gov (United States)

2017-09-01

Commercial Assays CytoTox 96 Non-Radioactive Cytotoxicity Assay Kit Promega Cat #G1780 Human IFN-g DuoSet ELISA R&D systems Cat #DY285 Human CCL21/6Ckine...DuoSet ELISA R&D systems Cat #DY366 Human IL-12 p70 DuoSet ELISA R&D systems Cat #DY1270 Cell Culture Reagents DMEM Life Technologies Cat #10569-044...after 24h and IFN-g concentration determined by Human IFN-g DuoSet ELISA (R&D systems, Min- neapolis, MN; catalog #DY285). Multiple-Output Circuit

Genetic Toxicology in the 21st Century: Reflections and Future Directions

Science.gov (United States)

Mahadevan, Brinda; Snyder, Ronald D.; Waters, Michael D.; Benz, R. Daniel; Kemper, Raymond A.; Tice, Raymond R.; Richard, Ann M.

2011-01-01

A symposium at the 40th anniversary of the Environmental Mutagen Society, held from October 24–28, 2009 in St. Louis, MO, surveyed the current status and future directions of genetic toxicology. This article summarizes the presentations and provides a perspective on the future. An abbreviated history is presented, highlighting the current standard battery of genotoxicity assays and persistent challenges. Application of computational toxicology to safety testing within a regulatory setting is discussed as a means for reducing the need for animal testing and human clinical trials, and current approaches and applications of in silico genotoxicity screening approaches across the pharmaceutical industry were surveyed and are reported here. The expanded use of toxicogenomics to illuminate mechanisms and bridge genotoxicity and carcinogenicity, and new public efforts to use high-throughput screening technologies to address lack of toxicity evaluation for the backlog of thousands of industrial chemicals in the environment are detailed. The Tox21 project involves coordinated efforts of four U.S. Government regulatory/research entities to use new and innovative assays to characterize key steps in toxicity pathways, including genotoxic and nongenotoxic mechanisms for carcinogenesis. Progress to date, highlighting preliminary test results from the National Toxicology Program is summarized. Finally, an overview is presented of ToxCast™, a related research program of the U.S. Environmental Protection Agency, using a broad array of high throughput and high content technologies for toxicity profiling of environmental chemicals, and computational toxicology modeling. Progress and challenges, including the pressing need to incorporate metabolic activation capability, are summarized. PMID:21538556

Modification of -Adenosyl--Homocysteine as Inhibitor of Nonstructural Protein 5 Methyltransferase Dengue Virus Through Molecular Docking and Molecular Dynamics Simulation

Directory of Open Access Journals (Sweden)

Usman Sumo Friend Tambunan

2017-04-01

Full Text Available Dengue fever is still a major threat worldwide, approximately threatening two-fifths of the world’s population in tropical and subtropical countries. Nonstructural protein 5 (NS5 methyltransferase enzyme plays a vital role in the process of messenger RNA capping of dengue by transferring methyl groups from S -adenosyl- l -methionine to N7 atom of the guanine bases of RNA and the RNA ribose group of 2′OH, resulting in S -adenosyl- l -homocysteine (SAH. The modification of SAH compound was screened using molecular docking and molecular dynamics simulation, along with computational ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity test. The 2 simulations were performed using Molecular Operating Environment (MOE 2008.10 software, whereas the ADME-Tox test was performed using various software. The modification of SAH compound was done using several functional groups that possess different polarities and properties, resulting in 3460 ligands to be docked. After conducting docking simulation, we earned 3 best ligands (SAH-M331, SAH-M2696, and SAH-M1356 based on ΔG binding and molecular interactions, which show better results than the standard ligands. Moreover, the results of molecular dynamics simulation show that the best ligands are still able to maintain the active site residue interaction with the binding site until the end of the simulation. After a series of molecular docking and molecular dynamics simulation were performed, we concluded that SAH-M1356 ligand is the most potential SAH-based compound to inhibit NS5 methyltransferase enzyme for treating dengue fever.

Modification of S-Adenosyl-l-Homocysteine as Inhibitor of Nonstructural Protein 5 Methyltransferase Dengue Virus Through Molecular Docking and Molecular Dynamics Simulation.

Science.gov (United States)

Tambunan, Usman Sumo Friend; Nasution, Mochammad Arfin Fardiansyah; Azhima, Fauziah; Parikesit, Arli Aditya; Toepak, Erwin Prasetya; Idrus, Syarifuddin; Kerami, Djati

2017-01-01

Dengue fever is still a major threat worldwide, approximately threatening two-fifths of the world's population in tropical and subtropical countries. Nonstructural protein 5 (NS5) methyltransferase enzyme plays a vital role in the process of messenger RNA capping of dengue by transferring methyl groups from S -adenosyl-l-methionine to N7 atom of the guanine bases of RNA and the RNA ribose group of 2'OH, resulting in S -adenosyl-l-homocysteine (SAH). The modification of SAH compound was screened using molecular docking and molecular dynamics simulation, along with computational ADME-Tox (absorption, distribution, metabolism, excretion, and toxicity) test. The 2 simulations were performed using Molecular Operating Environment (MOE) 2008.10 software, whereas the ADME-Tox test was performed using various software. The modification of SAH compound was done using several functional groups that possess different polarities and properties, resulting in 3460 ligands to be docked. After conducting docking simulation, we earned 3 best ligands (SAH-M331, SAH-M2696, and SAH-M1356) based on ΔG binding and molecular interactions, which show better results than the standard ligands. Moreover, the results of molecular dynamics simulation show that the best ligands are still able to maintain the active site residue interaction with the binding site until the end of the simulation. After a series of molecular docking and molecular dynamics simulation were performed, we concluded that SAH-M1356 ligand is the most potential SAH-based compound to inhibit NS5 methyltransferase enzyme for treating dengue fever.

Prevalence and antimicrobial susceptibility of Vibrio parahaemolyticus isolated from retail shrimps in Malaysia.

Science.gov (United States)

Letchumanan, Vengadesh; Yin, Wai-Fong; Lee, Learn-Han; Chan, Kok-Gan

2015-01-01

Vibrio parahaemolyticus is a marine and estuarine bacterium that has been the leading cause of foodborne outbreaks which leads to a significant threat to human health worldwide. Consumption of seafood contaminated with V. parahaemolyticus causes acute gastroenteritis in individuals. The bacterium poses two main virulence factor including the thermostable direct hemolysin (tdh) which is a pore-forming protein that contributes to the invasiveness of the bacterium in humans and TDH-related hemolysin (trh), which plays a similar role as tdh in the disease pathogenesis. This study aimed to investigate the antimicrobial resistance V. parahaemolyticus strains in shrimps purchased from wetmarkets and supermarkets. The toxR-based PCR assay indicated that a total of 57.8% (185/320) isolates were positive for V. parahaemolyticus. Only 10% (19/185) toxR-positive isolate exhibit the trh gene and none of the isolates were tested positive for tdh. The MAR index was measured for 14 common antimicrobial agents. The results indicated 98% of the isolates were highly susceptible to imipenem, ampicillin sulbactam (96%), chloramphenicol (95%), trimethoprim-sulfamethoxazole (93%), gentamicin (85%), levofloxacin (83%), and tetracycline (82%). The chloramphenicol (catA2) and kanamycin (aphA-3) resistance genes were detected in the resistant V. parahaemolyticus isolates. Our results demonstrate that shrimps are contaminated with V. parahaemolyticus, some of which carry the trh-gene thus being potential to cause food borne illness. The occurrence of multidrug resistance strains in the environment could be an indication of excessive usage of antibiotics in agriculture and aquaculture fields.

Prevalence and antimicrobial susceptibility of Vibrio parahaemolyticus isolated from retail shrimps in Malaysia

Directory of Open Access Journals (Sweden)

Vengadesh eLetchumanan

2015-01-01

Full Text Available Vibrio parahaemolyticus is a marine and estuarine bacterium that has been the leading cause of foodborne outbreaks which leads to a significant threat to human health worldwide. Consumption of seafood contaminated with Vibrio parahaemolyticus causes acute gastroenteritis in individuals. The bacterium poses two main virulence factor including the thermostable direct hemolysin (tdh which is a pore-forming protein that contributes to the invasiveness of the bacterium in humans and TDH-related hemolysin (trh, which plays a similar role as thermostable direct hemolysin (tdh in the disease pathogenesis. This study aimed to investigate the antimicrobial resistance Vibrio parahaemolyticus strains in shrimps purchased from wetmarkets and supermarkets. The toxR-based PCR assay indicated that a total of 57.8% (185/320 isolates were positive for V. parahaemolyticus. Only 10% (19/185 toxR-positive isolate exhibit the TDH-related hemolysin (trh gene and none of the isolates were tested positive for thermostable direct hemolysin (tdh. The MAR index was measured for 14 common antimicrobial agents. The results indicated 98% of the isolates were highly susceptible to imipenem, ampicillin sulbactam (96%, chloramphenicol (95%, trimethoprim-sulfamet (93%, gentamicin (85%, levofloxacin (83% and tetracycline (82%. The chloramphenicol (catA2 and kanamycin (aphA-3 resistance genes were detected in the resistant V. parahaemolyticus isolates. Our results demonstrate that shrimps are contaminated with V. parahaemolyticus, some of which carry the trh-gene thus being potential to cause food borne illness. The occurrence of multidrug resistance strains in the environment could be an indication of excessive usage of antibiotics in agriculture and aquaculture fields.

Analysis of Publically Available Skin Sensitization Data from REACH Registrations 2008–2014

Science.gov (United States)

Luechtefeld, Thomas; Maertens, Alexandra; Russo, Daniel P.; Rovida, Costanza; Zhu, Hao; Hartung, Thomas

2017-01-01

Summary The public data on skin sensitization from REACH registrations already included 19,111 studies on skin sensitization in December 2014, making it the largest repository of such data so far (1,470 substances with mouse LLNA, 2,787 with GPMT, 762 with both in vivo and in vitro and 139 with only in vitro data). 21% were classified as sensitizers. The extracted skin sensitization data was analyzed to identify relationships in skin sensitization guidelines, visualize structural relationships of sensitizers, and build models to predict sensitization. A chemical with molecular weight > 500 Da is generally considered non-sensitizing owing to low bioavailability, but 49 sensitizing chemicals with a molecular weight > 500 Da were found. A chemical similarity map was produced using PubChem’s 2D Tanimoto similarity metric and Gephi force layout visualization. Nine clusters of chemicals were identified by Blondel’s module recognition algorithm revealing wide module-dependent variation. Approximately 31% of mapped chemicals are Michael’s acceptors but alone this does not imply skin sensitization. A simple sensitization model using molecular weight and five ToxTree structural alerts showed a balanced accuracy of 65.8% (specificity 80.4%, sensitivity 51.4%), demonstrating that structural alerts have information value. A simple variant of k-nearest neighbors outperformed the ToxTree approach even at 75% similarity threshold (82% balanced accuracy at 0.95 threshold). At higher thresholds, the balanced accuracy increased. Lower similarity thresholds decrease sensitivity faster than specificity. This analysis scopes the landscape of chemical skin sensitization, demonstrating the value of large public datasets for health hazard prediction. PMID:26863411

Prevalence and antimicrobial susceptibility of Vibrio parahaemolyticus isolated from retail shrimps in Malaysia

Science.gov (United States)

Letchumanan, Vengadesh; Yin, Wai-Fong; Lee, Learn-Han; Chan, Kok-Gan

2015-01-01

Vibrio parahaemolyticus is a marine and estuarine bacterium that has been the leading cause of foodborne outbreaks which leads to a significant threat to human health worldwide. Consumption of seafood contaminated with V. parahaemolyticus causes acute gastroenteritis in individuals. The bacterium poses two main virulence factor including the thermostable direct hemolysin (tdh) which is a pore-forming protein that contributes to the invasiveness of the bacterium in humans and TDH-related hemolysin (trh), which plays a similar role as tdh in the disease pathogenesis. This study aimed to investigate the antimicrobial resistance V. parahaemolyticus strains in shrimps purchased from wetmarkets and supermarkets. The toxR-based PCR assay indicated that a total of 57.8% (185/320) isolates were positive for V. parahaemolyticus. Only 10% (19/185) toxR-positive isolate exhibit the trh gene and none of the isolates were tested positive for tdh. The MAR index was measured for 14 common antimicrobial agents. The results indicated 98% of the isolates were highly susceptible to imipenem, ampicillin sulbactam (96%), chloramphenicol (95%), trimethoprim-sulfamethoxazole (93%), gentamicin (85%), levofloxacin (83%), and tetracycline (82%). The chloramphenicol (catA2) and kanamycin (aphA-3) resistance genes were detected in the resistant V. parahaemolyticus isolates. Our results demonstrate that shrimps are contaminated with V. parahaemolyticus, some of which carry the trh-gene thus being potential to cause food borne illness. The occurrence of multidrug resistance strains in the environment could be an indication of excessive usage of antibiotics in agriculture and aquaculture fields. PMID:25688239

Merging Models and Biomonitoring Data to Characterize Sources andPathways of Human Exposure to Organophosphorous Pesticides in the SalinasValley of California

Energy Technology Data Exchange (ETDEWEB)

McKone, Thomas E.; Castorina, Rosemary; Kuwabara, Yu; Harnly,Martha E.; Eskenazi, Brenda; Bradman, Asa

2006-06-01

By drawing on human biomonitoring data and limited environmental samples together with outputs from the CalTOX multimedia, multipathway source-to-dose model, we characterize cumulative intake of organophosphorous (OP) pesticides in an agricultural region of California. We assemble regional OP pesticide use, environmental sampling, and biological tissue monitoring data for a large and geographically dispersed population cohort of 592 pregnant Latina women in California (the CHAMACOS cohort). We then use CalTOX with regional pesticide usage data to estimate the magnitude and uncertainty of exposure and intake from local sources. We combine model estimates of intake from local sources with food intake based on national residue data to estimate for the CHAMACOS cohort cumulative median OP intake, which corresponds to expected levels of urinary dialkylphosphate (DAP) metabolite excretion for this cohort. From these results we develop premises about relative contributions from different sources and pathways of exposure. We evaluate these premises by comparing the magnitude and variation of DAPs in the CHAMACOS cohort with the whole U.S. population using data from the National Health and Nutrition Evaluation Survey (NHANES). This comparison supports the premise that in both populations diet is the common and dominant exposure pathway. Both the model results and biomarker comparison supports the observation that the CHAMACOS population has a statistically significant higher intake of OP pesticides that appears as an almost constant additional dose among all participants. We attribute the magnitude and small variance of this intake to non-dietary exposure in residences from local sources.

Genetic variants at chromosomes 2q35, 5p12, 6q25.1, 10q26.13, and 16q12.1 influence the risk of breast cancer in men.

Directory of Open Access Journals (Sweden)

Nick Orr

2011-09-01

Full Text Available Male breast cancer accounts for approximately 1% of all breast cancer. To date, risk factors for male breast cancer are poorly defined, but certain risk factors and genetic features appear common to both male and female breast cancer. Genome-wide association studies (GWAS have recently identified common single nucleotide polymorphisms (SNPs that influence female breast cancer risk; 12 of these have been independently replicated. To examine if these variants contribute to male breast cancer risk, we genotyped 433 male breast cancer cases and 1,569 controls. Five SNPs showed a statistically significant association with male breast cancer: rs13387042 (2q35 (odds ratio (OR  = 1.30, p = 7.98×10⁻⁴, rs10941679 (5p12 (OR = 1.26, p = 0.007, rs9383938 (6q25.1 (OR = 1.39, p = 0.004, rs2981579 (FGFR2 (OR = 1.18, p = 0.03, and rs3803662 (TOX3 (OR = 1.48, p = 4.04×10⁻⁶. Comparing the ORs for male breast cancer with the published ORs for female breast cancer, three SNPs--rs13387042 (2q35, rs3803662 (TOX3, and rs6504950 (COX11--showed significant differences in ORs (p<0.05 between sexes. Breast cancer is a heterogeneous disease; the relative risks associated with loci identified to date show subtype and, based on these data, gender specificity. Additional studies of well-defined patient subgroups could provide further insight into the biological basis of breast cancer development.

Characterization of Vibrio cholerae O1 El Tor Biotype Variant Clinical Isolates from Bangladesh and Haiti, Including a Molecular Genetic Analysis of Virulence Genes ▿

Science.gov (United States)

Son, Mike S.; Megli, Christina J.; Kovacikova, Gabriela; Qadri, Firdausi; Taylor, Ronald K.

2011-01-01

Vibrio cholerae serogroup O1, the causative agent of the diarrheal disease cholera, is divided into two biotypes: classical and El Tor. Both biotypes produce the major virulence factors toxin-coregulated pilus (TCP) and cholera toxin (CT). Although possessing genotypic and phenotypic differences, El Tor biotype strains displaying classical biotype traits have been reported and subsequently were dubbed El Tor variants. Of particular interest are reports of El Tor variants that produce various levels of CT, including levels typical of classical biotype strains. Here, we report the characterization of 10 clinical isolates from the International Centre for Diarrhoeal Disease Research, Bangladesh, and a representative strain from the 2010 Haiti cholera outbreak. We observed that all 11 strains produced increased CT (2- to 10-fold) compared to that of wild-type El Tor strains under in vitro inducing conditions, but they possessed various TcpA and ToxT expression profiles. Particularly, El Tor variant MQ1795, which produced the highest level of CT and very high levels of TcpA and ToxT, demonstrated hypervirulence compared to the virulence of El Tor wild-type strains in the infant mouse cholera model. Additional genotypic and phenotypic tests were conducted to characterize the variants, including an assessment of biotype-distinguishing characteristics. Notably, the sequencing of ctxB in some El Tor variants revealed two copies of classical ctxB, one per chromosome, contrary to previous reports that located ctxAB only on the large chromosome of El Tor biotype strains. PMID:21880975

Characterization of halogenated DBPs and identification of new DBPs trihalomethanols in chlorine dioxide treated drinking water with multiple extractions.

Science.gov (United States)

Han, Jiarui; Zhang, Xiangru; Liu, Jiaqi; Zhu, Xiaohu; Gong, Tingting

2017-08-01

Chlorine dioxide (ClO 2 ) is a widely used alternative disinfectant due to its high biocidal efficiency and low-level formation of trihalomethanes and haloacetic acids. A major portion of total organic halogen (TOX), a collective parameter for all halogenated DBPs, formed in ClO 2 -treated drinking water is still unknown. A commonly used pretreatment method for analyzing halogenated DBPs in drinking water is one-time liquid-liquid extraction (LLE), which may lead to a substantial loss of DBPs prior to analysis. In this study, characterization and identification of polar halogenated DBPs in a ClO 2 -treated drinking water sample were conducted by pretreating the sample with multiple extractions. Compared to one-time LLE, the combined four-time LLEs improved the recovery of TOX by 2.3 times. The developmental toxicity of the drinking water sample pretreated with the combined four-time LLEs was 1.67 times higher than that pretreated with one-time LLE. With the aid of ultra-performance liquid chromatography/electrospray ionization-triple quadrupole mass spectrometry, a new group of polar halogenated DBPs, trihalomethanols, were detected in the drinking water sample pretreated with multiple extractions; two of them, trichloromethanol and bromodichloromethanol, were identified with synthesized standard compounds. Moreover, these trihalomethanols were found to be the transformation products of trihalomethanes formed during ClO 2 disinfection. The results indicate that multiple LLEs can significantly improve extraction efficiencies of polar halogenated DBPs and is a better pretreatment method for characterizing and identifying new polar halogenated DBPs in drinking water. Copyright © 2017. Published by Elsevier B.V.

Copper zinc tin sulfide-based thin film solar cells

CERN Document Server

Ito, Kentaro

2014-01-01

Beginning with an overview and historical background of Copper Zinc Tin Sulphide (CZTS) technology, subsequent chapters cover properties of CZTS thin films, different preparation methods of CZTS thin films, a comparative study of CZTS and CIGS solar cell, computational approach, and future applications of CZTS thin film solar modules to both ground-mount and rooftop installation. The semiconducting compound (CZTS) is made up earth-abundant, low-cost and non-toxic elements, which make it an ideal candidate to replace Cu(In,Ga)Se2 (CIGS) and CdTe solar cells which face material scarcity and tox

Induction and selection of mutants from in vitro cultured plant cells

Energy Technology Data Exchange (ETDEWEB)

Lee, Yung Il; Kim, Jae Sung; Shin, In Chul; Lee, Sang Jae [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of)

1994-07-01

Mutant cell lines are useful for biochemical, physiological and genetical material for marker in various genetic manipulation experiments and for the direct use in crop plant improvement. Mutant selection may lead to the production of plants showing resistance or tolerance to specific environmental stress, such as solinity, drought, toxed metals, herbicides, pathogens and low temperature. In this review, these included the production of the somatic variation, the selection process itself and stability of the selected characters in cell culture and regenerated plant. Which would seem to be useful for improving plants and securring genetic resources. 45 refs. (Author).

Induction and selection of mutants from in vitro cultured plant cells

International Nuclear Information System (INIS)

Lee, Yung Il; Kim, Jae Sung; Shin, In Chul; Lee, Sang Jae

1994-07-01

Mutant cell lines are useful for biochemical, physiological and genetical material for marker in various genetic manipulation experiments and for the direct use in crop plant improvement. Mutant selection may lead to the production of plants showing resistance or tolerance to specific environmental stress, such as solinity, drought, toxed metals, herbicides, pathogens and low temperature. In this review, these included the production of the somatic variation, the selection process itself and stability of the selected characters in cell culture and regenerated plant. Which would seem to be useful for improving plants and securring genetic resources. 45 refs. (Author)

Design synthesis and biological evaluation of 2-methylphenyl semicarbazone derivatives

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Manmohan Singhal

2011-03-01

Full Text Available We have used pharmacophore hybridization technique of drug design and designed a pharmacophore model 2-methylphenylsemicarbazone which is having hydrogen acceptor site, hydrogen donor site, lipophilic site etc using ligandscout-2.02 software. A series of 2-methylphenyl-semicarbazone was synthesized and evaluated for their antipyretic activity using boiled cow milk induced pyrexia in rabbits. Compound 11 was the most active compound. The possible metabolites of some selected synthesized chalconesemicarbazones were predicted by computational method using Pallas version-3.1 ADME-Tox prediction software. The major pathway of metabolism was found to be p-hydroxylation and amide hydrolysis.

Installation Restoration Program. Phase 2. Confirmation/Quantification. Stage 2. Elmendorf Air Force Base, Alaska.

Science.gov (United States)

1988-03-01

ALSK /. WEL 47 6 e WEL WEL 5 1 WEL 47- WELL 48 WELL 32 EL4 ~;:~:WELL WELL 47 WEL 24L4 WELL 2 7 WELL 25 WELL3 8A WELL 51 WEL 2LL9 WEL 1~’WEL 42 WELL...the abandoned cell of this landfill. Water quality in W-5 is degraded, with TOX at 80 Itrg/L and oil and grease at 5.8 mg/L. Specific conductance and...in a protective foam-lined case. The cell is tested before going into the field using the test feature and is repaired by the manufacturer as

Activities of the senspol and NICOLE network concerning field investigation at contaminated sites

Energy Technology Data Exchange (ETDEWEB)

Ree, C.C.D.F. von [GeoDelft, AB Delft (Netherlands); Alcock, S. [Cranfield Univ. of Silsoe, Bedfordshire (United Kingdom)

2003-07-01

At a European level several networks can be identified aimed at developments and exchange of knowledge relevant to sustainable management of the subsurface. Based on the common interests in the field of site characterisation and monitoring the SENSPOL and NICOLE networks have established links resulting in cooperation in several project-activities. In this presentation two projects will be addressed: - Seville technicalmeeting (Aznacollar mining site). - Bridging gaps between sensor developers and (end) users in a pragmatic approach (GAPS-project). The goal of the Seville technical meeting was to apply the latest sensing technologies at a site contaminated by metal mining activities, to properly evaluate the advances and limitations in the monitoring of contaminated sites for sustainable land management and to determine further steps to commercial exploitation. Some 17 different instruments have been brought including: - Electrochemical sensors using different forms of anodic stripping voltammetry and constant current chronopotentiometry combined with several types of screen printed electrodes. - An amperometric biosensor using screen printed electrodes, which measures toxicity by inhibition effects on urease and its sensitive to Hg(II), Ag(I), Cu(I) and to a lesser extent to Pb(II), Zn(II) and Cd(II) and a selectrochemical DNA biosensor measuring overall toxicity. - A luminescent bacterial sensors for measuring the bioavailable fraction of Cd, Pb, Zn, Cu, As, and Hg, and a bioluminescent fiber optic sensor for Hg and As. - Toxicity testing instruments (Checklight 'ToxScreen Multi-Shot Test, ToxAlert {sup registered} 100 and ToxAlert {sup registered} 10) - A fieldprobe for pH, EC, TDS measurement - A lead automatic analyser AQUAMET using a ion-selective electrode. - Pulse-neutron borehole device in which interaction of neutrons with the surrounding medium can be used to monitor changes. In a two-day field session on the mining site participants were provided

Identifying known unknowns using the US EPA's CompTox Chemistry Dashboard

Science.gov (United States)

Chemical features observed using high-resolution mass spectrometry can be tentatively identified using online chemical reference databases by searching molecular formulae and monoisotopic masses and then rank-ordering of the hits using appropriate relevance criteria. The most li...

Prediction of pharmacokinetic and toxicological parameters of a 4-phenylcoumarin isolated from geopropolis: In silico and in vitro approaches.

Science.gov (United States)

da Cunha, Marcos Guilherme; Franco, Gilson César Nobre; Franchin, Marcelo; Beutler, John A; de Alencar, Severino Matias; Ikegaki, Masaharu; Rosalen, Pedro Luiz

2016-11-30

In silico and in vitro methodologies have been used as important tools in the drug discovery process, including from natural sources. The aim of this study was to predict pharmacokinetic and toxicity (ADME/Tox) properties of a coumarin isolated from geopropolis using in silico and in vitro approaches. Cinnamoyloxy-mammeisin (CNM) isolated from Brazilian M. scutellaris geopropolis was evaluated for its pharmacokinetic parameters by in silico models (ACD/Percepta™ and MetaDrug™ software). Genotoxicity was assessed by in vitro DNA damage signaling PCR array. CNM did not pass all parameters of Lipinski's rule of five, with a predicted low oral bioavailability and high plasma protein binding, but with good predicted blood brain barrier penetration. CNM was predicted to show low affinity to cytochrome P450 family members. Furthermore, the predicted Ames test indicated potential mutagenicity of CNM. Also, the probability of toxicity for organs and tissues was classified as moderate and high for liver and kidney, and moderate and low for skin and eye irritation, respectively. The PCR array analysis showed that CNM significantly upregulated about 7% of all DNA damage-related genes. By exploring the biological function of these genes, it was found that the predicted CNM genotoxicity is likely to be mediated by apoptosis. The predicted ADME/Tox profile suggests that external use of CNM may be preferable to systemic exposure, while its genotoxicity was characterized by the upregulation of apoptosis-related genes after treatment. The combined use of in silico and in vitro approaches to evaluate these parameters generated useful hypotheses to guide further preclinical studies. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

Successful validation of genomic biomarkers for human immunotoxicity in Jurkat T cells in vitro.

Science.gov (United States)

Schmeits, Peter C J; Shao, Jia; van der Krieken, Danique A; Volger, Oscar L; van Loveren, Henk; Peijnenburg, Ad A C M; Hendriksen, Peter J M

2015-07-01

Previously, we identified 25 classifier genes that were able to assess immunotoxicity using human Jurkat T cells. The present study aimed to validate these classifiers. For that purpose, Jurkat cells were exposed for 6 h to subcytotoxic doses of nine immunotoxicants, five non-immunotoxicants and four compounds for which human immunotoxicity has not yet been fully established. RNA was isolated and subjected to Fluidigm quantitative real time (qRT)-PCR analysis. The sensitivity, specificity and accuracy of the screening assay as based on the nine immunotoxicants and five non-immunotoxicants used in this study were 100%, 80% and 93%, respectively, which is better than the performance in our previous study. Only one compound was classified as false positive (benzo-e-pyrene). Of the four potential (non-)immunotoxicants, chlorantraniliprole and Hidrasec were classified immunotoxic and Sunset yellow and imidacloprid as non-immunotoxic. ToxPi analysis of the PCR data provided insight in the molecular pathways that were affected by the compounds. The immunotoxicants 2,3-dichloro-propanol and cypermethrin, although structurally different, affected protein metabolism and cholesterol biosynthesis and transport. In addition, four compounds, i.e. chlorpyrifos, aldicarb, benzo-e-pyrene and anti-CD3, affected genes in cholesterol metabolism and transport, protein metabolism and transcription regulation. qRT-PCR on eight additional genes coding for similar processes as defined in ToxPi analyzes, supported these results. In conclusion, the 25 immunotoxic classifiers performed very well in a screening with new non-immunotoxic and immunotoxic compounds. Therefore, the Jurkat screening assay has great promise to be applied within a tiered approach for animal free testing of human immunotoxicity. Copyright © 2014 John Wiley & Sons, Ltd.

R and D progress report 1993

International Nuclear Information System (INIS)

1994-03-01

The Institute of Toxicology ITOX, established at the end of 1992 by the merger of the partial institute IGT/TOX with the biophysics task force HS, investigates health hazards from environmentally and technically relevant nocuous substances. The toxicological investigation material comprises informative cell models. They range from cells capable of immunity to multicellular spheroids. The objects of investigation are mainly material toxins such as gaseous pollutants, dust, heavy metals and their compounds as well as components of technical materials (for instance, fullerene). In addition, however, questions relating to the effects of low-frequency electromagnetic waves on human health are also studied. (orig./MG) [de

High Throughput Transcriptomics @ USEPA (Toxicology ...

Science.gov (United States)

The ideal chemical testing approach will provide complete coverage of all relevant toxicological responses. It should be sensitive and specific It should identify the mechanism/mode-of-action (with dose-dependence). It should identify responses relevant to the species of interest. Responses should ideally be translated into tissue-, organ-, and organism-level effects. It must be economical and scalable. Using a High Throughput Transcriptomics platform within US EPA provides broader coverage of biological activity space and toxicological MOAs and helps fill the toxicological data gap. Slide presentation at the 2016 ToxForum on using High Throughput Transcriptomics at US EPA for broader coverage biological activity space and toxicological MOAs.

The multimedia models for the evaluation of exposure bond to the atmospheric emissions of classified installations; Les modeles multimedia pour l'evaluation des expositions liees aux emissions atmospheriques des installations classees

Energy Technology Data Exchange (ETDEWEB)

Bonnard, R

2001-12-15

Risk assessment and environmental impacts studies are realized to preserve the public health. Today one of the most used approach is the use of an atmospheric dispersion model to assess the risks. The data are then injected in a calculation software of exposure bond to polluted soils, to evaluate the risks of non direct exposure. This report details and evaluates the models corresponding to the need: the methodology for assessing Health Risks associated with multiple pathways of exposure to combustor, human health risk assessment proto col for hazardous waste combustion facilities, EUSES, CALTOX, MEPAS, MEND-TOX, RESRAD, MMSOILS, FRAMES-HWIR, PC-GEMS and TRIM. (A.L.B.)

The multimedia models for the evaluation of exposure bond to the atmospheric emissions of classified installations

International Nuclear Information System (INIS)

Bonnard, R.

2001-12-01

Risk assessment and environmental impacts studies are realized to preserve the public health. Today one of the most used approach is the use of an atmospheric dispersion model to assess the risks. The data are then injected in a calculation software of exposure bond to polluted soils, to evaluate the risks of non direct exposure. This report details and evaluates the models corresponding to the need: the methodology for assessing Health Risks associated with multiple pathways of exposure to combustor, human health risk assessment proto col for hazardous waste combustion facilities, EUSES, CALTOX, MEPAS, MEND-TOX, RESRAD, MMSOILS, FRAMES-HWIR, PC-GEMS and TRIM. (A.L.B.)

Toxigenic Corynebacterium ulcerans isolated from a free-roaming red fox (Vulpes vulpes).

Science.gov (United States)

Sting, Reinhard; Ketterer-Pintur, Sandra; Contzen, Matthias; Mauder, Norman; Süss-Dombrowski, Christine

2015-01-01

Corynebacterium (C.) ulcerans could be isolated from the spleen of a red fox (Vulpes vulpes) that had been found dead in the state of Baden-Württemberg, Germany. Pathohistological examination suggested that the fox had died of distemper, as was confirmed by PCR. The isolate was identified biochemically, by MALDI-TOF MS, FT-IR and by partial 16S rRNA, rpoB and tox gene sequencing. Using the Elek test the C. ulcerans isolate demonstrated diphtheria toxin production. FT-IR and sequencing data obtained from the C. ulcerans isolate from the red fox showed higher similarity to isolates from humans than to those from wild game.

Recent trends in laboratory automation in the pharmaceutical industry.

Science.gov (United States)

Rutherford, M L; Stinger, T

2001-05-01

The impact of robotics and automation on the pharmaceutical industry over the last two decades has been significant. In the last ten years, the emphasis of laboratory automation has shifted from the support of manufactured products and quality control of laboratory applications, to research and development. This shift has been the direct result of an increased emphasis on the identification, development and eventual marketing of innovative new products. In this article, we will briefly identify and discuss some of the current trends in laboratory automation in the pharmaceutical industry as they apply to research and development, including screening, sample management, combinatorial chemistry, ADME/Tox and pharmacokinetics.

Iron exclusion in rice genotypes as affected by different vapor pressure deficit conditions

Directory of Open Access Journals (Sweden)

Ram Kumar Shrestha

2015-08-01

Full Text Available Root iron (Fe exclusion capacity of four lowland rice genotypes were evaluated in increasing rate of Fe2+ stresses (0, 500, 1000 and 1500 mg/L in growing medium under the conditions of low and high vapor pressure deficit. Rice root excluded significantly higher amount of iron under dry atmospheric condition (655 mg Fe/g root dry matter than moist atmospheric condition (118 mg Fe/g root dry matter. But their iron exclusion capacity reduced when they were gradually exposed to the higher levels of Fe stress. Tolerant genotype such as TOX3107 excluded more iron when they were exposed to dry atmospheric condition.

An exploration of the experience of compassion fatigue in clinical oncology nurses.

Science.gov (United States)

Perry, Beth; Toffner, Greg; Merrick, Trish; Dalton, Janice

2011-01-01

Compassion fatigue (CF) is "debilitating weariness brought about by repetitive, empathic responses to the pain and suffering of others" (LaRowe, 2005, p. 21). The work performed by oncology nurses, and the experiences of the people they care for, place oncology nurses at high risk for CF (Pierce et al., 2007; Ferrell & Coyle, 2008). Thus oncology nurses were chosen as the study focus. This paper details a descriptive exploratory qualitative research study that investigated the experience of CF in Canadian clinical oncology registered nurses (RNs). A conceptual stress process model by Aneshensel, Pearlin, Mullan, Zarit, and Whitlatch (1995) that considers caregivers' stress in four domains provided the study framework (see Figure 1). Nineteen study participants were recruited through an advertisement in the Canadian Oncology Nursing Journal (CONJ). The advertisement directed potential participants to a university-based online website developed for this study. Participants completed a questionnaire and wrote a narrative describing an experience with CF and submitted these through the secure research website. Data were analyzed thematically. Five themes include: defining CF, causes of CF, factors that worsen CF, factors that lessen CF, and outcomes of CF. Participants had limited knowledge about CF, about lack of external support, and that insufficient time to provide high quality, care may precipitate CF. The gap between quality of care nurses wanted to provide and what they were able to do, compounded by coexisting physical and emotional stress, worsened CF. CF was lessened by colleague support, work-life balance, connecting with others, acknowledgement, and maturity and experience. Outcomes of CF included profound fatigue of mind and body, negative effects on personal relationships, and considering leaving the specialty. Recommendations that may enhance oncology nurse well-being are provided.

Quantitative Prediction of Systemic Toxicity Points of Departure (OpenTox USA 2017)

Science.gov (United States)

Human health risk assessment associated with environmental chemical exposure is limited by the tens of thousands of chemicals little or no experimental in vivo toxicity data. Data gap filling techniques, such as quantitative models based on chemical structure information, are c...

Computational Model of Secondary Palate Fusion and Disruption ChemResTox Data

Data.gov (United States)

U.S. Environmental Protection Agency — Morphogenetic events are driven by cell-generated physical forces and complex cellular dynamics. To improve our capacity to predict developmental effects from...

The CompTox Chemistry Dashboard - A Community Data Resource for Environmental Chemistry

Science.gov (United States)

Despite an abundance of online databases providing access to chemical data, there is increasing demand for high-quality, structure-curated, open data to meet the various needs of the environmental sciences and computational toxicology communities. The U.S. Environmental Protectio...

Resurgence of diphtheria in rural areas of North Karnataka, India.

Science.gov (United States)

Parande, Mahantesh V; Roy, Subarna; Mantur, B G; Parande, Aisha M; Shinde, Rupali S

2017-01-01

A diphtheria outbreak was identified from Vijayapura (formerly Bijapur) district in the South Indian state of Karnataka in 2011. There was a surge in the number of throat swab samples received under the Integrated Disease Surveillance Programme (IDSP) in North Karnataka since then. A microbiological study was undertaken to generate information on the status of resurgence of the disease in the region. Throat swabs from 432 suspected cases of diphtheria during 2012-2015 were obtained from government hospitals and primary health centres of 8 districts in North Karnataka and were processed for the culture and identification of Corynebacterium diphtheriae. Polymerase chain reaction for the presence of toxin gene (toxA and toxB) was carried out on the isolates. Antibiotic sensitivity tests were performed on the isolates with a panel of 14 antibiotics. Thirty-eight (8.79%) out of 432 samples yielded C. diphtheriae on culture. All isolates possessed the diphtheria toxin gene. Out of the 38 confirmed cases, whereas 21 (55.26%) were between 1 and 5 years of age, 14 (36.84%) were aged between 5 and 10 years. Male children were three times more than females in confirmed cases. No information was available on the immunisation status of the cases. Emergence of resistance to penicillin was found with minimum inhibitory concentration reaching up to 6.00 μg/ml. Our study identified an upsurge in cases of diphtheria in North Karnataka, particularly in Vijayapura District, and to the best of our knowledge, reports the emergence of penicillin resistance for the first time in India. The study calls for enhanced surveillance for the disease, making antidiphtheritic serum available in key hospitals in the region and serves to provide a baseline for future assessment of the impact of the recently launched 'Mission Indradhanush' programme in strengthening Universal Immunisation Programme (UIP).

Direct evaluation of radiobiological parameters from clinical data in the case of ion beam therapy: an alternative approach to the relative biological effectiveness

International Nuclear Information System (INIS)

Cometto, A; Russo, G; Giordanengo, S; Marchetto, F; Cirio, R; Attili, A; Bourhaleb, F; Milian, F M

2014-01-01

The relative biological effectiveness (RBE) concept is commonly used in treatment planning for ion beam therapy. Whether models based on in vitro/in vivo RBE data can be used to predict human response to treatments is an open issue. In this work an alternative method, based on an effective radiobiological parameterization directly derived from clinical data, is presented. The method has been applied to the analysis of prostate cancer trials with protons and carbon ions. Prostate cancer trials with proton and carbon ion beams reporting 5 year-local control (LC5) and grade 2 (G2) or higher genitourinary toxicity rates (TOX) were selected from literature to test the method. Treatment simulations were performed on a representative subset of patients to produce dose and linear energy transfer distribution, which were used as explicative physical variables for the radiobiological modelling. Two models were taken into consideration: the microdosimetric kinetic model (MKM) and a linear model (LM). The radiobiological parameters of the LM and MKM were obtained by coupling them with the tumor control probability and normal tissue complication probability models to fit the LC5 and TOX data through likelihood maximization. The model ranking was based on the Akaike information criterion. Results showed large confidence intervals due to the limited variety of available treatment schedules. RBE values, such as RBE = 1.1 for protons in the treated volume, were derived as a by-product of the method, showing a consistency with current approaches. Carbon ion RBE values were also derived, showing lower values than those assumed for the original treatment planning in the target region, whereas higher values were found in the bladder. Most importantly, this work shows the possibility to infer the radiobiological parametrization for proton and carbon ion treatment directly from clinical data. (paper)

Organochlorine contaminant and stable isotope profiles in Arctic fox (Alopex lagopus) from the Alaskan and Canadian Arctic

Energy Technology Data Exchange (ETDEWEB)

Hoekstra, P.F.; Braune, B.M.; O' Hara, T.M.; Elkin, B.; Solomon, K.R.; Muir, D.C.G

2003-04-01

PCBs in Arctic fox are lower than reported in other Arctic populations and unlikely to cause significant impairment of reproductive success. - Arctic fox (Alopex lagopus) is a circumpolar species distributed across northern Canada and Alaska. Arctic fox muscle and liver were collected at Barrow, AK, USA (n=18), Holman, NT, Canada (n=20), and Arviat, NU, Canada (n=20) to elucidate the feeding ecology of this species and relate these findings to body residue patterns of organochlorine contaminants (OCs). Stable carbon ({delta}{sup 13}C) and nitrogen ({delta}{sup 15}N) isotope analyses of Arctic fox muscle indicated that trophic position (estimated by {delta}{sup 15}N) is positively correlated with increasing {delta}{sup 13}C values, suggesting that Arctic fox with a predominately marine-based foraging strategy occupy a higher trophic level than individuals mostly feeding from a terrestrial-based carbon source. At all sites, the rank order for OC groups in muscle was polychlorinated biphenyls ({sigma}PCB) > chlordane-related compounds ({sigma}CHLOR) > hexachlorocyclohexane ({sigma}HCH) > total toxaphene (TOX) {>=}chlorobenzenes ({sigma}ClBz) > DDT-related isomers ({sigma}DDT). In liver, {sigma}CHLOR was the most abundant OC group, followed by {sigma}PCB > TOX > {sigma}HCH > {sigma}ClBz > {sigma}DDT. The most abundant OC analytes detected from Arctic fox muscle and liver were oxychlordane, PCB-153, and PCB-180. The comparison of {delta}{sup 15}N with OC concentrations indicated that relative trophic position might not accurately predict OC bioaccumulation in Arctic fox. The bioaccumulation pattern of OCs in the Arctic fox is similar to the polar bear. While {sigma}PCB concentrations were highly variable, concentrations in the Arctic fox were generally below those associated with the toxicological endpoints for adverse effects on mammalian reproduction. Further research is required to properly elucidate the potential health impacts to this species from exposure to OCs.

Continuous Autoregulatory Indices Derived from Multi-Modal Monitoring: Each One Is Not Like the Other.

Science.gov (United States)

Zeiler, Frederick A; Donnelly, Joseph; Menon, David K; Smielewski, Peter; Zweifel, Christian; Brady, Ken; Czosnyka, Marek

2017-11-15

We assess the relationships between various continuous measures of autoregulatory capacity in a cohort of adults with traumatic brain injury (TBI). We assessed relationships between autoregulatory indices derived from intracranial pressure (ICP: PRx, PAx, RAC), transcranial Doppler (TCD: Mx, Sx, Dx), brain tissue-oxygenation (ORx), and spatially resolved near infrared spectroscopy (NIRS resolved: TOx, THx). Relationships between indices were assessed using Pearson correlation coefficient, Friedman test, principal component analysis (PCA), agglomerative hierarchal clustering (AHC) and k-means cluster analysis (KMCA). All analytic techniques were repeated for a range of temporal resolutions of data, including minute-by-minute averages, moving means of 30 samples, and grand mean for each patient. Thirty-seven patients were studied. The PRx displayed strong association with PAx/RAC across all the analytical techniques: Pearson correlation (r = 0.682/r = 0.677, p indices (Mx, Dx) were correlated and co-clustered on PCA, AHC, and KMCA. The Sx was found to be more closely associated with ICP-derived indices on Pearson correlation, PCA, AHC, and KMCA. The NIRS indices displayed variable correlation with each other and with indices derived from ICP and TCD signals. Of interest, TOx and THx co-cluster with ICP-based indices on PCA and AHC. The ORx failed to display any meaningful correlations with other indices in neither of the analytical method used. Thirty-minute moving average and minute-by-minute data set displayed similar results across all the methods. The RAC, Mx, and Sx were the strongest predictors of outcome at six months. Continuously updating autoregulatory indices are not all correlated with one another. Caution must be advised when utilizing less commonly described autoregulation indices (i.e., ORx) for the clinical assessment of autoregulatory capacity, because they appear to not be related to commonly measured/establish indices, such as PRx

Organochlorine contaminant and stable isotope profiles in Arctic fox (Alopex lagopus) from the Alaskan and Canadian Arctic

International Nuclear Information System (INIS)

Hoekstra, P.F.; Braune, B.M.; O'Hara, T.M.; Elkin, B.; Solomon, K.R.; Muir, D.C.G.

2003-01-01

PCBs in Arctic fox are lower than reported in other Arctic populations and unlikely to cause significant impairment of reproductive success. - Arctic fox (Alopex lagopus) is a circumpolar species distributed across northern Canada and Alaska. Arctic fox muscle and liver were collected at Barrow, AK, USA (n=18), Holman, NT, Canada (n=20), and Arviat, NU, Canada (n=20) to elucidate the feeding ecology of this species and relate these findings to body residue patterns of organochlorine contaminants (OCs). Stable carbon (δ 13 C) and nitrogen (δ 15 N) isotope analyses of Arctic fox muscle indicated that trophic position (estimated by δ 15 N) is positively correlated with increasing δ 13 C values, suggesting that Arctic fox with a predominately marine-based foraging strategy occupy a higher trophic level than individuals mostly feeding from a terrestrial-based carbon source. At all sites, the rank order for OC groups in muscle was polychlorinated biphenyls (ΣPCB) > chlordane-related compounds (ΣCHLOR) > hexachlorocyclohexane (ΣHCH) > total toxaphene (TOX) ≥chlorobenzenes (ΣClBz) > DDT-related isomers (ΣDDT). In liver, ΣCHLOR was the most abundant OC group, followed by ΣPCB > TOX > ΣHCH > ΣClBz > ΣDDT. The most abundant OC analytes detected from Arctic fox muscle and liver were oxychlordane, PCB-153, and PCB-180. The comparison of δ 15 N with OC concentrations indicated that relative trophic position might not accurately predict OC bioaccumulation in Arctic fox. The bioaccumulation pattern of OCs in the Arctic fox is similar to the polar bear. While ΣPCB concentrations were highly variable, concentrations in the Arctic fox were generally below those associated with the toxicological endpoints for adverse effects on mammalian reproduction. Further research is required to properly elucidate the potential health impacts to this species from exposure to OCs

Evaluation of terrestrial microcosms for assessing the fate and effects of genetically engineered microorganisms on ecological processes

Energy Technology Data Exchange (ETDEWEB)

Fredrickson, J.K.; Bentjen, S.A.; Bolton, H. Jr.; Li, S.W.; Ligotke, M.W.; McFadden, K.M.; Van Voris, P.

1989-04-01

This project evaluates and modifies the existing US Environmental Protection Agency's Office of Pesticides and Toxic Substances (EPA/OPTS) terrestrial microcosm test system and test protocols such that they can be used to determine the environmental fate and ecological hazards of genetically engineered microorganisms (GEMs). The intact soil-core microcosm represents terrestrial ecosystems, and when coupled with appropriate test protocols, such microcosms may be appropriate to define and limit risks associated with the intentional release of GEMs. The terrestrial microcosm test system was used to investigate the survival and transport of two model GEMs (Azospirillum lipoferum and Pseudomonas sp. Tn5 mutants) to various trophic levels and niches and through intact soil cores. Subsequent effects on nutrient cycling and displacement of indigenous microorganisms were evaluated. The model organisms were a diazotrophic root-colonizing bacterium (A. lipoferum) and a wheat root growth-inhibiting rhizobacterium (Pseudomonas sp.). The transposable element Tn5 was used as a genetic marker for both microorganisms in two separate experiments. The organisms were subjected to transposon mutagenesis using a broad host-range-mobilizable suicide plasmid. The transposon Tn5 conferred levels of kanamycin resistance up to 500 ..mu..g/ml (Pseudomonas sp.), which allowed for selection of the bacteria from environmental samples. The presence of Tn5 DNA in the genome of the model GEMs also allowed the use of Tn5 gene probes to confirm and enumerate the microorganisms in different samples from the microcosms. Two types of root growth-inhibiting Pseudomonas sp. Tn5 mutants were obtained and used in microcosm studies: those that lacked the ability to inhibit either wheat root growth or the growth of other microorganisms in vitro (tox/sup /minus//) and those which retained these properties (tox/sup +/). 53 refs., 7 figs., 6 tabs.

Evaluation of 309 environmental chemicals using a mouse embryonic stem cell adherent cell differentiation and cytotoxicity assay.

Directory of Open Access Journals (Sweden)

Kelly J Chandler

Full Text Available The vast landscape of environmental chemicals has motivated the need for alternative methods to traditional whole-animal bioassays in toxicity testing. Embryonic stem (ES cells provide an in vitro model of embryonic development and an alternative method for assessing developmental toxicity. Here, we evaluated 309 environmental chemicals, mostly food-use pesticides, from the ToxCast™ chemical library using a mouse ES cell platform. ES cells were cultured in the absence of pluripotency factors to promote spontaneous differentiation and in the presence of DMSO-solubilized chemicals at different concentrations to test the effects of exposure on differentiation and cytotoxicity. Cardiomyocyte differentiation (α,β myosin heavy chain; MYH6/MYH7 and cytotoxicity (DRAQ5™/Sapphire700™ were measured by In-Cell Western™ analysis. Half-maximal activity concentration (AC₅₀ values for differentiation and cytotoxicity endpoints were determined, with 18% of the chemical library showing significant activity on either endpoint. Mining these effects against the ToxCast Phase I assays (∼500 revealed significant associations for a subset of chemicals (26 that perturbed transcription-based activities and impaired ES cell differentiation. Increased transcriptional activity of several critical developmental genes including BMPR2, PAX6 and OCT1 were strongly associated with decreased ES cell differentiation. Multiple genes involved in reactive oxygen species signaling pathways (NRF2, ABCG2, GSTA2, HIF1A were strongly associated with decreased ES cell differentiation as well. A multivariate model built from these data revealed alterations in ABCG2 transporter was a strong predictor of impaired ES cell differentiation. Taken together, these results provide an initial characterization of metabolic and regulatory pathways by which some environmental chemicals may act to disrupt ES cell growth and differentiation.

Public Health Benefits of End-Use Electrical Energy Efficiency in California: An Exploratory Study

Energy Technology Data Exchange (ETDEWEB)

McKone, Thomas E.; Lobscheid, A.B.

2006-06-01

This study assesses for California how increasing end-use electrical energy efficiency from installing residential insulation impacts exposures and disease burden from power-plant pollutant emissions. Installation of fiberglass attic insulation in the nearly 3 million electricity-heated homes throughout California is used as a case study. The pollutants nitrous oxides (NO{sub x}), sulfur dioxide (SO{sub 2}), fine particulate matter (PM2.5), benzo(a)pyrene, benzene, and naphthalene are selected for the assessment. Exposure is characterized separately for rural and urban environments using the CalTOX model, which is a key input to the US Environmental Protection Agency (EPA) Tool for the Reduction and Assessment of Chemicals and other environmental Impacts (TRACI). The output of CalTOX provides for urban and rural populations emissions-to-intake factors, which are expressed as an individual intake fraction (iFi). The typical iFi from power plant emissions are on the order of 10{sup -13} (g intake per g emitted) in urban and rural regions. The cumulative (rural and urban) product of emissions, population, and iFi is combined with toxic effects factors to determine human damage factors (HDFs). HDF are expressed as disability adjusted life years (DALYs) per kilogram pollutant emitted. The HDF approach is applied to the insulation case study. Upgrading existing residential insulation to US Department of Energy (DOE) recommended levels eliminates over the assmned 50-year lifetime of the insulation an estimated 1000 DALYs from power-plant emissions per million tonne (Mt) of insulation installed, mostly from the elimination of PM2.5 emissions. In comparison, the estimated burden from the manufacture of this insulation in DALYs per Mt is roughly four orders of magnitude lower than that avoided.

High-content screening in zebrafish embryos identifies butafenacil as a potent inducer of anemia.

Directory of Open Access Journals (Sweden)

Jessica K Leet

Full Text Available Using transgenic zebrafish (fli1:egfp that stably express enhanced green fluorescent protein (eGFP within vascular endothelial cells, we recently developed and optimized a 384-well high-content screening (HCS assay that enables us to screen and identify chemicals affecting cardiovascular development and function at non-teratogenic concentrations. Within this assay, automated image acquisition procedures and custom image analysis protocols are used to quantify body length, heart rate, circulation, pericardial area, and intersegmental vessel area within individual live embryos exposed from 5 to 72 hours post-fertilization. After ranking developmental toxicity data generated from the U.S. Environmental Protection Agency's (EPA's zebrafish teratogenesis assay, we screened 26 of the most acutely toxic chemicals within EPA's ToxCast Phase-I library in concentration-response format (0.05-50 µM using this HCS assay. Based on this screen, we identified butafenacil as a potent inducer of anemia, as exposure from 0.39 to 3.125 µM butafenacil completely abolished arterial circulation in the absence of effects on all other endpoints evaluated. Butafenacil is an herbicide that inhibits protoporphyrinogen oxidase (PPO--an enzyme necessary for heme production in vertebrates. Using o-dianisidine staining, we then revealed that severe butafenacil-induced anemia in zebrafish was due to a complete loss of hemoglobin following exposure during early development. Therefore, six additional PPO inhibitors within the ToxCast Phase-I library were screened to determine whether anemia represents a common adverse outcome for these herbicides. Embryonic exposure to only one of these PPO inhibitors--flumioxazin--resulted in a similar phenotype as butafenacil, albeit not as severe as butafenacil. Overall, this study highlights the potential utility of this assay for (1 screening chemicals for cardiovascular toxicity and (2 prioritizing chemicals for future hypothesis

Genome-wide association study of susceptibility loci for breast cancer in Sardinian population.

Science.gov (United States)

Palomba, Grazia; Loi, Angela; Porcu, Eleonora; Cossu, Antonio; Zara, Ilenia; Budroni, Mario; Dei, Mariano; Lai, Sandra; Mulas, Antonella; Olmeo, Nina; Ionta, Maria Teresa; Atzori, Francesco; Cuccuru, Gianmauro; Pitzalis, Maristella; Zoledziewska, Magdalena; Olla, Nazario; Lovicu, Mario; Pisano, Marina; Abecasis, Gonçalo R; Uda, Manuela; Tanda, Francesco; Michailidou, Kyriaki; Easton, Douglas F; Chanock, Stephen J; Hoover, Robert N; Hunter, David J; Schlessinger, David; Sanna, Serena; Crisponi, Laura; Palmieri, Giuseppe

2015-05-10

Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p <  0(-6) level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10(-5), we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16 x 10(-5)), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts. This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population.

Occurrence Of Virulence Factors And Antimicrobial Resistance In Pasteurella Multocida Strains Isolated From Slaughter Cattle In Iran

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Faham eKhamesipour

2014-10-01

Full Text Available A total of 30 Pasteurella multocida strains isolated from 333 pneumonic and apparently health slaughter cattle were examined for capsule biosynthesis genes and 23 virulence associated genes by polymerase chain reaction. The disc diffusion technique was used to determine antimicrobial resistance profiles among the isolates. Of the isolates, 23 belonged to capsular type A, 5 to capsular type D and two isolates were untypeable. The distribution of the capsular types in pneumonic lungs and in apparently health lungs was statistically similar. All virulence genes tested were detected among the isolates derived from pneumonic lungs; whereas isolates derived from apparently health lungs carried 16 of the 23 genes. The frequently detected genes among isolates from pneumonic lungs were exbD, hgbA, hgbB, ompA, ompH, oma87 and sodC; whereas tadD, toxA and pmHAS genes occurred less frequently. Most of the adhesins and superoxide dismutases; and all of the iron acquisition and protectin proteins occurred at significantly (p≤0.05 higher frequencies in isolates from pneumonic lungs. Isolates from apparently healthy lungs didn’t carry the following genes; hsf-1, hsf-2, tadD, toxA, nanB, nanH and pmHAS. One adhesion (hsf-1 and two iron acquisition (exbD and tonB genes occurred at significantly (p≤0.05 higher frequencies among capA isolates. All the P. multocida isolates were susceptible to ciprofloxacin, co-trimoxazole, doxycycline, enrofloxacin, nitrofurantoin and tetracyclines. Different proportions of the isolates were however resistant to ampicillin, amoxicillin, erythromycin, lincomycin, penicillin, rifampin, streptomycin and florfenicol. Our results reveal presence of virulence factors in P. multocida strains isolated from symptomatic and asymptomatic bovids. A higher frequency of the factors among isolates from symptomatic study animals may suggest their role in pathogenesis of P. multocida-associated bovine respiratory disease. The results further

Contribution of new technologies to characterization and prediction of adverse effects.

Science.gov (United States)

Rouquié, David; Heneweer, Marjoke; Botham, Jane; Ketelslegers, Hans; Markell, Lauren; Pfister, Thomas; Steiling, Winfried; Strauss, Volker; Hennes, Christa

2015-02-01

Identification of the potential hazards of chemicals has traditionally relied on studies in laboratory animals where changes in clinical pathology and histopathology compared to untreated controls defined an adverse effect. In the past decades, increased consistency in the definition of adversity with chemically-induced effects in laboratory animals, as well as in the assessment of human relevance has been reached. More recently, a paradigm shift in toxicity testing has been proposed, mainly driven by concerns over animal welfare but also thanks to the development of new methods. Currently, in vitro approaches, toxicogenomic technologies and computational tools, are available to provide mechanistic insight in toxicological Mode of Action (MOA) of the adverse effects observed in laboratory animals. The vision described as Tox21c (Toxicity Testing in the 21st century) aims at predicting in vivo toxicity using a bottom-up-approach, starting with understanding of MOA based on in vitro data to ultimately predict adverse effects in humans. At present, a practical application of the Tox21c vision is still far away. While moving towards toxicity prediction based on in vitro data, a stepwise reduction of in vivo testing is foreseen by combining in vitro with in vivo tests. Furthermore, newly developed methods will also be increasingly applied, in conjunction with established methods in order to gain trust in these new methods. This confidence is based on a critical scientific prerequisite: the establishment of a causal link between data obtained with new technologies and adverse effects manifested in repeated-dose in vivo toxicity studies. It is proposed to apply the principles described in the WHO/IPCS framework of MOA to obtain this link. Finally, an international database of known MOAs obtained in laboratory animals using data-rich chemicals will facilitate regulatory acceptance and could further help in the validation of the toxicity pathway and adverse outcome pathway

Genome-wide association study of susceptibility loci for breast cancer in Sardinian population

International Nuclear Information System (INIS)

Palomba, Grazia; Loi, Angela; Porcu, Eleonora; Cossu, Antonio; Zara, Ilenia

2015-01-01

Despite progress in identifying genes associated with breast cancer, many more risk loci exist. Genome-wide association analyses in genetically-homogeneous populations, such as that of Sardinia (Italy), could represent an additional approach to detect low penetrance alleles. We performed a genome-wide association study comparing 1431 Sardinian patients with non-familial, BRCA1/2-mutation-negative breast cancer to 2171 healthy Sardinian blood donors. DNA was genotyped using GeneChip Human Mapping 500 K Arrays or Genome-Wide Human SNP Arrays 6.0. To increase genomic coverage, genotypes of additional SNPs were imputed using data from HapMap Phase II. After quality control filtering of genotype data, 1367 cases (9 men) and 1658 controls (1156 men) were analyzed on a total of 2,067,645 SNPs. Overall, 33 genomic regions (67 candidate SNPs) were associated with breast cancer risk at the p < 10 −6 level. Twenty of these regions contained defined genes, including one already associated with breast cancer risk: TOX3. With a lower threshold for preliminary significance to p < 10 −5 , we identified 11 additional SNPs in FGFR2, a well-established breast cancer-associated gene. Ten candidate SNPs were selected, excluding those already associated with breast cancer, for technical validation as well as replication in 1668 samples from the same population. Only SNP rs345299, located in intron 1 of VAV3, remained suggestively associated (p-value, 1.16x10 −5 ), but it did not associate with breast cancer risk in pooled data from two large, mixed-population cohorts. This study indicated the role of TOX3 and FGFR2 as breast cancer susceptibility genes in BRCA1/2-wild-type breast cancer patients from Sardinian population. The online version of this article (doi:10.1186/s12885-015-1392-9) contains supplementary material, which is available to authorized users

Fabrication of Josephson Junction without shadow evaporation

Science.gov (United States)

Wu, Xian; Ku, Hsiangsheng; Long, Junling; Pappas, David

We developed a new method of fabricating Josephson Junction (Al/AlOX/Al) without shadow evaporation. Statistics from room temperature junction resistance and measurement of qubits are presented. Unlike the traditional ``Dolan Bridge'' technique, this method requires two individual lithographies and straight evaporations of Al. Argon RF plasma is used to remove native AlOX after the first evaporation, followed by oxidation and second Al evaporation. Junction resistance measured at room temperature shows linear dependence on Pox (oxidation pressure), √{tox} (oxidation time), and inverse proportional to junction area. We have seen 100% yield of qubits made with this method. This method is promising because it eliminates angle dependence during Junction fabrication, facilitates large scale qubits fabrication.

Synthesis and research of benzylamides of some isocyclic and heterocyclic acids as potential anticonvulsants.

Science.gov (United States)

Strupińska, Marzanna; Rostafińska-Suchar, Grazyna; Pirianowicz-Chaber, Elzbieta; Stables, James P; Jiang, Jeff; Paruszewski, Ryszard

2013-01-01

A series of benzylamides of isocyclic and heterocyclic acids was synthesized and tested in Anticonvulsant Screening Project (ASP) of Antiepileptic Drug Development Program (ADDP) of NIH. Near all synthesized derivatives of heterocyclic acids showed activity. All obtained derivatives of mono- and bicyclic isocyclic acids were inactive. The power of action of heterocyclic acids derivatives seems does not depend upon kind of heteroatom (N, O or S). One of the compounds (2-furoic acid benzylamide (4)) appeared most promising. It showed in minimal clonic seizure (6Hz) test (ASP) in rats after i. p. administration: MES ED50 = 36.5 mg/kg, TOX TD50 = 269.75 mg/kg, and PI = 7.39.

Analytical modeling of threshold voltage for Cylindrical Gate All Around (CGAA MOSFET using center potential

Directory of Open Access Journals (Sweden)

K.P. Pradhan

2015-12-01

Full Text Available In this paper, an analytical threshold voltage model is proposed for a cylindrical gate-all-around (CGAA MOSFET by solving the 2-D Poisson’s equation in the cylindrical coordinate system. A comparison is made for both the center and the surface potential model of CGAA MOSFET. This paper claims that the calculation of threshold voltage using center potential is more accurate rather than the calculation from surface potential. The effects of the device parameters like the drain bias (VDS, oxide thickness (tox, channel thickness (r, etc., on the threshold voltage are also studied in this paper. The model is verified with 3D numerical device simulator Sentaurus from Synopsys Inc.

Determining leach rates of monolithic waste forms

International Nuclear Information System (INIS)

Gilliam, T.M.; Dole, L.R.

1986-01-01

The ANS 16.1 Leach Procedure provides a conservative means of predicting long-term release from monolithic waste forms, offering a simple and relatively quick means of determining effective solid diffusion coefficients. As presented here, these coefficients can be used in a simple model to predict maximum release rates or be used in more complex site-specific models to predict actual site performance. For waste forms that pass the structural integrity test, this model also allows the prediction of EP-Tox leachate concentrations from these coefficients. Thus, the results of the ANS 16.1 Leach Procedure provide a powerful tool that can be used to predict the waste concentration limits in order to comply with the EP-Toxicity criteria for characteristically nonhazardous waste. 12 refs., 3 figs

Retracted: Long-term copper toxicity in apple trees (Malus pumila Mill) and bioaccumulation in fruits.

Science.gov (United States)

Sun, Bai-Ye; Kan, Shi-Hong; Zhang, Yan-Zong; Wu, Jun; Deng, Shi-Huai; Liu, Chun-Sheng; Yang, Gang

2010-01-15

The following article from Environmental Toxicology, 'Long-term Copper Toxicity in Apple Trees (Malus pumila Mill) and Bioaccumulation in Fruits' by Bai-Ye Sun, Shi- Hong Kan, Yan-Zong Zhang, Jun Wu, Shi-Huai Deng, Chun-Sheng Liu and Gang Yang, published online on January 15, 2010 in Wiley InterScience (www.interscience.wiley.com; DOI: 10.1002/tox.20565), has been retracted by agreement between the authors, the journal Editor in Chief, Dr. Paul Tchounwou, and Wiley Periodicals, Inc. The retraction has been agreed at the request of the authors due to overlap with 'Copper Toxicity and Bioaccumulation in Chinese Cabbage (Brassica pekinensis Rupr.)' by Zhi-Ting Xiong and Hai Wang, published in Environmental Toxicology, Volume 20, pages 188-194, 2005.

Analysis of a ToxCast™ HTS Toxicity Signature for putative Vascular Disruptor Compounds

Science.gov (United States)

Recent studies have shown the importance of blood vessel formation during embryo development and the strong correlation to developmental toxicity. Several developmental toxicants, such as thalidomide, have been identified which specifically target the forming embryonic vasculatur...

Evaluation and comparison of bisphenol A analog activity using ToxCast data (SOT)

Science.gov (United States)

Bisphenol A (BPA) is used in consumer products and industrial applications, primarily in plastics, and has been detected in the environment, human urine, blood, and breast milk. Mainly studied as an endocrine disruptor, other toxicities, including obesity, metabolic conditions s...

Evaluation of food-relevant chemicals in the ToxCast high-throughput screening program

Data.gov (United States)

U.S. Environmental Protection Agency — Thousands of chemicals are directly added to or come in contact with food, many of which have undergone little to no toxicological evaluation. The landscape of the...

Minimal_Set_of_In_Vitro_ER_Agonist_Assays_Selection_RegToxPharm_Data

Data.gov (United States)

U.S. Environmental Protection Agency — A dataset for the manuscript which demonstrates that it is possible to achieve levels of performance equivalent to the full 16 assay ER agonist model against both in...

REGOSARC: Regorafenib versus placebo in doxorubicin-refractory soft-tissue sarcoma-A quality-adjusted time without symptoms of progression or toxicity analysis.

Science.gov (United States)

Berry, Vincent; Basson, Laurent; Bogart, Emilie; Mir, Olivier; Blay, Jean-Yves; Italiano, Antoine; Bertucci, François; Chevreau, Christine; Clisant-Delaine, Stéphanie; Liegl-Antzager, Bernadette; Tresch-Bruneel, Emmanuelle; Wallet, Jennifer; Taieb, Sophie; Decoupigny, Emilie; Le Cesne, Axel; Brodowicz, Thomas; Penel, Nicolas

2017-06-15

In a placebo-controlled, randomized phase 2 trial (ClinicalTrials.gov identifier NCT01900743), regorafenib improved progression-free survival (PFS) for patients with doxorubicin-pretreated advanced nonadipocytic sarcoma. A quality-adjusted time without symptoms of progression or toxicity (Q-TWiST) post hoc exploratory analysis was applied to provide an integrated measure of its clinical benefit. In the base-case analysis, each patient's overall survival (OS) was partitioned into 3 mutually exclusive health states: the time with a grade 3 or 4 adverse event (TOX), the time without symptoms of disease or grade 3 or 4 toxicity from treatment, and the time after tumor progression or relapse. The time spent in each state was weighted with a health-state utility associated with that state and was summed to calculate the Q-TWiST. The stability of the base-case analysis was explored with several sensitivity analyses. In nonadipocytic sarcoma, the PFS was (4.0 months [2.6-5.5 months] with regorafenib vs 1.0 month [0.9-1.8 months] with a placebo; hazard ratio, 0.36 [0.25-0.53]; P regorafenib and 9.0 months (6.8-12.5 months) with a placebo (hazard ratio, 0.67 [0.44-1.02]). With the classic definition of TOX (including all grade 3 and 4 clinical adverse events), the Q-TWiSTs were 8.0 months (7.0-9.0 months) with regorafenib and 5.7 months (4.9-6.4 months) with a placebo (P regorafenib significantly improved quality-adjusted survival in comparison with a placebo. Cancer 2017;123:2294-2302. © 2017 The Authors. Cancer published by Wiley Periodicals, Inc. on behalf of American Cancer Society. This is an open access article under the terms of the Creative Commons Attribution NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes. © 2017 American Cancer Society.

Resurgence of diphtheria in rural areas of North Karnataka, India

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Mahantesh V Parande

2017-01-01

Full Text Available Background: A diphtheria outbreak was identified from Vijayapura (formerly Bijapur district in the South Indian state of Karnataka in 2011. There was a surge in the number of throat swab samples received under the Integrated Disease Surveillance Programme (IDSP in North Karnataka since then. Objectives: A microbiological study was undertaken to generate information on the status of resurgence of the disease in the region. Materials and Methods: Throat swabs from 432 suspected cases of diphtheria during 2012–2015 were obtained from government hospitals and primary health centres of 8 districts in North Karnataka and were processed for the culture and identification of Corynebacterium diphtheriae. Polymerase chain reaction for the presence of toxin gene (toxA and toxB was carried out on the isolates. Antibiotic sensitivity tests were performed on the isolates with a panel of 14 antibiotics. Results: Thirty-eight (8.79% out of 432 samples yielded C. diphtheriae on culture. All isolates possessed the diphtheria toxin gene. Out of the 38 confirmed cases, whereas 21 (55.26% were between 1 and 5 years of age, 14 (36.84% were aged between 5 and 10 years. Male children were three times more than females in confirmed cases. No information was available on the immunisation status of the cases. Emergence of resistance to penicillin was found with minimum inhibitory concentration reaching up to 6.00 μg/ml. Conclusion and Discussion: Our study identified an upsurge in cases of diphtheria in North Karnataka, particularly in Vijayapura District, and to the best of our knowledge, reports the emergence of penicillin resistance for the first time in India. The study calls for enhanced surveillance for the disease, making antidiphtheritic serum available in key hospitals in the region and serves to provide a baseline for future assessment of the impact of the recently launched 'Mission Indradhanush' programme in strengthening Universal Immunisation Programme

A bistable switch and anatomical site control Vibrio cholerae virulence gene expression in the intestine.

Directory of Open Access Journals (Sweden)

Alex T Nielsen

2010-09-01

Full Text Available A fundamental, but unanswered question in host-pathogen interactions is the timing, localization and population distribution of virulence gene expression during infection. Here, microarray and in situ single cell expression methods were used to study Vibrio cholerae growth and virulence gene expression during infection of the rabbit ligated ileal loop model of cholera. Genes encoding the toxin-coregulated pilus (TCP and cholera toxin (CT were powerfully expressed early in the infectious process in bacteria adjacent to epithelial surfaces. Increased growth was found to co-localize with virulence gene expression. Significant heterogeneity in the expression of tcpA, the repeating subunit of TCP, was observed late in the infectious process. The expression of tcpA, studied in single cells in a homogeneous medium, demonstrated unimodal induction of tcpA after addition of bicarbonate, a chemical inducer of virulence gene expression. Striking bifurcation of the population occurred during entry into stationary phase: one subpopulation continued to express tcpA, whereas the expression declined in the other subpopulation. ctxA, encoding the A subunit of CT, and toxT, encoding the proximal master regulator of virulence gene expression also exhibited the bifurcation phenotype. The bifurcation phenotype was found to be reversible, epigenetic and to persist after removal of bicarbonate, features consistent with bistable switches. The bistable switch requires the positive-feedback circuit controlling ToxT expression and formation of the CRP-cAMP complex during entry into stationary phase. Key features of this bistable switch also were demonstrated in vivo, where striking heterogeneity in tcpA expression was observed in luminal fluid in later stages of the infection. When this fluid was diluted into artificial seawater, bacterial aggregates continued to express tcpA for prolonged periods of time. The bistable control of virulence gene expression points to a

Larval aquatic insect responses to cadmium and zinc in experimental streams.

Science.gov (United States)

Mebane, Christopher A; Schmidt, Travis S; Balistrieri, Laurie S

2017-03-01

To evaluate the risks of metal mixture effects to natural stream communities under ecologically relevant conditions, the authors conducted 30-d tests with benthic macroinvertebrates exposed to cadmium (Cd) and zinc (Zn) in experimental streams. The simultaneous exposures were with Cd and Zn singly and with Cd+Zn mixtures at environmentally relevant ratios. The tests produced concentration-response patterns that for individual taxa were interpreted in the same manner as classic single-species toxicity tests and for community metrics such as taxa richness and mayfly (Ephemeroptera) abundance were interpreted in the same manner as with stream survey data. Effect concentrations from the experimental stream exposures were usually 2 to 3 orders of magnitude lower than those from classic single-species tests. Relative to a response addition model, which assumes that the joint toxicity of the mixtures can be predicted from the product of their responses to individual toxicants, the Cd+Zn mixtures generally showed slightly less than additive toxicity. The authors applied a modeling approach called Tox to explore the mixture toxicity results and to relate the experimental stream results to field data. The approach predicts the accumulation of toxicants (hydrogen, Cd, and Zn) on organisms using a 2-pK a bidentate model that defines interactions between dissolved cations and biological receptors (biotic ligands) and relates that accumulation through a logistic equation to biological response. The Tox modeling was able to predict Cd+Zn mixture responses from the single-metal exposures as well as responses from field data. The similarity of response patterns between the 30-d experimental stream tests and field data supports the environmental relevance of testing aquatic insects in experimental streams. Environ Toxicol Chem 2017;36:749-762. Published 2016 Wiley Periodicals Inc. on behalf of SETAC. This article is a US government work and, as such, is in the public domain in the

Phenotypically anchored transcriptome profiling of developmental exposure to the antimicrobial agent, triclosan, reveals hepatotoxicity in embryonic zebrafish

International Nuclear Information System (INIS)

Haggard, Derik E.; Noyes, Pamela D.; Waters, Katrina M.; Tanguay, Robert L.

2016-01-01

Triclosan (TCS) is an antimicrobial agent commonly found in a variety of personal care products and cosmetics. TCS readily enters the environment through wastewater and is detected in human plasma, urine, and breast milk due to its widespread use. Studies have implicated TCS as a disruptor of thyroid and estrogen signaling; therefore, research examining the developmental effects of TCS is warranted. In this study, we used embryonic zebrafish to investigate the developmental toxicity and potential mechanism of action of TCS. Embryos were exposed to graded concentrations of TCS from 6 to 120 hours post-fertilization (hpf) and the concentration where 80% of the animals had mortality or morbidity at 120 hpf (EC 80 ) was calculated. Transcriptomic profiling was conducted on embryos exposed to the EC 80 (7.37 μM). We identified a total of 922 significant differentially expressed transcripts (FDR adjusted P-value ≤ 0.05; fold change ≥ 2). Pathway and gene ontology enrichment analyses identified biological networks and transcriptional hubs involving normal liver functioning, suggesting TCS may be hepatotoxic in zebrafish. Tissue-specific gene enrichment analysis further supported the role of the liver as a target organ for TCS toxicity. We also examined the in vitro bioactivity profile of TCS reported by the ToxCast screening program. TCS had a diverse bioactivity profile and was a hit in 217 of the 385 assay endpoints we identified. We observed similarities in gene expression and hepatic steatosis assays; however, hit data for TCS were more concordant with the hypothesized CAR/PXR activity of TCS from rodent and human in vitro studies. - Highlights: • Triclosan is a common antimicrobial agent with widespread human exposure. • Exposure to the triclosan EC 80 causes robust gene expression changes in zebrafish. • The liver may be a target organ of triclosan toxicity in embryonic zebrafish. • Triclosan disrupts normal liver functioning and development in

In silico toxicology for the pharmaceutical sciences

International Nuclear Information System (INIS)

Valerio, Luis G.

2009-01-01

The applied use of in silico technologies (a.k.a. computational toxicology, in silico toxicology, computer-assisted tox, e-tox, i-drug discovery, predictive ADME, etc.) for predicting preclinical toxicological endpoints, clinical adverse effects, and metabolism of pharmaceutical substances has become of high interest to the scientific community and the public. The increased accessibility of these technologies for scientists and recent regulations permitting their use for chemical risk assessment supports this notion. The scientific community is interested in the appropriate use of such technologies as a tool to enhance product development and safety of pharmaceuticals and other xenobiotics, while ensuring the reliability and accuracy of in silico approaches for the toxicological and pharmacological sciences. For pharmaceutical substances, this means active and impurity chemicals in the drug product may be screened using specialized software and databases designed to cover these substances through a chemical structure-based screening process and algorithm specific to a given software program. A major goal for use of these software programs is to enable industry scientists not only to enhance the discovery process but also to ensure the judicious use of in silico tools to support risk assessments of drug-induced toxicities and in safety evaluations. However, a great amount of applied research is still needed, and there are many limitations with these approaches which are described in this review. Currently, there is a wide range of endpoints available from predictive quantitative structure-activity relationship models driven by many different computational software programs and data sources, and this is only expected to grow. For example, there are models based on non-proprietary and/or proprietary information specific to assessing potential rodent carcinogenicity, in silico screens for ICH genetic toxicity assays, reproductive and developmental toxicity, theoretical

Phenotypically anchored transcriptome profiling of developmental exposure to the antimicrobial agent, triclosan, reveals hepatotoxicity in embryonic zebrafish

Energy Technology Data Exchange (ETDEWEB)

Haggard, Derik E. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR (United States); Noyes, Pamela D. [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR (United States); Office of Science Coordination and Policy (OSCP), Office of Chemical Safety and Pollution Prevention, U.S. Environmental Protection Agency, Washington, DC (United States); Waters, Katrina M. [Biological Sciences Division, Pacific Northwest National Laboratory, Richland, WA (United States); Tanguay, Robert L., E-mail: Robert.Tanguay@oregonstate.edu [Department of Environmental and Molecular Toxicology, Oregon State University, Corvallis, OR (United States)

2016-10-01

Triclosan (TCS) is an antimicrobial agent commonly found in a variety of personal care products and cosmetics. TCS readily enters the environment through wastewater and is detected in human plasma, urine, and breast milk due to its widespread use. Studies have implicated TCS as a disruptor of thyroid and estrogen signaling; therefore, research examining the developmental effects of TCS is warranted. In this study, we used embryonic zebrafish to investigate the developmental toxicity and potential mechanism of action of TCS. Embryos were exposed to graded concentrations of TCS from 6 to 120 hours post-fertilization (hpf) and the concentration where 80% of the animals had mortality or morbidity at 120 hpf (EC{sub 80}) was calculated. Transcriptomic profiling was conducted on embryos exposed to the EC{sub 80} (7.37 μM). We identified a total of 922 significant differentially expressed transcripts (FDR adjusted P-value ≤ 0.05; fold change ≥ 2). Pathway and gene ontology enrichment analyses identified biological networks and transcriptional hubs involving normal liver functioning, suggesting TCS may be hepatotoxic in zebrafish. Tissue-specific gene enrichment analysis further supported the role of the liver as a target organ for TCS toxicity. We also examined the in vitro bioactivity profile of TCS reported by the ToxCast screening program. TCS had a diverse bioactivity profile and was a hit in 217 of the 385 assay endpoints we identified. We observed similarities in gene expression and hepatic steatosis assays; however, hit data for TCS were more concordant with the hypothesized CAR/PXR activity of TCS from rodent and human in vitro studies. - Highlights: • Triclosan is a common antimicrobial agent with widespread human exposure. • Exposure to the triclosan EC{sub 80} causes robust gene expression changes in zebrafish. • The liver may be a target organ of triclosan toxicity in embryonic zebrafish. • Triclosan disrupts normal liver functioning and

Adsorption of benzene and toluene from aqueous solutions onto activated carbon and its acid and heat treated forms: influence of surface chemistry on adsorption.

Science.gov (United States)

Wibowo, N; Setyadhi, L; Wibowo, D; Setiawan, J; Ismadji, S

2007-07-19

The influence of surface chemistry and solution pH on the adsorption of benzene and toluene on activated carbon and its acid and heat treated forms were studied. A commercial coal-based activated carbon F-400 was chosen as carbon parent. The carbon samples were obtained by modification of F-400 by means of chemical treatment with HNO3 and thermal treatment under nitrogen flow. The treatment with nitric acid caused the introduction of a significant number of oxygenated acidic surface groups onto the carbon surface, while the heat treatment increases the basicity of carbon. The pore characteristics were not significantly changed after these modifications. The dispersive interactions are the most important factor in this adsorption process. Activated carbon with low oxygenated acidic surface groups (F-400Tox) has the best adsorption capacity.

ACToR - Aggregated Computational Toxicology Resource

International Nuclear Information System (INIS)

Judson, Richard; Richard, Ann; Dix, David; Houck, Keith; Elloumi, Fathi; Martin, Matthew; Cathey, Tommy; Transue, Thomas R.; Spencer, Richard; Wolf, Maritja

2008-01-01

ACToR (Aggregated Computational Toxicology Resource) is a database and set of software applications that bring into one central location many types and sources of data on environmental chemicals. Currently, the ACToR chemical database contains information on chemical structure, in vitro bioassays and in vivo toxicology assays derived from more than 150 sources including the U.S. Environmental Protection Agency (EPA), Centers for Disease Control (CDC), U.S. Food and Drug Administration (FDA), National Institutes of Health (NIH), state agencies, corresponding government agencies in Canada, Europe and Japan, universities, the World Health Organization (WHO) and non-governmental organizations (NGOs). At the EPA National Center for Computational Toxicology, ACToR helps manage large data sets being used in a high-throughput environmental chemical screening and prioritization program called ToxCast TM

A Bistable Switch and Anatomical Site Control Vibrio cholerae Virulence Gene Expression in the Intestine

DEFF Research Database (Denmark)

Nielsen, Alex Toftgaard; Dolganov, N. A.; Rasmussen, Thomas

2010-01-01

A fundamental, but unanswered question in host-pathogen interactions is the timing, localization and population distribution of virulence gene expression during infection. Here, microarray and in situ single cell expression methods were used to study Vibrio cholerae growth and virulence gene...... expression during infection of the rabbit ligated ileal loop model of cholera. Genes encoding the toxin-coregulated pilus (TCP) and cholera toxin (CT) were powerfully expressed early in the infectious process in bacteria adjacent to epithelial surfaces. Increased growth was found to co......, a chemical inducer of virulence gene expression. Striking bifurcation of the population occurred during entry into stationary phase: one subpopulation continued to express tcpA, whereas the expression declined in the other subpopulation. ctxA, encoding the A subunit of CT, and toxT, encoding the proximal...

HTS Data and In Silico Models for High-Throughout Risk Assessment (FutureTox II)

Science.gov (United States)

A significant challenge in toxicology is the “too many chemicals” problem. Humans and environmental species are exposed to as many as tens of thousands of chemicals, few of which have been thoroughly tested using standard in vivo test methods. This talk will discuss several appro...

ACToR Chemical Structure processing using Open Source ChemInformatics Libraries (FutureToxII)

Science.gov (United States)

ACToR (Aggregated Computational Toxicology Resource) is a centralized database repository developed by the National Center for Computational Toxicology (NCCT) at the U.S. Environmental Protection Agency (EPA). Free and open source tools were used to compile toxicity data from ove...

Case Study III: The Construction of a Nanotoxicity Database - The MOD-ENP-TOX Experience.

Science.gov (United States)

Vriens, Hanne; Mertens, Dominik; Regret, Renaud; Lin, Pinpin; Locquet, Jean-Pierre; Hoet, Peter

2017-01-01

The amount of experimental studies on the toxicity of nanomaterials is growing fast. Interpretation and comparison of these studies is a complex issue due to the high amount of variables possibly determining the toxicity of nanomaterials.Qualitative databases providing a structured combination, integration and quality evaluation of the existing data could reveal insights that cannot be seen from different studies alone. A few database initiatives are under development but in practice very little data is publicly available and collaboration between physicists, toxicologists, computer scientists and modellers is needed to further develop databases, standards and analysis tools.In this case study the process of building a database on the in vitro toxicity of amorphous silica nanoparticles (NPs) is described in detail. Experimental data were systematically collected from peer reviewed papers, manually curated and stored in a standardised format. The result is a database in ISA-Tab-Nano including 68 peer reviewed papers on the toxicity of 148 amorphous silica NPs. Both the physicochemical characterization of the particles and their biological effect (described in 230 in vitro assays) were stored in the database. A scoring system was elaborated in order to evaluate the reliability of the stored data.

Identifying Known Unknowns Using the USEPA CompTox Chemistry Dashboard AnalytBioanlytChem Data

Data.gov (United States)

U.S. Environmental Protection Agency — In this research, the performance of the Dashboard for identifying “known unknowns” was evaluated against that of the online ChemSpider database, one of the primary...

Herbal extracts in the treatment of Diabetic Foot Syndrome

Directory of Open Access Journals (Sweden)

Tatyana Kustova

2014-01-01

Full Text Available Introduction: One of the most serious complications of diabetes is the formation of Diabetic Foot Syndrome. Herbal extracts that combine high antioxidant and antimicrobial properties can be used to treat the resulting neuropathy. The aim of this study was to determine antimicrobial and antioxidant activities of crude extracts isolated from plants growing in Kazakhstan, which could be used to develop products for treatment of Diabetic Foot Syndrome. Method: Different solvents, including dichloromethane and ethanol, were used to prepare plant extracts. The crude extracts from the plants were tested for antimicrobial activity using a modified version of the CLSI/NCCLS methods. All organisms were obtained from American Type Culture Collection. These included the fungi Candida glabrata ATTC 90030, the bacteria Staphylococcus aureus ATCC 29213, and Methicillin-resistant S. aureus ATCC 43300. The 2,2-diphеnyl-1-picrylhydrazyl (DPPH assay, 2,2-azinobis (3-ethylbenzothiazoline-6-sulfonic acid diammonium salt (ABTS radical scavenging assay were used to analyzed the antioxidant capacity. Results: The results clearly indicate that antibacterial and antifungal activities vary with plant species. Dichloromethane extracts produced favorable results in all assays. Epilobium hirsutum, Rhodiola quadrifida, Rumex confertus showed antifungal activity against Candida glabrata in all extracts where IC50 less than 3 μg/ml. Rumex confertus, Glycyrrhiza Uralensis and Vexibia alopecuroides showed anti-fungal activity against Staphylococcus aureus (IC50 =10.80 μg/ml, (IC50 =11.10 μg/ml, (IC50 =3.05 μg/ml and Methicillin-resistant S. aureus (IC50 =16.20 μg/ml, (IC50 =11.00 μg/ml, (IC50 =2.90 μg/ml respectively.  In spite of this, Vexibia alopecuroides extract showed no antioxidant activity. The other extracts showed a dose dependent ABTS scavenging activity. IC50 values were for the following: 6.6 μg/ml Epilobium hirsutum; 4.5 μg/ml Rumex confertus; 3.8 �

USEtox - The UNEP-SETAC toxicity model: recommended characterisation factors for human toxicity and freshwater ecotoxicity in Life Cycle Impact Assessment

DEFF Research Database (Denmark)

Rosenbaum, Ralph K.; Bachmann, Till M; Gold, Lois S.

2008-01-01

, and (iii) to build a scientific consensus model from them, representing recommended practice. Methods. A chemical test set of 45 organics covering a wide range of property combinations was selected for this purpose. All models used this set. In three workshops, the model comparison participants identified......, defining a closed or open system environment, or nesting an urban box in a continental box. Discussion. The precision of the new characterisation factors (CFs) is within a factor of 100-1000 for human health and 10-100 for freshwater ecotoxicity of all other models compared to 12 orders of magnitude......Background, Aim and Scope. In 2005 a comprehensive comparison of LCIA toxicity characterisation models was initiated by the UNEP-SETAC Life Cycle Initiative, directly involving the model developers of CalTOX, IMPACT 2002, USES-LCA, BETR, EDIP, WATSON, and EcoSense. In this paper we describe...

Side event of the coordination office during the EWEA 2011 conference

International Nuclear Information System (INIS)

Lapierre, Anne; Toxe, Laurence; Cassin, Fabrice; Doisne, Fabien

2011-01-01

At the occasion of the 2011 edition of the Europe Wind energy event (EWEA), the French-German office for Renewable energies (OFAEnR) organised a conference entitled 'Fresh wind in the French regulatory framework'. In the framework of this French-German exchange of experience, participants exchanged views on the new fiscal and legal framework for the wind industry in France and its immediate and future impacts on the development of this industry. This document brings together the available presentations (slides) made during this event: 1 - Wind energy sector: the regulatory framework after 'Grenelle II' Law - Focus on the reform of business tax (Anne Lapierre, Laurence Toxe); 2 - The French planning exercise - Regional Wind Plan (SRe): Perspectives and Reality (Fabrice Cassin); 3 - Regional wind plan approach - Picardie: case study of the drawing up of a Regional Wind Plan (Fabien Doisne)

Colonie Interim Storage Site: Annual environmental report for calendar year 1990, Colonie, New York

International Nuclear Information System (INIS)

1991-09-01

Environmental monitoring of the US Department of Energy's (DOE) Colonie Interim Storage Site (CISS) and surrounding area began in 1984. CISS is part of the Formerly Utilized Sites Remedial Action Program (FUSRAP), a DOE program to decontaminate or otherwise control sties where residual radioactive materials remain from the early years of the nation's atomic energy program or from commercial operations causing conditions that Congress has authorized DOE to remedy. The routine environmental monitoring program at CISS includes sampling networks for external gamma radiation exposures and for radium-226, throium-232, an total uranium concentrations in surface water, sediment, and groundwater. Additionally, the nonradiological parameters volatile and semivolatile organics, pesticides/polychlorinated biphenyls (PCBs), metals, total organic carbon (TOC), total organic halides (TOX), specific conductivity, and pH are measured in groundwater. 14 refs., 20 figs., 25 tabs

Analysis of damaged DNA / proteins interactions: Methodological optimizations and applications to DNA lesions induced by platinum anticancer drugs

International Nuclear Information System (INIS)

Bounaix Morand du Puch, Ch

2010-10-01

DNA lesions contribute to the alteration of DNA structure, thereby inhibiting essential cellular processes. Such alterations may be beneficial for chemotherapies, for example in the case of platinum anticancer agents. They generate bulky adducts that, if not repaired, ultimately cause apoptosis. A better understanding of the biological response to such molecules can be obtained through the study of proteins that directly interact with the damages. These proteins constitute the DNA lesions interactome. This thesis presents the development of tools aiming at increasing the list of platinum adduct-associated proteins. Firstly, we designed a ligand fishing system made of damaged plasmids immobilized onto magnetic beads. Three platinum drugs were selected for our study: cisplatin, oxali-platin and satra-platin. Following exposure of the trap to nuclear extracts from HeLa cancer cells and identification of retained proteins by proteomics, we obtained already known candidates (HMGB1, hUBF, FACT complex) but also 29 new members of the platinated-DNA interactome. Among them, we noted the presence of PNUTS, TOX4 and WDR82, which associate to form the recently-discovered PTW/PP complex. Their capture was then confirmed with a second model, namely breast cancer cell line MDA MB 231, and the biological consequences of such an interaction now need to be elucidated. Secondly, we adapted a SPRi bio-chip to the study of platinum-damaged DNA/proteins interactions. Affinity of HMGB1 and newly characterized TOX4 for adducts generated by our three platinum drugs could be validated thanks to the bio-chip. Finally, we used our tools, as well as analytical chemistry and biochemistry methods, to evaluate the role of DDB2 (a factor involved in the recognition of UV-induced lesions) in the repair of cisplatin adducts. Our experiments using MDA MB 231 cells differentially expressing DDB2 showed that this protein is not responsible for the repair of platinum damages. Instead, it appears to act

Virulence factors of non-O1 non-O139 Vibrio cholerae isolated in Córdoba, Argentina Factores de virulencia de Vibrio cholerae no-O1 no-O139 aislados en Córdoba, Argentina

Directory of Open Access Journals (Sweden)

C. Bidinost

2004-12-01

Full Text Available V. cholerae non-O1 non-O139 serogroups isolated from clinical and environmental sources in Córdoba, Argentina, were analyzed for the presence and expression of virulence genes. Most of the strains studied contained the genes toxR and hlyA, but lacked ctxA, zot, ace, tcpA and stn. The culture supernatants were tested for hemolytic and cytotoxic activity. The enterotoxic potential of the strains was studied in a rabbit ileal loop assay and their genetic profiles were compared by PFGE. The environmental strains varied in their virulence phenotype and showed no-clonal relationships. The clinical strains were highly enterotoxic, hemolytic, proteolytic and showed indistinguishable PFGE profiles, although they differed in their cytotoxic activity. This is the first description, using cell culture and “in vivo” studies, of the virulence properties of non-O1 non-O139 V. cholerae from Argentina.En este trabajo se analizó la presencia y expresión de genes de virulencia en V. cholerae no-O1 no-O139 de origen clínico y ambiental, aislados en Córdoba, Argentina. La mayoría de las cepas estudiadas contiene los genes toxR y hlyA, pero no ctxA, zot, ace, tcpA y stn. Se analizó la actividad hemolítica y citotóxica de estas cepas en los sobrenadantes de cultivo, así como su potencial enterotóxico en ensayos de asa ileal ligada de conejo. Además, los aislamientos fueron comparados por sus perfiles genéticos en PFGE. Las cepas del medio ambiente mostraron variación en su fenotipo de virulencia y no mostraron relación clonal. Las cepas clínicas fueron muy enterotóxicas, hemolíticas, proteolíticas y mostraron perfiles indistinguibles de PFGE, aunque mostraron diferencias en su actividad citotóxica. En este trabajo se describen por primera vez, utilizando ensayos de cultivo celular e “in vivo”, propiedades de virulencia de V. cholerae no-O1 no-O139 aislados en Argentina.

Release, transport and toxicity of engineered nanoparticles.

Science.gov (United States)

Soni, Deepika; Naoghare, Pravin K; Saravanadevi, Sivanesan; Pandey, Ram Avatar

2015-01-01

Recent developments in nanotechnology have facilitated the synthesis of novel engineered nanoparticles (ENPs) that possess new and different physicochemical properties. These ENPs have been ex tensive ly used in various commercial sectors to achieve both social and economic benefits. However. the increasing production and consumption of ENPs by many different industries has raised concerns about their possible release and accumulation in the environment. Released EN Ps may either remain suspended in the atmosphere for several years or may accumulate and eventually be modified int o other substances. Settled nanoparticles can he easily washed away during ra in s. and therefore may easily enter the food chain via water and so il. Thus. EN Ps can contaminate air. water and soil and can subsequently pose adverse risks to the health of different organisms. Studies to date indicate that ENP transport to and within the ecosystem depend on their chemical and physical properties (viz .. size. shape and solubility) . Therefore. the EN Ps display variable behavior in the environment because of their individual properties th at affect their tendency for adsorption, absorption, diffusional and colloidal interaction. The transport of EN Ps also influences their fate and chemical transformation in ecosystems. The adsorption, absorption and colloidal interaction of ENPs affect their capacity to be degraded or transformed, whereas the tendency of ENPs to agglomerate fosters their sedimentation. How widely ENPs are transported and their environmental fate influence how tox ic they may become to environmental organisms. One barrier to fully understanding how EN Ps are transformed in the environment and how best to characterize their toxicity, is related to the nature of their ultrafine structure. Experiments with different animals, pl ants, and cell lines have revealed that ENPs induce toxicity via several cellular pathways that is linked to the size. shape. surface area

The Toxicology Investigators Consortium Case Registry-the 2015 Experience.

Science.gov (United States)

Farrugia, Lynn A; Rhyee, Sean H; Campleman, Sharan L; Ruha, Anne-Michelle; Weigand, Timothy; Wax, Paul M; Brent, Jeffrey

2016-09-01

The American College of Medical Toxicology established the Toxicology Investigators Consortium (ToxIC) Case Registry in 2010. The Registry contains all medical toxicology consultations performed at participating sites. The Registry has continued to grow since its inception, and as of December 31, 2015, contains 43,099 cases. This is the sixth annual report of the ToxIC Registry, summarizing the additional 8115 cases entered in 2015. Cases were identified by a query of the Registry for all cases entered between January 1 and December 31, 2015. Specific data reviewed for analysis included demographics (age, race, gender), source of consultation, reason for consultation, agents and agent classes involved in exposures, signs, symptoms, clinical findings, fatalities, and treatment. By the end of 2015, there were 50 active sites, consisting of 101 separate health-care facilities; 51.2 % of cases involved females. Adults between the ages of 19 and 65 made up the majority (64.2 %) of Registry cases. Caucasian race was the most commonly reported (55.6 %); 9.6 % of cases were identified as Hispanic ethnicity. Inpatient and emergency department referrals were by far the most common referral sources (92.9 %). Intentional pharmaceutical exposures remained the most frequent reason for consultation, making up 52.3 % of cases. Of these intentional pharmaceutical exposures, 69 % represented an attempt at self-harm, and 85.6 % of these were a suicide attempt. Nonopioid analgesics, sedative-hypnotics, and antidepressant agents were the most commonly reported agent classes in 2015. Almost one-third of Registry cases involved a diagnosed toxidrome (32.8 %), with a sedative-hypnotic toxidrome being the most frequently described. Significant vital sign abnormalities were recorded in 25.3 % of cases. There were 98 fatalities reported in the Registry (1.2 %). Adverse drug reactions were reported in 4.3 % of cases. Toxicological treatment was given in 65.3 % of cases, with 33.0�

Comparison and Evaluation of the Molecular Typing Methods for Toxigenic Vibrio cholerae in Southwest China.

Science.gov (United States)

Liao, Feng; Mo, Zhishuo; Chen, Meiling; Pang, Bo; Fu, Xiaoqing; Xu, Wen; Jing, Huaiqi; Kan, Biao; Gu, Wenpeng

2018-01-01

Vibrio cholerae O1 strains taken from the repository of Yunnan province, southwest China, were abundant and special. We selected 70 typical toxigenic V. cholerae (69 O1 and one O139 serogroup strains) isolated from Yunnan province, performed the pulsed field gel electrophoresis (PFGE), multilocus sequence typing (MLST), and MLST of virulence gene (V-MLST) methods, and evaluated the resolution abilities for typing methods. The ctxB subunit sequence analysis for all strains have shown that cholera between 1986 and 1995 was associated with mixed infections with El Tor and El Tor variants, while infections after 1996 were all caused by El Tor variant strains. Seventy V. cholerae obtained 50 PFGE patterns, with a high resolution. The strains could be divided into three groups with predominance of strains isolated during 1980s, 1990s, and 2000s, respectively, showing a good consistency with the epidemiological investigation. We also evaluated two MLST method for V. cholerae , one was used seven housekeeping genes ( adk , gyrB , metE , pntA , mdh , purM , and pyrC ), and all the isolates belonged to ST69; another was used nine housekeeping genes ( cat , chi , dnaE , gyrB , lap , pgm , recA , rstA , and gmd ). A total of seven sequence types (STs) were found by using this method for all the strains; among them, rstA gene had five alleles, recA and gmd have two alleles, and others had only one allele. The virulence gene sequence typing method ( ctxAB , tcpA , and toxR ) showed that 70 strains were divided into nine STs; among them, tcpA gene had six alleles, toxR had five alleles, while ctxAB was identical for all the strains. The latter two sequences based typing methods also had consistency with epidemiology of the strains. PFGE had a higher resolution ability compared with the sequence based typing method, and MLST used seven housekeeping genes showed the lower resolution power than nine housekeeping genes and virulence genes methods. These two sequence typing methods

ChLae1 and ChVel1 regulate T-toxin production, virulence, oxidative stress response, and development of the maize pathogen Cochliobolus heterostrophus.

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Dongliang Wu

2012-02-01

Full Text Available LaeA and VeA coordinate secondary metabolism and differentiation in response to light signals in Aspergillus spp. Their orthologs, ChLae1 and ChVel1, were identified in the maize pathogen Cochliobolus heterostrophus, known to produce a wealth of secondary metabolites, including the host selective toxin, T-toxin. Produced by race T, T-toxin promotes high virulence to maize carrying Texas male sterile cytoplasm (T-cms. T-toxin production is significantly increased in the dark in wild type (WT, whereas Chvel1 and Chlae1 mutant toxin levels are much reduced in the dark compared to WT. Correspondingly, expression of T-toxin biosynthetic genes (Tox1 is up-regulated in the dark in WT, while dark-induced expression is much reduced/minimal in Chvel1 and Chlae1 mutants. Toxin production and Tox1 gene expression are increased in ChVEL1 overexpression (OE strains grown in the dark and in ChLAE1 strains grown in either light or dark, compared to WT. These observations establish ChLae1 and ChVel1 as the first factors known to regulate host selective toxin production. Virulence of Chlae1 and Chvel1 mutants and OE strains is altered on both T-cms and normal cytoplasm maize, indicating that both T-toxin mediated super virulence and basic pathogenic ability are affected. Deletion of ChLAE1 or ChVEL1 reduces tolerance to H(2O(2. Expression of CAT3, one of the three catalase genes, is reduced in the Chvel1 mutant. Chlae1 and Chvel1 mutants also show decreased aerial hyphal growth, increased asexual sporulation and female sterility. ChLAE1 OE strains are female sterile, while ChVEL1 OE strains are more fertile than WT. ChLae1 and ChVel1 repress expression of 1,8-dihydroxynaphthalene (DHN melanin biosynthesis genes, and, accordingly, melanization is enhanced in Chlae1 and Chvel1 mutants, and reduced in OE strains. Thus, ChLae1 and ChVel1 positively regulate T-toxin biosynthesis, pathogenicity and super virulence, oxidative stress responses, sexual development, and

Physiological response of the nematode Caenorhabditis elegans exposed to binary mixture of uranium and cadmium

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Margerit, A.; Gilbin, R. [French Institute for Radiological Protection and Nuclear Safety - IRSN (France); Gomez, E. [Universite Montpellier 1 (France)

2014-07-01

Both uranium (U) and cadmium (Cd) are natural ubiquitous substances whose occurrence may be magnified in the vicinity of some Nuclear Fuel Cycle Facility (NFCF) (e.g. uranium mining area) or intensive farming areas. Natural U is a mainly chemo-toxic radioelement, with a slight radio-toxic activity, while Cd is a fully chemo-toxic trace metal. Due to their possible co-occurrence, the study of their combined effects on ecosystems may be of interest in a risk assessment perspective. MixTox tool is a simple descriptive model commonly used to study the effects of chemical mixtures. It relies on dose response, concentration addition and response addition concepts to describe combined toxicant effects and identify possible Synergistic/Antagonistic - Constant/Dose-level/Dose ratio dependent - interactions. In the present study, toxicity of binary mixture of U and Cd was assessed on physiological parameters, maximal length and brood size, in the soil nematode Caenorhabditis elegans. A 49 condition fractional factorial design was used with U and Cd concentrations ranging from 0.95 to 1.3 mM and 0.006 to 0.04 mM, respectively. Dose response curves obtained for U and Cd on maximal length and brood size were consistent with published data. Using MixTox tool, the best description of these endpoints was met with the response addition concept and the dose-ratio dependent interaction model. A significant antagonism was identified when Cd toxicity is preponderant in the mixture and was confirmed with experimental observations. On the other hand, no significant interaction could be identified when U toxicity was preponderant in the mixture. Interaction between the two chemicals may occur during the exposure, the toxicokinetics and/or during the toxico-dynamic phases. Based on the results of this study, a probable hypothesis would be that U, whose toxicity is in the mM range, reduces bioaccumulation of Cd, whose toxicity is in the range of 10 μM. A bioaccumulation assay of U and Cd

Establishment and Preliminary Application of the Duplex PCR to Detection of Vibrio vulnificus and Vibrio harveyi%创伤弧菌和哈氏弧菌双重PCR检测方法的建立及初步应用

Institute of Scientific and Technical Information of China (English)

陈福艳; 王瑞; 李丽萍; 韦明利; 程光平; 欧阳贤华; 陈晓汉; 梁万文; 韦友传; 黄婷; 杨学明; 陈明

2013-01-01

As Vibrio vulnificus and Vibrio harveyi mainly affects marine cultured animals, it is necessary to establish a rapid detection method. According to the cytolysin gene sequence of V. vulnificus and toxR gene sequence of V. harveyi, two pairs of primers were designed and synthesized. The diagnosis of duplex polymerase chain reaction (PCR) for rapid identification of V. vulnificus and V. harveyi was established by optimization of PCR conditions and by testing specificity and sensitiveness. The duplex PCR test results showed that two specific and amplified fragments were produced which sizes were 128 bp for V. vulnificus and 211 bp for V. harveyi, and no cross-reaction tests were done with Streptococcus agalactiae, Streptococcus iniae, Bibrio parahemolyticus, and Vibrio damsela. The lowest concentrations of 12 cfu/mL for V. vulnificus and 18 cfu /mL for V. harveyi could be detected. The duplex PCR would be a specific and sensitive method which was timesaving, laborsaving, quick and high-efficient for identification of duplex V. vulnificus and V. harveyi.%　　根据创伤弧菌（Vibrio vulnificus）的溶细胞毒素基因序列和哈氏弧菌（Vibrio harveyi）的toxR基因序列，分别设计并合成两对特异性引物，通过PCR反应条件优化，测试两种菌的特异性和敏感性，建立双重PCR方法，同时快速检测V. vulnificus和V. harveyi。结果表明：纯培养V. vulnificus和V. harveyi的检测灵敏度分别是12 cfu/mL和18 cfu/mL，与无乳链球菌、海豚链球菌、副溶血弧菌及美人发光杆菌无交叉反应；此PCR 检测方法具有良好的特异性、敏感性，具快速、高效等优点，对细菌V. vulnificus和V. harveyi诊断与防治具有较好的临床应用性。