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Sample records for mechanistic toxicogenomic analysis

  1. RNA-Seq-based toxicogenomic assessment of fresh frozen and formalin-fixed tissues yields similar mechanistic insights.

    Science.gov (United States)

    Auerbach, Scott S; Phadke, Dhiral P; Mav, Deepak; Holmgren, Stephanie; Gao, Yuan; Xie, Bin; Shin, Joo Heon; Shah, Ruchir R; Merrick, B Alex; Tice, Raymond R

    2015-07-01

    Formalin-fixed, paraffin-embedded (FFPE) pathology specimens represent a potentially vast resource for transcriptomic-based biomarker discovery. We present here a comparison of results from a whole transcriptome RNA-Seq analysis of RNA extracted from fresh frozen and FFPE livers. The samples were derived from rats exposed to aflatoxin B1 (AFB1 ) and a corresponding set of control animals. Principal components analysis indicated that samples were separated in the two groups representing presence or absence of chemical exposure, both in fresh frozen and FFPE sample types. Sixty-five percent of the differentially expressed transcripts (AFB1 vs. controls) in fresh frozen samples were also differentially expressed in FFPE samples (overlap significance: P < 0.0001). Genomic signature and gene set analysis of AFB1 differentially expressed transcript lists indicated highly similar results between fresh frozen and FFPE at the level of chemogenomic signatures (i.e., single chemical/dose/duration elicited transcriptomic signatures), mechanistic and pathology signatures, biological processes, canonical pathways and transcription factor networks. Overall, our results suggest that similar hypotheses about the biological mechanism of toxicity would be formulated from fresh frozen and FFPE samples. These results indicate that phenotypically anchored archival specimens represent a potentially informative resource for signature-based biomarker discovery and mechanistic characterization of toxicity. Copyright © 2014 John Wiley & Sons, Ltd.

  2. Toxicogenomic analysis of the hepatic effects of perfluorooctanoic acid on rare minnows (Gobiocypris rarus)

    International Nuclear Information System (INIS)

    Wei Yanhong; Liu Yang; Wang Jianshe; Tao Yi; Dai Jiayin

    2008-01-01

    Perfluorooctanoic acid (PFOA) is a ubiquitous environmental contaminant that has been detected in a variety of terrestrial and aquatic organisms. To assess the effects of PFOA in fish and predict its potential mode of action, a toxicogenomic approach was applied to hepatic gene expression profile analysis in male and female rare minnows (Gobiocypris rarus) using a custom cDNA microarray containing 1773 unique genes. Rare minnows were treated with continuous flow-through exposure to PFOA at concentrations of 3, 10, and 30 mg/L for 28 days. Based on the observed histopathological changes, the livers from fish exposed to 10 mg/L PFOA were selected for further hepatic gene expression analysis. While 124 and 171 genes were significantly altered by PFOA in males and females, respectively, of which 43 genes were commonly regulated in both sexes. The affected genes are involved in multiple biological processes, including lipid metabolism and transport, hormone action, immune responses, and mitochondrial functions. PFOA exposure significantly suppressed genes involved in fatty acid biosynthesis and transport but induced genes associated with intracellular trafficking of cholesterol. Alterations in expression of genes associated with mitochondrial fatty acid β-oxidation were only observed in female rare minnows. In addition, PFOA inhibited genes responsible for thyroid hormone biosynthesis and significantly induced estrogen-responsive genes. These findings implicate PFOA in endocrine disruption. This work contributes not only to the elucidation of the potential mode of toxicity of PFOA to aquatic organisms but also to the use of toxicogenomic approaches to address issues in environmental toxicology

  3. Integrating toxicogenomics into human health risk assessment: lessons learned from the benzo[a]pyrene case study.

    Science.gov (United States)

    Chepelev, Nikolai L; Moffat, Ivy D; Labib, Sarah; Bourdon-Lacombe, Julie; Kuo, Byron; Buick, Julie K; Lemieux, France; Malik, Amal I; Halappanavar, Sabina; Williams, Andrew; Yauk, Carole L

    2015-01-01

    The use of short-term toxicogenomic tests to predict cancer (or other health effects) offers considerable advantages relative to traditional toxicity testing methods. The advantages include increased throughput, increased mechanistic data, and significantly reduced costs. However, precisely how toxicogenomics data can be used to support human health risk assessment (RA) is unclear. In a companion paper ( Moffat et al. 2014 ), we present a case study evaluating the utility of toxicogenomics in the RA of benzo[a]pyrene (BaP), a known human carcinogen. The case study is meant as a proof-of-principle exercise using a well-established mode of action (MOA) that impacts multiple tissues, which should provide a best case example. We found that toxicogenomics provided rich mechanistic data applicable to hazard identification, dose-response analysis, and quantitative RA of BaP. Based on this work, here we share some useful lessons for both research and RA, and outline our perspective on how toxicogenomics can benefit RA in the short- and long-term. Specifically, we focus on (1) obtaining biologically relevant data that are readily suitable for establishing an MOA for toxicants, (2) examining the human relevance of an MOA from animal testing, and (3) proposing appropriate quantitative values for RA. We describe our envisioned strategy on how toxicogenomics can become a tool in RA, especially when anchored to other short-term toxicity tests (apical endpoints) to increase confidence in the proposed MOA, and emphasize the need for additional studies on other MOAs to define the best practices in the application of toxicogenomics in RA.

  4. Use of toxicogenomics in drug safety evaluation: Current status and an industry perspective.

    Science.gov (United States)

    Vahle, John L; Anderson, Ulf; Blomme, Eric A G; Hoflack, Jean-Christophe; Stiehl, Daniel P

    2018-04-18

    Toxicogenomics held great promise as an approach to enable early detection of toxicities induced by xenobiotics; however, there remain questions regarding the impact of the discipline on pharmaceutical nonclinical safety assessment. To understand the current state of toxicogenomics in the sector, an industry group surveyed companies to determine the frequency of toxicogenomics use in in vivo studies at various stages of drug discovery and development and to assess how toxicogenomics use has evolved over time. Survey data were compiled during 2016 from thirteen pharmaceutical companies. Toxicogenomic analyses were infrequently conducted in the development phase and when performed were done to address specific mechanistic questions. Prior to development, toxicogenomics use was more frequent; however, there were significant differences in approaches among companies. Across all phases, gaining mechanistic insight was the most frequent reason cited for pursing toxicogenomics with few companies using toxicogenomics to predict toxicities. These data were consistent with the commentary submitted in response to survey questions asking companies to describe the evolution of their toxicogenomics strategy. Overall, these survey data indicate that toxicogenomics is not widely used as a predictive tool in the pharmaceutical industry but is used regularly by some companies and serves a broader role in mechanistic investigations and as a complement to other technologies. Copyright © 2018. Published by Elsevier Inc.

  5. Toxicogenomic analysis of gene expression changes in rat liver after a 28-day oral benzene exposure

    NARCIS (Netherlands)

    Heijne, W.H.M.; Jonker, D.; Stierum, R.H.; Ommen, van B.; Groten, J.P.

    2005-01-01

    Benzene is an industrial chemical, component of automobile exhaust and cigarette smoke. After hepatic bioactivation benzene induces bone marrow, blood and hepatic toxicity. Using a toxicogenomics approach this study analysed the effects of benzene at three dose levels on gene expression in the liver

  6. Adaptation of a Bioinformatics Microarray Analysis Workflow for a Toxicogenomic Study in Rainbow Trout.

    Directory of Open Access Journals (Sweden)

    Sophie Depiereux

    Full Text Available Sex steroids play a key role in triggering sex differentiation in fish, the use of exogenous hormone treatment leading to partial or complete sex reversal. This phenomenon has attracted attention since the discovery that even low environmental doses of exogenous steroids can adversely affect gonad morphology (ovotestis development and induce reproductive failure. Modern genomic-based technologies have enhanced opportunities to find out mechanisms of actions (MOA and identify biomarkers related to the toxic action of a compound. However, high throughput data interpretation relies on statistical analysis, species genomic resources, and bioinformatics tools. The goals of this study are to improve the knowledge of feminisation in fish, by the analysis of molecular responses in the gonads of rainbow trout fry after chronic exposure to several doses (0.01, 0.1, 1 and 10 μg/L of ethynylestradiol (EE2 and to offer target genes as potential biomarkers of ovotestis development. We successfully adapted a bioinformatics microarray analysis workflow elaborated on human data to a toxicogenomic study using rainbow trout, a fish species lacking accurate functional annotation and genomic resources. The workflow allowed to obtain lists of genes supposed to be enriched in true positive differentially expressed genes (DEGs, which were subjected to over-representation analysis methods (ORA. Several pathways and ontologies, mostly related to cell division and metabolism, sexual reproduction and steroid production, were found significantly enriched in our analyses. Moreover, two sets of potential ovotestis biomarkers were selected using several criteria. The first group displayed specific potential biomarkers belonging to pathways/ontologies highlighted in the experiment. Among them, the early ovarian differentiation gene foxl2a was overexpressed. The second group, which was highly sensitive but not specific, included the DEGs presenting the highest fold change and

  7. Toxicogenomic analysis in the combined effect of tributyltin and benzo[a]pyrene on the development of zebrafish embryos.

    Science.gov (United States)

    Huang, Lixing; Zuo, Zhenghong; Zhang, Youyu; Wang, Chonggang

    2015-01-01

    There is a growing recognition that the toxic effects of chemical mixtures are been an important issue in toxicological sciences. Tributyltin (TBT) and benzo[a]pyrene (BaP) are widespread pollutants that occur simultaneously in the aquatic environments. This study was designed to examine comprehensively the combined effects of TBT and BaP on zebrafish (Danio rerio) embryos using toxicogenomic approach combined with biochemical detection and morphological analysis, and tried to gain insight into the mechanisms underlying the combined effects of TBT and BaP. The results of toxicogenomic data indicated that: (1) TBT cotreatment rescued the embryos from decreased hatching ratio caused by BaP alone, while the alteration of gene expression (in this article the phrase gene expression is used as a synonym to gene transcription, although in is acknowledged that gene expression can also be regulated by, e.g., translation and mRNA or protein stability) relative to zebrafish hatching in the BaP groups was resumed by the cotreatment with TBT; (2) BaP cotreatment decreased TBT-mediated dorsal curvature, and alleviated the perturbation of Notch pathway caused by TBT alone; (3) cotreatment with TBT decreased BaP-mediated bradycardia, which might be due to that TBT cotreatment alleviated the perturbation in expression of genes related to cardiac muscle cell development and calcium handling caused by BaP alone; 4) TBT cotreatment brought an antagonistic effect on the BaP-mediated oxidative stress and DNA damage. These results suggested that toxicogenomic approach was available for analyzing combined toxicity with high sensitivity and accuracy, which might improve our understanding and predictability for the combined effects of chemicals. Copyright © 2014 Elsevier B.V. All rights reserved.

  8. Conceptual models for waste tank mechanistic analysis

    International Nuclear Information System (INIS)

    Allemann, R.T.; Antoniak, Z.I.; Eyler, L.L.; Liljegren, L.M.; Roberts, J.S.

    1992-02-01

    Pacific Northwest Laboratory (PNL) is conducting a study for Westinghouse Hanford Company (Westinghouse Hanford), a contractor for the US Department of Energy (DOE). The purpose of the work is to study possible mechanisms and fluid dynamics contributing to the periodic release of gases from double-shell waste storage tanks at the Hanford Site in Richland, Washington. This interim report emphasizing the modeling work follows two other interim reports, Mechanistic Analysis of Double-Shell Tank Gas Release Progress Report -- November 1990 and Collection and Analysis of Existing Data for Waste Tank Mechanistic Analysis Progress Report -- December 1990, that emphasized data correlation and mechanisms. The approach in this study has been to assemble and compile data that are pertinent to the mechanisms, analyze the data, evaluate physical properties and parameters, evaluate hypothetical mechanisms, and develop mathematical models of mechanisms

  9. Evaluation of Bioinformatics Approaches for Next-Generation Sequencing Analysis of microRNAs with a Toxicogenomics Study Design

    Directory of Open Access Journals (Sweden)

    Halil Bisgin

    2018-02-01

    Full Text Available MicroRNAs (miRNAs are key post-transcriptional regulators that affect protein translation by targeting mRNAs. Their role in disease etiology and toxicity are well recognized. Given the rapid advancement of next-generation sequencing techniques, miRNA profiling has been increasingly conducted with RNA-seq, namely miRNA-seq. Analysis of miRNA-seq data requires several steps: (1 mapping the reads to miRBase, (2 considering mismatches during the hairpin alignment (windowing, and (3 counting the reads (quantification. The choice made in each step with respect to the parameter settings could affect miRNA quantification, differentially expressed miRNAs (DEMs detection and novel miRNA identification. Furthermore, these parameters do not act in isolation and their joint effects impact miRNA-seq results and interpretation. In toxicogenomics, the variation associated with parameter setting should not overpower the treatment effect (such as the dose/time-dependent effect. In this study, four commonly used miRNA-seq analysis tools (i.e., miRDeep2, miRExpress, miRNAkey, sRNAbench were comparatively evaluated with a standard toxicogenomics study design. We tested 30 different parameter settings on miRNA-seq data generated from thioacetamide-treated rat liver samples for three dose levels across four time points, followed by four normalization options. Because both miRExpress and miRNAkey yielded larger variation than that of the treatment effects across multiple parameter settings, our analyses mainly focused on the side-by-side comparison between miRDeep2 and sRNAbench. While the number of miRNAs detected by miRDeep2 was almost the subset of those detected by sRNAbench, the number of DEMs identified by both tools was comparable under the same parameter settings and normalization method. Change in the number of nucleotides out of the mature sequence in the hairpin alignment (window option yielded the largest variation for miRNA quantification and DEMs

  10. Toxicogenomic analysis identifies the apoptotic pathway as the main cause of hepatotoxicity induced by tributyltin.

    Science.gov (United States)

    Zhou, Mi; Feng, Mei; Fu, Ling-Ling; Ji, Lin-Dan; Zhao, Jin-Shun; Xu, Jin

    2016-11-01

    Tributyltin (TBT) is one of the most widely used organotin biocides, which has severe endocrine-disrupting effects on marine species and mammals. Given that TBT accumulates at higher levels in the liver than in any other organ, and it acts mainly as a hepatotoxic agent, it is important to clearly delineate the hepatotoxicity of TBT. However, most of the available studies on TBT have focused on observations at the cellular level, while studies at the level of genes and proteins are limited; therefore, the molecular mechanisms of TBT-induced hepatotoxicity remains largely unclear. In the present study, we applied a toxicogenomic approach to investigate the effects of TBT on gene expression in the human normal liver cell line HL7702. Gene expression profiling identified the apoptotic pathway as the major cause of hepatotoxicity induced by TBT. Flow cytometry assays confirmed that medium- and high-dose TBT treatments significantly increased the number of apoptotic cells, and more cells underwent late apoptosis in the high-dose TBT group. The genes encoding heat shock proteins (HSPs), kinases and tumor necrosis factor receptors mediated TBT-induced apoptosis. These findings revealed novel molecular mechanisms of TBT-induced hepatotoxicity, and the current microarray data may also provide clues for future studies. Copyright © 2016 Elsevier Ltd. All rights reserved.

  11. Mechanistic facility safety and source term analysis

    International Nuclear Information System (INIS)

    PLYS, M.G.

    1999-01-01

    A PC-based computer program was created for facility safety and source term analysis at Hanford The program has been successfully applied to mechanistic prediction of source terms from chemical reactions in underground storage tanks, hydrogen combustion in double contained receiver tanks, and proccss evaluation including the potential for runaway reactions in spent nuclear fuel processing. Model features include user-defined facility room, flow path geometry, and heat conductors, user-defined non-ideal vapor and aerosol species, pressure- and density-driven gas flows, aerosol transport and deposition, and structure to accommodate facility-specific source terms. Example applications are presented here

  12. EPA'S TOXICOGENOMICS PARTNERSHIPS ACROSS GOVERNMENT, ACADEMIA AND INDUSTRY

    Science.gov (United States)

    Genomics, proteomics and metabonomics technologies are transforming the science of toxicology, and concurrent advances in computing and informatics are providing management and analysis solutions for this onslaught of toxicogenomic data. EPA has been actively developing an intra...

  13. Mixture toxicity revisited from a toxicogenomic perspective.

    Science.gov (United States)

    Altenburger, Rolf; Scholz, Stefan; Schmitt-Jansen, Mechthild; Busch, Wibke; Escher, Beate I

    2012-03-06

    The advent of new genomic techniques has raised expectations that central questions of mixture toxicology such as for mechanisms of low dose interactions can now be answered. This review provides an overview on experimental studies from the past decade that address diagnostic and/or mechanistic questions regarding the combined effects of chemical mixtures using toxicogenomic techniques. From 2002 to 2011, 41 studies were published with a focus on mixture toxicity assessment. Primarily multiplexed quantification of gene transcripts was performed, though metabolomic and proteomic analysis of joint exposures have also been undertaken. It is now standard to explicitly state criteria for selecting concentrations and provide insight into data transformation and statistical treatment with respect to minimizing sources of undue variability. Bioinformatic analysis of toxicogenomic data, by contrast, is still a field with diverse and rapidly evolving tools. The reported combined effect assessments are discussed in the light of established toxicological dose-response and mixture toxicity models. Receptor-based assays seem to be the most advanced toward establishing quantitative relationships between exposure and biological responses. Often transcriptomic responses are discussed based on the presence or absence of signals, where the interpretation may remain ambiguous due to methodological problems. The majority of mixture studies design their studies to compare the recorded mixture outcome against responses for individual components only. This stands in stark contrast to our existing understanding of joint biological activity at the levels of chemical target interactions and apical combined effects. By joining established mixture effect models with toxicokinetic and -dynamic thinking, we suggest a conceptual framework that may help to overcome the current limitation of providing mainly anecdotal evidence on mixture effects. To achieve this we suggest (i) to design studies to

  14. Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models.

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    Liu, Shujie; Kawamoto, Taisuke; Morita, Osamu; Yoshinari, Kouichi; Honda, Hiroshi

    2017-03-01

    Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System were used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment. Copyright © 2017 Elsevier Inc. All rights reserved.

  15. Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models

    International Nuclear Information System (INIS)

    Liu, Shujie; Kawamoto, Taisuke; Morita, Osamu; Yoshinari, Kouichi; Honda, Hiroshi

    2017-01-01

    Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System were used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment. - Highlights: • Hypertrophy (H) and hypertrophic

  16. Discriminating between adaptive and carcinogenic liver hypertrophy in rat studies using logistic ridge regression analysis of toxicogenomic data: The mode of action and predictive models

    Energy Technology Data Exchange (ETDEWEB)

    Liu, Shujie; Kawamoto, Taisuke; Morita, Osamu [R& D, Safety Science Research, Kao Corporation, Tochigi (Japan); Yoshinari, Kouichi [Department of Molecular Toxicology, School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka (Japan); Honda, Hiroshi, E-mail: honda.hiroshi@kao.co.jp [R& D, Safety Science Research, Kao Corporation, Tochigi (Japan)

    2017-03-01

    Chemical exposure often results in liver hypertrophy in animal tests, characterized by increased liver weight, hepatocellular hypertrophy, and/or cell proliferation. While most of these changes are considered adaptive responses, there is concern that they may be associated with carcinogenesis. In this study, we have employed a toxicogenomic approach using a logistic ridge regression model to identify genes responsible for liver hypertrophy and hypertrophic hepatocarcinogenesis and to develop a predictive model for assessing hypertrophy-inducing compounds. Logistic regression models have previously been used in the quantification of epidemiological risk factors. DNA microarray data from the Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System were used to identify hypertrophy-related genes that are expressed differently in hypertrophy induced by carcinogens and non-carcinogens. Data were collected for 134 chemicals (72 non-hypertrophy-inducing chemicals, 27 hypertrophy-inducing non-carcinogenic chemicals, and 15 hypertrophy-inducing carcinogenic compounds). After applying logistic ridge regression analysis, 35 genes for liver hypertrophy (e.g., Acot1 and Abcc3) and 13 genes for hypertrophic hepatocarcinogenesis (e.g., Asns and Gpx2) were selected. The predictive models built using these genes were 94.8% and 82.7% accurate, respectively. Pathway analysis of the genes indicates that, aside from a xenobiotic metabolism-related pathway as an adaptive response for liver hypertrophy, amino acid biosynthesis and oxidative responses appear to be involved in hypertrophic hepatocarcinogenesis. Early detection and toxicogenomic characterization of liver hypertrophy using our models may be useful for predicting carcinogenesis. In addition, the identified genes provide novel insight into discrimination between adverse hypertrophy associated with carcinogenesis and adaptive hypertrophy in risk assessment. - Highlights: • Hypertrophy (H) and hypertrophic

  17. The metamorphosis of amphibian toxicogenomics

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    Caren eHelbing

    2012-03-01

    Full Text Available Amphibians are important vertebrates in toxicology often representing both aquatic and terrestrial forms within the life history of the same species. Of the thousands of species, only two have substantial genomics resources: the recently published genome of the Pipid, Xenopus (Silurana tropicalis, and transcript information (and ongoing genome sequencing project of Xenopus laevis. However, many more species representative of regional ecological niches and life strategies are used in toxicology worldwide. Since Xenopus species diverged from the most populous frog family, the Ranidae, ~200 million years ago, there are notable differences between them and the even more distant Caudates (salamanders and Caecilians. These differences include genome size, gene composition, and extent of polyploidization. Application of toxicogenomics to amphibians requires the mobilization of resources and expertise to develop de novo sequence assemblies and analysis strategies for a broader range of amphibian species. The present mini-review will present the advances in toxicogenomics as pertains to amphibians with particular emphasis upon the development and use of genomic techniques (inclusive of transcriptomics, proteomics, and metabolomics and the challenges inherent therein.

  18. Application of toxicogenomics in hepatic systems toxicology for risk assessment: Acetaminophen as a case study

    International Nuclear Information System (INIS)

    Kienhuis, Anne S.; Bessems, Jos G.M.; Pennings, Jeroen L.A.; Driessen, Marja; Luijten, Mirjam; Delft, Joost H.M. van

    2011-01-01

    Hepatic systems toxicology is the integrative analysis of toxicogenomic technologies, e.g., transcriptomics, proteomics, and metabolomics, in combination with traditional toxicology measures to improve the understanding of mechanisms of hepatotoxic action. Hepatic toxicology studies that have employed toxicogenomic technologies to date have already provided a proof of principle for the value of hepatic systems toxicology in hazard identification. In the present review, acetaminophen is used as a model compound to discuss the application of toxicogenomics in hepatic systems toxicology for its potential role in the risk assessment process, to progress from hazard identification towards hazard characterization. The toxicogenomics-based parallelogram is used to identify current achievements and limitations of acetaminophen toxicogenomic in vivo and in vitro studies for in vitro-to-in vivo and interspecies comparisons, with the ultimate aim to extrapolate animal studies to humans in vivo. This article provides a model for comparison of more species and more in vitro models enhancing the robustness of common toxicogenomic responses and their relevance to human risk assessment. To progress to quantitative dose-response analysis needed for hazard characterization, in hepatic systems toxicology studies, generation of toxicogenomic data of multiple doses/concentrations and time points is required. Newly developed bioinformatics tools for quantitative analysis of toxicogenomic data can aid in the elucidation of dose-responsive effects. The challenge herein is to assess which toxicogenomic responses are relevant for induction of the apical effect and whether perturbations are sufficient for the induction of downstream events, eventually causing toxicity.

  19. Bioinformatics Methods for Interpreting Toxicogenomics Data: The Role of Text-Mining

    NARCIS (Netherlands)

    Hettne, K.M.; Kleinjans, J.; Stierum, R.H.; Boorsma, A.; Kors, J.A.

    2014-01-01

    This chapter concerns the application of bioinformatics methods to the analysis of toxicogenomics data. The chapter starts with an introduction covering how bioinformatics has been applied in toxicogenomics data analysis, and continues with a description of the foundations of a specific

  20. Overview of the South African mechanistic pavement design analysis method

    CSIR Research Space (South Africa)

    Theyse, HL

    1996-01-01

    Full Text Available A historical overview of the South African mechanistic pavement design method, from its development in the early 1970s to the present, is presented. Material characterization, structural analysis, and pavement life prediction are discussed...

  1. Toxicogenomic markers for corticosteroid treatment in beef cattle: integrated analysis of transcriptomic data.

    Science.gov (United States)

    Pegolo, Sara; Di Camillo, Barbara; Montesissa, Clara; Cannizzo, Francesca Tiziana; Biolatti, Bartolomeo; Bargelloni, Luca

    2015-03-01

    In the present work, an integrated analysis was performed on DNA-microarray data of bovine muscle samples belonging to controls, animals treated with various growth promoters (GPs) and unknown commercial samples. The aim was identify a robust gene expression signature of corticosteroid treatment for the classification of commercial samples, despite the effects of biological variation and other confounding factors. DNA-Microarray data from 5 different batches of bovine skeletal muscle samples were analyzed (146 samples). After preprocessing, expression data from animals treated with corticosteroids and controls from the different batches (89 samples) were used to train a Support Vector Machines (SVMs) classifier. The optimal number of gene probes chosen by our classification framework was 73. The SVMs with linear kernel built on these 73 biomarker genes was predicted to perform on novel samples with a high classification accuracy (Matthew's correlation coefficient equal to 0.77) and an average percentage of false positive and false negative equal to 5% and 6%, respectively. Concluding, a relatively small set of genes was able to discriminate between controls and corticosteroid-treated animals, despite different breeds, animal ages, and combination of GPs. The results are extremely promising, suggesting that integrated analysis provides robust transcriptomic signatures for GP abuse. Copyright © 2014 Elsevier Ltd. All rights reserved.

  2. Microarray analysis of toxicogenomic effects of Ortho-phenylphenol in Staphylococcus aureus

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    Toghrol Freshteh

    2008-09-01

    Full Text Available Abstract Background Staphylococcus aureus (S. aureus, is responsible for many infectious diseases, ranging from benign skin infections to life-threatening endocarditis and toxic shock syndrome. Ortho-phenylphenol (OPP is an antimicrobial agent and an active ingredient of EPA-registered disinfectants with wide human exposure in various agricultural, hospital and veterinary disinfectant products. Despite many uses, an understanding of a cellular response to OPP and it's mechanism of action, targeted genes, and the connectivity between targeted genes and the rest of cell metabolism remains obscure. Results Herein, we performed a genome-wide transcriptome analysis of the cellular responses of S. aureus when exposed to 0.82 mM of OPP for 20 and 60 min. Our data indicated that OPP downregulated the biosynthesis of many amino acids, which are required for protein synthesis. In particular, the genes encoding the enzymes of the diaminopimelate (DAP pathway which results in lysine biosynthesis were significantly downregualted. Intriguingly, we revealed that the transcription of genes encoding ribosomal proteins was upregulated by OPP and at the same time, the genes encoding iron acquisition and transport were downregulated. The genes encoding virulence factors were upregulated and genes encoding phospholipids were downregulated upon 20 min exposure to OPP. Conclusion By using microarray analysis that enables us to simultaneously and globally examine the complete transcriptome during cellular responses, we have revealed novel information regarding the mode of action of OPP on Staphylococcus: OPP inhibits anabolism of many amino acids and highly downregulates the genes that encode the enzymes involved in the DAP pathway. Lysine and DAP are essential for building up the peptidoglycan cell wall. It was concluded that the mode of action of OPP is similar to the mechanism of action of some antibiotics. The discovery of this phenomenon provides useful

  3. Utilizing toxicogenomic data to understand chemical mechanism of action in risk assessment

    Energy Technology Data Exchange (ETDEWEB)

    Wilson, Vickie S., E-mail: wilson.vickie@epa.gov [National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States); Keshava, Nagalakshmi [National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, 1200 Pennsylvania Ave., NW, Washington, DC 20460 (United States); Hester, Susan [National Health and Environmental Effects Research Laboratory, Office of Research and Development, U.S. Environmental Protection Agency, Research Triangle Park, NC 27711 (United States); Segal, Deborah; Chiu, Weihsueh [National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, 1200 Pennsylvania Ave., NW, Washington, DC 20460 (United States); Thompson, Chad M. [ToxStrategies, Inc., 23501 Cinco Ranch Blvd., Suite G265, Katy, TX 77494 (United States); Euling, Susan Y. [National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, 1200 Pennsylvania Ave., NW, Washington, DC 20460 (United States)

    2013-09-15

    The predominant role of toxicogenomic data in risk assessment, thus far, has been one of augmentation of more traditional in vitro and in vivo toxicology data. This article focuses on the current available examples of instances where toxicogenomic data has been evaluated in human health risk assessment (e.g., acetochlor and arsenicals) which have been limited to the application of toxicogenomic data to inform mechanism of action. This article reviews the regulatory policy backdrop and highlights important efforts to ultimately achieve regulatory acceptance. A number of research efforts on specific chemicals that were designed for risk assessment purposes have employed mechanism or mode of action hypothesis testing and generating strategies. The strides made by large scale efforts to utilize toxicogenomic data in screening, testing, and risk assessment are also discussed. These efforts include both the refinement of methodologies for performing toxicogenomics studies and analysis of the resultant data sets. The current issues limiting the application of toxicogenomics to define mode or mechanism of action in risk assessment are discussed together with interrelated research needs. In summary, as chemical risk assessment moves away from a single mechanism of action approach toward a toxicity pathway-based paradigm, we envision that toxicogenomic data from multiple technologies (e.g., proteomics, metabolomics, transcriptomics, supportive RT-PCR studies) can be used in conjunction with one another to understand the complexities of multiple, and possibly interacting, pathways affected by chemicals which will impact human health risk assessment.

  4. Utilizing toxicogenomic data to understand chemical mechanism of action in risk assessment

    International Nuclear Information System (INIS)

    Wilson, Vickie S.; Keshava, Nagalakshmi; Hester, Susan; Segal, Deborah; Chiu, Weihsueh; Thompson, Chad M.; Euling, Susan Y.

    2013-01-01

    The predominant role of toxicogenomic data in risk assessment, thus far, has been one of augmentation of more traditional in vitro and in vivo toxicology data. This article focuses on the current available examples of instances where toxicogenomic data has been evaluated in human health risk assessment (e.g., acetochlor and arsenicals) which have been limited to the application of toxicogenomic data to inform mechanism of action. This article reviews the regulatory policy backdrop and highlights important efforts to ultimately achieve regulatory acceptance. A number of research efforts on specific chemicals that were designed for risk assessment purposes have employed mechanism or mode of action hypothesis testing and generating strategies. The strides made by large scale efforts to utilize toxicogenomic data in screening, testing, and risk assessment are also discussed. These efforts include both the refinement of methodologies for performing toxicogenomics studies and analysis of the resultant data sets. The current issues limiting the application of toxicogenomics to define mode or mechanism of action in risk assessment are discussed together with interrelated research needs. In summary, as chemical risk assessment moves away from a single mechanism of action approach toward a toxicity pathway-based paradigm, we envision that toxicogenomic data from multiple technologies (e.g., proteomics, metabolomics, transcriptomics, supportive RT-PCR studies) can be used in conjunction with one another to understand the complexities of multiple, and possibly interacting, pathways affected by chemicals which will impact human health risk assessment

  5. Application of toxicogenomics in hepatic systems toxicology for risk assessment: Acetaminophen as a case study

    NARCIS (Netherlands)

    Kienhuis, A.S.; Bessems, J.G.M.; Pennings, J.L.A.; Driessen, M.; Luijten, M.; Delft, van J.H.M.; Ven, van der L.T.M.

    2011-01-01

    Hepatic systems toxicology is the integrative analysis of toxicogenomic technologies, e.g., transcriptomics, proteomics, and metabolomics, in combination with traditional toxicology measures to improve the understanding of mechanisms of hepatotoxic action. Hepatic toxicology studies that have

  6. EPA SCIENCE FORUM - EPA'S TOXICOGENOMICS PARTNERSHIPS ACROSS GOVERNMENT, ACADEMIA AND INDUSTRY

    Science.gov (United States)

    Over the past decade genomics, proteomics and metabonomics technologies have transformed the science of toxicology, and concurrent advances in computing and informatics have provided management and analysis solutions for this onslaught of toxicogenomic data. EPA has been actively...

  7. The impact of classification of interest on predictive toxicogenomics

    Directory of Open Access Journals (Sweden)

    Pierre R. Bushel

    2012-02-01

    Full Text Available The era of toxicogenomics has introduced a new way of monitoring the effect of environmental stressors and toxicants on biological systems via quantification of changes in gene expression. Because the liver is one of the major organs for synthesis and secretion of substances which metabolize endogenous and exogenous materials, there has been a great deal of interest in elucidating predictive and mechanistic genomic markers of hepatotoxicity. This mini-review will bring context to a limited number of toxicogenomics studies which used genomics to evaluate the transcriptional changes in blood and liver in response to acetaminophen (APAP or other liver toxicants, but differed according to the classification of interest (COI, i.e. the partitioning of the samples a priori according to a common toxicological characteristic. The toxicogenomics studies highlighted are characterized by a classification of either no/low vs. high APAP dose exposure, none vs. observed necrosis, and severity of necrosis. The overlap or lack thereof between the gene classifiers and the modulated biological processes that are elucidated will be discussed to enhance the understanding of the effect of the particular COI model and experimental design used for prediction.

  8. Availability, quality and relevance of toxicogenomics data for human health risk assessment: A scoping review of the literature on trihalomethanes.

    Science.gov (United States)

    Vachon, Julien; Pagé-Larivière, Florence; Sirard, Marc-André; Rodriguez, Manuel J; Levallois, Patrick; Campagna, Céline

    2018-03-05

    Human health risk assessment (HHRA) must be adapted to the challenges of the 21st century, and the use of toxicogenomics data in HHRA is among the changes that regulatory agencies worldwide are trying to implement. However, the use of toxicogenomics data in HHRA is still limited. The purpose of this study was to explore the availability, quality and relevance to HHRA of toxicogenomics publications as potential barriers to their use in HHRA. We conducted a scoping review of available toxicogenomics literature, using trihalomethanes as a case study. Four bibliographic databases (including the Comparative Toxicogenomics Database) were assessed. An evaluation table was developed to characterise quality and relevance of studies included on the basis of criteria proposed in the literature. Studies were selected and analysed by two independent reviewers. Only nine studies, published between 1997 and 2015, were included in the analysis. Based on the selected criteria, critical methodological details were often missing; in fact, only three out of nine studies were considered to be of adequate quality for HHRA. No studies met more than three (out of seven) criteria of relevance to HHRA (e.g. adequate number of doses and sample size, etc.). This first scoping review of toxicogenomics publications on trihalomethanes shows that low availability, quality and relevance to HHRA of toxicogenomics publications presents potential barriers to their use in HHRA. Improved reporting of methodological details and study design is needed in the future so that toxicogenomics studies can be appropriately assessed regarding their quality and value for HHRA.

  9. Toxicogenomic analysis of N-nitrosomorpholine induced changes in rat liver: Comparison of genomic and proteomic responses and anchoring to histopathological parameters

    International Nuclear Information System (INIS)

    Oberemm, A.; Ahr, H.-J.; Bannasch, P.; Ellinger-Ziegelbauer, H.; Glueckmann, M.; Hellmann, J.; Ittrich, C.; Kopp-Schneider, A.; Kramer, P.-J.; Krause, E.; Kroeger, M.; Kiss, E.; Richter-Reichhelm, H.-B.; Scholz, G.; Seemann, K.; Weimer, M.; Gundert-Remy, U.

    2009-01-01

    A common animal model of chemical hepatocarcinogenesis was used to examine the utility of transcriptomic and proteomic data to identify early biomarkers related to chemically induced carcinogenesis. N-nitrosomorpholine, a frequently used genotoxic model carcinogen, was applied via drinking water at 120 mg/L to male Wistar rats for 7 weeks followed by an exposure-free period of 43 weeks. Seven specimens of each treatment group (untreated control and 120 mg/L N-nitrosomorpholine in drinking water) were sacrificed at nine time points during and after N-nitrosomorpholine treatment. Individual samples from the liver were prepared for histological and toxicogenomic analyses. For histological detection of preneoplastic and neoplastic tissue areas, sections were stained using antibodies against the placental form of glutathione-S-transferase (GST-P). Gene and protein expression profiles of liver tissue homogenates were analyzed using RG-U34A Affymetrix rat gene chips and two-dimensional gel electrophoresis-based proteomics, respectively. In order to compare results obtained by histopathology, transcriptomics and proteomics, GST-P-stained liver sections were evaluated morphometrically, which revealed a parallel time course of the area fraction of preneoplastic lesions and gene plus protein expression patterns. On the transcriptional level, an increase of hepatic GST-P expression was detectable as early as 3 weeks after study onset. Comparing deregulated genes and proteins, eight species were identified which showed a corresponding expression profile on both expression levels. Functional analysis suggests that these genes and corresponding proteins may be useful as biomarkers of early hepatocarcinogenesis.

  10. TOXICOGENOMIC ANALYSIS INCORPORATING OPERON-TRANSCRIPTIONAL COUPLING AND TOXICANT CONCENTRATRION-EXPRESSION RESPONSE: Analysis of MX-Treated Salmonella

    Science.gov (United States)

    What is the study? This study is the first to use microarray analysis in the Ames strains of Salmonella. The microarray chips were custom-designed for this study and are not commercially available, and we evaluated the well-studied drinking water mutagen, MX. Because much inform...

  11. Mechanistic approach to the sodium leakage and fire analysis

    International Nuclear Information System (INIS)

    Yamaguchi, Akira; Muramatsu, Toshiharu; Ohira, Hiroaki; Ida, Masao

    1997-04-01

    In December 1995, a thermocouple well was broken and liquid sodium leaked out of the intermediate heat transport system of the prototype fast breeder reactor Monju. In the initiating process of the incident, liquid sodium flowed out through the hollow thermocouple well, nipple and connector. As a result, liquid sodium, following ignition and combustion, was dropping from the connector to colide with the duct and grating placed below. The collision may cause fragmentation and scattering of the sodium droplet that finally was piled up on the floor. This report deals with the development of computer programs for the phenomena based on mechanistics approach. Numerical analyses are also made for fundamental sodium leakage and combustion phenomenon, sodium combustion experiment, and Monju incident condition. The contents of this report is listed below: (1) Analysis of chemical reaction process based on molecular orbital method, (2) Thermalhy draulic analysis of the sodium combustion experiment II performed in 1996 at O-arai Engineering Center, PNC, (3) Thermalhy draulic analysis of room A-446 of Monju reactor when the sodium leakage took place, (4) Direct numerical simulation of sodium droplet, (5) Sodium leakage and scattering analysis using three dimensional particle method, (6) Multi-dimensional combustion analysis and multi-point approximation combustion analysis code. Subsequent to the development work of the programs, they are to be applied to the safety analysis of the Fast Breeder Reactor. (author)

  12. Toxicogenomics in Environmental Science.

    Science.gov (United States)

    Brinke, Alexandra; Buchinger, Sebastian

    This chapter reviews the current knowledge and recent progress in the field of environmental, aquatic ecotoxicogenomics with a focus on transcriptomic methods. In ecotoxicogenomics the omics technologies are applied for the detection and assessment of adverse effects in the environment, and thus are to be distinguished from omics used in human toxicology [Snape et al., Aquat Toxicol 67:143-154, 2004]. Transcriptomic methods in ecotoxicology are applied to gain a mechanistic understanding of toxic effects on organisms or populations, and thus aim to bridge the gap between cause and effect. A worthwhile effect-based interpretation of stressor induced changes on the transcriptome is based on the principle of phenotypic-anchoring [Paules, Environ Health Perspect 111:A338-A339, 2003]. Thereby, changes on the transcriptomic level can only be identified as effects if they are clearly linked to a specific stressor-induced effect on the macroscopic level. By integrating those macroscopic and transcriptomic effects, conclusions on the effect-inducing type of the stressor can be drawn. Stressor-specific effects on the transcriptomic level can be identified as stressor-specific induced pathways, transcriptomic patterns, or stressors-specific genetic biomarkers. In this chapter, examples of the combined application of macroscopic and transcriptional effects for the identification of environmental stressors, such as aquatic pollutants, are given and discussed. By means of these examples, challenges on the way to a standardized application of transcriptomics in ecotoxicology are discussed. This is also done against the background of the application of transcriptomic methods in environmental regulation such as the EU regulation Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH).

  13. Mercury-induced hepatotoxicity in zebrafish: in vivo mechanistic insights from transcriptome analysis, phenotype anchoring and targeted gene expression validation

    Directory of Open Access Journals (Sweden)

    Mathavan Sinnakaruppan

    2010-03-01

    Full Text Available Abstract Background Mercury is a prominent environmental contaminant that causes detrimental effects to human health. Although the liver has been known to be a main target organ, there is limited information on in vivo molecular mechanism of mercury-induced toxicity in the liver. By using transcriptome analysis, phenotypic anchoring and validation of targeted gene expression in zebrafish, mercury-induced hepatotoxicity was investigated and a number of perturbed cellular processes were identified and compared with those captured in the in vitro human cell line studies. Results Hepato-transcriptome analysis of mercury-exposed zebrafish revealed that the earliest deregulated genes were associated with electron transport chain, mitochondrial fatty acid beta-oxidation, nuclear receptor signaling and apoptotic pathway, followed by complement system and proteasome pathway, and thereafter DNA damage, hypoxia, Wnt signaling, fatty acid synthesis, gluconeogenesis, cell cycle and motility. Comparative meta-analysis of microarray data between zebrafish liver and human HepG2 cells exposed to mercury identified some common toxicological effects of mercury-induced hepatotoxicity in both models. Histological analyses of liver from mercury-exposed fish revealed morphological changes of liver parenchyma, decreased nucleated cell count, increased lipid vesicles, glycogen and apoptotic bodies, thus providing phenotypic evidence for anchoring of the transcriptome analysis. Validation of targeted gene expression confirmed deregulated gene-pathways from enrichment analysis. Some of these genes responding to low concentrations of mercury may serve as toxicogenomic-based markers for detection and health risk assessment of environmental mercury contaminations. Conclusion Mercury-induced hepatotoxicity was triggered by oxidative stresses, intrinsic apoptotic pathway, deregulation of nuclear receptor and kinase activities including Gsk3 that deregulates Wnt signaling

  14. Toxicogenomic analysis of the particle dose- and size-response relationship of silica particles-induced toxicity in mice

    International Nuclear Information System (INIS)

    Lu Xiaoyan; Jin Tingting; Jin Yachao; Wu Leihong; Hu Bin; Tian Yu; Fan Xiaohui

    2013-01-01

    This study investigated the relationship between particle size and toxicity of silica particles (SP) with diameters of 30, 70, and 300 nm, which is essential to the safe design and application of SP. Data obtained from histopathological examinations suggested that SP of these sizes can all induce acute inflammation in the liver. In vivo imaging showed that intravenously administrated SP are mainly present in the liver, spleen and intestinal tract. Interestingly, in gene expression analysis, the cellular response pathways activated in the liver are predominantly conserved independently of particle dose when the same size SP are administered or are conserved independently of particle size, surface area and particle number when nano- or submicro-sized SP are administered at their toxic doses. Meanwhile, integrated analysis of transcriptomics, previous metabonomics and conventional toxicological results support the view that SP can result in inflammatory and oxidative stress, generate mitochondrial dysfunction, and eventually cause hepatocyte necrosis by neutrophil-mediated liver injury. (paper)

  15. Mechanistic analysis of cavitation assisted transesterification on biodiesel characteristics.

    Science.gov (United States)

    Sajjadi, Baharak; Abdul Aziz, A R; Ibrahim, Shaliza

    2015-01-01

    The influence of sonoluminescence transesterification on biodiesel physicochemical properties was investigated and the results were compared to those of traditional mechanical stirring. This study was conducted to identify the mechanistic features of ultrasonication by coupling statistical analysis of the experiments into the simulation of cavitation bubble. Different combinations of operational variables were employed for alkali-catalysis transesterification of palm oil. The experimental results showed that transesterification with ultrasound irradiation could change the biodiesel density by about 0.3kg/m(3); the viscosity by 0.12mm(2)/s; the pour point by about 1-2°C and the flash point by 5°C compared to the traditional method. Furthermore, 93.84% of yield with alcohol to oil molar ratio of 6:1 could be achieved through ultrasound assisted transesterification within only 20min. However, only 89.09% of reaction yield was obtained by traditional macro mixing/heating under the same condition. Based on the simulated oscillation velocity value, the cavitation phenomenon significantly contributed to generation of fine micro emulsion and was able to overcome mass transfer restriction. It was found that the sonoluminescence bubbles reached the temperature of 758-713K, pressure of 235.5-159.55bar, oscillation velocity of 3.5-6.5cm/s, and equilibrium radius of 17.9-13.7 times greater than its initial size under the ambient temperature of 50-64°C at the moment of collapse. This showed that the sonoluminescence bubbles were in the condition in which the decomposition phenomena were activated and the reaction rate was accelerated together with a change in the biodiesel properties. Copyright © 2014 Elsevier B.V. All rights reserved.

  16. Evaluation of DNA microarray results in the Toxicogenomics Project (TGP) consortium in Japan.

    Science.gov (United States)

    Noriyuki, Nakatsu; Igarashi, Yoshinobu; Ono, Atsushi; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro

    2012-01-01

    An important technology used in toxicogenomic drug discovery research is the microarray, which enables researchers to simultaneously analyze the expression of a large number of genes. To build a database and data analysis system for use in assessing the safety of drugs and drug candidates, in 2002 we conducted a 5-year collaborative study in the Toxicogenomics Project (TGP1) in Japan. Experimental data generated by such studies must be validated by different laboratories for robust and accurate analysis. For this purpose, we conducted intra- and inter-laboratory validation studies with participating companies in the second collaborative study in the Toxicogenomics Project (TGP2). Gene expression in the liver of rats treated with acetaminophen (APAP) was independently examined by the participating companies using Affymetrix GeneChip microarrays. The intra- and inter-laboratory reproducibility of the data was evaluated using hierarchical clustering analysis. The toxicogenomics results were highly reproducible, indicating that the gene expression data generated in our TGP1 project is reliable and compatible with the data generated by the participating laboratories.

  17. AIM analysis, synthetic, kinetic and mechanistic investigations of the ...

    Indian Academy of Sciences (India)

    analysis (NPA), atoms in molecules (AIM) methods and CHelpG keyword. ... obtained from studies of the effect of solvent, structure of reactions (different alkyl groups within the dialkyl ...... compounds) have provided useful evidence for steps 1.

  18. Design issues in toxicogenomics using DNA microarray experiment

    International Nuclear Information System (INIS)

    Lee, Kyoung-Mu; Kim, Ju-Han; Kang, Daehee

    2005-01-01

    The methods of toxicogenomics might be classified into omics study (e.g., genomics, proteomics, and metabolomics) and population study focusing on risk assessment and gene-environment interaction. In omics study, microarray is the most popular approach. Genes falling into several categories (e.g., xenobiotics metabolism, cell cycle control, DNA repair etc.) can be selected up to 20,000 according to a priori hypothesis. The appropriate type of samples and species should be selected in advance. Multiple doses and varied exposure durations are suggested to identify those genes clearly linked to toxic response. Microarray experiments can be affected by numerous nuisance variables including experimental designs, sample extraction, type of scanners, etc. The number of slides might be determined from the magnitude and variance of expression change, false-positive rate, and desired power. Instead, pooling samples is an alternative. Online databases on chemicals with known exposure-disease outcomes and genetic information can aid the interpretation of the normalized results. Gene function can be inferred from microarray data analyzed by bioinformatics methods such as cluster analysis. The population study often adopts hospital-based or nested case-control design. Biases in subject selection and exposure assessment should be minimized, and confounding bias should also be controlled for in stratified or multiple regression analysis. Optimal sample sizes are dependent on the statistical test for gene-to-environment or gene-to-gene interaction. The design issues addressed in this mini-review are crucial in conducting toxicogenomics study. In addition, integrative approach of exposure assessment, epidemiology, and clinical trial is required

  19. Mechanistic multidimensional analysis of horizontal two-phase flows

    International Nuclear Information System (INIS)

    Tselishcheva, Elena A.; Antal, Steven P.; Podowski, Michael Z.

    2010-01-01

    The purpose of this paper is to discuss the results of analysis of two-phase flow in horizontal tubes. Two flow situations have been considered: gas/liquid flow in a long straight pipe, and similar flow conditions in a pipe with 90 deg. elbow. The theoretical approach utilizes a multifield modeling concept. A complete three-dimensional two-phase flow model has been implemented in a state-of-the-art computational multiphase fluid dynamics (CMFD) computer code, NPHASE. The overall model has been tested parametrically. Also, the results of NPHASE simulations have been compared against experimental data for a pipe with 90 deg. elbow.

  20. Conceptual models for waste tank mechanistic analysis. Status report, January 1991

    Energy Technology Data Exchange (ETDEWEB)

    Allemann, R. T.; Antoniak, Z. I.; Eyler, L. L.; Liljegren, L. M.; Roberts, J. S.

    1992-02-01

    Pacific Northwest Laboratory (PNL) is conducting a study for Westinghouse Hanford Company (Westinghouse Hanford), a contractor for the US Department of Energy (DOE). The purpose of the work is to study possible mechanisms and fluid dynamics contributing to the periodic release of gases from double-shell waste storage tanks at the Hanford Site in Richland, Washington. This interim report emphasizing the modeling work follows two other interim reports, Mechanistic Analysis of Double-Shell Tank Gas Release Progress Report -- November 1990 and Collection and Analysis of Existing Data for Waste Tank Mechanistic Analysis Progress Report -- December 1990, that emphasized data correlation and mechanisms. The approach in this study has been to assemble and compile data that are pertinent to the mechanisms, analyze the data, evaluate physical properties and parameters, evaluate hypothetical mechanisms, and develop mathematical models of mechanisms.

  1. Prediction model of potential hepatocarcinogenicity of rat hepatocarcinogens using a large-scale toxicogenomics database

    International Nuclear Information System (INIS)

    Uehara, Takeki; Minowa, Yohsuke; Morikawa, Yuji; Kondo, Chiaki; Maruyama, Toshiyuki; Kato, Ikuo; Nakatsu, Noriyuki; Igarashi, Yoshinobu; Ono, Atsushi; Hayashi, Hitomi; Mitsumori, Kunitoshi; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro

    2011-01-01

    The present study was performed to develop a robust gene-based prediction model for early assessment of potential hepatocarcinogenicity of chemicals in rats by using our toxicogenomics database, TG-GATEs (Genomics-Assisted Toxicity Evaluation System developed by the Toxicogenomics Project in Japan). The positive training set consisted of high- or middle-dose groups that received 6 different non-genotoxic hepatocarcinogens during a 28-day period. The negative training set consisted of high- or middle-dose groups of 54 non-carcinogens. Support vector machine combined with wrapper-type gene selection algorithms was used for modeling. Consequently, our best classifier yielded prediction accuracies for hepatocarcinogenicity of 99% sensitivity and 97% specificity in the training data set, and false positive prediction was almost completely eliminated. Pathway analysis of feature genes revealed that the mitogen-activated protein kinase p38- and phosphatidylinositol-3-kinase-centered interactome and the v-myc myelocytomatosis viral oncogene homolog-centered interactome were the 2 most significant networks. The usefulness and robustness of our predictor were further confirmed in an independent validation data set obtained from the public database. Interestingly, similar positive predictions were obtained in several genotoxic hepatocarcinogens as well as non-genotoxic hepatocarcinogens. These results indicate that the expression profiles of our newly selected candidate biomarker genes might be common characteristics in the early stage of carcinogenesis for both genotoxic and non-genotoxic carcinogens in the rat liver. Our toxicogenomic model might be useful for the prospective screening of hepatocarcinogenicity of compounds and prioritization of compounds for carcinogenicity testing. - Highlights: →We developed a toxicogenomic model to predict hepatocarcinogenicity of chemicals. →The optimized model consisting of 9 probes had 99% sensitivity and 97% specificity.

  2. How can toxicogenomics inform risk assessment?

    International Nuclear Information System (INIS)

    Oberemm, Axel; Onyon, Lesley; Gundert-Remy, Ursula

    2005-01-01

    Technologies that generate information about the genome are being used to explore changes in gene expression and related proteins following exposure to chemicals. Conceptually, this information allows a greater understanding of genomic level mRNA expression (transcriptomics), cell and tissue protein expression (proteomics) and information about metabolite profiles (metabonomics). Having a greater understanding of this information alongside, empirical toxicological reference data provide for the continued evolution in our ability to understand toxicological modes of action, thereby providing a more scientific basis for extrapolation of toxicological information from animals to humans. Toxicogenomics also provides specific opportunities for improvements at different stages of the risk assessment process such as the development of new predictive models for identifying human health hazards and the identification of more precise molecular biomarkers of exposure. One possibility is that molecular fingerprinting in vivo or in vitro can be used to categorize chemicals and mixtures of chemicals into different mode of action groups. As there is indication that molecular signals differ at dose levels, it is hoped that toxicogenomic information can also contribute to the understanding and interpretation of effects seen with low dose exposure. Several gene polymorphisms have already been identified which play a role in the differing intra-species response to chemicals thus providing explanation for the observed differences in effects. It is therefore likely that a better understanding of genomic expression will enable a greater insight into the factors behind the observed variability in susceptibility to chemical exposure that can be seen in human populations

  3. Integrating genetic and toxicogenomic information for determining underlying susceptibility to developmental disorders.

    Science.gov (United States)

    Robinson, Joshua F; Port, Jesse A; Yu, Xiaozhong; Faustman, Elaine M

    2010-10-01

    To understand the complex etiology of developmental disorders, an understanding of both genetic and environmental risk factors is needed. Human and rodent genetic studies have identified a multitude of gene candidates for specific developmental disorders such as neural tube defects (NTDs). With the emergence of toxicogenomic-based assessments, scientists now also have the ability to compare and understand the expression of thousands of genes simultaneously across strain, time, and exposure in developmental models. Using a systems-based approach in which we are able to evaluate information from various parts and levels of the developing organism, we propose a framework for integrating genetic information with toxicogenomic-based studies to better understand gene-environmental interactions critical for developmental disorders. This approach has allowed us to characterize candidate genes in the context of variables critical for determining susceptibility such as strain, time, and exposure. Using a combination of toxicogenomic studies and complementary bioinformatic tools, we characterize NTD candidate genes during normal development by function (gene ontology), linked phenotype (disease outcome), location, and expression (temporally and strain-dependent). In addition, we show how environmental exposures (cadmium, methylmercury) can influence expression of these genes in a strain-dependent manner. Using NTDs as an example of developmental disorder, we show how simple integration of genetic information from previous studies into the standard microarray design can enhance analysis of gene-environment interactions to better define environmental exposure-disease pathways in sensitive and resistant mouse strains. © Wiley-Liss, Inc.

  4. Systems toxicology: applications of toxicogenomics, transcriptomics, proteomics and metabolomics in toxicology

    NARCIS (Netherlands)

    Heijne, W.H.M.; Kienhuis, A.S.; Ommen, van B.; Stierum, R.; Groten, J.P.

    2005-01-01

    Toxicogenomics can facilitate the identification and characterization of toxicity, as illustrated in this review. Toxicogenomics, the application of the functional genomics technologies (transcriptomics, proteomics and metabolomics) in toxicology enables the study of adverse effects of xenobiotic

  5. Toxicogenomics: A New Paradigm for Nanotoxicity Evaluation.

    Science.gov (United States)

    Dwivedi, Sourabh; Saquib, Quaiser; Ahmad, Bilal; Ansari, Sabiha M; Azam, Ameer; Musarrat, Javed

    2018-01-01

    The wider applications of nanoparticles (NPs) has evoked a world-wide concern due to their possible risk of toxicity in humans and other organisms. Aggregation and accumulation of NPs into cell leads to their interaction with biological macromolecules including proteins, nucleic acids and cellular organelles, which eventually induce toxicological effects. Application of toxicogenomics to investigate molecular pathway-based toxicological consequences has opened new vistas in nanotoxicology research. Indeed, genomic approaches appeared as a new paradigm in terms of providing information at molecular levels and have been proven to be as a powerful tool for identification and quantification of global shifts in gene expression. Toxicological responses of NPs have been discussed in this chapter with the aim to provide a clear understanding of the molecular mechanism of NPs induced toxicity both in in vivo and in vitro test models.

  6. Open TG-GATEs: a large-scale toxicogenomics database

    Science.gov (United States)

    Igarashi, Yoshinobu; Nakatsu, Noriyuki; Yamashita, Tomoya; Ono, Atsushi; Ohno, Yasuo; Urushidani, Tetsuro; Yamada, Hiroshi

    2015-01-01

    Toxicogenomics focuses on assessing the safety of compounds using gene expression profiles. Gene expression signatures from large toxicogenomics databases are expected to perform better than small databases in identifying biomarkers for the prediction and evaluation of drug safety based on a compound's toxicological mechanisms in animal target organs. Over the past 10 years, the Japanese Toxicogenomics Project consortium (TGP) has been developing a large-scale toxicogenomics database consisting of data from 170 compounds (mostly drugs) with the aim of improving and enhancing drug safety assessment. Most of the data generated by the project (e.g. gene expression, pathology, lot number) are freely available to the public via Open TG-GATEs (Toxicogenomics Project-Genomics Assisted Toxicity Evaluation System). Here, we provide a comprehensive overview of the database, including both gene expression data and metadata, with a description of experimental conditions and procedures used to generate the database. Open TG-GATEs is available from http://toxico.nibio.go.jp/english/index.html. PMID:25313160

  7. Mechanistic study of manganese-substituted glycerol dehydrogenase using a kinetic and thermodynamic analysis.

    Science.gov (United States)

    Fang, Baishan; Niu, Jin; Ren, Hong; Guo, Yingxia; Wang, Shizhen

    2014-01-01

    Mechanistic insights regarding the activity enhancement of dehydrogenase by metal ion substitution were investigated by a simple method using a kinetic and thermodynamic analysis. By profiling the binding energy of both the substrate and product, the metal ion's role in catalysis enhancement was revealed. Glycerol dehydrogenase (GDH) from Klebsiella pneumoniae sp., which demonstrated an improvement in activity by the substitution of a zinc ion with a manganese ion, was used as a model for the mechanistic study of metal ion substitution. A kinetic model based on an ordered Bi-Bi mechanism was proposed considering the noncompetitive product inhibition of dihydroxyacetone (DHA) and the competitive product inhibition of NADH. By obtaining preliminary kinetic parameters of substrate and product inhibition, the number of estimated parameters was reduced from 10 to 4 for a nonlinear regression-based kinetic parameter estimation. The simulated values of time-concentration curves fit the experimental values well, with an average relative error of 11.5% and 12.7% for Mn-GDH and GDH, respectively. A comparison of the binding energy of enzyme ternary complex for Mn-GDH and GDH derived from kinetic parameters indicated that metal ion substitution accelerated the release of dioxyacetone. The metal ion's role in catalysis enhancement was explicated.

  8. Mechanistic study of manganese-substituted glycerol dehydrogenase using a kinetic and thermodynamic analysis.

    Directory of Open Access Journals (Sweden)

    Baishan Fang

    Full Text Available Mechanistic insights regarding the activity enhancement of dehydrogenase by metal ion substitution were investigated by a simple method using a kinetic and thermodynamic analysis. By profiling the binding energy of both the substrate and product, the metal ion's role in catalysis enhancement was revealed. Glycerol dehydrogenase (GDH from Klebsiella pneumoniae sp., which demonstrated an improvement in activity by the substitution of a zinc ion with a manganese ion, was used as a model for the mechanistic study of metal ion substitution. A kinetic model based on an ordered Bi-Bi mechanism was proposed considering the noncompetitive product inhibition of dihydroxyacetone (DHA and the competitive product inhibition of NADH. By obtaining preliminary kinetic parameters of substrate and product inhibition, the number of estimated parameters was reduced from 10 to 4 for a nonlinear regression-based kinetic parameter estimation. The simulated values of time-concentration curves fit the experimental values well, with an average relative error of 11.5% and 12.7% for Mn-GDH and GDH, respectively. A comparison of the binding energy of enzyme ternary complex for Mn-GDH and GDH derived from kinetic parameters indicated that metal ion substitution accelerated the release of dioxyacetone. The metal ion's role in catalysis enhancement was explicated.

  9. Identification of molecular candidates and interaction networks via integrative toxicogenomic analysis in a human cell line following low-dose exposure to the carcinogenic metals cadmium and nickel.

    Science.gov (United States)

    Kwon, Jee Young; Weon, Jong-Il; Koedrith, Preeyaporn; Park, Kang-Sik; Kim, Im Soon; Seo, Young Rok

    2013-09-01

    Cadmium and nickel have been classified as carcinogenic to humans by the World Health Organization's International Agency for Research on Cancer. Given their prevalence in the environment, the fact that cadmium and nickel may cause diseases including cancer even at low doses is a cause for concern. However, the exact mechanisms underlying the toxicological effects induced by low-dose exposure to cadmium and nickel remain to be elucidated. Furthermore, it has recently been recognized that integrative analysis of DNA, mRNA and proteins is required to discover biomarkers and signaling networks relevant to human toxicant exposure. In the present study, we examined the deleterious effects of chronic low-dose exposure of either cadmium or nickel on global profiling of DNA copy number variation, mRNA and proteins. Array comparative genomic hybridization, gene expression microarray and functional proteomics were conducted, and a bioinformatics tool, which predicted signaling pathways, was applied to integrate data for each heavy metal separately and together. We found distinctive signaling networks associated with subchronic low-dose exposure to cadmium and nickel, and identified pathways common to both. ACTB, HSP90AA1, HSPA5 and HSPA8, which are key mediators of pathways related to apoptosis, proliferation and neoplastic processes, were key mediators of the same pathways in low-dose nickel and cadmium exposure in particular. CASP-associated signaling pathways involving CASP3, CASP7 and CASP9 were observed in cadmium-exposed cells. We found that HSP90AA1, one of the main modulators, interacted with HIF1A, AR and BCL2 in nickel-exposed cells. Interestingly, we found that HSP90AA1 was involved in the BCL2-associated apoptotic pathway in the nickel-only data, whereas this gene interacted with several genes functioning in CASP-associated apoptotic signaling in the cadmium-only data. Additionally, JUN and FASN were main modulators in nickel-responsive signaling pathways. Our

  10. Inter- and intra-laboratory study to determine the reproducibility of toxicogenomics datasets.

    Science.gov (United States)

    Scott, D J; Devonshire, A S; Adeleye, Y A; Schutte, M E; Rodrigues, M R; Wilkes, T M; Sacco, M G; Gribaldo, L; Fabbri, M; Coecke, S; Whelan, M; Skinner, N; Bennett, A; White, A; Foy, C A

    2011-11-28

    The application of toxicogenomics as a predictive tool for chemical risk assessment has been under evaluation by the toxicology community for more than a decade. However, it predominately remains a tool for investigative research rather than for regulatory risk assessment. In this study, we assessed whether the current generation of microarray technology in combination with an in vitro experimental design was capable of generating robust, reproducible data of sufficient quality to show promise as a tool for regulatory risk assessment. To this end, we designed a prospective collaborative study to determine the level of inter- and intra-laboratory reproducibility between three independent laboratories. All test centres (TCs) adopted the same protocols for all aspects of the toxicogenomic experiment including cell culture, chemical exposure, RNA extraction, microarray data generation and analysis. As a case study, the genotoxic carcinogen benzo[a]pyrene (B[a]P) and the human hepatoma cell line HepG2 were used to generate three comparable toxicogenomic data sets. High levels of technical reproducibility were demonstrated using a widely employed gene expression microarray platform. While differences at the global transcriptome level were observed between the TCs, a common subset of B[a]P responsive genes (n=400 gene probes) was identified at all TCs which included many genes previously reported in the literature as B[a]P responsive. These data show promise that the current generation of microarray technology, in combination with a standard in vitro experimental design, can produce robust data that can be generated reproducibly in independent laboratories. Future work will need to determine whether such reproducible in vitro model(s) can be predictive for a range of toxic chemicals with different mechanisms of action and thus be considered as part of future testing regimes for regulatory risk assessment. Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.

  11. Toxicogenomics: Applications of new functional genomics technologies in toxicology

    NARCIS (Netherlands)

    Heijne, W.H.M.

    2004-01-01

    Toxicogenomics studies toxic effects of substances on organisms in relation to the composition of the genome. It applies the functional genomics technologies transcriptomics, proteomics and metabolomics that determine expression of the genes, proteins and metabolites in a sample. These methods could

  12. Mechanistic Analysis of Cocrystal Dissolution as a Function of pH and Micellar Solubilization.

    Science.gov (United States)

    Cao, Fengjuan; Amidon, Gordon L; Rodriguez-Hornedo, Nair; Amidon, Gregory E

    2016-03-07

    The purpose of this work is to provide a mechanistic understanding of the dissolution behavior of cocrystals under the influence of ionization and micellar solubilization. Mass transport models were developed by applying Fick's law of diffusion to dissolution with simultaneous chemical reactions in the hydrodynamic boundary layer adjacent to the dissolving cocrystal surface to predict the pH at the dissolving solid-liquid interface (i.e., interfacial pH) and the flux of cocrystals. To evaluate the predictive power of these models, dissolution studies of carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) cocrystals were performed at varied pH and surfactant concentrations above the critical stabilization concentration (CSC), where the cocrystals were thermodynamically stable. The findings in this work demonstrate that the pH dependent dissolution behavior of cocrystals with ionizable components is dependent on interfacial pH. This mass transport analysis demonstrates the importance of pH, cocrystal solubility, diffusivity, and micellar solubilization on the dissolution rates of cocrystals.

  13. Structural and mechanistic analysis of a β-glycoside phosphorylase identified by screening a metagenomic library.

    Science.gov (United States)

    Macdonald, Spencer S; Patel, Ankoor; Larmour, Veronica L C; Morgan-Lang, Connor; Hallam, Steven J; Mark, Brian L; Withers, Stephen G

    2018-03-02

    Glycoside phosphorylases have considerable potential as catalysts for the assembly of useful glycans for products ranging from functional foods and prebiotics to novel materials. However, the substrate diversity of currently identified phosphorylases is relatively small, limiting their practical applications. To address this limitation, we developed a high-throughput screening approach using the activated substrate 2,4-dinitrophenyl β-d-glucoside (DNPGlc) and inorganic phosphate for identifying glycoside phosphorylase activity and used it to screen a large insert metagenomic library. The initial screen, based on release of 2,4-dinitrophenyl from DNPGlc in the presence of phosphate, identified the gene bglP, encoding a retaining β-glycoside phosphorylase from the CAZy GH3 family. Kinetic and mechanistic analysis of the gene product, BglP, confirmed a double displacement ping-pong mechanism involving a covalent glycosyl-enzyme intermediate. X-ray crystallographic analysis provided insights into the phosphate-binding mode and identified a key glutamine residue in the active site important for substrate recognition. Substituting this glutamine for a serine swapped the substrate specificity from glucoside to N -acetylglucosaminide. In summary, we present a high-throughput screening approach for identifying β-glycoside phosphorylases, which was robust, simple to implement, and useful in identifying active clones within a metagenomics library. Implementation of this screen enabled discovery of a new glycoside phosphorylase class and has paved the way to devising simple ways in which enzyme specificity can be encoded and swapped, which has implications for biotechnological applications. © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.

  14. Mechanistic modeling analysis of micro-evolutive responses from a Caenorhabditis elegans population exposed to a radioactive metallic stress

    International Nuclear Information System (INIS)

    Goussen, Benoit

    2013-01-01

    The evolution of toxic effects at a relevant scale is an important challenge for the ecosystem protection. Indeed, pollutants may impact populations over long-term and represent a new evolutionary force which can be adding itself to the natural selection forces. Thereby, it is necessary to acquire knowledge on the phenotypics and genetics changes that may appear in populations submitted to stress over several generations. Usually statistical analyses are performed to analyse such multi-generational studies. The use of a mechanistic mathematical model may provide a way to fully understand the impact of pollutants on the populations' dynamics. Such kind of model allows the integration of biological and toxic processes into the analysis of eco-toxicological data and the assessment of interactions between these processes. The aim of this Ph.D. project was to assess the contributions of the mechanistic modelling to the analysis of evolutionary experiment assessing long-term exposure. To do so, a three step strategy has been developed. Foremost, a multi-generational study was performed to assess the evolution of two populations of the ubiquitous nematode Caenorhabditis elegans in control conditions or exposed to 1.1 mM of uranium. Several generations were selected to assess growth, reproduction, and dose-responses relationships, through exposure to a range of concentrations (from 0 to 1.2 mM U) with all endpoints measured daily. A first statistical analysis was then performed. In a second step, a bio-energetic model adapted to the assessment of eco-toxicological data (DEBtox) was developed on C. elegans. Its numerical behaviour was analysed. Finally, this model was applied to all the selected generations in order to infer parameters values for the two populations and to assess their evolutions. Results highlighted an impact of the uranium starting from 0.4 mM U on both C. elegans' growth and reproduction. Results from the mechanistic analysis indicate this effect is due

  15. Uncertainty, sensitivity analysis and the role of data based mechanistic modeling in hydrology

    Science.gov (United States)

    Ratto, M.; Young, P. C.; Romanowicz, R.; Pappenberger, F.; Saltelli, A.; Pagano, A.

    2007-05-01

    In this paper, we discuss a joint approach to calibration and uncertainty estimation for hydrologic systems that combines a top-down, data-based mechanistic (DBM) modelling methodology; and a bottom-up, reductionist modelling methodology. The combined approach is applied to the modelling of the River Hodder catchment in North-West England. The top-down DBM model provides a well identified, statistically sound yet physically meaningful description of the rainfall-flow data, revealing important characteristics of the catchment-scale response, such as the nature of the effective rainfall nonlinearity and the partitioning of the effective rainfall into different flow pathways. These characteristics are defined inductively from the data without prior assumptions about the model structure, other than it is within the generic class of nonlinear differential-delay equations. The bottom-up modelling is developed using the TOPMODEL, whose structure is assumed a priori and is evaluated by global sensitivity analysis (GSA) in order to specify the most sensitive and important parameters. The subsequent exercises in calibration and validation, performed with Generalized Likelihood Uncertainty Estimation (GLUE), are carried out in the light of the GSA and DBM analyses. This allows for the pre-calibration of the the priors used for GLUE, in order to eliminate dynamical features of the TOPMODEL that have little effect on the model output and would be rejected at the structure identification phase of the DBM modelling analysis. In this way, the elements of meaningful subjectivity in the GLUE approach, which allow the modeler to interact in the modelling process by constraining the model to have a specific form prior to calibration, are combined with other more objective, data-based benchmarks for the final uncertainty estimation. GSA plays a major role in building a bridge between the hypothetico-deductive (bottom-up) and inductive (top-down) approaches and helps to improve the

  16. Application of comparative vibrational spectroscopic and mechanistic studies in analysis of fisetin structure.

    Science.gov (United States)

    Dimitrić Marković, Jasmina M; Marković, Zoran S; Milenković, Dejan; Jeremić, Svetlana

    2011-12-01

    This paper addresses experimental and theoretical research in fisetin (2-(3,4-dihydroxyphenyl)-3,7-dihydroxychromen-4-one) structure by means of experimental IR and Raman spectroscopies and mechanistic calculations. Density Functional Theory calculations, with M05-2X functional and the 6-311+G (2df, p) basis set implemented in the Gaussian 09 package, are performed with the aim to support molecular structure, vibrational bands' positions and their intensities. Potential energy distribution (PED) values and the description of the largest vibrational contributions to the normal modes are calculated. The most intense bands appear in the 1650-1500 cm(-1) wavenumber region. This region involves a combination of the CO, C2C3 and C-C stretching vibrational modes. Most of the bands in the 1500-1000 cm(-1) range involve C-C stretching, O-C stretching and in-plane C-C-H, C-O-H, C-C-O and C-C-C bending vibrations of the rings. The region below 1000 cm(-1) is characteristic to the combination of in plane C-C-C-H, H-C-C-H, C-C-C-C, C-C-O-C and out of plane O-C-C-C, C-C-O-C, C-C-C-C torsional modes. The Raman spectra of baicalein and quercetin were used for qualitative comparison with fisetin spectrum and verification of band assignments. The applied detailed vibrational spectral analysis and the assignments of the bands, proposed on the basis of fundamentals, reproduced the experimental results with high degree of accuracy. Copyright © 2011 Elsevier B.V. All rights reserved.

  17. Application of comparative vibrational spectroscopic and mechanistic studies in analysis of fisetin structure

    Science.gov (United States)

    Dimitrić Marković, Jasmina M.; Marković, Zoran S.; Milenković, Dejan; Jeremić, Svetlana

    2011-12-01

    This paper addresses experimental and theoretical research in fisetin (2-(3,4-dihydroxyphenyl)-3,7-dihydroxychromen-4-one) structure by means of experimental IR and Raman spectroscopies and mechanistic calculations. Density Functional Theory calculations, with M05-2X functional and the 6-311+G (2df, p) basis set implemented in the Gaussian 09 package, are performed with the aim to support molecular structure, vibrational bands' positions and their intensities. Potential energy distribution (PED) values and the description of the largest vibrational contributions to the normal modes are calculated. The most intense bands appear in the 1650-1500 cm -1 wavenumber region. This region involves a combination of the C dbnd O, C2 dbnd C3 and C-C stretching vibrational modes. Most of the bands in the 1500-1000 cm -1 range involve C-C stretching, O-C stretching and in-plane C-C-H, C-O-H, C-C-O and C-C-C bending vibrations of the rings. The region below 1000 cm -1 is characteristic to the combination of in plane C-C-C-H, H-C-C-H, C-C-C-C, C-C-O-C and out of plane O-C-C-C, C-C-O-C, C-C-C-C torsional modes. The Raman spectra of baicalein and quercetin were used for qualitative comparison with fisetin spectrum and verification of band assignments. The applied detailed vibrational spectral analysis and the assignments of the bands, proposed on the basis of fundamentals, reproduced the experimental results with high degree of accuracy.

  18. SENSITIVITY ANALYSIS IN FLEXIBLE PAVEMENT PERFORMANCE USING MECHANISTIC EMPIRICAL METHOD (CASE STUDY: CIREBON–LOSARI ROAD SEGMENT, WEST JAVA

    Directory of Open Access Journals (Sweden)

    E. Samad

    2012-02-01

    Full Text Available Cirebon – Losari flexible pavement which is located on the North Coast of Java, Indonesia, is in the severe damage condition caused by overloading vehicles passing the road. The need for developing improved pavement design and analysis methods is very necessary. The increment of loads and quality of material properties can be evaluated through Mechanistic-Empirical (M-E method. M-E software like KENLAYER has been developed to facilitate the transition from empirical to mechanistic design methods. From the KENLAYER analysis, it can be concluded that the effect of overloading to the pavement structure performance is difficult to minimize even though the first two layers have relatively high modulus of elasticity. The occurrence of 150%, 200%, and 250% overloading have a very significant effect in reducing 84%, 95%, and 98% of the pavement design life, respectively. For the purpose of increasing the pavement service life, it is more effective to manage the allowable load.

  19. Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action

    Science.gov (United States)

    Currie, Richard A.; Peffer, Richard C.; Goetz, Amber K.; Omiecinski, Curtis J.; Goodman, Jay I.

    2014-01-01

    Toxicogenomics (TGx) is employed frequently to investigate underlying molecular mechanisms of the compound of interest and, thus, has become an aid to mode of action determination. However, the results and interpretation of a TGx dataset are influenced by the experimental design and methods of analysis employed. This article describes an evaluation and reanalysis, by two independent laboratories, of previously published TGx mouse liver microarray data for a triazole fungicide, propiconazole (PPZ), and the anticonvulsant drug phenobarbital (PB). Propiconazole produced an increase incidence of liver tumors in male CD-1 mice only at a dose that exceeded the maximum tolerated dose (2500 ppm). Firstly, we illustrate how experimental design differences between two in vivo studies with PPZ and PB may impact the comparisons of TGx results. Secondly, we demonstrate that different researchers using different pathway analysis tools can come to different conclusions on specific mechanistic pathways, even when using the same datasets. Finally, despite these differences the results across three different analyses also show a striking degree of similarity observed for PPZ and PB treated livers when the expression data are viewed as major signaling pathways and cell processes affected. Additional studies described here show that the postulated key event of hepatocellular proliferation was observed in CD-1 mice for both PPZ and PB, and that PPZ is also a potent activator of the mouse CAR nuclear receptor. Thus, with regard to the events which are hallmarks of CAR-induced effects that are key events in the mode of action (MOA) of mouse liver carcinogenesis with PB, PPZ-induced tumors can be viewed as being promoted by a similar PB-like CAR-dependent MOA. PMID:24675475

  20. Phenobarbital and propiconazole toxicogenomic profiles in mice show major similarities consistent with the key role that constitutive androstane receptor (CAR) activation plays in their mode of action

    International Nuclear Information System (INIS)

    Currie, Richard A.; Peffer, Richard C.; Goetz, Amber K.; Omiecinski, Curtis J.; Goodman, Jay I.

    2014-01-01

    Toxicogenomics (TGx) is employed frequently to investigate underlying molecular mechanisms of the compound of interest and, thus, has become an aid to mode of action determination. However, the results and interpretation of a TGx dataset are influenced by the experimental design and methods of analysis employed. This article describes an evaluation and reanalysis, by two independent laboratories, of previously published TGx mouse liver microarray data for a triazole fungicide, propiconazole (PPZ), and the anticonvulsant drug phenobarbital (PB). Propiconazole produced an increase incidence of liver tumors in male CD-1 mice only at a dose that exceeded the maximum tolerated dose (2500 ppm). Firstly, we illustrate how experimental design differences between two in vivo studies with PPZ and PB may impact the comparisons of TGx results. Secondly, we demonstrate that different researchers using different pathway analysis tools can come to different conclusions on specific mechanistic pathways, even when using the same datasets. Finally, despite these differences the results across three different analyses also show a striking degree of similarity observed for PPZ and PB treated livers when the expression data are viewed as major signaling pathways and cell processes affected. Additional studies described here show that the postulated key event of hepatocellular proliferation was observed in CD-1 mice for both PPZ and PB, and that PPZ is also a potent activator of the mouse CAR nuclear receptor. Thus, with regard to the events which are hallmarks of CAR-induced effects that are key events in the mode of action (MOA) of mouse liver carcinogenesis with PB, PPZ-induced tumors can be viewed as being promoted by a similar PB-like CAR-dependent MOA

  1. Toxicogenomic multigene biomarker for predicting the future onset of proximal tubular injury in rats

    International Nuclear Information System (INIS)

    Minowa, Yohsuke; Kondo, Chiaki; Uehara, Takeki; Morikawa, Yuji; Okuno, Yasushi; Nakatsu, Noriyuki; Ono, Atsushi; Maruyama, Toshiyuki; Kato, Ikuo; Yamate, Jyoji; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro

    2012-01-01

    Drug-induced renal tubular injury is a major concern in the preclinical safety evaluation of drug candidates. Toxicogenomics is now a generally accepted tool for identifying chemicals with potential safety problems. The specific aim of the present study was to develop a model for use in predicting the future onset of drug-induced proximal tubular injury following repeated dosing with various nephrotoxicants. In total, 41 nephrotoxic and nonnephrotoxic compounds were used for the present analysis. Male Sprague-Dawley rats were dosed orally or intravenously once daily. Animals were exposed to three different doses (low, middle, and high) of each compound, and kidney tissue was collected at 3, 6, 9, and 24 h after single dosing, and on days 4, 8, 15, and 29 after repeated dosing. Gene expression profiles were generated from kidney total RNA using Affymetrix DNA microarrays. Filter-type gene selection and linear classification algorithms were employed to discriminate future onset of proximal tubular injury. We identified genomic biomarkers for use in future onset prediction using the gene expression profiles determined on day 1, when most of the nephrotoxicants had yet to produce detectable histopathological changes. The model was evaluated using a five-fold cross validation, and achieved a sensitivity of 93% and selectivity of 90% with 19 probes. We also found that the prediction accuracy of the optimized model was substantially higher than that produced by any of the single genomic biomarkers or histopathology. The genes included in our model were primarily involved in DNA replication, cell cycle control, apoptosis, and responses to oxidative stress and chemical stimuli. In summary, our toxicogenomic model is particularly useful for predicting the future onset of proximal tubular injury.

  2. Fast charging technique for high power LiFePO4 batteries: A mechanistic analysis of aging

    Science.gov (United States)

    Anseán, D.; Dubarry, M.; Devie, A.; Liaw, B. Y.; García, V. M.; Viera, J. C.; González, M.

    2016-07-01

    One of the major issues hampering the acceptance of electric vehicles (EVs) is the anxiety associated with long charging time. Hence, the ability to fast charging lithium-ion battery (LIB) systems is gaining notable interest. However, fast charging is not tolerated by all LIB chemistries because it affects battery functionality and accelerates its aging processes. Here, we investigate the long-term effects of multistage fast charging on a commercial high power LiFePO4-based cell and compare it to another cell tested under standard charging. Coupling incremental capacity (IC) and IC peak area analysis together with mechanistic model simulations ('Alawa' toolbox with harvested half-cell data), we quantify the degradation modes that cause aging of the tested cells. The results show that the proposed fast charging technique caused similar aging effects as standard charging. The degradation is caused by a linear loss of lithium inventory, coupled with a less degree of linear loss of active material on the negative electrode. This study validates fast charging as a feasible mean of operation for this particular LIB chemistry and cell architecture. It also illustrates the benefits of a mechanistic approach to understand cell degradation on commercial cells.

  3. Predicting residential exposure to phthalate plasticizer emitted from vinyl flooring: a mechanistic analysis.

    Science.gov (United States)

    Xu, Ying; Hubal, Elaine A Cohen; Clausen, Per A; Little, John C

    2009-04-01

    A two-room model is developed to estimate the emission rate of di-2-ethylhexyl phthalate (DEHP) from vinyl flooring and the evolving gas-phase and adsorbed surface concentrations in a realistic indoor environment. Because the DEHP emission rate measured in a test chamber may be quite different from the emission rate from the same material in the indoor environment the model provides a convenient means to predict emissions and transport in a more realistic setting. Adsorption isotherms for phthalates and plasticizers on interior surfaces, such as carpet, wood, dust, and human skin, are derived from previous field and laboratory studies. Log-linear relationships between equilibrium parameters and chemical vapor pressure are obtained. The predicted indoor air DEHP concentration at steady state is 0.15 microg/m3. Room 1 reaches steady state within about one year, while the adjacent room reaches steady state about three months later. Ventilation rate has a strong influence on DEHP emission rate while total suspended particle concentration has a substantial impact on gas-phase concentration. Exposure to DEHP via inhalation, dermal absorption, and oral ingestion of dust is evaluated. The model clarifies the mechanisms that govern the release of DEHP from vinyl flooring and the subsequent interactions with interior surfaces, airborne particles, dust, and human skin. Although further model development, parameter identification, and model validation are needed, our preliminary model provides a mechanistic framework that elucidates exposure pathways for phthalate plasticizers, and can most likely be adapted to predict emissions and transport of other semivolatile organic compounds, such as brominated flame retardants and biocides, in a residential environment.

  4. Further analysis of open-respirometry systems: an a-compartmental mechanistic approach

    Directory of Open Access Journals (Sweden)

    Chaui-Berlinck J.G.

    2000-01-01

    Full Text Available A system is said to be "instantaneous" when for a given constant input an equilibrium output is obtained after a while. In the meantime, the output is changing from its initial value towards the equilibrium one. This is the transient period of the system and transients are important features of open-respirometry systems. During transients, one cannot compute the input amplitude directly from the output. The existing models (e.g., first or second order dynamics cannot account for many of the features observed in real open-respirometry systems, such as time lag. Also, these models do not explain what should be expected when a system is speeded up or slowed down. The purpose of the present study was to develop a mechanistic approach to the dynamics of open-respirometry systems, employing basic thermodynamic concepts. It is demonstrated that all the main relevant features of the output dynamics are due to and can be adequately explained by a distribution of apparent velocities within the set of molecules travelling along the system. The importance of the rate at which the molecules leave the sensor is explored for the first time. The study approaches the difference in calibrating a system with a continuous input and with a "unit impulse": the former truly reveals the dynamics of the system while the latter represents the first derivative (in time of the former and, thus, cannot adequately be employed in the apparent time-constant determination. Also, we demonstrate why the apparent order of the output changes with volume or flow.

  5. Use of Genomic Data in Risk Assessment Caes Study: II. Evaluation of the Dibutyl Phthalate Toxicogenomic Dataset

    Science.gov (United States)

    An evaluation of the toxicogenomic data set for dibutyl phthalate (DBP) and male reproductive developmental effects was performed as part of a larger case study to test an approach for incorporating genomic data in risk assessment. The DBP toxicogenomic data set is composed of ni...

  6. A MECHANISTIC-EMPIRICAL IMPACT ANALYSIS OF DIFFERENT TRUCK CONFIGURATIONS ON A JOINTED PLAIN CONCRETE PAVEMENT (JPCP

    Directory of Open Access Journals (Sweden)

    Lubinda F. Walubita

    2017-12-01

    Full Text Available Until the last decade, the 1993 American Association of State Highway and Transportation Officials (AASHTO design guide has been traditionally used for the design of flexible and rigid pavements in the USA and some parts of the world. However, because of its inability to meet the new traffic and material challenges, a Mechanistic Empirical Pavement Design Guide (MEPDG was introduced based on an NCHRP 1-37 A study conducted in 2004. This study used the MEPDG software and associated models to determine, through comparative truck damage analysis, the effects of nine different truck configurations on a 12 inch-jointed plain concrete pavement (JPCP. The study recorded truck damages at the end of each analysis period (40 years and comparatively analyzed the relative pavement damage in terms of fatigue cracking, faulting, and surface roughness. The results indicated that the most critical damage to the concrete pavement was caused by truck cases with high and uneven load distribution and relatively smaller size axles group (e.g. tandem. Other key findings included the following; (1 increase in damage when the truckloads were shifted between the same size axles, (2 decrease in truck damage when the truckloads were shifted from tandem axle to quad axles, and (3 no change in truck damage when the axle spacing was increased between wheels of a quad axle.

  7. Mechanistic approach to generalized technical analysis of share prices and stock market indices

    Science.gov (United States)

    Ausloos, M.; Ivanova, K.

    2002-05-01

    Classical technical analysis methods of stock evolution are recalled, i.e. the notion of moving averages and momentum indicators. The moving averages lead to define death and gold crosses, resistance and support lines. Momentum indicators lead the price trend, thus give signals before the price trend turns over. The classical technical analysis investment strategy is thereby sketched. Next, we present a generalization of these tricks drawing on physical principles, i.e. taking into account not only the price of a stock but also the volume of transactions. The latter becomes a time dependent generalized mass. The notion of pressure, acceleration and force are deduced. A generalized (kinetic) energy is easily defined. It is understood that the momentum indicators take into account the sign of the fluctuations, while the energy is geared toward the absolute value of the fluctuations. They have different patterns which are checked by searching for the crossing points of their respective moving averages. The case of IBM evolution over 1990-2000 is used for illustrations.

  8. Crystal structure of the pestivirus envelope glycoprotein E(rns) and mechanistic analysis of its ribonuclease activity.

    Science.gov (United States)

    Krey, Thomas; Bontems, Francois; Vonrhein, Clemens; Vaney, Marie-Christine; Bricogne, Gerard; Rümenapf, Till; Rey, Félix A

    2012-05-09

    Pestiviruses, which belong to the Flaviviridae family of RNA viruses, are important agents of veterinary diseases causing substantial economical losses in animal farming worldwide. Pestivirus particles display three envelope glycoproteins at their surface: E(rns), E1, and E2. We report here the crystal structure of the catalytic domain of E(rns), the ribonucleolytic activity of which is believed to counteract the innate immunity of the host. The structure reveals a three-dimensional fold corresponding to T2 ribonucleases from plants and fungi. Cocrystallization experiments with mono- and oligonucleotides revealed the structural basis for substrate recognition at two binding sites previously identified for T2 RNases. A detailed analysis of poly-U cleavage products using (31)P-NMR and size exclusion chromatography, together with molecular docking studies, provides a comprehensive mechanistic picture of E(rns) activity on its substrates and reveals the presence of at least one additional nucleotide binding site. Copyright © 2012 Elsevier Ltd. All rights reserved.

  9. Mechanistic modeling of zircaloy deformation and fracture in fuel element analysis

    International Nuclear Information System (INIS)

    Nichols, F.A.

    1987-01-01

    A review is given of the comprehensive model developed in the 1960s at the Bettis Atomic Power Laboratory to explain the creep of Zircaloy during neutron irradiation and applied to fuel element analysis and design. The in-pile softening observed at low stresses was hypothesized to be due to a combination of the growth-directed Roberts-Cottrell yielding creep originally proposed for α-uranium and the formation of point defect loops preferentially on certain planes in response to the applied stress, with the second process being of relatively greater importance. The in-pile hardening observed at high stresses (or strain-rates) was proposed to be due to the cutting by dislocations of radiation-produced obstacles. In this stress (strain-rate) region, in-pile behavior was proposed to be identical to post-irradiation behavior. At intermediate stresses (strain-rates) a mechanism of radiation-enhanced climb around obstacles was suggested as being rate-controlling. As the stress is decreased, the climb process becomes easier, and the rate was then predicted to be controlled by glide at a flow-stress characteristic of unirradiated, annealed material, where radiation-enhanced diffusion enabled climbing around the normal strain-hardening obstacles. At still lower stresses, this glide process became negligibly slow compared with the growth-connected creep mechanism that was presumed to operate independently. The overall scheme was shown to be in good agreement with all the in-pile data then available and implemented into the computer analysis of fuel element behavior

  10. Mechanistic analysis of solute transport in an in vitro physiological two-phase dissolution apparatus.

    Science.gov (United States)

    Mudie, Deanna M; Shi, Yi; Ping, Haili; Gao, Ping; Amidon, Gordon L; Amidon, Gregory E

    2012-10-01

    In vitro dissolution methodologies that adequately capture the oral bioperformance of solid dosage forms are critical tools needed to aid formulation development. Such methodologies must encompass important physiological parameters and be designed with drug properties in mind. Two-phase dissolution apparatuses, which contain an aqueous phase in which the drug dissolves (representing the dissolution/solubility component) and an organic phase into which the drug partitions (representing the absorption component), have the potential to provide meaningful predictions of in vivo oral bioperformance for some BCS II, and possibly some BCS IV drug products. Before such an apparatus can be evaluated properly, it is important to understand the kinetics of drug substance partitioning from the aqueous to the organic medium. A mass transport analysis was performed of the kinetics of partitioning of drug substance solutions from the aqueous to the organic phase of a two-phase dissolution apparatus. Major assumptions include pseudo-steady-state conditions, a dilute aqueous solution and diffusion-controlled transport. Input parameters can be measured or estimated a priori. This paper presents the theory and derivation of our analysis, compares it with a recent kinetic approach, and demonstrates its effectiveness in predicting in vitro partitioning profiles of three BCS II weak acids in four different in vitro two-phase dissolution apparatuses. Very importantly, the paper discusses how a two-phase apparatus can be scaled to reflect in vivo absorption kinetics and for which drug substances the two-phase dissolution systems may be appropriate tools for measuring oral bioperformance. Copyright © 2012 John Wiley & Sons, Ltd.

  11. Mechanistic multidimensional analysis of two-phase flow in horizontal tube with 90 deg elbow

    International Nuclear Information System (INIS)

    Tselishcheva, E.A.; Antal, St.P.; Podowski, M.Z.; Marshall, S.

    2007-01-01

    The development of modeling and simulation capabilities of two-phase flow and heat transfer is very important for the design, operation and safety of nuclear reactors. Whereas a significant progress in this field has been made over the recent years, further advancements are clearly needed for new concepts of advanced (Generation-IV in particular) reactors. Difficulties in analyzing gas/liquid flows are due to the fact that such two-phase mixtures can assume several different flow patterns, each characterized by flow-regime specific interfacial phenomena of mass, momentum and energy transfer. The level of difficulty increases even further in the case of a complex tube geometries and spatial orientations. The purpose of this paper is to discuss the results of the analysis of a two-phase flow in a horizontal pipe with a 90-degree elbow. The overall objective of the present work is the development of a 3-dimensional computational model of a two-phase high-Reynolds number turbulent flow. The overall new model has been encoded in the next-generation Computational Multiphase Fluid Dynamics (CMFD) computer code, NPHASE. The model has been tested parametrically and the results of NPHASE calculations have been compared against experimental data. It has been demonstrated that the proposed model is consistent both physically and numerically, the predictions are in a reasonable agreement with the measurements

  12. A DATABASE FOR TRACKING TOXICOGENOMIC SAMPLES AND PROCEDURES WITH GENOMIC, PROTEOMIC AND METABONOMIC COMPONENTS

    Science.gov (United States)

    A Database for Tracking Toxicogenomic Samples and Procedures with Genomic, Proteomic and Metabonomic Components Wenjun Bao1, Jennifer Fostel2, Michael D. Waters2, B. Alex Merrick2, Drew Ekman3, Mitchell Kostich4, Judith Schmid1, David Dix1Office of Research and Developmen...

  13. Toxicogenomics concepts and applications to study hepatic effects of food additives and chemicals

    International Nuclear Information System (INIS)

    Stierum, Rob; Heijne, Wilbert; Kienhuis, Anne; Ommen, Ben van; Groten, John

    2005-01-01

    Transcriptomics, proteomics and metabolomics are genomics technologies with great potential in toxicological sciences. Toxicogenomics involves the integration of conventional toxicological examinations with gene, protein or metabolite expression profiles. An overview together with selected examples of the possibilities of genomics in toxicology is given. The expectations raised by toxicogenomics are earlier and more sensitive detection of toxicity. Furthermore, toxicogenomics will provide a better understanding of the mechanism of toxicity and may facilitate the prediction of toxicity of unknown compounds. Mechanism-based markers of toxicity can be discovered and improved interspecies and in vitro-in vivo extrapolations will drive model developments in toxicology. Toxicological assessment of chemical mixtures will benefit from the new molecular biological tools. In our laboratory, toxicogenomics is predominantly applied for elucidation of mechanisms of action and discovery of novel pathway-supported mechanism-based markers of liver toxicity. In addition, we aim to integrate transcriptome, proteome and metabolome data, supported by bioinformatics to develop a systems biology approach for toxicology. Transcriptomics and proteomics studies on bromobenzene-mediated hepatotoxicity in the rat are discussed. Finally, an example is shown in which gene expression profiling together with conventional biochemistry led to the discovery of novel markers for the hepatic effects of the food additives butylated hydroxytoluene, curcumin, propyl gallate and thiabendazole

  14. Recognizing Mechanistic Reasoning in Student Scientific Inquiry: A Framework for Discourse Analysis Developed from Philosophy of Science

    Science.gov (United States)

    Russ, Rosemary S.; Scherr, Rachel E.; Hammer, David; Mikeska, Jamie

    2008-01-01

    Science education reform has long focused on assessing student inquiry, and there has been progress in developing tools specifically with respect to experimentation and argumentation. We suggest the need for attention to another aspect of inquiry, namely "mechanistic reasoning." Scientific inquiry focuses largely on understanding causal…

  15. Characteristics of genomic signatures derived using univariate methods and mechanistically anchored functional descriptors for predicting drug- and xenobiotic-induced nephrotoxicity.

    Science.gov (United States)

    Shi, Weiwei; Bugrim, Andrej; Nikolsky, Yuri; Nikolskya, Tatiana; Brennan, Richard J

    2008-01-01

    ABSTRACT The ideal toxicity biomarker is composed of the properties of prediction (is detected prior to traditional pathological signs of injury), accuracy (high sensitivity and specificity), and mechanistic relationships to the endpoint measured (biological relevance). Gene expression-based toxicity biomarkers ("signatures") have shown good predictive power and accuracy, but are difficult to interpret biologically. We have compared different statistical methods of feature selection with knowledge-based approaches, using GeneGo's database of canonical pathway maps, to generate gene sets for the classification of renal tubule toxicity. The gene set selection algorithms include four univariate analyses: t-statistics, fold-change, B-statistics, and RankProd, and their combination and overlap for the identification of differentially expressed probes. Enrichment analysis following the results of the four univariate analyses, Hotelling T-square test, and, finally out-of-bag selection, a variant of cross-validation, were used to identify canonical pathway maps-sets of genes coordinately involved in key biological processes-with classification power. Differentially expressed genes identified by the different statistical univariate analyses all generated reasonably performing classifiers of tubule toxicity. Maps identified by enrichment analysis or Hotelling T-square had lower classification power, but highlighted perturbed lipid homeostasis as a common discriminator of nephrotoxic treatments. The out-of-bag method yielded the best functionally integrated classifier. The map "ephrins signaling" performed comparably to a classifier derived using sparse linear programming, a machine learning algorithm, and represents a signaling network specifically involved in renal tubule development and integrity. Such functional descriptors of toxicity promise to better integrate predictive toxicogenomics with mechanistic analysis, facilitating the interpretation and risk assessment of

  16. 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.

  17. 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

  18. Degradation of sulfamethoxazole using ozone and chlorine dioxide - Compound-specific stable isotope analysis, transformation product analysis and mechanistic aspects.

    Science.gov (United States)

    Willach, Sarah; Lutze, Holger V; Eckey, Kevin; Löppenberg, Katja; Lüling, Michelle; Terhalle, Jens; Wolbert, Jens-Benjamin; Jochmann, Maik A; Karst, Uwe; Schmidt, Torsten C

    2017-10-01

    The sulfonamide antibiotic sulfamethoxazole (SMX) is a widely detected micropollutant in surface and groundwaters. Oxidative treatment with e.g. ozone or chlorine dioxide is regularly applied for disinfection purposes at the same time exhibiting a high potential for removal of micropollutants. Especially for nitrogen containing compounds such as SMX, the related reaction mechanisms are largely unknown. In this study, we systematically investigated reaction stoichiometry, product formation and reaction mechanisms in reactions of SMX with ozone and chlorine dioxide. To this end, the neutral and anionic SMX species, which may occur at typical pH-values of water treatment were studied. Two moles of chlorine dioxide and approximately three moles of ozone were consumed per mole SMX degraded. Oxidation of SMX with ozone and chlorine dioxide leads in both cases to six major transformation products (TPs) as revealed by high-resolution mass spectrometry (HRMS). Tentatively formulated TP structures from other studies could partly be confirmed by compound-specific stable isotope analysis (CSIA). However, for one TP, a hydroxylated SMX, it was not possible by HRMS alone to identify whether hydroxylation occurred at the aromatic ring, as suggested in literature before, or at the anilinic nitrogen. By means of CSIA and an analytical standard it was possible to identify sulfamethoxazole hydroxylamine unequivocally as one of the TPs of the reaction of SMX with ozone as well as with chlorine dioxide. H-abstraction and electron transfer at the anilinic nitrogen are suggested as likely initial reactions of ozone and chlorine dioxide, respectively, leading to its formation. Oxidation of anionic SMX with ozone did not show any significant isotopic fractionation whereas the other reactions studied resulted in a significant carbon isotope fractionation. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Mechanistic insights into nanotoxicity determined by synchrotron radiation-based Fourier-transform infrared imaging and multivariate analysis.

    Science.gov (United States)

    Riding, Matthew J; Trevisan, Júlio; Hirschmugl, Carol J; Jones, Kevin C; Semple, Kirk T; Martin, Francis L

    2012-12-01

    Our ability to identify the mechanisms by which carbon-based nanomaterials (CBNs) exert toxicity in cells is constrained by the lack of standardized methodologies to assay endpoint effects. Herein we describe a method of mechanistically identifying the effects of various CBN types in both prokaryotic and eukaryotic cells using multi-beam synchrotron radiation-based Fourier-transform infrared imaging (SR-FTIRI) at diffraction-limited resolution. This technique overcomes many of the inherent difficulties of assaying nanotoxicity and demonstrates exceptional sensitivity in identifying the effects of CBNs in cells at environmentally-relevant concentrations. We identify key mechanisms of nanotoxicity as the alteration of Amide and lipid biomolecules, but propose more specific bioactivity of CBNs occurs as a result of specific interactions between CBN structural conformation and cellular characteristics. Copyright © 2012 Elsevier Ltd. All rights reserved.

  20. Mechanism-based risk assessment strategy for drug-induced cholestasis using the transcriptional benchmark dose derived by toxicogenomics.

    Science.gov (United States)

    Kawamoto, Taisuke; Ito, Yuichi; Morita, Osamu; Honda, Hiroshi

    2017-01-01

    Cholestasis is one of the major causes of drug-induced liver injury (DILI), which can result in withdrawal of approved drugs from the market. Early identification of cholestatic drugs is difficult due to the complex mechanisms involved. In order to develop a strategy for mechanism-based risk assessment of cholestatic drugs, we analyzed gene expression data obtained from the livers of rats that had been orally administered with 12 known cholestatic compounds repeatedly for 28 days at three dose levels. Qualitative analyses were performed using two statistical approaches (hierarchical clustering and principle component analysis), in addition to pathway analysis. The transcriptional benchmark dose (tBMD) and tBMD 95% lower limit (tBMDL) were used for quantitative analyses, which revealed three compound sub-groups that produced different types of differential gene expression; these groups of genes were mainly involved in inflammation, cholesterol biosynthesis, and oxidative stress. Furthermore, the tBMDL values for each test compound were in good agreement with the relevant no observed adverse effect level. These results indicate that our novel strategy for drug safety evaluation using mechanism-based classification and tBMDL would facilitate the application of toxicogenomics for risk assessment of cholestatic DILI.

  1. Use of genomic data in risk assessment case study: II. Evaluation of the dibutyl phthalate toxicogenomic data set

    Energy Technology Data Exchange (ETDEWEB)

    Euling, Susan Y., E-mail: euling.susan@epa.gov [National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC (United States); White, Lori D. [National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Kim, Andrea S. [National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC (United States); Sen, Banalata [National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Wilson, Vickie S. [National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Keshava, Channa; Keshava, Nagalakshmi [National Center for Environmental Assessment, U.S. Environmental Protection Agency, Washington, DC (United States); Hester, Susan [National Health and Environmental Effects Research Laboratory, U.S. Environmental Protection Agency, Research Triangle Park, NC (United States); Ovacik, Meric A.; Ierapetritou, Marianthi G.; Androulakis, Ioannis P. [National Center for Environmental Research Science to Achieve Results (STAR) Bioinformatics Center, Environmental Bioinformatics and Computational Toxicology Center (ebCTC), Rutgers University and University of Medicine and Dentistry of New Jersey, Piscataway, NJ (United States); Gaido, Kevin W. [Center for Veterinary Medicine, U.S. Food and Drug Administration, Rockville, MD 20855 (United States)

    2013-09-15

    An evaluation of the toxicogenomic data set for dibutyl phthalate (DBP) and male reproductive developmental effects was performed as part of a larger case study to test an approach for incorporating genomic data in risk assessment. The DBP toxicogenomic data set is composed of nine in vivo studies from the published literature that exposed rats to DBP during gestation and evaluated gene expression changes in testes or Wolffian ducts of male fetuses. The exercise focused on qualitative evaluation, based on a lack of available dose–response data, of the DBP toxicogenomic data set to postulate modes and mechanisms of action for the male reproductive developmental outcomes, which occur in the lower dose range. A weight-of-evidence evaluation was performed on the eight DBP toxicogenomic studies of the rat testis at the gene and pathway levels. The results showed relatively strong evidence of DBP-induced downregulation of genes in the steroidogenesis pathway and lipid/sterol/cholesterol transport pathway as well as effects on immediate early gene/growth/differentiation, transcription, peroxisome proliferator-activated receptor signaling and apoptosis pathways in the testis. Since two established modes of action (MOAs), reduced fetal testicular testosterone production and Insl3 gene expression, explain some but not all of the testis effects observed in rats after in utero DBP exposure, other MOAs are likely to be operative. A reanalysis of one DBP microarray study identified additional pathways within cell signaling, metabolism, hormone, disease, and cell adhesion biological processes. These putative new pathways may be associated with DBP effects on the testes that are currently unexplained. This case study on DBP identified data gaps and research needs for the use of toxicogenomic data in risk assessment. Furthermore, this study demonstrated an approach for evaluating toxicogenomic data in human health risk assessment that could be applied to future chemicals

  2. Immunohistochemical analysis of the mechanistic target of rapamycin and hypoxia signalling pathways in basal cell carcinoma and trichoepithelioma.

    Directory of Open Access Journals (Sweden)

    Tjinta Brinkhuizen

    Full Text Available BACKGROUND: Basal cell carcinoma (BCC is the most common cancer in Caucasians. Trichoepithelioma (TE is a benign neoplasm that strongly resembles BCC. Both are hair follicle (HF tumours. HFs are hypoxic microenvironments, therefore we hypothesized that hypoxia-induced signalling pathways could be involved in BCC and TE as they are in other human malignancies. Hypoxia-inducible factor 1 (HIF1 and mechanistic/mammalian target of rapamycin (mTOR are key players in these pathways. OBJECTIVES: To determine whether HIF1/mTOR signalling is involved in BCC and TE. METHODS: We used immunohistochemical staining of formalin-fixed paraffin-embedded BCC (n = 45 and TE (n = 35 samples to assess activity of HIF1, mTORC1 and their most important target genes. The percentage positive tumour cells was assessed manually in a semi-quantitative manner and categorized (0%, 80%. RESULTS: Among 45 BCC and 35 TE examined, expression levels were respectively 81% and 57% (BNIP3, 73% and 75% (CAIX, 79% and 86% (GLUT1, 50% and 19% (HIF1α, 89% and 88% (pAKT, 55% and 61% (pS6, 15% and 25% (pMTOR, 44% and 63% (PHD2 and 44% and 49% (VEGF-A. CAIX, Glut1 and PHD2 expression levels were significantly higher in TE when only samples with at least 80% expression were included. CONCLUSIONS: HIF and mTORC1 signalling seems active in both BCC and TE. There are no appreciable differences between the two with respect to pathway activity. At this moment immunohistochemical analyses of HIF, mTORC1 and their target genes does not provide a reliable diagnostic tool for the discrimination of BCC and TE.

  3. Parallelogram approach using rat-human In vitro and rat in vivo toxicogenomics predicts acetaminophen-induced hepatotoxicity in humans

    NARCIS (Netherlands)

    Kienhuis, A.S.; Poll, M.C.G. van de; Wortelboer, H.; Herwijnen, M. van; Gottschalk, R.; Jong, C.H.C. de; Boorsma, A.; Paules, R.S.; Kleinjans, J.C.S.; Stierum, R.H.; Delft, J.H.M. van

    2009-01-01

    The frequent use of rodent hepatic in vitro systems in pharmacological and toxicological investigations challenges extrapolation of in vitro results to the situation in vivo and interspecies extrapolation from rodents to humans. The toxicogenomics approach may aid in evaluating relevance of these

  4. An information-rich alternative, chemicals testing strategy using a high definition toxicogenomics and zebrafish (Danio rerio) embryos

    NARCIS (Netherlands)

    Sawle, Ashley D.; Wit, Ernst; Whale, Graham; Cossins, Andrew R.

    2010-01-01

    Large-scale toxicogenomic screening approaches offer great promise for generating a bias-free system-wide view of toxicological effects and modes-of-action of chemicals and ecotoxicants. However, early applications of microarray technology have identified relatively small groups of responding genes

  5. 75 FR 1770 - An Approach to Using Toxicogenomic Data in U.S. EPA Human Health Risk Assessments: A Dibutyl...

    Science.gov (United States)

    2010-01-13

    ... qualitative aspects of the risk assessment because of the type of genomic data available for DBP. It is... Assessment (NCEA) within EPA's Office of Research and Development (ORD). Toxicogenomics is the application of... exploratory methods for analyzing genomic data for application to risk assessment and some preliminary results...

  6. Development of boiling transition analysis code TCAPE-INS/B based on mechanistic methods for BWR fuel bundles. Models and validations with boiling transition experimental data

    International Nuclear Information System (INIS)

    Ishida, Naoyuki; Utsuno, Hideaki; Kasahara, Fumio

    2003-01-01

    The Boiling Transition (BT) analysis code TCAPE-INS/B based on the mechanistic methods coupled with subchannel analysis has been developed for the evaluation of the integrity of Boiling Water Reactor (BWR) fuel rod bundles under abnormal operations. Objective of the development is the evaluation of the BT without using empirical BT and rewetting correlations needed for different bundle designs in the current analysis methods. TCAPE-INS/B consisted mainly of the drift-flux model, the film flow model, the cross-flow model, the thermal conductivity model and the heat transfer correlations. These models were validated systematically with the experimental data. The accuracy of the prediction for the steady-state Critical Heat Flux (CHF) and the transient temperature of the fuel rod surface after the occurrence of BT were evaluated on the validations. The calculations for the experiments with the single tube and bundles were carried out for the validations of the models incorporated in the code. The results showed that the steady-state CHF was predicted within about 6% average error. In the transient calculations, BT timing and temperature of the fuel rod surface gradient agreed well with experimental results, but rewetting was predicted lately. So, modeling of heat transfer phenomena during post-BT is under modification. (author)

  7. The natural food colorant Peonidin from cranberries as a potential radical scavenger - A DFT based mechanistic analysis.

    Science.gov (United States)

    Rajan, Vijisha K; Hasna, C K; Muraleedharan, K

    2018-10-01

    A theoretical evaluation of the antioxidant property of a natural food colorant Peonidin has been performed. The most suitable mechanism for explaining the radical scavenging capacity of Peonidin is the Hydrogen Atom Transfer and the most active site for radical formation is position 3 and is confirmed through Mulliken charge analysis, pKa value evaluation, Bond Dissociation Energy values, and Natural Bond Orbital analysis. Position 3 and 5 in Peonidin exists in blood as deprotonated as their pKa values are lower than the pH of blood. Peonidin is highly reactive than Quercetin and less stable than flavan-3-ols due to the small band gap. Global descriptor analysis shows that PN prefers to accept electrons than to donate. The effect of number of OH groups and the nature of substituents are well explained through this work. Copyright © 2018 Elsevier Ltd. All rights reserved.

  8. Text mining effectively scores and ranks the literature for improving chemical-gene-disease curation at the comparative toxicogenomics database.

    Directory of Open Access Journals (Sweden)

    Allan Peter Davis

    Full Text Available The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/ is a public resource that curates interactions between environmental chemicals and gene products, and their relationships to diseases, as a means of understanding the effects of environmental chemicals on human health. CTD provides a triad of core information in the form of chemical-gene, chemical-disease, and gene-disease interactions that are manually curated from scientific articles. To increase the efficiency, productivity, and data coverage of manual curation, we have leveraged text mining to help rank and prioritize the triaged literature. Here, we describe our text-mining process that computes and assigns each article a document relevancy score (DRS, wherein a high DRS suggests that an article is more likely to be relevant for curation at CTD. We evaluated our process by first text mining a corpus of 14,904 articles triaged for seven heavy metals (cadmium, cobalt, copper, lead, manganese, mercury, and nickel. Based upon initial analysis, a representative subset corpus of 3,583 articles was then selected from the 14,094 articles and sent to five CTD biocurators for review. The resulting curation of these 3,583 articles was analyzed for a variety of parameters, including article relevancy, novel data content, interaction yield rate, mean average precision, and biological and toxicological interpretability. We show that for all measured parameters, the DRS is an effective indicator for scoring and improving the ranking of literature for the curation of chemical-gene-disease information at CTD. Here, we demonstrate how fully incorporating text mining-based DRS scoring into our curation pipeline enhances manual curation by prioritizing more relevant articles, thereby increasing data content, productivity, and efficiency.

  9. Generating Gene Ontology-Disease Inferences to Explore Mechanisms of Human Disease at the Comparative Toxicogenomics Database.

    Directory of Open Access Journals (Sweden)

    Allan Peter Davis

    Full Text Available Strategies for discovering common molecular events among disparate diseases hold promise for improving understanding of disease etiology and expanding treatment options. One technique is to leverage curated datasets found in the public domain. The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/ manually curates chemical-gene, chemical-disease, and gene-disease interactions from the scientific literature. The use of official gene symbols in CTD interactions enables this information to be combined with the Gene Ontology (GO file from NCBI Gene. By integrating these GO-gene annotations with CTD's gene-disease dataset, we produce 753,000 inferences between 15,700 GO terms and 4,200 diseases, providing opportunities to explore presumptive molecular underpinnings of diseases and identify biological similarities. Through a variety of applications, we demonstrate the utility of this novel resource. As a proof-of-concept, we first analyze known repositioned drugs (e.g., raloxifene and sildenafil and see that their target diseases have a greater degree of similarity when comparing GO terms vs. genes. Next, a computational analysis predicts seemingly non-intuitive diseases (e.g., stomach ulcers and atherosclerosis as being similar to bipolar disorder, and these are validated in the literature as reported co-diseases. Additionally, we leverage other CTD content to develop testable hypotheses about thalidomide-gene networks to treat seemingly disparate diseases. Finally, we illustrate how CTD tools can rank a series of drugs as potential candidates for repositioning against B-cell chronic lymphocytic leukemia and predict cisplatin and the small molecule inhibitor JQ1 as lead compounds. The CTD dataset is freely available for users to navigate pathologies within the context of extensive biological processes, molecular functions, and cellular components conferred by GO. This inference set should aid researchers, bioinformaticists, and

  10. Text Mining Effectively Scores and Ranks the Literature for Improving Chemical-Gene-Disease Curation at the Comparative Toxicogenomics Database

    Science.gov (United States)

    Johnson, Robin J.; Lay, Jean M.; Lennon-Hopkins, Kelley; Saraceni-Richards, Cynthia; Sciaky, Daniela; Murphy, Cynthia Grondin; Mattingly, Carolyn J.

    2013-01-01

    The Comparative Toxicogenomics Database (CTD; http://ctdbase.org/) is a public resource that curates interactions between environmental chemicals and gene products, and their relationships to diseases, as a means of understanding the effects of environmental chemicals on human health. CTD provides a triad of core information in the form of chemical-gene, chemical-disease, and gene-disease interactions that are manually curated from scientific articles. To increase the efficiency, productivity, and data coverage of manual curation, we have leveraged text mining to help rank and prioritize the triaged literature. Here, we describe our text-mining process that computes and assigns each article a document relevancy score (DRS), wherein a high DRS suggests that an article is more likely to be relevant for curation at CTD. We evaluated our process by first text mining a corpus of 14,904 articles triaged for seven heavy metals (cadmium, cobalt, copper, lead, manganese, mercury, and nickel). Based upon initial analysis, a representative subset corpus of 3,583 articles was then selected from the 14,094 articles and sent to five CTD biocurators for review. The resulting curation of these 3,583 articles was analyzed for a variety of parameters, including article relevancy, novel data content, interaction yield rate, mean average precision, and biological and toxicological interpretability. We show that for all measured parameters, the DRS is an effective indicator for scoring and improving the ranking of literature for the curation of chemical-gene-disease information at CTD. Here, we demonstrate how fully incorporating text mining-based DRS scoring into our curation pipeline enhances manual curation by prioritizing more relevant articles, thereby increasing data content, productivity, and efficiency. PMID:23613709

  11. Advanced Mechanistic 3D Spatial Modeling and Analysis Methods to Accurately Represent Nuclear Facility External Event Scenarios

    Energy Technology Data Exchange (ETDEWEB)

    Sezen, Halil [The Ohio State Univ., Columbus, OH (United States). Dept. of Civil, Environmental and Geodetic Engineering; Aldemir, Tunc [The Ohio State Univ., Columbus, OH (United States). College of Engineering, Nuclear Engineering Program, Dept. of Mechanical and Aerospace Engineering; Denning, R. [The Ohio State Univ., Columbus, OH (United States); Vaidya, N. [Rizzo Associates, Pittsburgh, PA (United States)

    2017-12-29

    Probabilistic risk assessment of nuclear power plants initially focused on events initiated by internal faults at the plant, rather than external hazards including earthquakes and flooding. Although the importance of external hazards risk analysis is now well recognized, the methods for analyzing low probability external hazards rely heavily on subjective judgment of specialists, often resulting in substantial conservatism. This research developed a framework to integrate the risk of seismic and flooding events using realistic structural models and simulation of response of nuclear structures. The results of four application case studies are presented.

  12. Analysis of the formation of Ta2O5 passive films in acid media through mechanistic modeling

    International Nuclear Information System (INIS)

    Cabrera-Sierra, R.; Vazquez-Arenas, J.; Cardoso, S.; Luna-Sanchez, R.M.; Trejo, M.A.; Marin-Cruz, J.; Hallen, J.M.

    2011-01-01

    Electrochemical impedance spectroscopy (EIS) analyses are carried out to evaluate the passive features of tantalum oxide films (Ta 2 O 5 ) formed at different potentiostatic conditions (0.5, 1.0, 1.5 and 2.0 V vs SSE). A supporting electrolyte of 0.1 M H 2 SO 4 (pH 1) has been used to emulate acidic corrosive conditions for the growth of films with an n-type electronic character. A modification of the point defect model (PDM) accounting for the formation of molecular hydrogen (blistering damage) is used to fit the experimental EIS diagrams, and obtain the kinetic parameters that best describe the semiconductive behavior of the passive films. After this analysis, diffusivities in the order of 5.37 ± 1.6 x 10 -17 and 1.98 ± 1.4 x 10 -20 cm 2 s -1 were obtained for the oxygen (D VO·· ) and hydroxyl vacancies (D VOH· ), respectively. These findings show the capabilities of the EIS and the physicochemical modeling to account for the formation of valve-metal oxide films on a different range of conditions.

  13. Structural and mechanistic analysis of engineered trichodiene synthase enzymes from Trichoderma harzianum: towards higher catalytic activities empowering sustainable agriculture.

    Science.gov (United States)

    Kumari, Indu; Chaudhary, Nitika; Sandhu, Padmani; Ahmed, Mushtaq; Akhter, Yusuf

    2016-06-01

    Trichoderma spp. are well-known bioagents for the plant growth promotion and pathogen suppression. The beneficial activities of the fungus Trichoderma spp. are attributed to their ability to produce and secrete certain secondary metabolites such as trichodermin that belongs to trichothecene family of molecules. The initial steps of trichodermin biosynthetic pathway in Trichoderma are similar to the trichothecenes from Fusarium sporotrichioides. Trichodiene synthase (TS) encoded by tri5 gene in Trichoderma catalyses the conversion of farnesyl pyrophosphate to trichodiene as reported earlier. In this study, we have carried out a comprehensive comparative sequence and structural analysis of the TS, which revealed the conserved residues involved in catalytic activity of the protein. In silico, modelled tertiary structure of TS protein showed stable structural behaviour during simulations. Two single-substitution mutants, i.e. D109E, D248Y and one double-substitution mutant (D109E and D248Y) of TS with potentially higher activities are screened out. The mutant proteins showed more stability than the wild type, an increased number of electrostatic interactions and better binding energies with the ligand, which further elucidates the amino acid residues involved in the reaction mechanism. These results will lead to devise strategies for higher TS activity to ultimately enhance the trichodermin production by Trichoderma spp. for its better exploitation in the sustainable agricultural practices.

  14. On the air cleansing efficiency of an extended green wall: a CFD analysis of mechanistic details of transport processes.

    Science.gov (United States)

    Joshi, Saumitra V; Ghosh, Sat

    2014-11-21

    The detrimental impact of rising air pollution levels in urban landscapes has become conspicuous over the last decade, particularly in developing countries. This novel numerical study quantifies the cleansing efficiency of green façades draped with a copiously growing tropical creeper Vernonia elaeagnifolia. Turbulent transport of SO2 to the leaf boundary layer and subsequent diffusion across stomatal pores into the mesophyllic cells is modeled at the micro level, including its ionic dissociation in the leaf׳s interior. A SEM analysis indicates stomatal dimensions and density. Whilst previous studies have used either spatially averaged equations or resistance models, a spatially discretized computational approach is adopted in this study. The resulting concentration distribution is used to calculate the deposition velocity on stomatal pores, which is then extrapolated over the entire façade to yield bulk pollutant removal rates. A deposition velocity of 1.53mms(-1) and 0.72mms(-1) is obtained for open and closed pores respectively, with removal rates equal to 1.11×10(-6)s(-1) and 1.05×10(-6)s(-1) for dry and humid weather respectively. Sensitivity studies on the removal rate are carried out based on humidity, stomatal aperture and leaf temperature. The removal rate dependence on the Leaf Area Index (LAI) is also investigated. It is inferred from simulations that vegetated façades are efficient at mitigation of residual pollution. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Gene coexpression network analysis of fruit transcriptomes uncovers a possible mechanistically distinct class of sugar/acid ratio-associated genes in sweet orange.

    Science.gov (United States)

    Qiao, Liang; Cao, Minghao; Zheng, Jian; Zhao, Yihong; Zheng, Zhi-Liang

    2017-10-30

    The ratio of sugars to organic acids, two of the major metabolites in fleshy fruits, has been considered the most important contributor to fruit sweetness. Although accumulation of sugars and acids have been extensively studied, whether plants evolve a mechanism to maintain, sense or respond to the fruit sugar/acid ratio remains a mystery. In a prior study, we used an integrated systems biology tool to identify a group of 39 acid-associated genes from the fruit transcriptomes in four sweet orange varieties (Citrus sinensis L. Osbeck) with varying fruit acidity, Succari (acidless), Bingtang (low acid), and Newhall and Xinhui (normal acid). We reanalyzed the prior sweet orange fruit transcriptome data, leading to the identification of 72 genes highly correlated with the fruit sugar/acid ratio. The majority of these sugar/acid ratio-related genes are predicted to be involved in regulatory functions such as transport, signaling and transcription or encode enzymes involved in metabolism. Surprisingly, only three of these sugar/acid ratio-correlated genes are weakly correlated with sugar level and none of them overlaps with the acid-associated genes. Weighted Gene Coexpression Network Analysis (WGCNA) has revealed that these genes belong to four modules, Blue, Grey, Brown and Turquoise, with the former two modules being unique to the sugar/acid ratio control. Our results indicate that orange fruits contain a possible mechanistically distinct class of genes that may potentially be involved in maintaining fruit sugar/acid ratios and/or responding to the cellular sugar/acid ratio status. Therefore, our analysis of orange transcriptomes provides an intriguing insight into the potentially novel genetic or molecular mechanisms controlling the sugar/acid ratio in fruits.

  16. Use of toxicogenomics for identifying genetic markers of pulmonary oedema

    International Nuclear Information System (INIS)

    Balharry, Dominique; Oreffo, Victor; Richards, Roy

    2005-01-01

    This study was undertaken primarily to identify genetic markers of oedema and inflammation. Mild pulmonary injury was induced following the instillation of the oedema-producing agent, bleomycin (0.5 units). Oedema was then confirmed by conventional toxicology (lavage protein levels, free cell counts and lung/body weight ratios) and histology 3 days post-bleomycin instillation.The expression profile of 1176 mRNA species was determined for bleomycin-exposed lung (Clontech Atlas macroarray, n = 9). To obtain pertinent results from these data, it was necessary to develop a simple, effective method for bioinformatic analysis of altered gene expression. Data were log 10 transformed followed by global normalisation. Differential gene expression was accepted if: (a) genes were statistically significant (P ≤ 0.05) from a two-tailed t test; (b) genes were consistently outside a two standard deviation (SD) range from control levels. A combination of these techniques identified 31 mRNA transcripts (approximately 3%) which were significantly altered in bleomycin treated tissue. Of these genes, 26 were down-regulated whilst only five were up-regulated. Two distinct clusters were identified, with 17 genes classified as encoding hormone receptors, and nine as encoding ion channels. Both these clusters were consistently down-regulated.The magnitude of the changes in gene expression were quantified and confirmed by Q-PCR (n = 6), validating the macroarray data and the bioinformatic analysis employed.In conclusion, this study has developed a suitable macroarray analysis procedure and provides the basis for a better understanding of the gene expression changes occurring during the early phase of drug-induced pulmonary oedema

  17. Assessing uncertainty in mechanistic models

    Science.gov (United States)

    Edwin J. Green; David W. MacFarlane; Harry T. Valentine

    2000-01-01

    Concern over potential global change has led to increased interest in the use of mechanistic models for predicting forest growth. The rationale for this interest is that empirical models may be of limited usefulness if environmental conditions change. Intuitively, we expect that mechanistic models, grounded as far as possible in an understanding of the biology of tree...

  18. Yeast Toxicogenomics: genome-wide responses to chemical stresses with impact in Environmental Health, Pharmacology and Biotechnology

    Directory of Open Access Journals (Sweden)

    Sandra Costa dos Santos

    2012-04-01

    Full Text Available The emerging transdisciplinary field of Toxicogenomics aims to study the cell response to a given toxicant at the genome, transcriptome, proteome and metabolome levels. This approach is expected to provide earlier and more sensitive biomarkers of toxicological responses and help in the delineation of regulatory risk assessment. The use of model organisms to gather such genomic information, through the exploitation of Omics and Bioinformatics approaches and tools, together with more focused molecular and cellular biology studies are rapidly increasing our understanding and providing an integrative view on how cells interact with their environment. The use of the model eukaryote Saccharomyces cerevisiae in the field of Toxicogenomics is discussed in this review. Despite the limitations intrinsic to the use of such a simple single cell experimental model, S. cerevisiae appears to be very useful as a first screening tool, limiting the use of animal models. Moreover, it is also one of the most interesting systems to obtain a truly global understanding of the toxicological response and resistance mechanisms, being in the frontline of systems biology research and developments. The impact of the knowledge gathered in the yeast model, through the use of Toxicogenomics approaches, is highlighted here by its use in prediction of toxicological outcomes of exposure to pesticides and pharmaceutical drugs, but also by its impact in biotechnology, namely in the development of more robust crops and in the improvement of yeast strains as cell factories.

  19. Toxicogenomics-based identification of mechanisms for direct immunotoxicity.

    Science.gov (United States)

    Shao, Jia; Katika, Madhumohan R; Schmeits, Peter C J; Hendriksen, Peter J M; van Loveren, Henk; Peijnenburg, Ad A C M; Volger, Oscar L

    2013-10-01

    Compounds with direct immunotoxic properties, including metals, mycotoxins, agricultural pesticides, and industrial chemicals, form potential human health risks due to exposure through food, drinking water, and the environment. Insights into the mechanisms of action are currently lacking for the majority of these direct immunotoxicants. Therefore, the present work aimed to gain insights into the molecular mechanisms underlying direct immunotoxicity. To this end, we assessed in vitro the effects of 31 test compounds on the transcriptome of the human Jurkat T-cell line. These compounds included direct immunotoxicants, immunosuppressive drugs with different mode of actions, and nonimmunotoxic control chemicals. Pathway analysis of the microarray data allowed us to identify canonical pathways and Gene Ontology processes that were transcriptionally regulated in common by immunotoxicants (1) with structural similarities, such as tributyltin chloride and tributyltin oxide that activated the retinoic acid/X receptor signaling pathway and (2) without structural similarities, such as As2O3, dibutyltin chloride, diazinon, MeHg, ochratoxin A (OTA), S9-treated OTA, S9-treated cyclophosphamide, and S9-treated benzo[a]pyrene, which activated unfolded protein response, and FTY720, lindane, and propanil, which activated the cholesterol biosynthesis pathway. In addition, processes uniquely affected by individual immunotoxicants were identified, such as the induction of Notch receptor signaling and the downregulation of acute-phase response genes by OTA. These findings were validated by quantitative real-time PCR analysis of genes involved in these processes. Our study indicated that diverse modes of action are involved in direct immunotoxicity and that a set of pathways or genes, rather than one single gene, can be used to screen compounds for direct immunotoxicity.

  20. Asymmetric author-topic model for knowledge discovering of big data in toxicogenomics.

    Science.gov (United States)

    Chung, Ming-Hua; Wang, Yuping; Tang, Hailin; Zou, Wen; Basinger, John; Xu, Xiaowei; Tong, Weida

    2015-01-01

    The advancement of high-throughput screening technologies facilitates the generation of massive amount of biological data, a big data phenomena in biomedical science. Yet, researchers still heavily rely on keyword search and/or literature review to navigate the databases and analyses are often done in rather small-scale. As a result, the rich information of a database has not been fully utilized, particularly for the information embedded in the interactive nature between data points that are largely ignored and buried. For the past 10 years, probabilistic topic modeling has been recognized as an effective machine learning algorithm to annotate the hidden thematic structure of massive collection of documents. The analogy between text corpus and large-scale genomic data enables the application of text mining tools, like probabilistic topic models, to explore hidden patterns of genomic data and to the extension of altered biological functions. In this paper, we developed a generalized probabilistic topic model to analyze a toxicogenomics dataset that consists of a large number of gene expression data from the rat livers treated with drugs in multiple dose and time-points. We discovered the hidden patterns in gene expression associated with the effect of doses and time-points of treatment. Finally, we illustrated the ability of our model to identify the evidence of potential reduction of animal use.

  1. Functional toxicogenomic profiling expands insight into modulators of formaldehyde toxicity in yeast

    Directory of Open Access Journals (Sweden)

    Matthew North

    2016-11-01

    Full Text Available Formaldehyde (FA is a commercially important chemical with numerous and diverse uses. Accordingly, occupational and environmental exposure to FA is prevalent worldwide. Various adverse effects, including nasopharyngeal, sinonasal, and lymphohematopoietic cancers, have been linked to FA exposure, prompting designation of FA as a human carcinogen by U.S. and international scientific entities. Although the mechanism(s of FA toxicity have been well studied, additional insight is needed in regard to the genetic requirements for FA tolerance. In this study, a functional toxicogenomics approach was utilized in the model eukaryotic yeast Saccharomyces cerevisiae to identify genes and cellular processes modulating the cellular toxicity of FA. Our results demonstrate mutant strains deficient in multiple DNA repair pathways–including homologous recombination, single strand annealing, and postreplication repair–were sensitive to FA, indicating FA may cause various forms of DNA damage in yeast. The SKI complex and its associated factors, which regulate mRNA degradation by the exosome, were also required for FA tolerance, suggesting FA may have unappreciated effects on RNA stability. Furthermore, various strains involved in osmoregulation and stress response were sensitive to FA. Together, our results are generally consistent with FA-mediated damage to both DNA and RNA. Considering DNA repair and RNA degradation pathways are evolutionarily conserved from yeast to humans, mechanisms of FA toxicity identified in yeast may be relevant to human disease and genetic susceptibility.

  2. Prioritizing PubMed articles for the Comparative Toxicogenomic Database utilizing semantic information.

    Science.gov (United States)

    Kim, Sun; Kim, Won; Wei, Chih-Hsuan; Lu, Zhiyong; Wilbur, W John

    2012-01-01

    The Comparative Toxicogenomics Database (CTD) contains manually curated literature that describes chemical-gene interactions, chemical-disease relationships and gene-disease relationships. Finding articles containing this information is the first and an important step to assist manual curation efficiency. However, the complex nature of named entities and their relationships make it challenging to choose relevant articles. In this article, we introduce a machine learning framework for prioritizing CTD-relevant articles based on our prior system for the protein-protein interaction article classification task in BioCreative III. To address new challenges in the CTD task, we explore a new entity identification method for genes, chemicals and diseases. In addition, latent topics are analyzed and used as a feature type to overcome the small size of the training set. Applied to the BioCreative 2012 Triage dataset, our method achieved 0.8030 mean average precision (MAP) in the official runs, resulting in the top MAP system among participants. Integrated with PubTator, a Web interface for annotating biomedical literature, the proposed system also received a positive review from the CTD curation team.

  3. Asymmetric author-topic model for knowledge discovering of big data in toxicogenomics

    Directory of Open Access Journals (Sweden)

    Ming-Hua eChung

    2015-04-01

    Full Text Available The advancement of high-throughput screening technologies facilitates the generation of massive amount of biological data, a big data phenomena in biomedical science. Yet, researchers still heavily rely on keyword search and/or literature review to navigate the databases and analyses are often done in rather small-scale. As a result, the rich information of a database has not been fully utilized, particularly for the information embedded in the interactive nature between data points that are largely ignored and buried. For the past ten years, probabilistic topic modeling has been recognized as an effective machine learning algorithm to annotate the hidden thematic structure of massive collection of documents. The analogy between text corpus and large-scale genomic data enables the application of text mining tools, like probabilistic topic models, to explore hidden patterns of genomic data and to the extension of altered biological functions. In this paper, we developed a generalized probabilistic topic model to analyze a toxicogenomics dataset that consists of a large number of gene expression data from the rat livers treated with drugs in multiple dose and time-points. We discovered the hidden patterns in gene expression associated with the effect of doses and time-points of treatment. Finally, we illustrated the ability of our model to identify the evidence of potential reduction of animal use.

  4. Global scale analysis and evaluation of an improved mechanistic representation of plant nitrogen and carbon dynamics in the Community Land Model (CLM)

    Science.gov (United States)

    Ghimire, B.; Riley, W. J.; Koven, C. D.; Randerson, J. T.; Mu, M.; Kattge, J.; Rogers, A.; Reich, P. B.

    2014-12-01

    In many ecosystems, nitrogen is the most limiting nutrient for plant growth and productivity. However mechanistic representation of nitrogen uptake linked to root traits, and functional nitrogen allocation among different leaf enzymes involved in respiration and photosynthesis is currently lacking in Earth System models. The linkage between nitrogen availability and plant productivity is simplistically represented by potential photosynthesis rates, and is subsequently downregulated depending on nitrogen supply and other nitrogen consumers in the model (e.g., nitrification). This type of potential photosynthesis rate calculation is problematic for several reasons. Firstly, plants do not photosynthesize at potential rates and then downregulate. Secondly, there is considerable subjectivity on the meaning of potential photosynthesis rates. Thirdly, there exists lack of understanding on modeling these potential photosynthesis rates in a changing climate. In addition to model structural issues in representing photosynthesis rates, the role of plant roots in nutrient acquisition have been largely ignored in Earth System models. For example, in CLM4.5, nitrogen uptake is linked to leaf level processes (e.g., primarily productivity) rather than root scale process involved in nitrogen uptake. We present a new plant model for CLM with an improved mechanistic presentation of plant nitrogen uptake based on root scale Michaelis Menten kinetics, and stronger linkages between leaf nitrogen and plant productivity by inferring relationships observed in global databases of plant traits (including the TRY database and several individual studies). We also incorporate improved representation of plant nitrogen leaf allocation, especially in tropical regions where significant over-prediction of plant growth and productivity in CLM4.5 simulations exist. We evaluate our improved global model simulations using the International Land Model Benchmarking (ILAMB) framework. We conclude that

  5. An Approach to Using Toxicogenomic Data in U.S. EPA Human Health Risk Assessments: A Dibutyl Phthalate Case Study (Final Report, 2010)

    Science.gov (United States)

    EPA announced the availability of the final report, An Approach to Using Toxicogenomic Data in U.S. EPA Human Health Risk Assessments: A Dibutyl Phthalate Case Study. This report outlines an approach to evaluate genomic data for use in risk assessment and a case study to ...

  6. Inter-laboratory study of human in vitro toxicogenomics-based tests as alternative methods for evaluating chemical carcinogenicity : a bioinformatics perspective

    NARCIS (Netherlands)

    Herwig, R; Gmuender, H; Corvi, Raffaella; Bloch, K.M.; Brandenburg, A.; Castell, J; Ceelen, L; Chesne, C; Doktorova, T Y; Jennen, D; Jennings, P; Limonciel, A; Lock, E A; McMorrow, T; Phrakonkham, P; Radford-Smith, G.; Slattery, C; Stierum, R; Vilardell, M; Wittenberger, T; Yildirimman, R; Ryan, M.; Rogiers, Vera; Kleinjans, Jos

    The assessment of the carcinogenic potential of chemicals with alternative, human-based in vitro systems has become a major goal of toxicogenomics. The central read-out of these assays is the transcriptome, and while many studies exist that explored the gene expression responses of such systems,

  7. In vitro immunotoxicity of bis(tri-n-butyltin)oxide (TBTO) studied by toxicogenomics

    International Nuclear Information System (INIS)

    Baken, Kirsten A.; Arkusz, Joanna; Pennings, Jeroen L.A.; Vandebriel, Rob J.; Loveren, Henk van

    2007-01-01

    The biocide and environmental pollutant bis(tri-n-butyltin)oxide (TBTO) causes thymus atrophy in rodents. Whether the depletion of thymic lymphocytes by tributyltin compounds may be the result of inhibition of cell proliferation or induction of apoptosis is subject of debate. We examined gene expression profiles in primary rat thymocytes exposed to TBTO in vitro at dose levels of 0, 0.1, 0.3, 0.5, and 1.0 μM. By measuring cell viability and apoptosis, exposure conditions were selected that would provide information on changes in gene expression preceding or accompanying functional effects of TBTO. Several processes related to TBTO-induced toxicity were detected at the transcriptome level. Effects on lipid metabolisms appeared to be the first indication of disruption of cellular function. Many transcriptional effects of TBTO at higher dose levels were related to apoptotic processes, which corresponded to present or subsequent thymocyte apoptosis observed phenotypically. The gene expression profile was, however, not unambiguous since expression of apoptosis-related genes was both increased and decreased. Stimulation of glucocorticoid receptor signaling appeared to be a relevant underlying mechanism of action. These findings suggest that TBTO exerts its toxic effects on the thymus primarily by affecting apoptotic processes, but the possibility is discussed that this may in fact represent an early effect that precedes inhibition of cell proliferation. At the highest dose level tested, TBTO additionally repressed mitochondrial function and immune cell activation. Our in vitro toxicogenomics approach thus identified several cellular and molecular targets of TBTO that may mediate the toxicity towards thymocytes and thereby its immunosuppressive effects

  8. A Drosophila model for toxicogenomics: Genetic variation in susceptibility to heavy metal exposure.

    Directory of Open Access Journals (Sweden)

    Shanshan Zhou

    2017-07-01

    Full Text Available The genetic factors that give rise to variation in susceptibility to environmental toxins remain largely unexplored. Studies on genetic variation in susceptibility to environmental toxins are challenging in human populations, due to the variety of clinical symptoms and difficulty in determining which symptoms causally result from toxic exposure; uncontrolled environments, often with exposure to multiple toxicants; and difficulty in relating phenotypic effect size to toxic dose, especially when symptoms become manifest with a substantial time lag. Drosophila melanogaster is a powerful model that enables genome-wide studies for the identification of allelic variants that contribute to variation in susceptibility to environmental toxins, since the genetic background, environmental rearing conditions and toxic exposure can be precisely controlled. Here, we used extreme QTL mapping in an outbred population derived from the D. melanogaster Genetic Reference Panel to identify alleles associated with resistance to lead and/or cadmium, two ubiquitous environmental toxins that present serious health risks. We identified single nucleotide polymorphisms (SNPs associated with variation in resistance to both heavy metals as well as SNPs associated with resistance specific to each of them. The effects of these SNPs were largely sex-specific. We applied mutational and RNAi analyses to 33 candidate genes and functionally validated 28 of them. We constructed networks of candidate genes as blueprints for orthologous networks of human genes. The latter not only provided functional contexts for known human targets of heavy metal toxicity, but also implicated novel candidate susceptibility genes. These studies validate Drosophila as a translational toxicogenomics gene discovery system.

  9. An approach for integrating toxicogenomic data in risk assessment: The dibutyl phthalate case study

    Energy Technology Data Exchange (ETDEWEB)

    Euling, Susan Y., E-mail: euling.susan@epa.gov [National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC (United States); Thompson, Chad M. [ToxStrategies, Inc., 23501 Cinco Ranch Blvd., Suite G265, Katy, TX 77494 (United States); Chiu, Weihsueh A. [National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC (United States); Benson, Robert [U.S. Environmental Protection Agency, Region 8, Mail code 8P-W, 1595 Wynkoop Street, Denver, CO 80202 (United States)

    2013-09-15

    An approach for evaluating and integrating genomic data in chemical risk assessment was developed based on the lessons learned from performing a case study for the chemical dibutyl phthalate. A case study prototype approach was first developed in accordance with EPA guidance and recommendations of the scientific community. Dibutyl phthalate (DBP) was selected for the case study exercise. The scoping phase of the dibutyl phthalate case study was conducted by considering the available DBP genomic data, taken together with the entire data set, for whether they could inform various risk assessment aspects, such as toxicodynamics, toxicokinetics, and dose–response. A description of weighing the available dibutyl phthalate data set for utility in risk assessment provides an example for considering genomic data for future chemical assessments. As a result of conducting the scoping process, two questions—Do the DBP toxicogenomic data inform 1) the mechanisms or modes of action?, and 2) the interspecies differences in toxicodynamics?—were selected to focus the case study exercise. Principles of the general approach include considering the genomics data in conjunction with all other data to determine their ability to inform the various qualitative and/or quantitative aspects of risk assessment, and evaluating the relationship between the available genomic and toxicity outcome data with respect to study comparability and phenotypic anchoring. Based on experience from the DBP case study, recommendations and a general approach for integrating genomic data in chemical assessment were developed to advance the broader effort to utilize 21st century data in risk assessment. - Highlights: • Performed DBP case study for integrating genomic data in risk assessment • Present approach for considering genomic data in chemical risk assessment • Present recommendations for use of genomic data in chemical risk assessment.

  10. The curation paradigm and application tool used for manual curation of the scientific literature at the Comparative Toxicogenomics Database

    Science.gov (United States)

    Davis, Allan Peter; Wiegers, Thomas C.; Murphy, Cynthia G.; Mattingly, Carolyn J.

    2011-01-01

    The Comparative Toxicogenomics Database (CTD) is a public resource that promotes understanding about the effects of environmental chemicals on human health. CTD biocurators read the scientific literature and convert free-text information into a structured format using official nomenclature, integrating third party controlled vocabularies for chemicals, genes, diseases and organisms, and a novel controlled vocabulary for molecular interactions. Manual curation produces a robust, richly annotated dataset of highly accurate and detailed information. Currently, CTD describes over 349 000 molecular interactions between 6800 chemicals, 20 900 genes (for 330 organisms) and 4300 diseases that have been manually curated from over 25 400 peer-reviewed articles. This manually curated data are further integrated with other third party data (e.g. Gene Ontology, KEGG and Reactome annotations) to generate a wealth of toxicogenomic relationships. Here, we describe our approach to manual curation that uses a powerful and efficient paradigm involving mnemonic codes. This strategy allows biocurators to quickly capture detailed information from articles by generating simple statements using codes to represent the relationships between data types. The paradigm is versatile, expandable, and able to accommodate new data challenges that arise. We have incorporated this strategy into a web-based curation tool to further increase efficiency and productivity, implement quality control in real-time and accommodate biocurators working remotely. Database URL: http://ctd.mdibl.org PMID:21933848

  11. Explaining Ethnic Variability of Transporter Substrate Pharmacokinetics in Healthy Asian and Caucasian Subjects with Allele Frequencies of OATP1B1 and BCRP: A Mechanistic Modeling Analysis.

    Science.gov (United States)

    Li, Rui; Barton, Hugh A

    2018-04-01

    Ethnic variability in the pharmacokinetics of organic anion transporting polypeptide (OATP) 1B1 substrates has been observed, but its basis is unclear. A previous study hypothesizes that, without applying an intrinsic ethnic variability in transporter activity, allele frequencies of transporters cannot explain observed ethnic variability in pharmacokinetics. However, this hypothesis contradicts the data collected from compounds that are OATP1B1 substrates but not breast cancer resistance protein (BCRP) substrates. The objective of this study is to evaluate a hypothesis that is physiologically reasonable and more consistent with clinical observations. We evaluated if allele frequencies of two transporters (OATP1B1 and BCRP) are key contributors to ethnic variability. In this hypothesis, the same genotype leads to the same activity independent of ethnicity, in contrast to the previous hypothesis of intrinsic ethnic variability in OATP1B1 activity. As a validation, we perform mechanistic pharmacokinetic modeling for SLCO1B1 (encoding OATP1B1) and ABCG2 (encoding BCRP) genotyped pharmacokinetic data from 18 clinical studies with healthy Caucasian and/or Asian subjects. Simulations based on the current hypothesis reasonably describe SLCO1B1 and ABCG2 genotyped pharmacokinetic time course data for five transporter substrates (atorvastatin, pitavastatin, pravastatin, repaglinide, and rosuvastatin) in Caucasian and Asian populations. This hypothesis covers the observations that can (e.g., ethnic differences in rosuvastatin pharmacokinetics) or cannot (e.g., lack of differences for pitavastatin pharmacokinetics) be explained by the previous hypothesis. It helps to characterize sources of ethnic variability and provides a foundation for predicting ethnic variability in transporter substrate pharmacokinetics.

  12. High-Density Real-Time PCR-Based in Vivo Toxicogenomic Screen to Predict Organ-Specific Toxicity

    Directory of Open Access Journals (Sweden)

    Laszlo G. Puskas

    2011-09-01

    Full Text Available Toxicogenomics, based on the temporal effects of drugs on gene expression, is able to predict toxic effects earlier than traditional technologies by analyzing changes in genomic biomarkers that could precede subsequent protein translation and initiation of histological organ damage. In the present study our objective was to extend in vivo toxicogenomic screening from analyzing one or a few tissues to multiple organs, including heart, kidney, brain, liver and spleen. Nanocapillary quantitative real-time PCR (QRT-PCR was used in the study, due to its higher throughput, sensitivity and reproducibility, and larger dynamic range compared to DNA microarray technologies. Based on previous data, 56 gene markers were selected coding for proteins with different functions, such as proteins for acute phase response, inflammation, oxidative stress, metabolic processes, heat-shock response, cell cycle/apoptosis regulation and enzymes which are involved in detoxification. Some of the marker genes are specific to certain organs, and some of them are general indicators of toxicity in multiple organs. Utility of the nanocapillary QRT-PCR platform was demonstrated by screening different references, as well as discovery of drug-like compounds for their gene expression profiles in different organs of treated mice in an acute experiment. For each compound, 896 QRT-PCR were done: four organs were used from each of the treated four animals to monitor the relative expression of 56 genes. Based on expression data of the discovery gene set of toxicology biomarkers the cardio- and nephrotoxicity of doxorubicin and sulfasalazin, the hepato- and nephrotoxicity of rotenone, dihydrocoumarin and aniline, and the liver toxicity of 2,4-diaminotoluene could be confirmed. The acute heart and kidney toxicity of the active metabolite SN-38 from its less toxic prodrug, irinotecan could be differentiated, and two novel gene markers for hormone replacement therapy were identified

  13. Gene expression analysis in rat lungs after intratracheal exposure to nanoparticles doped with cadmium

    Energy Technology Data Exchange (ETDEWEB)

    Coccini, Teresa; Manzo, Luigi [Toxicology Division, Salvatore Maugeri Foundation IRCCS, Pavia (Italy); Fabbri, Marco; Sacco, Maria Grazia; Gribaldo, Laura [European Commission, Joint Research Centre, IHCP- 21027 Ispra (Italy); Roda, Elisa [European Centre for Nanomedicine, University of Pavia, 27100 Pavia (Italy)

    2011-07-06

    Silica nanoparticles (NPs) incorporating cadmium (Cd) have been developed for a range of potential application including drug delivery devices. Occupational Cd inhalation has been associated with emphysema, pulmonary fibrosis and lung tumours. Mechanistically, Cd can induce oxidative stress and mediate cell-signalling pathways that are involved in inflammation.This in vivo study aimed at investigating pulmonary molecular effects of NPs doped with Cd (NP-Cd, 1 mg/animal) compared to soluble CdCl{sub 2} (400 {mu}g/animal), in Sprague Dawley rats treated intra-tracheally, 7 and 30 days after administration. NPs of silica containing Cd salt were prepared starting from commercial nano-size silica powder (HiSil{sup TM} T700 Degussa) with average pore size of 20 nm and surface area of 240 m{sup 2}/g. Toxicogenomic analysis was performed by the DNA microarray technology (using Agilent Whole Rat Genome Microarray 4x44K) to evaluate changes in gene expression of the entire genome. These findings indicate that the whole genome analysis may represent a valuable approach to assess the whole spectrum of biological responses to cadmium containing nanomaterials.

  14. Gene expression analysis in rat lungs after intratracheal exposure to nanoparticles doped with cadmium

    International Nuclear Information System (INIS)

    Coccini, Teresa; Manzo, Luigi; Fabbri, Marco; Sacco, Maria Grazia; Gribaldo, Laura; Roda, Elisa

    2011-01-01

    Silica nanoparticles (NPs) incorporating cadmium (Cd) have been developed for a range of potential application including drug delivery devices. Occupational Cd inhalation has been associated with emphysema, pulmonary fibrosis and lung tumours. Mechanistically, Cd can induce oxidative stress and mediate cell-signalling pathways that are involved in inflammation.This in vivo study aimed at investigating pulmonary molecular effects of NPs doped with Cd (NP-Cd, 1 mg/animal) compared to soluble CdCl 2 (400 μg/animal), in Sprague Dawley rats treated intra-tracheally, 7 and 30 days after administration. NPs of silica containing Cd salt were prepared starting from commercial nano-size silica powder (HiSil T M T700 Degussa) with average pore size of 20 nm and surface area of 240 m 2 /g. Toxicogenomic analysis was performed by the DNA microarray technology (using Agilent Whole Rat Genome Microarray 4x44K) to evaluate changes in gene expression of the entire genome. These findings indicate that the whole genome analysis may represent a valuable approach to assess the whole spectrum of biological responses to cadmium containing nanomaterials.

  15. Gene expression analysis in rat lungs after intratracheal exposure to nanoparticles doped with cadmium

    Science.gov (United States)

    Coccini, Teresa; Fabbri, Marco; Roda, Elisa; Grazia Sacco, Maria; Manzo, Luigi; Gribaldo, Laura

    2011-07-01

    Silica nanoparticles (NPs) incorporating cadmium (Cd) have been developed for a range of potential application including drug delivery devices. Occupational Cd inhalation has been associated with emphysema, pulmonary fibrosis and lung tumours. Mechanistically, Cd can induce oxidative stress and mediate cell-signalling pathways that are involved in inflammation.This in vivo study aimed at investigating pulmonary molecular effects of NPs doped with Cd (NP-Cd, 1 mg/animal) compared to soluble CdCl2 (400 μg/animal), in Sprague Dawley rats treated intra-tracheally, 7 and 30 days after administration. NPs of silica containing Cd salt were prepared starting from commercial nano-size silica powder (HiSil™ T700 Degussa) with average pore size of 20 nm and surface area of 240 m2/g. Toxicogenomic analysis was performed by the DNA microarray technology (using Agilent Whole Rat Genome Microarray 4×44K) to evaluate changes in gene expression of the entire genome. These findings indicate that the whole genome analysis may represent a valuable approach to assess the whole spectrum of biological responses to cadmium containing nanomaterials.

  16. Toxicogenomic analysis reveals profibrogenic effects of trichloroethylene in autoimmune-mediated cholangitis in mice.

    Science.gov (United States)

    Kopec, Anna K; Sullivan, Bradley P; Kassel, Karen M; Joshi, Nikita; Luyendyk, James P

    2014-10-01

    Epidemiological studies suggest that exposure to environmental chemicals increases the risk of developing autoimmune liver disease. However, the identity of specific chemical perpetrators and the mechanisms whereby environmental chemicals modify liver disease is unclear. Previous studies link exposure to trichloroethylene (TCE) with the development of autoimmune liver disease and exacerbation of autoimmunity in lupus-prone MRL mice. In this study, we utilized NOD.c3c4 mice, which spontaneously develop autoimmune cholangitis bearing resemblance to some features of primary biliary cirrhosis. Nine-week-old female NOD.c3c4 mice were given TCE (0.5 mg/ml) or its vehicle (1% Cremophor-EL) in drinking water for 4 weeks. TCE had little effect on clinical chemistry, biliary cyst formation, or hepatic CD3+ T-cell accumulation. Hepatic microarray profiling revealed a dramatic suppression of early growth response 1 (EGR1) mRNA in livers of TCE-treated mice, which was verified by qPCR and immunohistochemical staining. Consistent with a reported link between reduced EGR1 expression and liver fibrosis, TCE increased hepatic type I collagen (COL1A1) mRNA and protein levels in livers of NOD.c3c4 mice. In contrast, TCE did not increase COL1A1 expression in NOD.ShiLtJ mice, which do not develop autoimmune cholangitis. These results suggest that in the context of concurrent autoimmune liver disease with a genetic basis, modification of hepatic gene expression by TCE may increase profibrogenic signaling in the liver. Moreover, these studies suggest that NOD.c3c4 mice may be a novel model to study gene-environment interactions critical for the development of autoimmune liver disease. © The Author 2014. Published by Oxford University Press on behalf of the Society of Toxicology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  17. TOXICOGENOMIC ANALYSIS OF TOLUENE EXPOSURE AT 3 AGES IN BROWN NORWAY RATS.

    Science.gov (United States)

    A major concern in assessing toxicity to environmental exposures is differentialsusceptibility in subsets of the population. Aging adults, who comprise the fastestgrowing segment of the population, may possess a greater sensitivity due to changes inmetabol...

  18. Proposed key characteristics of male reproductive toxicants as a method for organizing and screening mechanistic evidence for non-cancer outcomes.

    Science.gov (United States)

    The adoption of systematic review practices for risk assessment includes integration of evidence obtained from experimental, epidemiological, and mechanistic studies. Although mechanistic evidence plays an important role in mode of action analysis, the process of sorting and anal...

  19. Rational and Mechanistic Perspectives on Reinforcement Learning

    Science.gov (United States)

    Chater, Nick

    2009-01-01

    This special issue describes important recent developments in applying reinforcement learning models to capture neural and cognitive function. But reinforcement learning, as a theoretical framework, can apply at two very different levels of description: "mechanistic" and "rational." Reinforcement learning is often viewed in mechanistic terms--as…

  20. Investigation of the biological properties of Cinnulin PF in the context of diabetes: mechanistic insights by genome-wide mRNA-Seq analysis.

    Science.gov (United States)

    Rafehi, Haloom; Ververis, Katherine; Balcerczyk, Aneta; Ziemann, Mark; Ooi, Jenny; Hu, Sean; Kwa, Faith A A; Loveridge, Shanon J; Georgiadis, George T; El-Osta, Assam; Karagiannis, Tom C

    2012-01-01

    The accumulating evidence of the beneficial effects of cinnamon (Cinnamomum burmanni) in type-2 diabetes, a chronic age-associated disease, has prompted the commercialisation of various supplemental forms of the spice. One such supplement, Cinnulin PF(®), represents the water soluble fraction containing relatively high levels of the double-linked procyanidin type-A polymers of flavanoids. The overall aim of this study was to utilize genome-wide mRNA-Seq analysis to characterise the changes in gene expression caused by Cinnulin PF in immortalised human keratinocytes and microvascular endothelial cells, which are relevant with respect to diabetic complications. In summary, our findings provide insights into the mechanisms of action of Cinnulin PF in diabetes and diabetic complications. More generally, we identify relevant candidate genes which could provide the basis for further investigation.

  1. Investigation of the biological properties of Cinnulin PF in the context of diabetes: mechanistic insights by genome-wide mRNA-Seq analysis

    Directory of Open Access Journals (Sweden)

    Katherine Ververis

    2012-02-01

    Full Text Available The accumulating evidence of the beneficial effects of cinnamon (Cinnamomum burmanni in type-2 diabetes, a chronic age-associated disease, has prompted the commercialisation of various supplemental forms of the spice. One such supplement, Cinnulin PF®, represents the water soluble fraction containing relatively high levels of the double-linked procyanidin type-A polymers of flavanoids. The overall aim of this study was to utilize genome-wide mRNA-Seq analysis to characterise the changes in gene expression caused by Cinnulin PF in immortalised human keratinocytes and microvascular endothelial cells, which are relevant with respect to diabetic complications. In summary, our findings provide insights into the mechanisms of action of Cinnulin PF in diabetes and diabetic complications. More generally, we identify relevant candidate genes which could provide the basis for further investigation. To access the supplementary material to this article: ‘Supplementary tables 1–3’ please see Supplementary files under Reading Tools online.

  2. Identifying specific profiles in patients with different degrees of painful knee osteoarthritis based on serological biochemical and mechanistic pain biomarkers: a diagnostic approach based on cluster analysis.

    Science.gov (United States)

    Egsgaard, Line Lindhardt; Eskehave, Thomas Navndrup; Bay-Jensen, Anne C; Hoeck, Hans Christian; Arendt-Nielsen, Lars

    2015-01-01

    Biochemical and pain biomarkers can be applied to patients with painful osteoarthritis profiles and may provide more details compared with conventional clinical tools. The aim of this study was to identify an optimal combination of biochemical and pain biomarkers for classification of patients with different degrees of knee pain and joint damage. Such profiling may provide new diagnostic and therapeutic options. A total of 216 patients with different degrees of knee pain (maximal pain during the last 24 hours rated on a visual analog scale [VAS]) (VAS 0-100) and 64 controls (VAS 0-9) were recruited. Patients were separated into 3 groups: VAS 10 to 39 (N = 81), VAS 40 to 69 (N = 70), and VAS 70 to 100 (N = 65). Pressure pain thresholds, temporal summation to pressure stimuli, and conditioning pain modulation were measured from the peripatellar and extrasegmental sites. Biochemical markers indicative for autoinflammation and immunity (VICM, CRP, and CRPM), synovial inflammation (CIIIM), cartilage loss (CIIM), and bone degradation (CIM) were analyzed. WOMAC, Lequesne, and pain catastrophizing scores were collected. Principal component analysis was applied to select the optimal variable subset, and cluster analysis was applied to this subset to create distinctly different knee pain profiles. Four distinct knee pain profiles were identified: profile A (N = 27), profile B (N = 59), profile C (N = 85), and profile D (N = 41). Each knee pain profile had a unique combination of biochemical markers, pain biomarkers, physical impairments, and psychological factors that may provide the basis for mechanism-based diagnosis, individualized treatment, and selection of patients for clinical trials evaluating analgesic compounds. These results introduce a new profiling for knee OA and should be regarded as preliminary.

  3. Use of genomic data in risk assessment case study: I. Evaluation of the dibutyl phthalate male reproductive development toxicity data set

    Energy Technology Data Exchange (ETDEWEB)

    Makris, Susan L., E-mail: makris.susan@epa.gov [U.S. Environmental Protection Agency, National Center for Environmental Assessment, Office of Research and Development, (Mail code 8623P), 1200 Pennsylvania Ave., NW, Washington, DC 20460 (United States); Euling, Susan Y. [U.S. Environmental Protection Agency, National Center for Environmental Assessment, Office of Research and Development, (Mail code 8623P), 1200 Pennsylvania Ave., NW, Washington, DC 20460 (United States); Gray, L. Earl [U.S. Environmental Protection Agency, National Health and Environmental Effects Research Laboratory, Office of Research and Development, (MD-72), Highway 54, Research Triangle Park, NC 27711 (United States); Benson, Robert [U.S. Environmental Protection Agency, Region 8, (Mail code 8P-W), 1595 Wynkoop Street, Denver, CO 80202 (United States); Foster, Paul M.D. [National Toxicology Program, National Institute of Environmental Health Sciences, P.O. Box 12233 (MD K2-12), Research Triangle Park, NC 27709 (United States)

    2013-09-15

    A case study was conducted, using dibutyl phthalate (DBP), to explore an approach to using toxicogenomic data in risk assessment. The toxicity and toxicogenomic data sets relative to DBP-related male reproductive developmental outcomes were considered conjointly to derive information about mode and mechanism of action. In this manuscript, we describe the case study evaluation of the toxicological database for DBP, focusing on identifying the full spectrum of male reproductive developmental effects. The data were assessed to 1) evaluate low dose and low incidence findings and 2) identify male reproductive toxicity endpoints without well-established modes of action (MOAs). These efforts led to the characterization of data gaps and research needs for the toxicity and toxicogenomic studies in a risk assessment context. Further, the identification of endpoints with unexplained MOAs in the toxicity data set was useful in the subsequent evaluation of the mechanistic information that the toxicogenomic data set evaluation could provide. The extensive analysis of the toxicology data set within the MOA context provided a resource of information for DBP in attempts to hypothesize MOAs (for endpoints without a well-established MOA) and to phenotypically anchor toxicogenomic and other mechanistic data both to toxicity endpoints and to available toxicogenomic data. This case study serves as an example of the steps that can be taken to develop a toxicological data source for a risk assessment, both in general and especially for risk assessments that include toxicogenomic data.

  4. Analysis of the formation of Ta{sub 2}O{sub 5} passive films in acid media through mechanistic modeling

    Energy Technology Data Exchange (ETDEWEB)

    Cabrera-Sierra, R., E-mail: roma_ipn@yahoo.com [Instituto Politecnico Nacional, Escuela Superior de Ingenieria Quimica e Industrias Extractivas, Departamento de Ingenieria Quimica Industrial, UPALM Ed. 7, 1er. Piso CP 07738, D.F. (Mexico); Vazquez-Arenas, J. [Chemical Engineering Department, University of Waterloo, 200 University Avenue West, Waterloo, Ontario N2L 3G (Canada); Cardoso, S. [Instituto Politecnico Nacional, Escuela Superior de Ingenieria Quimica e Industrias Extractivas, Departamento de Ingenieria Quimica Industrial, UPALM Ed. 7, 1er. Piso CP 07738, D.F. (Mexico); Luna-Sanchez, R.M. [Universidad Autonoma Metropolitana-Azcapotzalco, Departamento de Energia, Av. San Pablo No. 180, Col. Reynosa Tamaulipas, CP 02200, D.F. (Mexico); Trejo, M.A. [Instituto Politecnico Nacional, Escuela Superior de Ingenieria Quimica e Industrias Extractivas, Departamento de Ingenieria Quimica Industrial, UPALM Ed. 7, 1er. Piso CP 07738, D.F. (Mexico); Marin-Cruz, J. [Instituto Mexicano del Petroleo, Coordinacion de Ingenieria Molecular, Competencia de Quimica Aplicada. Eje Central Lazaro Cardenas Norte 152, CP 07730, D.F. (Mexico); Hallen, J.M. [Instituto Politecnico Nacional, Escuela Superior de Ingenieria Quimica e Industrias Extractivas, Departamento de Ingenieria Quimica Industrial, UPALM Ed. 7, 1er. Piso CP 07738, D.F. (Mexico)

    2011-09-30

    Electrochemical impedance spectroscopy (EIS) analyses are carried out to evaluate the passive features of tantalum oxide films (Ta{sub 2}O{sub 5}) formed at different potentiostatic conditions (0.5, 1.0, 1.5 and 2.0 V vs SSE). A supporting electrolyte of 0.1 M H{sub 2}SO{sub 4} (pH 1) has been used to emulate acidic corrosive conditions for the growth of films with an n-type electronic character. A modification of the point defect model (PDM) accounting for the formation of molecular hydrogen (blistering damage) is used to fit the experimental EIS diagrams, and obtain the kinetic parameters that best describe the semiconductive behavior of the passive films. After this analysis, diffusivities in the order of 5.37 {+-} 1.6 x 10{sup -17} and 1.98 {+-} 1.4 x 10{sup -20} cm{sup 2} s{sup -1} were obtained for the oxygen (D{sub VO}{center_dot}{center_dot}) and hydroxyl vacancies (D{sub VOH}{center_dot}), respectively. These findings show the capabilities of the EIS and the physicochemical modeling to account for the formation of valve-metal oxide films on a different range of conditions.

  5. Proceedings of the international workshop on mechanistic understanding of radionuclide migration in compacted/intact systems

    International Nuclear Information System (INIS)

    Tachi, Yukio; Yui, Mikazu

    2010-03-01

    The international workshop on mechanistic understanding of radionuclide migration in compacted / intact systems was held at ENTRY, JAEA, Tokai on 21st - 23rd January, 2009. This workshop was hosted by Japan Atomic Energy Agency (JAEA) as part of the project on the mechanistic model/database development for radionuclide sorption and diffusion behavior in compacted / intact systems. The overall goal of the project is to develop the mechanistic model / database for a consistent understanding and prediction of migration parameters and its uncertainties for performance assessment of geological disposal of radioactive waste. The objective of the workshop is to integrate the state-of-the-art of mechanistic sorption and diffusion model in compacted / intact systems, especially in bentonite / clay systems, and discuss the JAEA's mechanistic approaches and future challenges, especially the following discussions points; 1) What's the status and difficulties for mechanistic model/database development? 2) What's the status and difficulties for applicability of mechanistic model to the compacted/intact system? 3) What's the status and difficulties for obtaining evidences for mechanistic model? 4) What's the status and difficulties for standardization of experimental methodology for batch sorption and diffusion? 5) What's the uncertainties of transport parameters in radionuclides migration analysis due to a lack of understanding/experimental methodologies, and how do we derive them? This report includes workshop program, overview and materials of each presentation, summary of discussions. (author)

  6. Transcriptome analysis of the human T lymphocyte cell line Jurkat and human peripheral blood mononuclear cells exposed to deoxynivalenol (DON): New mechanistic insights

    Energy Technology Data Exchange (ETDEWEB)

    Katika, Madhumohan R. [RIKILT-Institute of Food Safety, Wageningen University and Research Centre, Wageningen (Netherlands); Department of Health Risk Analysis and Toxicology, Maastricht University (Netherlands); Netherlands Toxicogenomics Centre (Netherlands); Hendriksen, Peter J.M. [RIKILT-Institute of Food Safety, Wageningen University and Research Centre, Wageningen (Netherlands); Netherlands Toxicogenomics Centre (Netherlands); Shao, Jia [RIKILT-Institute of Food Safety, Wageningen University and Research Centre, Wageningen (Netherlands); Department of Health Risk Analysis and Toxicology, Maastricht University (Netherlands); Netherlands Toxicogenomics Centre (Netherlands); Loveren, Henk van [Department of Health Risk Analysis and Toxicology, Maastricht University (Netherlands); National Institute for Public Health and the Environment (RIVM), Bilthoven (Netherlands); Netherlands Toxicogenomics Centre (Netherlands); Peijnenburg, Ad, E-mail: ad.peijnenburg@wur.nl [RIKILT-Institute of Food Safety, Wageningen University and Research Centre, Wageningen (Netherlands); Netherlands Toxicogenomics Centre (Netherlands)

    2012-10-01

    Deoxynivalenol (DON) or vomitoxin is a commonly encountered type-B trichothecene mycotoxin, produced by Fusarium species predominantly found in cereals and grains. DON is known to exert toxic effects on the gastrointestinal, reproductive and neuroendocrine systems, and particularly on the immune system. Depending on dose and exposure time, it can either stimulate or suppress immune function. The main objective of this study was to obtain a deeper insight into DON-induced effects on lymphoid cells. For this, we exposed the human T-lymphocyte cell line Jurkat and human peripheral blood mononuclear cells (PBMCs) to various concentrations of DON for various times and examined gene expression changes by DNA microarray analysis. Jurkat cells were exposed to 0.25 and 0.5 μM DON for 3, 6 and 24 h. Biological interpretation of the microarray data indicated that DON affects various processes in these cells: It upregulates genes involved in ribosome structure and function, RNA/protein synthesis and processing, endoplasmic reticulum (ER) stress, calcium-mediated signaling, mitochondrial function, oxidative stress, the NFAT and NF-κB/TNF-α pathways, T cell activation and apoptosis. The effects of DON on the expression of genes involved in ER stress, NFAT activation and apoptosis were confirmed by qRT-PCR. Other biochemical experiments confirmed that DON activates calcium-dependent proteins such as calcineurin and M-calpain that are known to be involved in T cell activation and apoptosis. Induction of T cell activation was also confirmed by demonstrating that DON activates NFATC1 and induces its translocation from the cytoplasm to the nucleus. For the gene expression profiling of PBMCs, cells were exposed to 2 and 4 μM DON for 6 and 24 h. Comparison of the Jurkat microarray data with those obtained with PBMCs showed that most of the processes affected by DON in the Jurkat cell line were also affected in the PBMCs. -- Highlights: ► The human T cell line Jurkat and human

  7. Activation of phosphoinositide 3-kinase/Akt/mechanistic target of rapamycin pathway and response to everolimus in endocrine receptor-positive metastatic breast cancer – A retrospective pilot analysis and viewpoint

    Directory of Open Access Journals (Sweden)

    Jyoti Bajpai

    2017-01-01

    Full Text Available Introduction: Biomarkers predictive of response to mechanistic target of rapamycin (mTOR inhibitor, everolimus, in endocrine receptor (ER-positive metastatic breast cancer (MBC are a work in progress. We evaluated the feasibility of directly measuring mTOR activity and phosphatase and tensin homolog (PTEN expression and correlating their expression with response and survival. Materials and Methods: MBC patients who received everolimus with endocrine therapy (ET after progression on an aromatase inhibitor and had adequate tissue preservation for estimation of mTOR activity and PTEN expression were selected for analysis from a prospectively maintained database. Progression-free survival (PFS and overall survival (OS were estimated by Kaplan–Meier method, and correlation between mTOR activity and PTEN expression with survival was done by log-rank test. Results: Thirteen ER-positive MBC patients were available for analysis. PTEN expression was lost in 11/13 (84.6% patients and retained in 2/13 patients (15.4%. mTOR activity was absent in four patients (30.7%, weak in six patients (46.1%, and moderate in 3 patients (23.2%. Median PFS for the entire population was 2.5 months while median OS was not reached. Patients with an absent mTOR activity showed a longer PFS (5 vs. 1.5 vs. 2 months than those with weak and moderate activity, respectively (P = 0.043. There was no correlation between loss of PTEN expression and PFS. Conclusions: Measurement of direct mTOR activity in patients with MBC receiving everolimus/ET combination appears feasible. Absent mTOR activity may predict for longer PFS with everolimus-ET combination and requires further study.

  8. Fascinating Organic Transformations: Rational Mechanistic Analysis

    Indian Academy of Sciences (India)

    plan to set up (without government assistance). "Vidyanantha Education. Centre", to promote education, art and culture. R. R ... was initiated in the early decades of this century, .... a computer program to identify appropriate precursors for a.

  9. Mechanistic Basis of Cocrystal Dissolution Advantage.

    Science.gov (United States)

    Cao, Fengjuan; Amidon, Gordon L; Rodríguez-Hornedo, Naír; Amidon, Gregory E

    2018-01-01

    Current interest in cocrystal development resides in the advantages that the cocrystal may have in solubility and dissolution compared with the parent drug. This work provides a mechanistic analysis and comparison of the dissolution behavior of carbamazepine (CBZ) and its 2 cocrystals, carbamazepine-saccharin (CBZ-SAC) and carbamazepine-salicylic acid (CBZ-SLC) under the influence of pH and micellar solubilization. A simple mathematical equation is derived based on the mass transport analyses to describe the dissolution advantage of cocrystals. The dissolution advantage is the ratio of the cocrystal flux to drug flux and is defined as the solubility advantage (cocrystal to drug solubility ratio) times the diffusivity advantage (cocrystal to drug diffusivity ratio). In this work, the effective diffusivity of CBZ in the presence of surfactant was determined to be different and less than those of the cocrystals. The higher effective diffusivity of drug from the dissolved cocrystals, the diffusivity advantage, can impart a dissolution advantage to cocrystals with lower solubility than the parent drug while still maintaining thermodynamic stability. Dissolution conditions where cocrystals can display both thermodynamic stability and a dissolution advantage can be obtained from the mass transport models, and this information is useful for both cocrystal selection and formulation development. Copyright © 2018 American Pharmacists Association®. Published by Elsevier Inc. All rights reserved.

  10. Toxicogenomic outcomes predictive of forestomach carcinogenesis following exposure to benzo(a)pyrene: Relevance to human cancer risk

    Energy Technology Data Exchange (ETDEWEB)

    Labib, Sarah, E-mail: Sarah.Labib@hc-sc.gc.ca; Guo, Charles H., E-mail: Charles.Guo@hc-sc.gc.ca; Williams, Andrew, E-mail: Andrew.Williams@hc-sc.gc.ca; Yauk, Carole L., E-mail: Carole.Yauk@hc-sc.gc.ca; White, Paul A., E-mail: Paul.White@hc-sc.gc.ca; Halappanavar, Sabina, E-mail: Sabina.Halappanavar@hc-sc.gc.ca

    2013-12-01

    Forestomach tumors are observed in mice exposed to environmental carcinogens. However, the relevance of this data to humans is controversial because humans lack a forestomach. We hypothesize that an understanding of early molecular changes after exposure to a carcinogen in the forestomach will provide mode-of-action information to evaluate the applicability of forestomach cancers to human cancer risk assessment. In the present study we exposed mice to benzo(a)pyrene (BaP), an environmental carcinogen commonly associated with tumors of the rodent forestomach. Toxicogenomic tools were used to profile gene expression response in the forestomach. Adult Muta™Mouse males were orally exposed to 25, 50, and 75 mg BaP/kg-body-weight/day for 28 consecutive days. The forestomach was collected three days post-exposure. DNA microarrays, real-time RT-qPCR arrays, and protein analyses were employed to characterize responses in the forestomach. Microarray results showed altered expression of 414 genes across all treatment groups (± 1.5 fold; false discovery rate adjusted P ≤ 0.05). Significant downregulation of genes associated with phase II xenobiotic metabolism and increased expression of genes implicated in antigen processing and presentation, immune response, chemotaxis, and keratinocyte differentiation were observed in treated groups in a dose-dependent manner. A systematic comparison of the differentially expressed genes in the forestomach from the present study to differentially expressed genes identified in human diseases including human gastrointestinal tract cancers using the NextBio Human Disease Atlas showed significant commonalities between the two models. Our results provide molecular evidence supporting the use of the mouse forestomach model to evaluate chemically-induced gastrointestinal carcinogenesis in humans. - Highlights: • Benzo(a)pyrene-mediated transcriptomic response in the forestomach was examined. • The immunoproteosome subunits and MHC class I

  11. Toxicogenomic responses in rainbow trout (Oncorhynchus mykiss) hepatocytes exposed to model chemicals and a synthetic mixture

    International Nuclear Information System (INIS)

    Finne, E.F.; Cooper, G.A.; Koop, B.F.; Hylland, K.; Tollefsen, K.E.

    2007-01-01

    As more salmon gene expression data has become available, the cDNA microarray platform has emerged as an appealing alternative in ecotoxicological screening of single chemicals and environmental samples relevant to the aquatic environment. This study was performed to validate biomarker gene responses of in vitro cultured rainbow trout (Oncorhynchus mykiss) hepatocytes exposed to model chemicals, and to investigate effects of mixture toxicity in a synthetic mixture. Chemicals used for 24 h single chemical- and mixture exposures were 10 nM 17α-ethinylestradiol (EE2), 0.75 nM 2,3,7,8-tetrachloro-di-benzodioxin (TCDD), 100 μM paraquat (PQ) and 0.75 μM 4-nitroquinoline-1-oxide (NQO). RNA was isolated from exposed cells, DNAse treated and quality controlled before cDNA synthesis, fluorescent labelling and hybridisation to a 16k salmonid microarray. The salmonid 16k cDNA array identified differential gene expression predictive of exposure, which could be verified by quantitative real time PCR. More precisely, the responses of biomarker genes such as cytochrome p4501A and UDP-glucuronosyl transferase to TCDD exposure, glutathione reductase and gammaglutamyl cysteine synthetase to paraquat exposure, as well as vitellogenin and vitelline envelope protein to EE2 exposure validated the use of microarray applied to RNA extracted from in vitro exposed hepatocytes. The mutagenic compound NQO did not result in any change in gene expression. Results from exposure to a synthetic mixture of the same four chemicals, using identical concentrations as for single chemical exposures, revealed combined effects that were not predicted by results for individual chemicals alone. In general, the response of exposure to this mixture led to an average loss of approximately 60% of the transcriptomic signature found for single chemical exposure. The present findings show that microarray analyses may contribute to our mechanistic understanding of single contaminant mode of action as well as

  12. Toxicogenomic responses in rainbow trout (Oncorhynchus mykiss) hepatocytes exposed to model chemicals and a synthetic mixture

    Energy Technology Data Exchange (ETDEWEB)

    Finne, E.F. [Norwegian Institute for Water Research, Gaustadalleen 21, N-0349 Oslo (Norway) and University of Oslo, Department of Biology, P.O. Box 1066, Blindern, N-0316 Oslo (Norway)]. E-mail: eivind.finne@niva.no; Cooper, G.A. [Centre for Biomedical Research, University of Victoria, BC V8P5C2 (Canada); Koop, B.F. [Centre for Biomedical Research, University of Victoria, BC V8P5C2 (Canada); Hylland, K. [Norwegian Institute for Water Research, Gaustadalleen 21, N-0349 Oslo (Norway); University of Oslo, Department of Biology, P.O. Box 1066, Blindern, N-0316 Oslo (Norway); Tollefsen, K.E. [Norwegian Institute for Water Research, Gaustadalleen 21, N-0349 Oslo (Norway)

    2007-03-10

    As more salmon gene expression data has become available, the cDNA microarray platform has emerged as an appealing alternative in ecotoxicological screening of single chemicals and environmental samples relevant to the aquatic environment. This study was performed to validate biomarker gene responses of in vitro cultured rainbow trout (Oncorhynchus mykiss) hepatocytes exposed to model chemicals, and to investigate effects of mixture toxicity in a synthetic mixture. Chemicals used for 24 h single chemical- and mixture exposures were 10 nM 17{alpha}-ethinylestradiol (EE2), 0.75 nM 2,3,7,8-tetrachloro-di-benzodioxin (TCDD), 100 {mu}M paraquat (PQ) and 0.75 {mu}M 4-nitroquinoline-1-oxide (NQO). RNA was isolated from exposed cells, DNAse treated and quality controlled before cDNA synthesis, fluorescent labelling and hybridisation to a 16k salmonid microarray. The salmonid 16k cDNA array identified differential gene expression predictive of exposure, which could be verified by quantitative real time PCR. More precisely, the responses of biomarker genes such as cytochrome p4501A and UDP-glucuronosyl transferase to TCDD exposure, glutathione reductase and gammaglutamyl cysteine synthetase to paraquat exposure, as well as vitellogenin and vitelline envelope protein to EE2 exposure validated the use of microarray applied to RNA extracted from in vitro exposed hepatocytes. The mutagenic compound NQO did not result in any change in gene expression. Results from exposure to a synthetic mixture of the same four chemicals, using identical concentrations as for single chemical exposures, revealed combined effects that were not predicted by results for individual chemicals alone. In general, the response of exposure to this mixture led to an average loss of approximately 60% of the transcriptomic signature found for single chemical exposure. The present findings show that microarray analyses may contribute to our mechanistic understanding of single contaminant mode of action as

  13. Mechanistic aspects of carotenoid biosynthesis

    KAUST Repository

    Moïse, Alexander R.

    2014-01-08

    Carotenoid synthesis is based on the analysis of the phenotype of several mutant strains of tomato lacking carotenoid synthetic genes. Carotenoids are tetraterpenes derived through the condensation of the five-carbon (C5) universal isoprenoid precursors isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). A recently developed concept that could explain the role of the poly-cis pathway in carotenoid synthesis is that the intermediates of this pathway have additional physiological roles that extend beyond serving as precursors of lycopene. This concept is based on the analysis of the phenotype of several mutant strains of tomato lacking carotenoid synthetic genes. The feedback regulation of early carotenoid synthetic genes in response to a block in upstream metabolism represents a paradigm shift in our understanding of the mechanism and regulation of carotenoid synthesis and of metabolic regulation in general. The molecular details of a signaling pathway that regulates carotenogenesis in response to the levels of carotenoid precursors are still unclear.

  14. Testing mechanistic models of growth in insects.

    Science.gov (United States)

    Maino, James L; Kearney, Michael R

    2015-11-22

    Insects are typified by their small size, large numbers, impressive reproductive output and rapid growth. However, insect growth is not simply rapid; rather, insects follow a qualitatively distinct trajectory to many other animals. Here we present a mechanistic growth model for insects and show that increasing specific assimilation during the growth phase can explain the near-exponential growth trajectory of insects. The presented model is tested against growth data on 50 insects, and compared against other mechanistic growth models. Unlike the other mechanistic models, our growth model predicts energy reserves per biomass to increase with age, which implies a higher production efficiency and energy density of biomass in later instars. These predictions are tested against data compiled from the literature whereby it is confirmed that insects increase their production efficiency (by 24 percentage points) and energy density (by 4 J mg(-1)) between hatching and the attainment of full size. The model suggests that insects achieve greater production efficiencies and enhanced growth rates by increasing specific assimilation and increasing energy reserves per biomass, which are less costly to maintain than structural biomass. Our findings illustrate how the explanatory and predictive power of mechanistic growth models comes from their grounding in underlying biological processes. © 2015 The Author(s).

  15. Mechanistic model for microbial growth on hydrocarbons

    Energy Technology Data Exchange (ETDEWEB)

    Mallee, F M; Blanch, H W

    1977-12-01

    Based on available information describing the transport and consumption of insoluble alkanes, a mechanistic model is proposed for microbial growth on hydrocarbons. The model describes the atypical growth kinetics observed, and has implications in the design of large scale equipment for single cell protein (SCP) manufacture from hydrocarbons. The model presents a framework for comparison of the previously published experimental kinetic data.

  16. Mechanistic Indicators of Childhood Asthma (MICA) Study

    Science.gov (United States)

    The Mechanistic Indicators of Childhood Asthma (MICA) Study has been designed to incorporate state-of-the-art technologies to examine the physiological and environmental factors that interact to increase the risk of asthmatic responses. MICA is primarily a clinically-bases obser...

  17. Mechanistic aspects of ionic reactions in flames

    DEFF Research Database (Denmark)

    Egsgaard, H.; Carlsen, L.

    1993-01-01

    Some fundamentals of the ion chemistry of flames are summarized. Mechanistic aspects of ionic reactions in flames have been studied using a VG PlasmaQuad, the ICP-system being substituted by a simple quartz burner. Simple hydrocarbon flames as well as sulfur-containing flames have been investigated...

  18. Development of Improved Mechanistic Deterioration Models for Flexible Pavements

    DEFF Research Database (Denmark)

    Ullidtz, Per; Ertman, Hans Larsen

    1998-01-01

    The paper describes a pilot study in Denmark with the main objective of developing improved mechanistic deterioration models for flexible pavements based on an accelerated full scale test on an instrumented pavement in the Danish Road Tessting Machine. The study was the first in "International...... Pavement Subgrade Performance Study" sponsored by the Federal Highway Administration (FHWA), USA. The paper describes in detail the data analysis and the resulting models for rutting, roughness, and a model for the plastic strain in the subgrade.The reader will get an understanding of the work needed...

  19. Mechanistic modelling of the drying behaviour of single pharmaceutical granules

    DEFF Research Database (Denmark)

    Thérèse F.C. Mortier, Séverine; Beer, Thomas De; Gernaey, Krist

    2012-01-01

    The trend to move towards continuous production processes in pharmaceutical applications enhances the necessity to develop mechanistic models to understand and control these processes. This work focuses on the drying behaviour of a single wet granule before tabletting, using a six...... phase (submodel 2), the water inside the granule evaporates. The second submodel contains an empirical power coefficient, b. A sensitivity analysis was performed to study the influence of parameters on the moisture content of single pharmaceutical granules, which clearly points towards the importance...

  20. Toward mechanistic classification of enzyme functions.

    Science.gov (United States)

    Almonacid, Daniel E; Babbitt, Patricia C

    2011-06-01

    Classification of enzyme function should be quantitative, computationally accessible, and informed by sequences and structures to enable use of genomic information for functional inference and other applications. Large-scale studies have established that divergently evolved enzymes share conserved elements of structure and common mechanistic steps and that convergently evolved enzymes often converge to similar mechanisms too, suggesting that reaction mechanisms could be used to develop finer-grained functional descriptions than provided by the Enzyme Commission (EC) system currently in use. Here we describe how evolution informs these structure-function mappings and review the databases that store mechanisms of enzyme reactions along with recent developments to measure ligand and mechanistic similarities. Together, these provide a foundation for new classifications of enzyme function. Copyright © 2011 Elsevier Ltd. All rights reserved.

  1. Mechanistic and Economical Characteristics of Asphalt Rubber Mixtures

    Directory of Open Access Journals (Sweden)

    Mena I. Souliman

    2016-01-01

    Full Text Available Load associated fatigue cracking is one of the major distress types occurring in flexible pavement systems. Flexural bending beam fatigue laboratory test has been used for several decades and is considered to be an integral part of the new superpave advanced characterization procedure. One of the most significant solutions to prolong the fatigue life for an asphaltic mixture is to utilize flexible materials as rubber. A laboratory testing program was performed on a conventional and Asphalt Rubber- (AR- gap-graded mixtures to investigate the impact of added rubber on the mechanical, mechanistic, and economical attributes of asphaltic mixtures. Strain controlled fatigue tests were conducted according to American Association of State Highway and Transportation Officials (AASHTO procedures. The results from the beam fatigue tests indicated that the AR-gap-graded mixtures would have much longer fatigue life compared with the reference (conventional mixtures. In addition, a mechanistic analysis using 3D-Move software coupled with a cost analysis study based on the fatigue performance on the two mixtures was performed. Overall, analysis showed that AR modified asphalt mixtures exhibited significantly lower cost of pavement per 1000 cycles of fatigue life per mile compared to conventional HMA mixture.

  2. Supporting Mechanistic Reasoning in Domain-Specific Contexts

    Science.gov (United States)

    Weinberg, Paul J.

    2017-01-01

    Mechanistic reasoning is an epistemic practice central within science, technology, engineering, and mathematics disciplines. Although there has been some work on mechanistic reasoning in the research literature and standards documents, much of this work targets domain-general characterizations of mechanistic reasoning; this study provides…

  3. Identification of genomic biomarkers for concurrent diagnosis of drug-induced renal tubular injury using a large-scale toxicogenomics database

    International Nuclear Information System (INIS)

    Kondo, Chiaki; Minowa, Yohsuke; Uehara, Takeki; Okuno, Yasushi; Nakatsu, Noriyuki; Ono, Atsushi; Maruyama, Toshiyuki; Kato, Ikuo; Yamate, Jyoji; Yamada, Hiroshi; Ohno, Yasuo; Urushidani, Tetsuro

    2009-01-01

    Drug-induced renal tubular injury is one of the major concerns in preclinical safety evaluations. Toxicogenomics is becoming a generally accepted approach for identifying chemicals with potential safety problems. In the present study, we analyzed 33 nephrotoxicants and 8 non-nephrotoxic hepatotoxicants to elucidate time- and dose-dependent global gene expression changes associated with proximal tubular toxicity. The compounds were administered orally or intravenously once daily to male Sprague-Dawley rats. The animals were exposed to four different doses of the compounds, and kidney tissues were collected on days 4, 8, 15, and 29. Gene expression profiles were generated from kidney RNA by using Affymetrix GeneChips and analyzed in conjunction with the histopathological changes. We used the filter-type gene selection algorithm based on t-statistics conjugated with the SVM classifier, and achieved a sensitivity of 90% with a selectivity of 90%. Then, 92 genes were extracted as the genomic biomarker candidates that were used to construct the classifier. The gene list contains well-known biomarkers, such as Kidney injury molecule 1, Ceruloplasmin, Clusterin, Tissue inhibitor of metallopeptidase 1, and also novel biomarker candidates. Most of the genes involved in tissue remodeling, the immune/inflammatory response, cell adhesion/proliferation/migration, and metabolism were predominantly up-regulated. Down-regulated genes participated in cell adhesion/proliferation/migration, membrane transport, and signal transduction. Our classifier has better prediction accuracy than any of the well-known biomarkers. Therefore, the toxicogenomics approach would be useful for concurrent diagnosis of renal tubular injury.

  4. Reconciled Rat and Human Metabolic Networks for Comparative Toxicogenomics and Biomarker Predictions

    Science.gov (United States)

    2017-02-08

    reconstructions for comparative systems analysis. PLoS Comput. Biol. 7, e1001116 (2011). 26. Bartell, J. A., Yen, P., Varga, J. J., Goldberg , J. B. & Papin, J. A...Rat Genome Database 2015: genomic, phenotypic and environmental variations and disease. Nucleic Acids Res. 43, D743–D750 (2015). 34. NCBI Resource

  5. Evaluation of a toxicogenomic approach to the local lymph node assay (LLNA).

    Science.gov (United States)

    Boverhof, Darrell R; Gollapudi, B Bhaskar; Hotchkiss, Jon A; Osterloh-Quiroz, Mandy; Woolhiser, Michael R

    2009-02-01

    Genomic technologies have the potential to enhance and complement existing toxicology endpoints; however, assessment of these approaches requires a systematic evaluation including a robust experimental design with genomic endpoints anchored to traditional toxicology endpoints. The present study was conducted to assess the sensitivity of genomic responses when compared with the traditional local lymph node assay (LLNA) endpoint of lymph node cell proliferation and to evaluate the responses for their ability to provide insights into mode of action. Female BALB/c mice were treated with the sensitizer trimellitic anhydride (TMA), following the standard LLNA dosing regimen, at doses of 0.1, 1, or 10% and traditional tritiated thymidine ((3)HTdR) incorporation and gene expression responses were monitored in the auricular lymph nodes. Additional mice dosed with either vehicle or 10% TMA and sacrificed on day 4 or 10, were also included to examine temporal effects on gene expression. Analysis of (3)HTdR incorporation revealed TMA-induced stimulation indices of 2.8, 22.9, and 61.0 relative to vehicle with an EC(3) of 0.11%. Examination of the dose-response gene expression responses identified 9, 833, and 2122 differentially expressed genes relative to vehicle for the 0.1, 1, and 10% TMA dose groups, respectively. Calculation of EC(3) values for differentially expressed genes did not identify a response that was more sensitive than the (3)HTdR value, although a number of genes displayed comparable sensitivity. Examination of temporal responses revealed 1760, 1870, and 953 differentially expressed genes at the 4-, 6-, and 10-day time points respectively. Functional analysis revealed many responses displayed dose- and time-specific induction patterns within the functional categories of cellular proliferation and immune response, including numerous immunoglobin genes which were highly induced at the day 10 time point. Overall, these experiments have systematically illustrated

  6. The position of place in governing global problems: A mechanistic account of place-as-context, and analysis of transitions towards spatially explicit approaches to climate science and policy

    International Nuclear Information System (INIS)

    MacGillivray, Brian H.

    2015-01-01

    Highlights: • Place is a central yet undertheorised concept within sustainability science. • Introduces an account of place as the context in which social and environmental mechanisms operate. • Uses this account to critique historical aspatial approaches to climate science and policy. • Traces out shifts towards spatially explicit approaches to climate governance. • A focus on place, heterogeneity, and context maximizes the credibility and policy-relevance of climate science. - Abstract: Place is a central concept within the sustainability sciences, yet it remains somewhat undertheorised, and its relationship to generalisation and scale is unclear. Here, we develop a mechanistic account of place as the fundamental context in which social and environmental mechanisms operate. It is premised on the view that the social and environmental sciences are typically concerned with causal processes and their interaction with context, rather than with a search for laws. We deploy our mechanistic account to critique the neglect of place that characterised the early stages of climate governance, ranging from the highly idealised general circulation and integrated assessment models used to analyze climate change, to the global institutions and technologies designed to manage it. We implicate this neglect of place in the limited progress in tackling climate change in both public and policy spheres, before tracing out recent shifts towards more spatially explicit approaches to climate change science and policy-making. These shifts reflect a move towards an ontology which acknowledges that even where causal drivers are in a sense global in nature (e.g. atmospheric levels of greenhouse gases), their impacts are often mediated through variables that are spatially clustered at multiple scales, moderated by contextual features of the local environment, and interact with the presence of other (localised) stressors in synergistic rather than additive ways. We conclude that a

  7. Toxicogenomic study in rat thymus of F1 generation offspring following maternal exposure to silver ion

    Directory of Open Access Journals (Sweden)

    Xiugong Gao

    2015-01-01

    Full Text Available Male and female rats (26-day-old were exposed to 0.0, 0.4, 4 or 40 mg/kg body weight silver acetate (AgAc in drinking water for 10 weeks prior to and during mating. Sperm-positive females remained within their dose groups and were exposed to silver acetate during gestation and lactation. At postnatal day 26, the effect of silver ions on the developing F1 generation rat thymus was evaluated at the transcriptional level using whole-genome microarrays. Gene expression profiling analyses identified a dozen differentially expressed genes (DEGs in each dose group using a loose criterion of fold change (FC >1.5 and unadjusted p < 0.05, regardless of whether the analysis was conducted within each gender group or with both gender groups combined. No dose-dependent effect was observed on the number of DEGs. In addition, none of these genes had a false discovery rate (FDR <0.05 after correction for multiple testing. These results in combination with the observation that thymus-to-body-weight ratios were not affected and no histopathological abnormalities were identified indicate that in utero exposure to silver ions up to 26.0 mg/kg (equivalent to 40.0 mg/kg silver acetate did not have an adverse effect on the developing thymus.

  8. Toxicogenomic profiling in maternal and fetal rodent brains following gestational exposure to chlorpyrifos

    International Nuclear Information System (INIS)

    Moreira, Estefania G.; Yu Xiaozhong; Robinson, Joshua F.; Griffith, Willian; Hong, Sung Woo; Beyer, Richard P.; Bammler, Theo K.; Faustman, Elaine M.

    2010-01-01

    Considering the wide variety of effects that have been reported to occur in the developmental neurotoxicity of chlorpyrifos (CP) and the lack of consensus on their dependence of brain acetylcholinesterase (AChE) activity inhibition, we applied microarray technology to explore dose-dependent alterations in transcriptional response in the fetal and maternal C57BL/6 mouse brain after daily gestational exposure (days 6 to 17) to CP (2, 4, 10, 12 or 15 mg/kg, sc). We identified significantly altered genes across doses and assessed for overrepresentation of Gene Ontology (GO) biological processes and KEGG pathways. We further clustered genes based on their expression profiles across doses and repeated the GO/pathways analysis for each cluster. The dose-effect relationship of CP on gene expression, both at the gene and pathway levels was non-monotonic and not necessarily related to brain AChE inhibition. The largest impact was observed in the 10 mg/kg dose group which was also the LOAEL for brain AChE inhibition. In the maternal brain, lower doses (4 mg/kg) influenced GO categories and pathways such as cell adhesion, behavior, lipid metabolism, long-term potentiation, nervous system development, neurogenesis, synaptic transmission. In the fetal brain, lower doses (2 and/or 4 mg/kg) significantly altered cell division, translation, transmission of nerve impulse, chromatin modification, long-term potentiation. In addition, some genes involved in nervous system development and signaling were shown to be specifically influenced by these lower CP doses. Our approach was sensitive and reflected the diversity of responses known to be disrupted by CP and highlighted possible additional consequences of CP neurotoxicity, such as disturbance of the ubiquitin proteasome system.

  9. Mechanistic studies of carbon monoxide reduction

    Energy Technology Data Exchange (ETDEWEB)

    Geoffroy, G.L.

    1990-06-12

    The progress made during the current grant period (1 January 1988--1 April 1990) in three different areas of research is summarized. The research areas are: (1) oxidatively-induced double carbonylation reactions to form {alpha}-ketoacyl complexes and studies of the reactivity of the resulting compounds, (2) mechanistic studies of the carbonylation of nitroaromatics to form isocyanates, carbamates, and ureas, and (3) studies of the formation and reactivity of unusual metallacycles and alkylidene ligands supported on binuclear iron carbonyl fragments. 18 refs., 5 figs., 1 tab.

  10. Melanie Klein's metapsychology: phenomenological and mechanistic perspective.

    Science.gov (United States)

    Mackay, N

    1981-01-01

    Freud's metapsychology is the subject of an important debate. This is over whether psychoanalysis is best construed as a science of the natural science type or as a special human science. The same debate applies to Melanie Klein's work. In Klein's metapsychology are two different and incompatible models of explanation. One is taken over from Freud's structural theory and appears to be similarly mechanistic. The other is clinically based and phenomenological. These two are discussed with special reference to the concepts of "phantasy" and "internal object".

  11. Fuel swelling importance in PCI mechanistic modelling

    International Nuclear Information System (INIS)

    Arimescu, V.I.

    2005-01-01

    Under certain conditions, fuel pellet swelling is the most important factor in determining the intensity of the pellet-to-cladding mechanical interaction (PCMI). This is especially true during power ramps, which lead to a temperature increase to a higher terminal plateau that is maintained for hours. The time-dependent gaseous swelling is proportional to temperature and is also enhanced by the increased gas atom migration to the grain boundary during the power ramp. On the other hand, gaseous swelling is inhibited by a compressive hydrostatic stress in the pellet. Therefore, PCMI is the net result of combining gaseous swelling and pellet thermal expansion with the opposing feedback from the cladding mechanical reaction. The coupling of the thermal and mechanical processes, mentioned above, with various feedback loops is best simulated by a mechanistic fuel code. This paper discusses a mechanistic swelling model that is coupled with a fission gas release model as well as a mechanical model of the fuel pellet. The role of fuel swelling is demonstrated for typical power ramps at different burn-ups. Also, fuel swelling plays a significant role in avoiding the thermal instability for larger gap fuel rods, by limiting the potentially exponentially increasing gap due to the positive feedback loop effect of increasing fission gas release and the associated over-pressure inside the cladding. (author)

  12. Appropriateness of mechanistic and non-mechanistic models for the application of ultrafiltration to mixed waste

    International Nuclear Information System (INIS)

    Foust, Henry; Ghosehajra, Malay

    2007-01-01

    This study asks two questions: (1) How appropriate is the use of a basic filtration equation to the application of ultrafiltration of mixed waste, and (2) How appropriate are non-parametric models for permeate rates (volumes)? To answer these questions, mechanistic and non-mechanistic approaches are developed for permeate rates and volumes associated with an ultrafiltration/mixed waste system in dia-filtration mode. The mechanistic approach is based on a filtration equation which states that t/V vs. V is a linear relationship. The coefficients associated with this linear regression are composed of physical/chemical parameters of the system and based the mass balance equation associated with the membrane and associated developing cake layer. For several sets of data, a high correlation is shown that supports the assertion that t/V vs. V is a linear relationship. It is also shown that non-mechanistic approaches, i.e., the use of regression models to are not appropriate. One models considered is Q(p) = a*ln(Cb)+b. Regression models are inappropriate because the scale-up from a bench scale (pilot scale) study to full-scale for permeate rates (volumes) is not simply the ratio of the two membrane surface areas. (authors)

  13. Causation at Different Levels: Tracking the Commitments of Mechanistic Explanations

    DEFF Research Database (Denmark)

    Fazekas, Peter; Kertész, Gergely

    2011-01-01

    connections transparent. These general commitments get confronted with two claims made by certain proponents of the mechanistic approach: William Bechtel often argues that within the mechanistic framework it is possible to balance between reducing higher levels and maintaining their autonomy at the same time...... their autonomy at the same time than standard reductive accounts are, and that what mechanistic explanations are able to do at best is showing that downward causation does not exist....

  14. Mechanistic modelling of genetic and epigenetic events in radiation carcinogenesis

    International Nuclear Information System (INIS)

    Andreev, S. G.; Eidelman, Y. A.; Salnikov, I. V.; Khvostunov, I. K.

    2006-01-01

    Methodological problems arise on the way of radiation carcinogenesis modelling with the incorporation of radiobiological and cancer biology mechanistic data. The results of biophysical modelling of different endpoints [DNA DSB induction, repair, chromosome aberrations (CA) and cell proliferation] are presented and applied to the analysis of RBE-LET relationships for radiation-induced neoplastic transformation (RINT) of C3H/10T1/2 cells in culture. Predicted values for some endpoints correlate well with the data. It is concluded that slowly repaired DSB clusters, as well as some kind of CA, may be initiating events for RINT. As an alternative interpretation, it is possible that DNA damage can induce RINT indirectly via epigenetic process. A hypothetical epigenetic pathway for RINT is discussed. (authors)

  15. Mechanistic curiosity will not kill the Bayesian cat

    NARCIS (Netherlands)

    Borsboom, D.; Wagenmakers, E.-J.; Romeijn, J.-W.

    2011-01-01

    Jones & Love (J&L) suggest that Bayesian approaches to the explanation of human behavior should be constrained by mechanistic theories. We argue that their proposal misconstrues the relation between process models, such as the Bayesian model, and mechanisms. While mechanistic theories can answer

  16. Mechanistic curiosity will not kill the Bayesian cat

    NARCIS (Netherlands)

    Borsboom, Denny; Wagenmakers, Eric-Jan; Romeijn, Jan-Willem

    Jones & Love (J&L) suggest that Bayesian approaches to the explanation of human behavior should be constrained by mechanistic theories. We argue that their proposal misconstrues the relation between process models, such as the Bayesian model, and mechanisms. While mechanistic theories can answer

  17. "Ratio via Machina": Three Standards of Mechanistic Explanation in Sociology

    Science.gov (United States)

    Aviles, Natalie B.; Reed, Isaac Ariail

    2017-01-01

    Recently, sociologists have expended much effort in attempts to define social mechanisms. We intervene in these debates by proposing that sociologists in fact have a choice to make between three standards of what constitutes a good mechanistic explanation: substantial, formal, and metaphorical mechanistic explanation. All three standards are…

  18. Mechanistic site-based emulation of a global ocean biogeochemical model (MEDUSA 1.0 for parametric analysis and calibration: an application of the Marine Model Optimization Testbed (MarMOT 1.1

    Directory of Open Access Journals (Sweden)

    J. C. P. Hemmings

    2015-03-01

    Full Text Available Biogeochemical ocean circulation models used to investigate the role of plankton ecosystems in global change rely on adjustable parameters to capture the dominant biogeochemical dynamics of a complex biological system. In principle, optimal parameter values can be estimated by fitting models to observational data, including satellite ocean colour products such as chlorophyll that achieve good spatial and temporal coverage of the surface ocean. However, comprehensive parametric analyses require large ensemble experiments that are computationally infeasible with global 3-D simulations. Site-based simulations provide an efficient alternative but can only be used to make reliable inferences about global model performance if robust quantitative descriptions of their relationships with the corresponding 3-D simulations can be established. The feasibility of establishing such a relationship is investigated for an intermediate complexity biogeochemistry model (MEDUSA coupled with a widely used global ocean model (NEMO. A site-based mechanistic emulator is constructed for surface chlorophyll output from this target model as a function of model parameters. The emulator comprises an array of 1-D simulators and a statistical quantification of the uncertainty in their predictions. The unknown parameter-dependent biogeochemical environment, in terms of initial tracer concentrations and lateral flux information required by the simulators, is a significant source of uncertainty. It is approximated by a mean environment derived from a small ensemble of 3-D simulations representing variability of the target model behaviour over the parameter space of interest. The performance of two alternative uncertainty quantification schemes is examined: a direct method based on comparisons between simulator output and a sample of known target model "truths" and an indirect method that is only partially reliant on knowledge of the target model output. In general, chlorophyll

  19. Mechanistic Indicators of Childhood Asthma (MICA): piloting ...

    Science.gov (United States)

    Background: Modem methods in molecular biology and advanced computational tools show promise in elucidating complex interactions that occur between genes and environmental factors in diseases such as asthma; however appropriately designed studies are critical for these methods to reach their full potential. Objective: We used a case-control study to investigate whether genomic data (blood gene expression), viewed together with a spectrum of exposure effects and susceptibility markers (blood, urine and nail), can provide a mechanistic explanation for the increased susceptibility of asthmatics to ambient air pollutants. Methods: We studied 205 non-asthmatic and asthmatic children, (9-12 years of age) who participated in a clinical study in Detroit, Michigan. The study combines a traditional epidemiological design with an integrative approach to investigate the environmental exposure of children to indoor-outdoor air. The study includes measurements of internal dose (metals, allergen specific IgE, PAH and VOC metabolites) and clinical measures of health outcome (immunological, cardiovascular and respiratory). Results: Expected immunological indications of asthma have been obtained. In addition, initial results from our analyses point to the complex nature of childhood health and risk factors linked to metabolic syndrome (obesity, blood pressure and dyslipidemia). For example, 31% and 34% of the asthmatic MICA subjects were either overweight (BMI > 25) o

  20. Mechanistic movement models to understand epidemic spread.

    Science.gov (United States)

    Fofana, Abdou Moutalab; Hurford, Amy

    2017-05-05

    An overlooked aspect of disease ecology is considering how and why animals come into contact with one and other resulting in disease transmission. Mathematical models of disease spread frequently assume mass-action transmission, justified by stating that susceptible and infectious hosts mix readily, and foregoing any detailed description of host movement. Numerous recent studies have recorded, analysed and modelled animal movement. These movement models describe how animals move with respect to resources, conspecifics and previous movement directions and have been used to understand the conditions for the occurrence and the spread of infectious diseases when hosts perform a type of movement. Here, we summarize the effect of the different types of movement on the threshold conditions for disease spread. We identify gaps in the literature and suggest several promising directions for future research. The mechanistic inclusion of movement in epidemic models may be beneficial for the following two reasons. Firstly, the estimation of the transmission coefficient in an epidemic model is possible because animal movement data can be used to estimate the rate of contacts between conspecifics. Secondly, unsuccessful transmission events, where a susceptible host contacts an infectious host but does not become infected can be quantified. Following an outbreak, this enables disease ecologists to identify 'near misses' and to explore possible alternative epidemic outcomes given shifts in ecological or immunological parameters.This article is part of the themed issue 'Opening the black box: re-examining the ecology and evolution of parasite transmission'. © 2017 The Author(s).

  1. Regulatory Technology Development Plan - Sodium Fast Reactor: Mechanistic Source Term - Trial Calculation

    International Nuclear Information System (INIS)

    Grabaskas, David

    2016-01-01

    The potential release of radioactive material during a plant incident, referred to as the source term, is a vital design metric and will be a major focus of advanced reactor licensing. The U.S. Nuclear Regulatory Commission has stated an expectation for advanced reactor vendors to present a mechanistic assessment of the potential source term in their license applications. The mechanistic source term presents an opportunity for vendors to realistically assess the radiological consequences of an incident, and may allow reduced emergency planning zones and smaller plant sites. However, the development of a mechanistic source term for advanced reactors is not without challenges, as there are often numerous phenomena impacting the transportation and retention of radionuclides. This project sought to evaluate U.S. capabilities regarding the mechanistic assessment of radionuclide release from core damage incidents at metal fueled, pool-type sodium fast reactors (SFRs). The purpose of the analysis was to identify, and prioritize, any gaps regarding computational tools or data necessary for the modeling of radionuclide transport and retention phenomena. To accomplish this task, a parallel-path analysis approach was utilized. One path, led by Argonne and Sandia National Laboratories, sought to perform a mechanistic source term assessment using available codes, data, and models, with the goal to identify gaps in the current knowledge base. The second path, performed by an independent contractor, performed sensitivity analyses to determine the importance of particular radionuclides and transport phenomena in regards to offsite consequences. The results of the two pathways were combined to prioritize gaps in current capabilities.

  2. Regulatory Technology Development Plan - Sodium Fast Reactor: Mechanistic Source Term – Trial Calculation

    Energy Technology Data Exchange (ETDEWEB)

    Grabaskas, David [Argonne National Lab. (ANL), Argonne, IL (United States). Nuclear Engineering Division; Bucknor, Matthew [Argonne National Lab. (ANL), Argonne, IL (United States). Nuclear Engineering Division; Jerden, James [Argonne National Lab. (ANL), Argonne, IL (United States). Nuclear Engineering Division; Brunett, Acacia J. [Argonne National Lab. (ANL), Argonne, IL (United States). Nuclear Engineering Division; Denman, Matthew [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Nuclear Engineering Division; Clark, Andrew [Sandia National Lab. (SNL-NM), Albuquerque, NM (United States). Nuclear Engineering Division; Denning, Richard S. [Consultant, Columbus, OH (United States)

    2016-10-01

    The potential release of radioactive material during a plant incident, referred to as the source term, is a vital design metric and will be a major focus of advanced reactor licensing. The U.S. Nuclear Regulatory Commission has stated an expectation for advanced reactor vendors to present a mechanistic assessment of the potential source term in their license applications. The mechanistic source term presents an opportunity for vendors to realistically assess the radiological consequences of an incident, and may allow reduced emergency planning zones and smaller plant sites. However, the development of a mechanistic source term for advanced reactors is not without challenges, as there are often numerous phenomena impacting the transportation and retention of radionuclides. This project sought to evaluate U.S. capabilities regarding the mechanistic assessment of radionuclide release from core damage incidents at metal fueled, pool-type sodium fast reactors (SFRs). The purpose of the analysis was to identify, and prioritize, any gaps regarding computational tools or data necessary for the modeling of radionuclide transport and retention phenomena. To accomplish this task, a parallel-path analysis approach was utilized. One path, led by Argonne and Sandia National Laboratories, sought to perform a mechanistic source term assessment using available codes, data, and models, with the goal to identify gaps in the current knowledge base. The second path, performed by an independent contractor, performed sensitivity analyses to determine the importance of particular radionuclides and transport phenomena in regards to offsite consequences. The results of the two pathways were combined to prioritize gaps in current capabilities.

  3. Identifying mechanistic similarities in drug responses

    KAUST Repository

    Zhao, C.

    2012-05-15

    Motivation: In early drug development, it would be beneficial to be able to identify those dynamic patterns of gene response that indicate that drugs targeting a particular gene will be likely or not to elicit the desired response. One approach would be to quantitate the degree of similarity between the responses that cells show when exposed to drugs, so that consistencies in the regulation of cellular response processes that produce success or failure can be more readily identified.Results: We track drug response using fluorescent proteins as transcription activity reporters. Our basic assumption is that drugs inducing very similar alteration in transcriptional regulation will produce similar temporal trajectories on many of the reporter proteins and hence be identified as having similarities in their mechanisms of action (MOA). The main body of this work is devoted to characterizing similarity in temporal trajectories/signals. To do so, we must first identify the key points that determine mechanistic similarity between two drug responses. Directly comparing points on the two signals is unrealistic, as it cannot handle delays and speed variations on the time axis. Hence, to capture the similarities between reporter responses, we develop an alignment algorithm that is robust to noise, time delays and is able to find all the contiguous parts of signals centered about a core alignment (reflecting a core mechanism in drug response). Applying the proposed algorithm to a range of real drug experiments shows that the result agrees well with the prior drug MOA knowledge. © The Author 2012. Published by Oxford University Press. All rights reserved.

  4. Mechanistic modeling for mammography screening risks

    International Nuclear Information System (INIS)

    Bijwaard, Harmen

    2008-01-01

    Full text: Western populations show a very high incidence of breast cancer and in many countries mammography screening programs have been set up for the early detection of these cancers. Through these programs large numbers of women (in the Netherlands, 700.000 per year) are exposed to low but not insignificant X-ray doses. ICRP based risk estimates indicate that the number of breast cancer casualties due to mammography screening can be as high as 50 in the Netherlands per year. The number of lives saved is estimated to be much higher, but for an accurate calculation of the benefits of screening a better estimate of these risks is indispensable. Here it is attempted to better quantify the radiological risks of mammography screening through the application of a biologically based model for breast tumor induction by X-rays. The model is applied to data obtained from the National Institutes of Health in the U.S. These concern epidemiological data of female TB patients who received high X-ray breast doses in the period 1930-1950 through frequent fluoroscopy of their lungs. The mechanistic model that is used to describe the increased breast cancer incidence is based on an earlier study by Moolgavkar et al. (1980), in which the natural background incidence of breast cancer was modeled. The model allows for a more sophisticated extrapolation of risks to the low dose X-ray exposures that are common in mammography screening and to the higher ages that are usually involved. Furthermore, it allows for risk transfer to other (non-western) populations. The results have implications for decisions on the frequency of screening, the number of mammograms taken at each screening, minimum and maximum ages for screening and the transfer to digital equipment. (author)

  5. The Combined Use of Correlative and Mechanistic Species Distribution Models Benefits Low Conservation Status Species.

    Directory of Open Access Journals (Sweden)

    Thibaud Rougier

    Full Text Available Species can respond to climate change by tracking appropriate environmental conditions in space, resulting in a range shift. Species Distribution Models (SDMs can help forecast such range shift responses. For few species, both correlative and mechanistic SDMs were built, but allis shad (Alosa alosa, an endangered anadromous fish species, is one of them. The main purpose of this study was to provide a framework for joint analyses of correlative and mechanistic SDMs projections in order to strengthen conservation measures for species of conservation concern. Guidelines for joint representation and subsequent interpretation of models outputs were defined and applied. The present joint analysis was based on the novel mechanistic model GR3D (Global Repositioning Dynamics of Diadromous fish Distribution which was parameterized on allis shad and then used to predict its future distribution along the European Atlantic coast under different climate change scenarios (RCP 4.5 and RCP 8.5. We then used a correlative SDM for this species to forecast its distribution across the same geographic area and under the same climate change scenarios. First, projections from correlative and mechanistic models provided congruent trends in probability of habitat suitability and population dynamics. This agreement was preferentially interpreted as referring to the species vulnerability to climate change. Climate change could not be accordingly listed as a major threat for allis shad. The congruence in predicted range limits between SDMs projections was the next point of interest. The difference, when noticed, required to deepen our understanding of the niche modelled by each approach. In this respect, the relative position of the northern range limit between the two methods strongly suggested here that a key biological process related to intraspecific variability was potentially lacking in the mechanistic SDM. Based on our knowledge, we hypothesized that local

  6. Mechanistic Links Between PARP, NAD, and Brain Inflammation After TBI

    Science.gov (United States)

    2015-10-01

    1 AWARD NUMBER: W81XWH-13-2-0091 TITLE: Mechanistic Links Between PARP, NAD , and Brain Inflammation After TBI PRINCIPAL INVESTIGATOR...COVERED 25 Sep 2014 - 24 Sep 2015 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Mechanistic Links Between PARP, NAD , and Brain Inflammation After TBI 5b. GRANT...efficacy of veliparib and NAD as agents for suppressing inflammation and improving outcomes after traumatic brain injury. The animal models include

  7. Mechanistic rationalization of unusual sigmoidal kinetic profiles in the Machetti-De Sarlo cycloaddition reaction.

    Science.gov (United States)

    Mower, Matthew P; Blackmond, Donna G

    2015-02-18

    Unusual sigmoidal kinetic profiles in the Machetti-De Sarlo base-catalyzed 1,3-dipolar cycloaddition of acrylamide to N-methylnitroacetamide are rationalized by detailed in situ kinetic analysis. A dual role is uncovered in which a substrate acts as a precursor to catalyze its own reaction. Such kinetic studies provide a general protocol for distinguishing among different mechanistic origins of induction periods in complex organic reactions.

  8. A mechanistic approach to postirradiation spoilage kinetics of fish

    International Nuclear Information System (INIS)

    Tukenmez, I.

    2004-01-01

    Full text: In order to simulate postirradiation spoilage of fish, the mechanistic aspects of the growth of surviving microorganisms during chill storage and their product formation in irradiated fish were analyzed. Anchovy (Engraulis encrasicholus) samples those unirradiated and irradiated at 1, 2 and 3 kGy doses of gamma radiation were stored at +2 o C for 21 days. Total bacterial counts (TBC) and trimethylamine (TMA) analysis of the samples were done periodically during storage. Depending on the proposed spoilage mechanism, kinetic model equations were derived. By using experimental data of TBC and TMA in the developed model, the postirradiation spoilage parameters including growth rate constant, inital and maximum attainable TBC, lag time and TMA yield were evaluated and microbial spoilage of fish was simulated for postirradiation storage. Shelf life of irradiated fish was estimated depending on the spoilage kinetics. Dose effects on the kinetic parameters were analyzed. It is suggested that the kinetic evaluation method developed in this study may be used for quality assessment, shelf life determination and dose optimization for radiation preservation of fish

  9. Mechanistic Modeling of Water Replenishment Rate of Zeer Refrigerator

    Directory of Open Access Journals (Sweden)

    B. N. Nwankwojike

    2017-06-01

    Full Text Available A model for predicting the water replenishment rate of zeer pot refrigerator was developed in this study using mechanistic modeling approach and evaluated at Obowo, Imo State, Nigeria using six fruits, tomatoes, guava, okra, banana, orange and avocado pear. The developed model confirmed zeer pot water replenishment rate as a function of ambient temperature, relative humidity, wind speed, thermal conductivity of the pot materials and sand, density of air and water vapor, permeability coefficient of clay and heat transfer coefficient of water into air, circumferential length, height of pot, geometrical profile of the pot, heat load of the food preserved, heat flow into the device and gradient at which the pot is placed above ground level. Compared to the conventional approach of water replenishment, performance analysis results revealed 44% to 58% water economy when the zeer pot’s water was replenished based on the model’s prediction; while there was no significant difference in the shelf-life of the fruits preserved with both replenishment methods. Application of the developed water replenishment model facilitates optimal water usage in this system, thereby reducing operational cost of zeer pot refrigerator.

  10. Polymerization kinetics of wheat gluten upon thermosetting. A mechanistic model.

    Science.gov (United States)

    Domenek, Sandra; Morel, Marie-Hélène; Bonicel, Joëlle; Guilbert, Stéphane

    2002-10-09

    Size exclusion high-performance liquid chromatography analysis was carried out on wheat gluten-glycerol blends subjected to different heat treatments. The elution profiles were analyzed in order to follow the solubility loss of protein fractions with specific molecular size. Owing to the known biochemical changes involved during the heat denaturation of gluten, a mechanistic mathematical model was developed, which divided the protein denaturation into two distinct reaction steps: (i) reversible change in protein conformation and (ii) protein precipitation through disulfide bonding between initially SDS-soluble and SDS-insoluble reaction partners. Activation energies of gluten unfolding, refolding, and precipitation were calculated with the Arrhenius law to 53.9 kJ x mol(-1), 29.5 kJ x mol(-1), and 172 kJ x mol(-1), respectively. The rate of protein solubility loss decreased as the cross-linking reaction proceeded, which may be attributed to the formation of a three-dimensional network progressively hindering the reaction. The enhanced susceptibility to aggregation of large molecules was assigned to a risen reaction probability due to their higher number of cysteine residues and to the increased percentage of unfolded and thereby activated proteins as complete protein refolding seemed to be an anticooperative process.

  11. Mechanistic Features of Nanodiamonds in the Lapping of Magnetic Heads

    Directory of Open Access Journals (Sweden)

    Xionghua Jiang

    2014-01-01

    Full Text Available Nanodiamonds, which are the main components of slurry in the precision lapping process of magnetic heads, play an important role in surface quality. This paper studies the mechanistic features of nanodiamond embedment into a Sn plate in the lapping process. This is the first study to develop mathematical models for nanodiamond embedment. Such models can predict the optimum parameters for particle embedment. From the modeling calculations, the embedded pressure satisfies p0=3/2·W/πa2 and the indentation depth satisfies δ=k1P/HV. Calculation results reveal that the largest embedded pressure is 731.48 GPa and the critical indentation depth δ is 7 nm. Atomic force microscopy (AFM, scanning electron microscopy (SEM, and Auger electron spectroscopy (AES were used to carry out surface quality detection and analysis of the disk head. Both the formation of black spots on the surface and the removal rate have an important correlation with the size of nanodiamonds. The results demonstrate that an improved removal rate (21 nm·min−1 can be obtained with 100 nm diamonds embedded in the plate.

  12. Mechanistic features of nanodiamonds in the lapping of magnetic heads.

    Science.gov (United States)

    Jiang, Xionghua; Chen, Zhenxing; Wolfram, Joy; Yang, Zhizhou

    2014-01-01

    Nanodiamonds, which are the main components of slurry in the precision lapping process of magnetic heads, play an important role in surface quality. This paper studies the mechanistic features of nanodiamond embedment into a Sn plate in the lapping process. This is the first study to develop mathematical models for nanodiamond embedment. Such models can predict the optimum parameters for particle embedment. From the modeling calculations, the embedded pressure satisfies p 0 = (3/2) · (W/πa (2)) and the indentation depth satisfies δ = k1√P/HV. Calculation results reveal that the largest embedded pressure is 731.48 GPa and the critical indentation depth δ is 7 nm. Atomic force microscopy (AFM), scanning electron microscopy (SEM), and Auger electron spectroscopy (AES) were used to carry out surface quality detection and analysis of the disk head. Both the formation of black spots on the surface and the removal rate have an important correlation with the size of nanodiamonds. The results demonstrate that an improved removal rate (21 nm · min(-1)) can be obtained with 100 nm diamonds embedded in the plate.

  13. Generative mechanistic explanation building in undergraduate molecular and cellular biology

    Science.gov (United States)

    Southard, Katelyn M.; Espindola, Melissa R.; Zaepfel, Samantha D.; Bolger, Molly S.

    2017-09-01

    When conducting scientific research, experts in molecular and cellular biology (MCB) use specific reasoning strategies to construct mechanistic explanations for the underlying causal features of molecular phenomena. We explored how undergraduate students applied this scientific practice in MCB. Drawing from studies of explanation building among scientists, we created and applied a theoretical framework to explore the strategies students use to construct explanations for 'novel' biological phenomena. Specifically, we explored how students navigated the multi-level nature of complex biological systems using generative mechanistic reasoning. Interviews were conducted with introductory and upper-division biology students at a large public university in the United States. Results of qualitative coding revealed key features of students' explanation building. Students used modular thinking to consider the functional subdivisions of the system, which they 'filled in' to varying degrees with mechanistic elements. They also hypothesised the involvement of mechanistic entities and instantiated abstract schema to adapt their explanations to unfamiliar biological contexts. Finally, we explored the flexible thinking that students used to hypothesise the impact of mutations on multi-leveled biological systems. Results revealed a number of ways that students drew mechanistic connections between molecules, functional modules (sets of molecules with an emergent function), cells, tissues, organisms and populations.

  14. Predicting interactions from mechanistic information: Can omic data validate theories?

    International Nuclear Information System (INIS)

    Borgert, Christopher J.

    2007-01-01

    To address the most pressing and relevant issues for improving mixture risk assessment, researchers must first recognize that risk assessment is driven by both regulatory requirements and scientific research, and that regulatory concerns may expand beyond the purely scientific interests of researchers. Concepts of 'mode of action' and 'mechanism of action' are used in particular ways within the regulatory arena, depending on the specific assessment goals. The data requirements for delineating a mode of action and predicting interactive toxicity in mixtures are not well defined from a scientific standpoint due largely to inherent difficulties in testing certain underlying assumptions. Understanding the regulatory perspective on mechanistic concepts will be important for designing experiments that can be interpreted clearly and applied in risk assessments without undue reliance on extrapolation and assumption. In like fashion, regulators and risk assessors can be better equipped to apply mechanistic data if the concepts underlying mechanistic research and the limitations that must be placed on interpretation of mechanistic data are understood. This will be critically important for applying new technologies to risk assessment, such as functional genomics, proteomics, and metabolomics. It will be essential not only for risk assessors to become conversant with the language and concepts of mechanistic research, including new omic technologies, but also, for researchers to become more intimately familiar with the challenges and needs of risk assessment

  15. Explanation and inference: Mechanistic and functional explanations guide property generalization

    Directory of Open Access Journals (Sweden)

    Tania eLombrozo

    2014-09-01

    Full Text Available The ability to generalize from the known to the unknown is central to learning and inference. Two experiments explore the relationship between how a property is explained and how that property is generalized to novel species and artifacts. The experiments contrast the consequences of explaining a property mechanistically, by appeal to parts and processes, with the consequences of explaining the property functionally, by appeal to functions and goals. The findings suggest that properties that are explained functionally are more likely to be generalized on the basis of shared functions, with a weaker relationship between mechanistic explanations and generalization on the basis of shared parts and processes. The influence of explanation type on generalization holds even though all participants are provided with the same mechanistic and functional information, and whether an explanation type is freely generated (Experiment 1, experimentally provided (Experiment 2, or experimentally induced (Experiment 2. The experiments also demonstrate that explanations and generalizations of a particular type (mechanistic or functional can be experimentally induced by providing sample explanations of that type, with a comparable effect when the sample explanations come from the same domain or from a different domains. These results suggest that explanations serve as a guide to generalization, and contribute to a growing body of work supporting the value of distinguishing mechanistic and functional explanations.

  16. Explanation and inference: mechanistic and functional explanations guide property generalization.

    Science.gov (United States)

    Lombrozo, Tania; Gwynne, Nicholas Z

    2014-01-01

    The ability to generalize from the known to the unknown is central to learning and inference. Two experiments explore the relationship between how a property is explained and how that property is generalized to novel species and artifacts. The experiments contrast the consequences of explaining a property mechanistically, by appeal to parts and processes, with the consequences of explaining the property functionally, by appeal to functions and goals. The findings suggest that properties that are explained functionally are more likely to be generalized on the basis of shared functions, with a weaker relationship between mechanistic explanations and generalization on the basis of shared parts and processes. The influence of explanation type on generalization holds even though all participants are provided with the same mechanistic and functional information, and whether an explanation type is freely generated (Experiment 1), experimentally provided (Experiment 2), or experimentally induced (Experiment 2). The experiments also demonstrate that explanations and generalizations of a particular type (mechanistic or functional) can be experimentally induced by providing sample explanations of that type, with a comparable effect when the sample explanations come from the same domain or from a different domains. These results suggest that explanations serve as a guide to generalization, and contribute to a growing body of work supporting the value of distinguishing mechanistic and functional explanations.

  17. Managing mechanistic and organic structure in health care organizations.

    Science.gov (United States)

    Olden, Peter C

    2012-01-01

    Managers at all levels in a health care organization must organize work to achieve the organization's mission and goals. This requires managers to decide the organization structure, which involves dividing the work among jobs and departments and then coordinating them all toward the common purpose. Organization structure, which is reflected in an organization chart, may range on a continuum from very mechanistic to very organic. Managers must decide how mechanistic versus how organic to make the entire organization and each of its departments. To do this, managers should carefully consider 5 factors for the organization and for each individual department: external environment, goals, work production, size, and culture. Some factors may push toward more mechanistic structure, whereas others may push in the opposite direction toward more organic structure. Practical advice can help managers at all levels design appropriate structure for their departments and organization.

  18. Why did Jacques Monod make the choice of mechanistic determinism?

    Science.gov (United States)

    Loison, Laurent

    2015-06-01

    The development of molecular biology placed in the foreground a mechanistic and deterministic conception of the functioning of macromolecules. In this article, I show that this conception was neither obvious, nor necessary. Taking Jacques Monod as a case study, I detail the way he gradually came loose from a statistical understanding of determinism to finally support a mechanistic understanding. The reasons of the choice made by Monod at the beginning of the 1950s can be understood only in the light of the general theoretical schema supported by the concept of mechanistic determinism. This schema articulates three fundamental notions for Monod, namely that of the rigidity of the sequence of the genetic program, that of the intrinsic stability of macromolecules (DNA and proteins), and that of the specificity of molecular interactions. Copyright © 2015 Académie des sciences. Published by Elsevier SAS. All rights reserved.

  19. Cognitive science as an interface between rational and mechanistic explanation.

    Science.gov (United States)

    Chater, Nick

    2014-04-01

    Cognitive science views thought as computation; and computation, by its very nature, can be understood in both rational and mechanistic terms. In rational terms, a computation solves some information processing problem (e.g., mapping sensory information into a description of the external world; parsing a sentence; selecting among a set of possible actions). In mechanistic terms, a computation corresponds to causal chain of events in a physical device (in engineering context, a silicon chip; in biological context, the nervous system). The discipline is thus at the interface between two very different styles of explanation--as the papers in the current special issue well illustrate, it explores the interplay of rational and mechanistic forces. Copyright © 2014 Cognitive Science Society, Inc.

  20. Modeling systems-level dynamics: Understanding without mechanistic explanation in integrative systems biology.

    Science.gov (United States)

    MacLeod, Miles; Nersessian, Nancy J

    2015-02-01

    In this paper we draw upon rich ethnographic data of two systems biology labs to explore the roles of explanation and understanding in large-scale systems modeling. We illustrate practices that depart from the goal of dynamic mechanistic explanation for the sake of more limited modeling goals. These processes use abstract mathematical formulations of bio-molecular interactions and data fitting techniques which we call top-down abstraction to trade away accurate mechanistic accounts of large-scale systems for specific information about aspects of those systems. We characterize these practices as pragmatic responses to the constraints many modelers of large-scale systems face, which in turn generate more limited pragmatic non-mechanistic forms of understanding of systems. These forms aim at knowledge of how to predict system responses in order to manipulate and control some aspects of them. We propose that this analysis of understanding provides a way to interpret what many systems biologists are aiming for in practice when they talk about the objective of a "systems-level understanding." Copyright © 2014 Elsevier Ltd. All rights reserved.

  1. A Physics-Inspired Mechanistic Model of Migratory Movement Patterns in Birds.

    Science.gov (United States)

    Revell, Christopher; Somveille, Marius

    2017-08-29

    In this paper, we introduce a mechanistic model of migratory movement patterns in birds, inspired by ideas and methods from physics. Previous studies have shed light on the factors influencing bird migration but have mainly relied on statistical correlative analysis of tracking data. Our novel method offers a bottom up explanation of population-level migratory movement patterns. It differs from previous mechanistic models of animal migration and enables predictions of pathways and destinations from a given starting location. We define an environmental potential landscape from environmental data and simulate bird movement within this landscape based on simple decision rules drawn from statistical mechanics. We explore the capacity of the model by qualitatively comparing simulation results to the non-breeding migration patterns of a seabird species, the Black-browed Albatross (Thalassarche melanophris). This minimal, two-parameter model was able to capture remarkably well the previously documented migration patterns of the Black-browed Albatross, with the best combination of parameter values conserved across multiple geographically separate populations. Our physics-inspired mechanistic model could be applied to other bird and highly-mobile species, improving our understanding of the relative importance of various factors driving migration and making predictions that could be useful for conservation.

  2. Quantitative assessment of biological impact using transcriptomic data and mechanistic network models

    International Nuclear Information System (INIS)

    Thomson, Ty M.; Sewer, Alain; Martin, Florian; Belcastro, Vincenzo; Frushour, Brian P.; Gebel, Stephan; Park, Jennifer; Schlage, Walter K.; Talikka, Marja; Vasilyev, Dmitry M.; Westra, Jurjen W.; Hoeng, Julia; Peitsch, Manuel C.

    2013-01-01

    Exposure to biologically active substances such as therapeutic drugs or environmental toxicants can impact biological systems at various levels, affecting individual molecules, signaling pathways, and overall cellular processes. The ability to derive mechanistic insights from the resulting system responses requires the integration of experimental measures with a priori knowledge about the system and the interacting molecules therein. We developed a novel systems biology-based methodology that leverages mechanistic network models and transcriptomic data to quantitatively assess the biological impact of exposures to active substances. Hierarchically organized network models were first constructed to provide a coherent framework for investigating the impact of exposures at the molecular, pathway and process levels. We then validated our methodology using novel and previously published experiments. For both in vitro systems with simple exposure and in vivo systems with complex exposures, our methodology was able to recapitulate known biological responses matching expected or measured phenotypes. In addition, the quantitative results were in agreement with experimental endpoint data for many of the mechanistic effects that were assessed, providing further objective confirmation of the approach. We conclude that our methodology evaluates the biological impact of exposures in an objective, systematic, and quantifiable manner, enabling the computation of a systems-wide and pan-mechanistic biological impact measure for a given active substance or mixture. Our results suggest that various fields of human disease research, from drug development to consumer product testing and environmental impact analysis, could benefit from using this methodology. - Highlights: • The impact of biologically active substances is quantified at multiple levels. • The systems-level impact integrates the perturbations of individual networks. • The networks capture the relationships between

  3. Toward a mechanistic modeling of nitrogen limitation on vegetation dynamics.

    Directory of Open Access Journals (Sweden)

    Chonggang Xu

    Full Text Available Nitrogen is a dominant regulator of vegetation dynamics, net primary production, and terrestrial carbon cycles; however, most ecosystem models use a rather simplistic relationship between leaf nitrogen content and photosynthetic capacity. Such an approach does not consider how patterns of nitrogen allocation may change with differences in light intensity, growing-season temperature and CO(2 concentration. To account for this known variability in nitrogen-photosynthesis relationships, we develop a mechanistic nitrogen allocation model based on a trade-off of nitrogen allocated between growth and storage, and an optimization of nitrogen allocated among light capture, electron transport, carboxylation, and respiration. The developed model is able to predict the acclimation of photosynthetic capacity to changes in CO(2 concentration, temperature, and radiation when evaluated against published data of V(c,max (maximum carboxylation rate and J(max (maximum electron transport rate. A sensitivity analysis of the model for herbaceous plants, deciduous and evergreen trees implies that elevated CO(2 concentrations lead to lower allocation of nitrogen to carboxylation but higher allocation to storage. Higher growing-season temperatures cause lower allocation of nitrogen to carboxylation, due to higher nitrogen requirements for light capture pigments and for storage. Lower levels of radiation have a much stronger effect on allocation of nitrogen to carboxylation for herbaceous plants than for trees, resulting from higher nitrogen requirements for light capture for herbaceous plants. As far as we know, this is the first model of complete nitrogen allocation that simultaneously considers nitrogen allocation to light capture, electron transport, carboxylation, respiration and storage, and the responses of each to altered environmental conditions. We expect this model could potentially improve our confidence in simulations of carbon-nitrogen interactions and the

  4. Toward a mechanistic modeling of nitrogen limitation on vegetation dynamics.

    Science.gov (United States)

    Xu, Chonggang; Fisher, Rosie; Wullschleger, Stan D; Wilson, Cathy J; Cai, Michael; McDowell, Nate G

    2012-01-01

    Nitrogen is a dominant regulator of vegetation dynamics, net primary production, and terrestrial carbon cycles; however, most ecosystem models use a rather simplistic relationship between leaf nitrogen content and photosynthetic capacity. Such an approach does not consider how patterns of nitrogen allocation may change with differences in light intensity, growing-season temperature and CO(2) concentration. To account for this known variability in nitrogen-photosynthesis relationships, we develop a mechanistic nitrogen allocation model based on a trade-off of nitrogen allocated between growth and storage, and an optimization of nitrogen allocated among light capture, electron transport, carboxylation, and respiration. The developed model is able to predict the acclimation of photosynthetic capacity to changes in CO(2) concentration, temperature, and radiation when evaluated against published data of V(c,max) (maximum carboxylation rate) and J(max) (maximum electron transport rate). A sensitivity analysis of the model for herbaceous plants, deciduous and evergreen trees implies that elevated CO(2) concentrations lead to lower allocation of nitrogen to carboxylation but higher allocation to storage. Higher growing-season temperatures cause lower allocation of nitrogen to carboxylation, due to higher nitrogen requirements for light capture pigments and for storage. Lower levels of radiation have a much stronger effect on allocation of nitrogen to carboxylation for herbaceous plants than for trees, resulting from higher nitrogen requirements for light capture for herbaceous plants. As far as we know, this is the first model of complete nitrogen allocation that simultaneously considers nitrogen allocation to light capture, electron transport, carboxylation, respiration and storage, and the responses of each to altered environmental conditions. We expect this model could potentially improve our confidence in simulations of carbon-nitrogen interactions and the vegetation

  5. Toward a Mechanistic Modeling of Nitrogen Limitation on Vegetation Dynamics

    Science.gov (United States)

    Xu, Chonggang; Fisher, Rosie; Wullschleger, Stan D.; Wilson, Cathy J.; Cai, Michael; McDowell, Nate G.

    2012-01-01

    Nitrogen is a dominant regulator of vegetation dynamics, net primary production, and terrestrial carbon cycles; however, most ecosystem models use a rather simplistic relationship between leaf nitrogen content and photosynthetic capacity. Such an approach does not consider how patterns of nitrogen allocation may change with differences in light intensity, growing-season temperature and CO2 concentration. To account for this known variability in nitrogen-photosynthesis relationships, we develop a mechanistic nitrogen allocation model based on a trade-off of nitrogen allocated between growth and storage, and an optimization of nitrogen allocated among light capture, electron transport, carboxylation, and respiration. The developed model is able to predict the acclimation of photosynthetic capacity to changes in CO2 concentration, temperature, and radiation when evaluated against published data of Vc,max (maximum carboxylation rate) and Jmax (maximum electron transport rate). A sensitivity analysis of the model for herbaceous plants, deciduous and evergreen trees implies that elevated CO2 concentrations lead to lower allocation of nitrogen to carboxylation but higher allocation to storage. Higher growing-season temperatures cause lower allocation of nitrogen to carboxylation, due to higher nitrogen requirements for light capture pigments and for storage. Lower levels of radiation have a much stronger effect on allocation of nitrogen to carboxylation for herbaceous plants than for trees, resulting from higher nitrogen requirements for light capture for herbaceous plants. As far as we know, this is the first model of complete nitrogen allocation that simultaneously considers nitrogen allocation to light capture, electron transport, carboxylation, respiration and storage, and the responses of each to altered environmental conditions. We expect this model could potentially improve our confidence in simulations of carbon-nitrogen interactions and the vegetation feedbacks

  6. Mechanistic analysis of double-shell tank gas release

    Energy Technology Data Exchange (ETDEWEB)

    Allemann, R.T.; Antoniak, Z.I.; Friley, J.R.; Haines, C.E.; Liljegren, L.M.; Somasundaram, S.

    1991-12-01

    Pacific Northwest Laboratory (PNL) is studying possible mechanisms and fluid dynamics contributing to the periodic release of gases from the double-shell waste storage tanks at Hanford. This study is being conducted for Westinghouse Hanford Company (WHC), a contractor for the US Department of Energy (DOE). This interim report discusses the work done through November 1990. Safe management of the wastes at Hanford depends on an understanding of the chemical and physical mechanisms that take place in the waste tanks. An example of the need to understand these mechanisms is tank 101-SY. The waste in this tank is generating and periodically releasing potentially flammable gases into the tank vent system according to observations of the tank. How these gases are generated and become trapped, the causes of periodic release, and the mechanism of the release are not known in detail. In order to develop a safe mitigation strategy, possible physical mechanisms for the periodic release of flammable gases need to be understood.

  7. A mechanistic analysis of density dependence in algal population dynamics

    Directory of Open Access Journals (Sweden)

    Adrian eBorlestean

    2015-04-01

    Full Text Available Population density regulation is a fundamental principle in ecology, but the specific process underlying functional expression of density dependence remains to be fully elucidated. One view contends that patterns of density dependence are largely fixed across a species irrespective of environmental conditions, whereas another is that the strength and expression of density dependence are fundamentally variable depending on the nature of exogenous or endogenous constraints acting on the population. We conducted a study investigating the expression of density dependence in Chlamydomonas spp. grown under a gradient from low to high nutrient density. We predicted that the relationship between per capita growth rate (pgr and population density would vary from concave up to concave down as nutrient density became less limiting and populations experienced weaker density regulation. Contrary to prediction, we found that the relationship between pgr and density became increasingly concave-up as nutrient levels increased. We also found that variation in pgr increased, and pgr levels reached higher maxima in nutrient-limited environments. Most likely, these results are attributable to population growth suppression in environments with high intraspecific competition due to limited nutrient resources. Our results suggest that density regulation is strongly variable depending on exogenous and endogenous processes acting on the population, implying that expression of density dependence depends extensively on local conditions. Additional experimental work should reveal the mechanisms influencing how the expression of density dependence varies across populations through space and time.

  8. Mechanistic Insights into Human Brain Impact Dynamics through Modal Analysis

    Science.gov (United States)

    Laksari, Kaveh; Kurt, Mehmet; Babaee, Hessam; Kleiven, Svein; Camarillo, David

    2018-03-01

    Although concussion is one of the greatest health challenges today, our physical understanding of the cause of injury is limited. In this Letter, we simulated football head impacts in a finite element model and extracted the most dominant modal behavior of the brain's deformation. We showed that the brain's deformation is most sensitive in low frequency regimes close to 30 Hz, and discovered that for most subconcussive head impacts, the dynamics of brain deformation is dominated by a single global mode. In this Letter, we show the existence of localized modes and multimodal behavior in the brain as a hyperviscoelastic medium. This dynamical phenomenon leads to strain concentration patterns, particularly in deep brain regions, which is consistent with reported concussion pathology.

  9. Carbon elimination from silicon kerf: Thermogravimetric analysis and mechanistic considerations.

    Science.gov (United States)

    Vazquez-Pufleau, Miguel; Chadha, Tandeep S; Yablonsky, Gregory; Biswas, Pratim

    2017-01-18

    40% of ultrapure silicon is lost as kerf during slicing to produce wafers. Kerf is currently not being recycled due to engineering challenges and costs associated with removing its abundant impurities. Carbon left behind from the lubricant remains as one of the most difficult contaminants to remove in kerf without significant silicon oxidation. The present work enables to better understand the mechanism of carbon elimination in kerf which can aid the design of better processes for kef recycling and low cost photovoltaics. In this paper, we studied the kinetics of carbon elimination from silicon kerf in two atmospheres: air and N 2, under a regime of no-diffusion-limitation. We report the apparent activation energy in both atmospheres using three methods: Kissinger, and two isoconversional approaches. In both atmospheres, a bimodal apparent activation energy is observed, suggesting a two stage process. A reaction mechanism is proposed in which (a) C-C and C-O bond cleavage reactions occur in parallel with polymer formation; (b) at higher temperatures, this polymer fully degrades in air but leaves a tarry residue in N 2 that accounts for about 12% of the initial total carbon.

  10. Profiling the biological activity of oxide nanomaterials with mechanistic models

    NARCIS (Netherlands)

    Burello, E.

    2013-01-01

    In this study we present three mechanistic models for profiling the potential biological and toxicological effects of oxide nanomaterials. The models attempt to describe the reactivity, protein adsorption and membrane adhesion processes of a large range of oxide materials and are based on properties

  11. Bridging Mechanistic and Phenomenological Models of Complex Biological Systems.

    Science.gov (United States)

    Transtrum, Mark K; Qiu, Peng

    2016-05-01

    The inherent complexity of biological systems gives rise to complicated mechanistic models with a large number of parameters. On the other hand, the collective behavior of these systems can often be characterized by a relatively small number of phenomenological parameters. We use the Manifold Boundary Approximation Method (MBAM) as a tool for deriving simple phenomenological models from complicated mechanistic models. The resulting models are not black boxes, but remain expressed in terms of the microscopic parameters. In this way, we explicitly connect the macroscopic and microscopic descriptions, characterize the equivalence class of distinct systems exhibiting the same range of collective behavior, and identify the combinations of components that function as tunable control knobs for the behavior. We demonstrate the procedure for adaptation behavior exhibited by the EGFR pathway. From a 48 parameter mechanistic model, the system can be effectively described by a single adaptation parameter τ characterizing the ratio of time scales for the initial response and recovery time of the system which can in turn be expressed as a combination of microscopic reaction rates, Michaelis-Menten constants, and biochemical concentrations. The situation is not unlike modeling in physics in which microscopically complex processes can often be renormalized into simple phenomenological models with only a few effective parameters. The proposed method additionally provides a mechanistic explanation for non-universal features of the behavior.

  12. Descriptive and mechanistic models of crop–weed competition

    NARCIS (Netherlands)

    Bastiaans, L.; Storkey, J.

    2017-01-01

    Crop-weed competitive relations are an important element of agroecosystems. Quantifying and understanding them helps to design appropriate weed management at operational, tactical and strategic level. This chapter presents and discusses simple descriptive and more mechanistic models for crop-weed

  13. A mechanistic model on methane oxidation in the rice rhizosphere

    NARCIS (Netherlands)

    Bodegom, van P.M.; Leffelaar, P.A.; Goudriaan, J.

    2001-01-01

    A mechanistic model is presented on the processes leading to methane oxidation in rice rhizosphere. The model is driven by oxygen release from a rice root into anaerobic rice soil. Oxygen is consumed by heterotrophic and methanotrophic respiration, described by double Monod kinetics, and by iron

  14. Precision and accuracy of mechanistic-empirical pavement design

    CSIR Research Space (South Africa)

    Theyse, HL

    2006-09-01

    Full Text Available are discussed in general. The effects of variability and error on the design accuracy and design risk are lastly illustrated at the hand of a simple mechanistic-empirical design problem, showing that the engineering models alone determine the accuracy...

  15. The mechanistic bases of the power-time relationship

    DEFF Research Database (Denmark)

    Vanhatalo, Anni; Black, Matthew I; DiMenna, Fred J

    2016-01-01

    .025) and inversely correlated with muscle type IIx fibre proportion (r = -0.76, P = 0.01). There was no relationship between W' (19.4 ± 6.3 kJ) and muscle fibre type. These data indicate a mechanistic link between the bioenergetic characteristics of different muscle fibre types and the power-duration relationship...

  16. Advanced reach tool (ART) : Development of the mechanistic model

    NARCIS (Netherlands)

    Fransman, W.; Tongeren, M. van; Cherrie, J.W.; Tischer, M.; Schneider, T.; Schinkel, J.; Kromhout, H.; Warren, N.; Goede, H.; Tielemans, E.

    2011-01-01

    This paper describes the development of the mechanistic model within a collaborative project, referred to as the Advanced REACH Tool (ART) project, to develop a tool to model inhalation exposure for workers sharing similar operational conditions across different industries and locations in Europe.

  17. Mathematical Description and Mechanistic Reasoning: A Pathway toward STEM Integration

    Science.gov (United States)

    Weinberg, Paul J.

    2017-01-01

    Because reasoning about mechanism is critical to disciplined inquiry in science, technology, engineering, and mathematics (STEM) domains, this study focuses on ways to support the development of this form of reasoning. This study attends to how mechanistic reasoning is constituted through mathematical description. This study draws upon Smith's…

  18. Generative Mechanistic Explanation Building in Undergraduate Molecular and Cellular Biology

    Science.gov (United States)

    Southard, Katelyn M.; Espindola, Melissa R.; Zaepfel, Samantha D.; Bolger, Molly S.

    2017-01-01

    When conducting scientific research, experts in molecular and cellular biology (MCB) use specific reasoning strategies to construct mechanistic explanations for the underlying causal features of molecular phenomena. We explored how undergraduate students applied this scientific practice in MCB. Drawing from studies of explanation building among…

  19. Does Mechanistic Thinking Improve Student Success in Organic Chemistry?

    Science.gov (United States)

    Grove, Nathaniel P.; Cooper, Melanie M.; Cox, Elizabeth L.

    2012-01-01

    The use of the curved-arrow notation to depict electron flow during mechanistic processes is one of the most important representational conventions in the organic chemistry curriculum. Our previous research documented a disturbing trend: when asked to predict the products of a series of reactions, many students do not spontaneously engage in…

  20. Calibrating mechanistic-empirical pavement performance models with an expert matrix

    Energy Technology Data Exchange (ETDEWEB)

    Tighe, S.; AlAssar, R.; Haas, R. [Waterloo Univ., ON (Canada). Dept. of Civil Engineering; Zhiwei, H. [Stantec Consulting Ltd., Cambridge, ON (Canada)

    2001-07-01

    Proper management of pavement infrastructure requires pavement performance modelling. For the past 20 years, the Ontario Ministry of Transportation has used the Ontario Pavement Analysis of Costs (OPAC) system for pavement design. Pavement needs, however, have changed substantially during that time. To address this need, a new research contract is underway to enhance the model and verify the predictions, particularly at extreme points such as low and high traffic volume pavement design. This initiative included a complete evaluation of the existing OPAC pavement design method, the construction of a new set of pavement performance prediction models, and the development of the flexible pavement design procedure that incorporates reliability analysis. The design was also expanded to include rigid pavement designs and modification of the existing life cycle cost analysis procedure which includes both the agency cost and road user cost. Performance prediction and life-cycle costs were developed based on several factors, including material properties, traffic loads and climate. Construction and maintenance schedules were also considered. The methodology for the calibration and validation of a mechanistic-empirical flexible pavement performance model was described. Mechanistic-empirical design methods combine theory based design such as calculated stresses, strains or deflections with empirical methods, where a measured response is associated with thickness and pavement performance. Elastic layer analysis was used to determine pavement response to determine the most effective design using cumulative Equivalent Single Axle Loads (ESALs), below grade type and layer thickness.The new mechanistic-empirical model separates the environment and traffic effects on performance. This makes it possible to quantify regional differences between Southern and Northern Ontario. In addition, roughness can be calculated in terms of the International Roughness Index or Riding comfort Index

  1. Multiple-endpoints gene alteration-based (MEGA) assay: A toxicogenomics approach for water quality assessment of wastewater effluents.

    Science.gov (United States)

    Fukushima, Toshikazu; Hara-Yamamura, Hiroe; Nakashima, Koji; Tan, Lea Chua; Okabe, Satoshi

    2017-12-01

    Wastewater effluents contain a significant number of toxic contaminants, which, even at low concentrations, display a wide variety of toxic actions. In this study, we developed a multiple-endpoints gene alteration-based (MEGA) assay, a real-time PCR-based transcriptomic analysis, to assess the water quality of wastewater effluents for human health risk assessment and management. Twenty-one genes from the human hepatoblastoma cell line (HepG2), covering the basic health-relevant stress responses such as response to xenobiotics, genotoxicity, and cytotoxicity, were selected and incorporated into the MEGA assay. The genes related to the p53-mediated DNA damage response and cytochrome P450 were selected as markers for genotoxicity and response to xenobiotics, respectively. Additionally, the genes that were dose-dependently regulated by exposure to the wastewater effluents were chosen as markers for cytotoxicity. The alterations in the expression of an individual gene, induced by exposure to the wastewater effluents, were evaluated by real-time PCR and the results were validated by genotoxicity (e.g., comet assay) and cell-based cytotoxicity tests. In summary, the MEGA assay is a real-time PCR-based assay that targets cellular responses to contaminants present in wastewater effluents at the transcriptional level; it is rapid, cost-effective, and high-throughput and can thus complement any chemical analysis for water quality assessment and management. Copyright © 2017 Elsevier Ltd. All rights reserved.

  2. Mechanistic and kinetic insights into the thermally induced rearrangement of alpha-pinene.

    Science.gov (United States)

    Stolle, Achim; Ondruschka, Bernd; Findeisen, Matthias

    2008-11-07

    The thermal rearrangement of alpha-pinene (1) is interesting from mechanistic as well as kinetic point of view. Carrier gas pyrolyses with 1 and its acyclic isomers ocimene (2) and alloocimene (3) were performed to investigate the thermal network of these hydrocarbons. Kinetic analysis of the major reaction steps allows for a deeper insight in the reaction mechanism. Thus it was possible to explain the racemization of 1, the formation of racemic limonene (4), and the absence of the primary pyrolysis product 2 in the reaction mixture resulting from thermal rearrangement of 1. Results supported the conclusion that the reactions starting with 1 involve biradical transition states.

  3. A predictive toxicogenomics signature to classify genotoxic versus non-genotoxic chemicals in human TK6 cells

    Directory of Open Access Journals (Sweden)

    Andrew Williams

    2015-12-01

    Full Text Available Genotoxicity testing is a critical component of chemical assessment. The use of integrated approaches in genetic toxicology, including the incorporation of gene expression data to determine the DNA damage response pathways involved in response, is becoming more common. In companion papers previously published in Environmental and Molecular Mutagenesis, Li et al. (2015 [6] developed a dose optimization protocol that was based on evaluating expression changes in several well-characterized stress-response genes using quantitative real-time PCR in human lymphoblastoid TK6 cells in culture. This optimization approach was applied to the analysis of TK6 cells exposed to one of 14 genotoxic or 14 non-genotoxic agents, with sampling 4 h post-exposure. Microarray-based transcriptomic analyses were then used to develop a classifier for genotoxicity using the nearest shrunken centroids method. A panel of 65 genes was identified that could accurately classify toxicants as genotoxic or non-genotoxic. In Buick et al. (2015 [1], the utility of the biomarker for chemicals that require metabolic activation was evaluated. In this study, TK6 cells were exposed to increasing doses of four chemicals (two genotoxic that require metabolic activation and two non-genotoxic chemicals in the presence of rat liver S9 to demonstrate that S9 does not impair the ability to classify genotoxicity using this genomic biomarker in TK6cells.

  4. Mechanistic Fermentation Models for Process Design, Monitoring, and Control

    DEFF Research Database (Denmark)

    Mears, Lisa; Stocks, Stuart M.; Albæk, Mads Orla

    2017-01-01

    Mechanistic models require a significant investment of time and resources, but their application to multiple stages of fermentation process development and operation can make this investment highly valuable. This Opinion article discusses how an established fermentation model may be adapted...... for application to different stages of fermentation process development: planning, process design, monitoring, and control. Although a longer development time is required for such modeling methods in comparison to purely data-based model techniques, the wide range of applications makes them a highly valuable tool...... for fermentation research and development. In addition, in a research environment, where collaboration is important, developing mechanistic models provides a platform for knowledge sharing and consolidation of existing process understanding....

  5. Effects of Asphalt Mix Design Properties on Pavement Performance: A Mechanistic Approach

    Directory of Open Access Journals (Sweden)

    Ahmad M. Abu Abdo

    2016-01-01

    Full Text Available The main objective of this study was to investigate the effects of hot mix asphalt material properties on the performance of flexible pavements via mechanistic approach. 3D Move Analysis software was utilized to determine rutting and cracking distresses in an asphalt concrete (AC layer. Fourteen different Superpave mixes were evaluated by utilizing results of the Dynamic Modulus (|E⁎| Test and the Dynamic Shear Modulus (|G⁎| Test. Results showed that with the increase of binder content, the tendency of rutting in AC layer increased. However, with the increase of binder content, the cracking of AC layer lessened. Furthermore, when different binder grades were evaluated, results showed that with the increase of the upper binder grade number, rutting decreased, and with the increase of the lower binder grade number, rutting increased. Furthermore, analysis showed that with the increase of the lower binder grade number, higher percent of bottom up cracks would result. As a result of the analysis, binder grade should not be solely considered for cracking in AC layer; binder content and aggregate structure play a big role. Finally, results illustrated that the mechanistic approach is a better tool to determine the performance of asphalt pavement than commonly used methods.

  6. Evaluation of mechanistic DNB models using HCLWR CHF data

    International Nuclear Information System (INIS)

    Iwamura, Takamichi; Watanabe, Hironori; Okubo, Tsutomu; Araya, Fumimasa; Murao, Yoshio.

    1992-03-01

    An onset of departure from nucleate boiling (DNB) in light water reactor (LWR) has been generally predicted with empirical correlations. Since these correlations have less physical bases and contain adjustable empirical constants determined by best fitting of test data, applicable geometries and flow conditions are limited within the original experiment ranges. In order to obtain more universal prediction method, several mechanistic DNB models based on physical approaches have been proposed in recent years. However, the predictive capabilities of mechanistic DNB models have not been verified successfully especially for advanced LWR design purposes. In this report, typical DNB mechanistic models are reviewed and compared with critical heat flux (CHF) data for high conversion light water reactor (HCLWR). The experiments were performed using triangular 7-rods array with non-uniform axial heat flux distribution. Test pressure was 16 MPa, mass velocities ranged from 800 t0 3100 kg/s·m 2 and exit qualities from -0.07 to 0.19. The evaluated models are: 1) Wisman-Pei, 2) Chang-Lee, 3) Lee-Mudawwar, 4) Lin-Lee-Pei, and 5) Katto. The first two models are based on near-wall bubble crowding model and the other three models on sublayer dryout model. The comparison with experimental data indicated that the Weisman-Pei model agreed relatively well with the CHF data. Effects of empirical constants in each model on CHF calculation were clarified by sensitivity studies. It was also found that the magnitudes of physical quantities obtained in the course of calculation were significantly different for each model. Therefore, microscopic observation of the onset of DNB on heated surface is essential to clarify the DNB mechanism and establish a general DNB mechanistic model based on physical phenomenon. (author)

  7. Analysis of baseline gene expression levels from ...

    Science.gov (United States)

    The use of gene expression profiling to predict chemical mode of action would be enhanced by better characterization of variance due to individual, environmental, and technical factors. Meta-analysis of microarray data from untreated or vehicle-treated animals within the control arm of toxicogenomics studies has yielded useful information on baseline fluctuations in gene expression. A dataset of control animal microarray expression data was assembled by a working group of the Health and Environmental Sciences Institute's Technical Committee on the Application of Genomics in Mechanism Based Risk Assessment in order to provide a public resource for assessments of variability in baseline gene expression. Data from over 500 Affymetrix microarrays from control rat liver and kidney were collected from 16 different institutions. Thirty-five biological and technical factors were obtained for each animal, describing a wide range of study characteristics, and a subset were evaluated in detail for their contribution to total variability using multivariate statistical and graphical techniques. The study factors that emerged as key sources of variability included gender, organ section, strain, and fasting state. These and other study factors were identified as key descriptors that should be included in the minimal information about a toxicogenomics study needed for interpretation of results by an independent source. Genes that are the most and least variable, gender-selectiv

  8. Specialists without spirit: limitations of the mechanistic biomedical model.

    Science.gov (United States)

    Hewa, S; Hetherington, R W

    1995-06-01

    This paper examines the origin and the development of the mechanistic model of the human body and health in terms of Max Weber's theory of rationalization. It is argued that the development of Western scientific medicine is a part of the broad process of rationalization that began in sixteenth century Europe as a result of the Reformation. The development of the mechanistic view of the human body in Western medicine is consistent with the ideas of calculability, predictability, and control-the major tenets of the process of rationalization as described by Weber. In recent years, however, the limitations of the mechanistic model have been the topic of many discussions. George Engel, a leading advocate of general systems theory, is one of the leading proponents of a new medical model which includes the general quality of life, clean environment, and psychological, or spiritual stability of life. The paper concludes with consideration of the potential of Engel's proposed new model in the context of the current state of rationalization in modern industrialized society.

  9. Numerical simulation in steam injection process by a mechanistic approach

    Energy Technology Data Exchange (ETDEWEB)

    De Souza, J.C.Jr.; Campos, W.; Lopes, D.; Moura, L.S.S. [Petrobras, Rio de Janeiro (Brazil)

    2008-10-15

    Steam injection is a common thermal recovery method used in very viscous oil reservoirs. The method involves the injection of heat to reduce viscosity and mobilize oil. A steam generation and injection system consists primarily of a steam source, distribution lines, injection wells and a discarding tank. In order to optimize injection and improve the oil recovery factor, one must determine the parameters of steam flow such as pressure, temperature and steam quality. This study focused on developing a unified mathematical model by means of a mechanistic approach for two-phase steam flow in pipelines and wells. The hydrodynamic and heat transfer mechanistic model was implemented in a computer simulator to model the parameters of steam injection while trying to avoid the use of empirical correlations. A marching algorithm was used to determine the distribution of pressure and temperature along the pipelines and wellbores. The mathematical model for steam flow in injection systems, developed by a mechanistic approach (VapMec) performed well when the simulated values of pressures and temperatures were compared with the values measured during field tests. The newly developed VapMec model was incorporated in the LinVap-3 simulator that constitutes an engineering supporting tool for steam injection wells operated by Petrobras. 23 refs., 7 tabs., 6 figs.

  10. Mechanistic phenotypes: an aggregative phenotyping strategy to identify disease mechanisms using GWAS data.

    Directory of Open Access Journals (Sweden)

    Jonathan D Mosley

    Full Text Available A single mutation can alter cellular and global homeostatic mechanisms and give rise to multiple clinical diseases. We hypothesized that these disease mechanisms could be identified using low minor allele frequency (MAF<0.1 non-synonymous SNPs (nsSNPs associated with "mechanistic phenotypes", comprised of collections of related diagnoses. We studied two mechanistic phenotypes: (1 thrombosis, evaluated in a population of 1,655 African Americans; and (2 four groupings of cancer diagnoses, evaluated in 3,009 white European Americans. We tested associations between nsSNPs represented on GWAS platforms and mechanistic phenotypes ascertained from electronic medical records (EMRs, and sought enrichment in functional ontologies across the top-ranked associations. We used a two-step analytic approach whereby nsSNPs were first sorted by the strength of their association with a phenotype. We tested associations using two reverse genetic models and standard additive and recessive models. In the second step, we employed a hypothesis-free ontological enrichment analysis using the sorted nsSNPs to identify functional mechanisms underlying the diagnoses comprising the mechanistic phenotypes. The thrombosis phenotype was solely associated with ontologies related to blood coagulation (Fisher's p = 0.0001, FDR p = 0.03, driven by the F5, P2RY12 and F2RL2 genes. For the cancer phenotypes, the reverse genetics models were enriched in DNA repair functions (p = 2×10-5, FDR p = 0.03 (POLG/FANCI, SLX4/FANCP, XRCC1, BRCA1, FANCA, CHD1L while the additive model showed enrichment related to chromatid segregation (p = 4×10-6, FDR p = 0.005 (KIF25, PINX1. We were able to replicate nsSNP associations for POLG/FANCI, BRCA1, FANCA and CHD1L in independent data sets. Mechanism-oriented phenotyping using collections of EMR-derived diagnoses can elucidate fundamental disease mechanisms.

  11. Mechanistic species distribution modeling reveals a niche shift during invasion.

    Science.gov (United States)

    Chapman, Daniel S; Scalone, Romain; Štefanić, Edita; Bullock, James M

    2017-06-01

    Niche shifts of nonnative plants can occur when they colonize novel climatic conditions. However, the mechanistic basis for niche shifts during invasion is poorly understood and has rarely been captured within species distribution models. We quantified the consequence of between-population variation in phenology for invasion of common ragweed (Ambrosia artemisiifolia L.) across Europe. Ragweed is of serious concern because of its harmful effects as a crop weed and because of its impact on public health as a major aeroallergen. We developed a forward mechanistic species distribution model based on responses of ragweed development rates to temperature and photoperiod. The model was parameterized and validated from the literature and by reanalyzing data from a reciprocal common garden experiment in which native and invasive populations were grown within and beyond the current invaded range. It could therefore accommodate between-population variation in the physiological requirements for flowering, and predict the potentially invaded ranges of individual populations. Northern-origin populations that were established outside the generally accepted climate envelope of the species had lower thermal requirements for bud development, suggesting local adaptation of phenology had occurred during the invasion. The model predicts that this will extend the potentially invaded range northward and increase the average suitability across Europe by 90% in the current climate and 20% in the future climate. Therefore, trait variation observed at the population scale can trigger a climatic niche shift at the biogeographic scale. For ragweed, earlier flowering phenology in established northern populations could allow the species to spread beyond its current invasive range, substantially increasing its risk to agriculture and public health. Mechanistic species distribution models offer the possibility to represent niche shifts by varying the traits and niche responses of individual

  12. Mechanistic study of aerosol dry deposition on vegetated canopies

    International Nuclear Information System (INIS)

    Petroff, A.

    2005-04-01

    The dry deposition of aerosols onto vegetated canopies is modelled through a mechanistic approach. The interaction between aerosols and vegetation is first formulated by using a set of parameters, which are defined at the local scale of one surface. The overall deposition is then deduced at the canopy scale through an up-scaling procedure based on the statistic distribution parameters. This model takes into account the canopy structural and morphological properties, and the main characteristics of the turbulent flow. Deposition mechanisms considered are Brownian diffusion, interception, initial and turbulent impaction, initially with coniferous branches and then with entire canopies of different roughness, such as grass, crop field and forest. (author)

  13. Mechanistic modeling of CHF in forced-convection subcooled boiling

    International Nuclear Information System (INIS)

    Podowski, M.Z.; Alajbegovic, A.; Kurul, N.; Drew, D.A.; Lahey, R.T. Jr.

    1997-05-01

    Because of the complexity of phenomena governing boiling heat transfer, the approach to solve practical problems has traditionally been based on experimental correlations rather than mechanistic models. The recent progress in computational fluid dynamics (CFD), combined with improved experimental techniques in two-phase flow and heat transfer, makes the use of rigorous physically-based models a realistic alternative to the current simplistic phenomenological approach. The objective of this paper is to present a new CFD model for critical heat flux (CHF) in low quality (in particular, in subcooled boiling) forced-convection flows in heated channels

  14. Mechanistic CHF modeling for natural circulation applications in SMR

    Energy Technology Data Exchange (ETDEWEB)

    Luitjens, Jeffrey [Department of Nuclear Engineering and Radiation Health Physics, Oregon State University, 3451 SW Jefferson Way, Corvallis, OR 97331 (United States); Wu, Qiao, E-mail: qiao.wu@oregonstate.edu [Department of Nuclear Engineering and Radiation Health Physics, Oregon State University, 3451 SW Jefferson Way, Corvallis, OR 97331 (United States); Greenwood, Scott; Corradini, Michael [Department of Engineering Physics, University of Wisconsin, 1415 Engineering Drive, Madison, WI 53706 (United States)

    2016-12-15

    A mechanistic critical heat flux correlation has been developed for a wide range of operating conditions which include low mass fluxes of 540–890 kg/m{sup 2}-s, high pressures of 12–13 MPa, and critical heat fluxes of 835–1100 kW/m{sup 2}. Eleven experimental data points have been collected over these conditions to inform the development of the model using bundle geometry. Errors of within 15% have been obtained with the proposed model for predicting the critical heat flux value, location, and critical pin power for a non-uniform heat flux applied to a 2 × 2 bundle configuration.

  15. Experimental investigation and mechanistic modelling of dilute bubbly bulk boiling

    Energy Technology Data Exchange (ETDEWEB)

    Kutnjak, Josip

    2013-06-27

    During evaporation the geometric shape of the vapour is not described using thermodynamics. In bubbly flows the bubble shape is considered spheric with small diameters and changing into various shapes upon growth. The heat and mass transfer happens at the interfacial area. The forces acting on the bubbles depend on the bubble diameter and shape. In this work the prediction of the bubble diameter and/or bubble number density in bulk boiling was considered outside the vicinity of the heat input area. Thus the boiling effects that happened inside the nearly saturated bulk were under investigation. This situation is relevant for nuclear safety analysis concerning a stagnant coolant in the spent fuel pool. In this research project a new experimental set-up to investigate was built. The experimental set-up consists of an instrumented, partly transparent, high and slender boiling container for visual observation. The direct visual observation of the boiling phenomena is necessary for the identification of basic mechanisms, which should be incorporated in the simulation model. The boiling process has been recorded by means of video images and subsequently was evaluated by digital image processing methods, and by that data concerning the characteristics of the boiling process were generated for the model development and validation. Mechanistic modelling is based on the derivation of relevant mechanisms concluded from observation, which is in line with physical knowledge. In this context two mechanisms were identified; the growth/-shrink mechanism (GSM) of the vapour bubbles and sudden increases of the bubble number density. The GSM was implemented into the CFD-Code ANSYS-CFX using the CFX Expression Language (CEL) by calculation of the internal bubble pressure using the Young-Laplace-Equation. This way a hysteresis is realised as smaller bubbles have an increased internal pressure. The sudden increases of the bubble number density are explainable by liquid super

  16. Experimental investigation and mechanistic modelling of dilute bubbly bulk boiling

    International Nuclear Information System (INIS)

    Kutnjak, Josip

    2013-01-01

    During evaporation the geometric shape of the vapour is not described using thermodynamics. In bubbly flows the bubble shape is considered spheric with small diameters and changing into various shapes upon growth. The heat and mass transfer happens at the interfacial area. The forces acting on the bubbles depend on the bubble diameter and shape. In this work the prediction of the bubble diameter and/or bubble number density in bulk boiling was considered outside the vicinity of the heat input area. Thus the boiling effects that happened inside the nearly saturated bulk were under investigation. This situation is relevant for nuclear safety analysis concerning a stagnant coolant in the spent fuel pool. In this research project a new experimental set-up to investigate was built. The experimental set-up consists of an instrumented, partly transparent, high and slender boiling container for visual observation. The direct visual observation of the boiling phenomena is necessary for the identification of basic mechanisms, which should be incorporated in the simulation model. The boiling process has been recorded by means of video images and subsequently was evaluated by digital image processing methods, and by that data concerning the characteristics of the boiling process were generated for the model development and validation. Mechanistic modelling is based on the derivation of relevant mechanisms concluded from observation, which is in line with physical knowledge. In this context two mechanisms were identified; the growth/-shrink mechanism (GSM) of the vapour bubbles and sudden increases of the bubble number density. The GSM was implemented into the CFD-Code ANSYS-CFX using the CFX Expression Language (CEL) by calculation of the internal bubble pressure using the Young-Laplace-Equation. This way a hysteresis is realised as smaller bubbles have an increased internal pressure. The sudden increases of the bubble number density are explainable by liquid super

  17. Application of mechanistic empirical approach to predict rutting of superpave mixtures in Iraq

    Directory of Open Access Journals (Sweden)

    Qasim Zaynab

    2018-01-01

    Full Text Available In Iraq rutting is considered as a real distress in flexible pavements as a result of high summer temperature, and increased axle loads. This distress majorly affects asphalt pavement performance, lessens the pavement useful service life and makes serious hazards for highway users. Performance of HMA mixtures against rutting using Mechanistic- Empirical approach is predicted by considering Wheel-Tracking test and employing the Superpave mix design requirements. Roller Wheel Compactor has been locally manufactured to prepare slab specimens. In view of study laboratory outcomes that are judged to be simulative of field loading conditions, models are developed for predicting permanent strain of compacted samples of local asphalt concrete mixtures after considering the stress level, properties of local material and environmental impacts variables. All in all, laboratory results were produced utilizing statistical analysis with the aid of SPSS software. Permanent strain models for asphalt concrete mixtures were developed as a function of: number of passes, temperature, asphalt content, viscosity, air voids and additive content. Mechanistic Empirical design approach through the MnPAVE software was applied to characterize rutting in HMA and to predict allowable number of loading repetitions of mixtures as a function of expected traffic loads, material properties, and environmental temperature.

  18. Mutual Dependence Between Sedimentary Organic Carbon and Infaunal Macrobenthos Resolved by Mechanistic Modeling

    Science.gov (United States)

    Zhang, Wenyan; Wirtz, Kai

    2017-10-01

    The mutual dependence between sedimentary total organic carbon (TOC) and infaunal macrobenthos is here quantified by a mechanistic model. The model describes (i) the vertical distribution of infaunal macrobenthic biomass resulting from a trade-off between nutritional benefit (quantity and quality of TOC) and the costs of burial (respiration) and mortality, and (ii) the variable vertical distribution of TOC being in turn shaped by bioturbation of local macrobenthos. In contrast to conventional approaches, our model emphasizes variations of bioturbation both spatially and temporally depending on local food resources and macrobenthic biomass. Our implementation of the dynamic interaction between TOC and infaunal macrobenthos is able to capture a temporal benthic response to both depositional and erosional environments and provides improved estimates of the material exchange flux at the sediment-water interface. Applications to literature data for the North Sea demonstrate the robustness and accuracy of the model and its potential as an analysis tool for the status of TOC and macrobenthos in marine sediments. Results indicate that the vertical distribution of infaunal biomass is shaped by both the quantity and the quality of OC, while the community structure is determined only by the quality of OC. Bioturbation intensity may differ by 1 order of magnitude over different seasons owing to variations in the OC input, resulting in a significant modulation on the distribution of OC. Our relatively simple implementation may further improve models of early diagenesis and marine food web dynamics by mechanistically connecting the vertical distribution of both TOC and macrobenthic biomass.

  19. A Mechanistic Reliability Assessment of RVACS and Metal Fuel Inherent Reactivity Feedbacks

    Energy Technology Data Exchange (ETDEWEB)

    Grabaskas, David; Brunett, Acacia J.; Passerini, Stefano; Grelle, Austin

    2017-09-24

    GE Hitachi Nuclear Energy (GEH) and Argonne National Laboratory (Argonne) participated in a two year collaboration to modernize and update the probabilistic risk assessment (PRA) for the PRISM sodium fast reactor. At a high level, the primary outcome of the project was the development of a next-generation PRA that is intended to enable risk-informed prioritization of safety- and reliability-focused research and development. A central Argonne task during this project was a reliability assessment of passive safety systems, which included the Reactor Vessel Auxiliary Cooling System (RVACS) and the inherent reactivity feedbacks of the metal fuel core. Both systems were examined utilizing a methodology derived from the Reliability Method for Passive Safety Functions (RMPS), with an emphasis on developing success criteria based on mechanistic system modeling while also maintaining consistency with the Fuel Damage Categories (FDCs) of the mechanistic source term assessment. This paper provides an overview of the reliability analyses of both systems, including highlights of the FMEAs, the construction of best-estimate models, uncertain parameter screening and propagation, and the quantification of system failure probability. In particular, special focus is given to the methodologies to perform the analysis of uncertainty propagation and the determination of the likelihood of violating FDC limits. Additionally, important lessons learned are also reviewed, such as optimal sampling methodologies for the discovery of low likelihood failure events and strategies for the combined treatment of aleatory and epistemic uncertainties.

  20. Applicability of one-dimensional mechanistic post-dryout prediction model

    International Nuclear Information System (INIS)

    Jeong, Hae Yong; No Hee Cheon

    1996-01-01

    Through the analysis of many experimental post-dryout data, it is shown that the most probable flow regime near dryout or quench front is not annular flow but churn-turbulent flow when the mass flux is low. A correlation describing the initial droplet size just after the CHF position at low mass flux is low. A correlation describing the initial droplet size just after the CHF position at low mass flux is suggested through regression analysis. In the post-dryout region at low pressure and low flow, it is found that the suggested one-dimensional mechanistic model is not applicable when the vapor superficial velocity is very low, i. e., when the flow is bubbly or slug flow regime. This is explained by the change of main entrainment mechanism with the change of flow regime. Therefore, the suggested correlation is valid only in the churn-turbulent flow regime (j * g = 0.5 ∼ 4.5)

  1. A Mechanistic Source Term Calculation for a Metal Fuel Sodium Fast Reactor

    Energy Technology Data Exchange (ETDEWEB)

    Grabaskas, David; Bucknor, Matthew; Jerden, James

    2017-06-26

    A mechanistic source term (MST) calculation attempts to realistically assess the transport and release of radionuclides from a reactor system to the environment during a specific accident sequence. The U.S. Nuclear Regulatory Commission (NRC) has repeatedly stated its expectation that advanced reactor vendors will utilize an MST during the U.S. reactor licensing process. As part of a project to examine possible impediments to sodium fast reactor (SFR) licensing in the U.S., an analysis was conducted regarding the current capabilities to perform an MST for a metal fuel SFR. The purpose of the project was to identify and prioritize any gaps in current computational tools, and the associated database, for the accurate assessment of an MST. The results of the study demonstrate that an SFR MST is possible with current tools and data, but several gaps exist that may lead to possibly unacceptable levels of uncertainty, depending on the goals of the MST analysis.

  2. Trichloroethylene: Mechanistic, epidemiologic and other supporting evidence of carcinogenic hazard.

    Science.gov (United States)

    Rusyn, Ivan; Chiu, Weihsueh A; Lash, Lawrence H; Kromhout, Hans; Hansen, Johnni; Guyton, Kathryn Z

    2014-01-01

    The chlorinated solvent trichloroethylene (TCE) is a ubiquitous environmental pollutant. The carcinogenic hazard of TCE was the subject of a 2012 evaluation by a Working Group of the International Agency for Research on Cancer (IARC). Information on exposures, relevant data from epidemiologic studies, bioassays in experimental animals, and toxicity and mechanism of action studies was used to conclude that TCE is carcinogenic to humans (Group 1). This article summarizes the key evidence forming the scientific bases for the IARC classification. Exposure to TCE from environmental sources (including hazardous waste sites and contaminated water) is common throughout the world. While workplace use of TCE has been declining, occupational exposures remain of concern, especially in developing countries. The strongest human evidence is from studies of occupational TCE exposure and kidney cancer. Positive, although less consistent, associations were reported for liver cancer and non-Hodgkin lymphoma. TCE is carcinogenic at multiple sites in multiple species and strains of experimental animals. The mechanistic evidence includes extensive data on the toxicokinetics and genotoxicity of TCE and its metabolites. Together, available evidence provided a cohesive database supporting the human cancer hazard of TCE, particularly in the kidney. For other target sites of carcinogenicity, mechanistic and other data were found to be more limited. Important sources of susceptibility to TCE toxicity and carcinogenicity were also reviewed by the Working Group. In all, consideration of the multiple evidence streams presented herein informed the IARC conclusions regarding the carcinogenicity of TCE. © 2013.

  3. The coefficient of restitution of pressurized balls: a mechanistic model

    Science.gov (United States)

    Georgallas, Alex; Landry, Gaëtan

    2016-01-01

    Pressurized, inflated balls used in professional sports are regulated so that their behaviour upon impact can be anticipated and allow the game to have its distinctive character. However, the dynamics governing the impacts of such balls, even on stationary hard surfaces, can be extremely complex. The energy transformations, which arise from the compression of the gas within the ball and from the shear forces associated with the deformation of the wall, are examined in this paper. We develop a simple mechanistic model of the dependence of the coefficient of restitution, e, upon both the gauge pressure, P_G, of the gas and the shear modulus, G, of the wall. The model is validated using the results from a simple series of experiments using three different sports balls. The fits to the data are extremely good for P_G > 25 kPa and consistent values are obtained for the value of G for the wall material. As far as the authors can tell, this simple, mechanistic model of the pressure dependence of the coefficient of restitution is the first in the literature. *%K Coefficient of Restitution, Dynamics, Inflated Balls, Pressure, Impact Model

  4. New web-based applications for mechanistic case diagramming

    Directory of Open Access Journals (Sweden)

    Fred R. Dee

    2014-07-01

    Full Text Available The goal of mechanistic case diagraming (MCD is to provide students with more in-depth understanding of cause and effect relationships and basic mechanistic pathways in medicine. This will enable them to better explain how observed clinical findings develop from preceding pathogenic and pathophysiological events. The pedagogic function of MCD is in relating risk factors, disease entities and morphology, signs and symptoms, and test and procedure findings in a specific case scenario with etiologic pathogenic and pathophysiological sequences within a flow diagram. In this paper, we describe the addition of automation and predetermined lists to further develop the original concept of MCD as described by Engelberg in 1992 and Guerrero in 2001. We demonstrate that with these modifications, MCD is effective and efficient in small group case-based teaching for second-year medical students (ratings of ~3.4 on a 4.0 scale. There was also a significant correlation with other measures of competency, with a ‘true’ score correlation of 0.54. A traditional calculation of reliability showed promising results (α =0.47 within a low stakes, ungraded environment. Further, we have demonstrated MCD's potential for use in independent learning and TBL. Future studies are needed to evaluate MCD's potential for use in medium stakes assessment or self-paced independent learning and assessment. MCD may be especially relevant in returning students to the application of basic medical science mechanisms in the clinical years.

  5. 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...

  6. Toxicogenomic response of Mycobacterium bovis BCG to peracetic acid and a comparative analysis of the M. bovis BCG response to three oxidative disinfectants.

    Science.gov (United States)

    Nde, Chantal W; Toghrol, Freshteh; Jang, Hyeung-Jin; Bentley, William E

    2011-04-01

    Tuberculosis is a leading cause of death worldwide and infects thousands of Americans annually. Mycobacterium bovis causes tuberculosis in humans and several animal species. Peracetic acid is an approved tuberculocide in hospital and domestic environments. This study presents for the first time the transcriptomic changes in M. bovis BCG after treatment with 0.1 mM peracetic acid for 10 and 20 min. This study also presents for the first time a comparison among the transcriptomic responses of M. bovis BCG to three oxidative disinfectants: peracetic acid, sodium hypochlorite, and hydrogen peroxide after 10 min of treatment. Results indicate that arginine biosynthesis, virulence, and oxidative stress response genes were upregulated after both peracetic acid treatment times. Three DNA repair genes were downregulated after 10 and 20 min and cell wall component genes were upregulated after 20 min. The devR-devS signal transduction system was upregulated after 10 min, suggesting a role in the protection against peracetic acid treatment. Results also suggest that peracetic acid and sodium hypochlorite both induce the expression of the ctpF gene which is upregulated in hypoxic environments. Further, this study reveals that in M. bovis BCG, hydrogen peroxide and peracetic acid both induce the expression of katG involved in oxidative stress response and the mbtD and mbtI genes involved in iron regulation/virulence.

  7. Detailed Mechanistic Studies on Palladium-Catalyzed Selective C-H Olefination with Aliphatic Alkenes: A Significant Influence of Proton Shuttling.

    Science.gov (United States)

    Deb, Arghya; Hazra, Avijit; Peng, Qian; Paton, Robert S; Maiti, Debabrata

    2017-01-18

    Directing group-assisted regioselective C-H olefination with electronically biased olefins is well studied. However, the incorporation of unactivated olefins has remained largely unsuccessful. A proper mechanistic understanding of olefination involving unactivated alkenes is therefore essential for enhancing their usage in future. In this Article, detailed experimental and computational mechanistic studies on palladium catalyzed C-H olefination with unactivated, aliphatic alkenes are described. The isolation of Pd(II) intermediates is shown to be effective for elucidating the elementary steps involved in catalytic olefination. Reaction rate and order determination, control experiments, isotopic labeling studies, and Hammett analysis have been used to understand the reaction mechanism. The results from these experimental studies implicate β-hydride elimination as the rate-determining step and that a mechanistic switch occurs between cationic and neutral pathway. Computational studies support this interpretation of the experimental evidence and are used to uncover the origins of selectivity.

  8. Application of mechanistic models to fermentation and biocatalysis for next-generation processes

    DEFF Research Database (Denmark)

    Gernaey, Krist; Eliasson Lantz, Anna; Tufvesson, Pär

    2010-01-01

    of variables required for measurement, control and process design. In the near future, mechanistic models with a higher degree of detail will play key roles in the development of efficient next-generation fermentation and biocatalytic processes. Moreover, mechanistic models will be used increasingly......Mechanistic models are based on deterministic principles, and recently, interest in them has grown substantially. Herein we present an overview of mechanistic models and their applications in biotechnology, including future perspectives. Model utility is highlighted with respect to selection...

  9. From patterns to emerging processes in mechanistic urban ecology.

    Science.gov (United States)

    Shochat, Eyal; Warren, Paige S; Faeth, Stanley H; McIntyre, Nancy E; Hope, Diane

    2006-04-01

    Rapid urbanization has become an area of crucial concern in conservation owing to the radical changes in habitat structure and loss of species engendered by urban and suburban development. Here, we draw on recent mechanistic ecological studies to argue that, in addition to altered habitat structure, three major processes contribute to the patterns of reduced species diversity and elevated abundance of many species in urban environments. These activities, in turn, lead to changes in animal behavior, morphology and genetics, as well as in selection pressures on animals and plants. Thus, the key to understanding urban patterns is to balance studying processes at the individual level with an integrated examination of environmental forces at the ecosystem scale.

  10. Mechanistic model for void distribution in flashing flow

    International Nuclear Information System (INIS)

    Riznic, J.; Ishii, M.; Afgan, N.

    1987-01-01

    A problem of discharging of an initially subcooled liquid from a high pressure condition into a low pressure environment is quite important in several industrial systems such as nuclear reactors and chemical reactors. A new model for the flashing process is proposed here based on the wall nucleation theory, bubble growth model and drift-flux bubble transport model. In order to calculate the bubble number density, the bubble number transport equation with a distributed source from the wall nucleation sites is used. The model predictions in terms of the void fraction are compared to Moby Dick and BNL experimental data. It shows that satisfactory agreements could be obtained from the present model without any floating parameter to be adjusted with data. This result indicates that, at least for the experimental conditions considered here, the mechanistic prediction of the flashing phenomenon is possible based on the present wall nucleation based model. 43 refs., 4 figs

  11. Toward a Rational and Mechanistic Account of Mental Effort.

    Science.gov (United States)

    Shenhav, Amitai; Musslick, Sebastian; Lieder, Falk; Kool, Wouter; Griffiths, Thomas L; Cohen, Jonathan D; Botvinick, Matthew M

    2017-07-25

    In spite of its familiar phenomenology, the mechanistic basis for mental effort remains poorly understood. Although most researchers agree that mental effort is aversive and stems from limitations in our capacity to exercise cognitive control, it is unclear what gives rise to those limitations and why they result in an experience of control as costly. The presence of these control costs also raises further questions regarding how best to allocate mental effort to minimize those costs and maximize the attendant benefits. This review explores recent advances in computational modeling and empirical research aimed at addressing these questions at the level of psychological process and neural mechanism, examining both the limitations to mental effort exertion and how we manage those limited cognitive resources. We conclude by identifying remaining challenges for theoretical accounts of mental effort as well as possible applications of the available findings to understanding the causes of and potential solutions for apparent failures to exert the mental effort required of us.

  12. Mechanistic failure mode investigation and resolution of parvovirus retentive filters.

    Science.gov (United States)

    LaCasse, Daniel; Lute, Scott; Fiadeiro, Marcus; Basha, Jonida; Stork, Matthew; Brorson, Kurt; Godavarti, Ranga; Gallo, Chris

    2016-07-08

    Virus retentive filters are a key product safety measure for biopharmaceuticals. A simplistic perception is that they function solely based on a size-based particle removal mechanism of mechanical sieving and retention of particles based on their hydrodynamic size. Recent observations have revealed a more nuanced picture, indicating that changes in viral particle retention can result from process pressure and/or flow interruptions. In this study, a mechanistic investigation was performed to help identify a potential mechanism leading to the reported reduced particle retention in small virus filters. Permeate flow rate or permeate driving force were varied and analyzed for their impact on particle retention in three commercially available small virus retentive filters. © 2016 American Institute of Chemical Engineers Biotechnol. Prog., 32:959-970, 2016. © 2016 American Institute of Chemical Engineers.

  13. A mechanistic model for the evolution of multicellularity

    Science.gov (United States)

    Amado, André; Batista, Carlos; Campos, Paulo R. A.

    2018-02-01

    Through a mechanistic approach we investigate the formation of aggregates of variable sizes, accounting mechanisms of aggregation, dissociation, death and reproduction. In our model, cells can produce two metabolites, but the simultaneous production of both metabolites is costly in terms of fitness. Thus, the formation of larger groups can favor the aggregates to evolve to a configuration where division of labor arises. It is assumed that the states of the cells in a group are those that maximize organismal fitness. In the model it is considered that the groups can grow linearly, forming a chain, or compactly keeping a roughly spherical shape. Starting from a population consisting of single-celled organisms, we observe the formation of groups with variable sizes and usually much larger than two-cell aggregates. Natural selection can favor the formation of large groups, which allows the system to achieve new and larger fitness maxima.

  14. Mechanistic systems modeling to guide drug discovery and development.

    Science.gov (United States)

    Schmidt, Brian J; Papin, Jason A; Musante, Cynthia J

    2013-02-01

    A crucial question that must be addressed in the drug development process is whether the proposed therapeutic target will yield the desired effect in the clinical population. Pharmaceutical and biotechnology companies place a large investment on research and development, long before confirmatory data are available from human trials. Basic science has greatly expanded the computable knowledge of disease processes, both through the generation of large omics data sets and a compendium of studies assessing cellular and systemic responses to physiologic and pathophysiologic stimuli. Given inherent uncertainties in drug development, mechanistic systems models can better inform target selection and the decision process for advancing compounds through preclinical and clinical research. Copyright © 2012 Elsevier Ltd. All rights reserved.

  15. Synthetic and mechanistic aspects of titanium-mediated carbonyl olefinations

    Energy Technology Data Exchange (ETDEWEB)

    Petasis, N.A.; Staszewski, J.P.; Hu, Yong-Han; Lu, Shao-Po [Univ. of Southern California, Los Angeles, CA (United States)

    1995-12-31

    A new method for the olefination of carbonyl compounds with dimethyl titanocene, and other related bishydrocarbyl titanocene derivatives has been recently developed in the author`s laboratories. This process is experimentally convenient and works with various types of carbonyl compounds, including aldehydes, ketones, esters, lactones, carbonates, anhydrides, amides, imides, lactams, thioesters, selenoesters, and acylsilanes. More recent studies have focused on the scope and utility of this reaction, including mechanistic studies and synthetic applications. In addition to varying the reaction conditions, the authors have examined several mixed titanocene derivatives and have found ways for carrying out this type of olefination at room temperature, such as the use of tris(trimethylsilyl) titanacyclobutene. The authors have also employed this reaction in the modification of carbohydrates and cyclobutenediones. This olefination was also followed-up with subsequent transformations to produce carbocycles and heterocycles, including tetrahydrofurans and tetrahydropyrans.

  16. Behavioural Procedural Models – a multipurpose mechanistic account

    Directory of Open Access Journals (Sweden)

    Leonardo Ivarola

    2012-05-01

    Full Text Available In this paper we outline an epistemological defence of what wecall Behavioural Procedural Models (BPMs, which represent the processes of individual decisions that lead to relevant economic patterns as psychologically (rather than rationally driven. Their general structure, and the way in which they may be incorporated to a multipurpose view of models, where the representational and interventionist goals are combined, is shown. It is argued that BPMs may provide “mechanistic-based explanations” in the sense defended by Hedström and Ylikoski (2010, which involve invariant regularities in Woodward’s sense. Such mechanisms provide a causal sort of explanation of anomalous economic patterns, which allow for extra marketintervention and manipulability in order to correct and improve some key individual decisions. This capability sets the basis for the so called libertarian paternalism (Sunstein and Thaler 2003.

  17. Mechanistic modelling of gaseous fission product behaviour in UO2 fuel by Rtop code

    International Nuclear Information System (INIS)

    Kanukova, V.D.; Khoruzhii, O.V.; Kourtchatov, S.Y.; Likhanskii, V.V.; Matveew, L.V.

    2002-01-01

    The current status of a mechanistic modelling by the RTOP code of the fission product behaviour in polycrystalline UO 2 fuel is described. An outline of the code and implemented physical models is presented. The general approach to code validation is discussed. It is exemplified by the results of validation of the models of fuel oxidation and grain growth. The different models of intragranular and intergranular gas bubble behaviour have been tested and the sensitivity of the code in the framework of these models has been analysed. An analysis of available models of the resolution of grain face bubbles is also presented. The possibilities of the RTOP code are presented through the example of modelling behaviour of WWER fuel over the course of a comparative WWER-PWR experiment performed at Halden and by comparison with Yanagisawa experiments. (author)

  18. Combined In Situ Illumination-NMR-UV/Vis Spectroscopy: A New Mechanistic Tool in Photochemistry.

    Science.gov (United States)

    Seegerer, Andreas; Nitschke, Philipp; Gschwind, Ruth M

    2018-06-18

    Synthetic applications in photochemistry are booming. Despite great progress in the development of new reactions, mechanistic investigations are still challenging. Therefore, we present a fully automated in situ combination of NMR spectroscopy, UV/Vis spectroscopy, and illumination to allow simultaneous and time-resolved detection of paramagnetic and diamagnetic species. This optical fiber-based setup enables the first acquisition of combined UV/Vis and NMR spectra in photocatalysis, as demonstrated on a conPET process. Furthermore, the broad applicability of combined UVNMR spectroscopy for light-induced processes is demonstrated on a structural and quantitative analysis of a photoswitch, including rate modulation and stabilization of transient species by temperature variation. Owing to the flexibility regarding the NMR hardware, temperature, and light sources, we expect wide-ranging applications of this setup in various research fields. © 2018 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA.

  19. A mechanistic Eulerian-Lagrangian model for dispersed flow film boiling

    International Nuclear Information System (INIS)

    Andreani, M.; Yadigaroglu, G.

    1991-01-01

    In this paper a new mechanistic model of heat transfer in the dispersed flow regime is presented. The usual assumptions that render most of the available models unsuitable for the analysis of the reflooding phase of the LOCA are discussed, and a two-dimensional time-independent numerical model is developed. The gas temperature field is solved in a fixed-grid (Eulerian) mesh, with the droplets behaving as mass and energy sources. The histories of a large number of computational droplets are followed in a Lagrangian frame, considering evaporation, break-up and interactions with the vapor and with the wall. comparisons of calculated wall and vapor temperatures with experimental data are shown for two reflooding tests

  20. Toxic neuropathies: Mechanistic insights based on a chemical perspective.

    Science.gov (United States)

    LoPachin, Richard M; Gavin, Terrence

    2015-06-02

    2,5-Hexanedione (HD) and acrylamide (ACR) are considered to be prototypical among chemical toxicants that cause central-peripheral axonopathies characterized by distal axon swelling and degeneration. Because the demise of distal regions was assumed to be causally related to the onset of neurotoxicity, substantial effort was devoted to deciphering the respective mechanisms. Continued research, however, revealed that expression of the presumed hallmark morphological features was dependent upon the daily rate of toxicant exposure. Indeed, many studies reported that the corresponding axonopathic changes were late developing effects that occurred independent of behavioral and/or functional neurotoxicity. This suggested that the toxic axonopathy classification might be based on epiphenomena related to dose-rate. Therefore, the goal of this mini-review is to discuss how quantitative morphometric analyses and the establishment of dose-dependent relationships helped distinguish primary, mechanistically relevant toxicant effects from non-specific consequences. Perhaps more importantly, we will discuss how knowledge of neurotoxicant chemical nature can guide molecular-level research toward a better, more rational understanding of mechanism. Our discussion will focus on HD, the neurotoxic γ-diketone metabolite of the industrial solvents n-hexane and methyl-n-butyl ketone. Early investigations suggested that HD caused giant neurofilamentous axonal swellings and eventual degeneration in CNS and PNS. However, as our review will point out, this interpretation underwent several iterations as the understanding of γ-diketone chemistry improved and more quantitative experimental approaches were implemented. The chemical concepts and design strategies discussed in this mini-review are broadly applicable to the mechanistic studies of other chemicals (e.g., n-propyl bromine, methyl methacrylate) that cause toxic neuropathies. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  1. A Mechanistic Beta-Binomial Probability Model for mRNA Sequencing Data.

    Science.gov (United States)

    Smith, Gregory R; Birtwistle, Marc R

    2016-01-01

    A main application for mRNA sequencing (mRNAseq) is determining lists of differentially-expressed genes (DEGs) between two or more conditions. Several software packages exist to produce DEGs from mRNAseq data, but they typically yield different DEGs, sometimes markedly so. The underlying probability model used to describe mRNAseq data is central to deriving DEGs, and not surprisingly most softwares use different models and assumptions to analyze mRNAseq data. Here, we propose a mechanistic justification to model mRNAseq as a binomial process, with data from technical replicates given by a binomial distribution, and data from biological replicates well-described by a beta-binomial distribution. We demonstrate good agreement of this model with two large datasets. We show that an emergent feature of the beta-binomial distribution, given parameter regimes typical for mRNAseq experiments, is the well-known quadratic polynomial scaling of variance with the mean. The so-called dispersion parameter controls this scaling, and our analysis suggests that the dispersion parameter is a continually decreasing function of the mean, as opposed to current approaches that impose an asymptotic value to the dispersion parameter at moderate mean read counts. We show how this leads to current approaches overestimating variance for moderately to highly expressed genes, which inflates false negative rates. Describing mRNAseq data with a beta-binomial distribution thus may be preferred since its parameters are relatable to the mechanistic underpinnings of the technique and may improve the consistency of DEG analysis across softwares, particularly for moderately to highly expressed genes.

  2. Improving the International Agency for Research on Cancer's consideration of mechanistic evidence

    International Nuclear Information System (INIS)

    Goodman, Julie; Lynch, Heather

    2017-01-01

    Background: The International Agency for Research on Cancer (IARC) recently developed a framework for evaluating mechanistic evidence that includes a list of 10 key characteristics of carcinogens. This framework is useful for identifying and organizing large bodies of literature on carcinogenic mechanisms, but it lacks sufficient guidance for conducting evaluations that fully integrate mechanistic evidence into hazard assessments. Objectives: We summarize the framework, and suggest approaches to strengthen the evaluation of mechanistic evidence using this framework. Discussion: While the framework is useful for organizing mechanistic evidence, its lack of guidance for implementation limits its utility for understanding human carcinogenic potential. Specifically, it does not include explicit guidance for evaluating the biological significance of mechanistic endpoints, inter- and intra-individual variability, or study quality and relevance. It also does not explicitly address how mechanistic evidence should be integrated with other realms of evidence. Because mechanistic evidence is critical to understanding human cancer hazards, we recommend that IARC develop transparent and systematic guidelines for the use of this framework so that mechanistic evidence will be evaluated and integrated in a robust manner, and concurrently with other realms of evidence, to reach a final human cancer hazard conclusion. Conclusions: IARC does not currently provide a standardized approach to evaluating mechanistic evidence. Incorporating the recommendations discussed here will make IARC analyses of mechanistic evidence more transparent, and lead to assessments of cancer hazards that reflect the weight of the scientific evidence and allow for scientifically defensible decision-making. - Highlights: • IARC has a revised framework for evaluating literature on carcinogenic mechanisms. • The framework is based on 10 key characteristics of carcinogens. • IARC should develop transparent

  3. Improving the International Agency for Research on Cancer's consideration of mechanistic evidence

    Energy Technology Data Exchange (ETDEWEB)

    Goodman, Julie, E-mail: jgoodman@gradientcorp.com; Lynch, Heather

    2017-03-15

    Background: The International Agency for Research on Cancer (IARC) recently developed a framework for evaluating mechanistic evidence that includes a list of 10 key characteristics of carcinogens. This framework is useful for identifying and organizing large bodies of literature on carcinogenic mechanisms, but it lacks sufficient guidance for conducting evaluations that fully integrate mechanistic evidence into hazard assessments. Objectives: We summarize the framework, and suggest approaches to strengthen the evaluation of mechanistic evidence using this framework. Discussion: While the framework is useful for organizing mechanistic evidence, its lack of guidance for implementation limits its utility for understanding human carcinogenic potential. Specifically, it does not include explicit guidance for evaluating the biological significance of mechanistic endpoints, inter- and intra-individual variability, or study quality and relevance. It also does not explicitly address how mechanistic evidence should be integrated with other realms of evidence. Because mechanistic evidence is critical to understanding human cancer hazards, we recommend that IARC develop transparent and systematic guidelines for the use of this framework so that mechanistic evidence will be evaluated and integrated in a robust manner, and concurrently with other realms of evidence, to reach a final human cancer hazard conclusion. Conclusions: IARC does not currently provide a standardized approach to evaluating mechanistic evidence. Incorporating the recommendations discussed here will make IARC analyses of mechanistic evidence more transparent, and lead to assessments of cancer hazards that reflect the weight of the scientific evidence and allow for scientifically defensible decision-making. - Highlights: • IARC has a revised framework for evaluating literature on carcinogenic mechanisms. • The framework is based on 10 key characteristics of carcinogens. • IARC should develop transparent

  4. Linking spring phenology with mechanistic models of host movement to predict disease transmission risk

    Science.gov (United States)

    Merkle, Jerod A.; Cross, Paul C.; Scurlock, Brandon M.; Cole, Eric K.; Courtemanch, Alyson B.; Dewey, Sarah R.; Kauffman, Matthew J.

    2018-01-01

    Disease models typically focus on temporal dynamics of infection, while often neglecting environmental processes that determine host movement. In many systems, however, temporal disease dynamics may be slow compared to the scale at which environmental conditions alter host space-use and accelerate disease transmission.Using a mechanistic movement modelling approach, we made space-use predictions of a mobile host (elk [Cervus Canadensis] carrying the bacterial disease brucellosis) under environmental conditions that change daily and annually (e.g., plant phenology, snow depth), and we used these predictions to infer how spring phenology influences the risk of brucellosis transmission from elk (through aborted foetuses) to livestock in the Greater Yellowstone Ecosystem.Using data from 288 female elk monitored with GPS collars, we fit step selection functions (SSFs) during the spring abortion season and then implemented a master equation approach to translate SSFs into predictions of daily elk distribution for five plausible winter weather scenarios (from a heavy snow, to an extreme winter drought year). We predicted abortion events by combining elk distributions with empirical estimates of daily abortion rates, spatially varying elk seroprevelance and elk population counts.Our results reveal strong spatial variation in disease transmission risk at daily and annual scales that is strongly governed by variation in host movement in response to spring phenology. For example, in comparison with an average snow year, years with early snowmelt are predicted to have 64% of the abortions occurring on feedgrounds shift to occurring on mainly public lands, and to a lesser extent on private lands.Synthesis and applications. Linking mechanistic models of host movement with disease dynamics leads to a novel bridge between movement and disease ecology. Our analysis framework offers new avenues for predicting disease spread, while providing managers tools to proactively mitigate

  5. LASSIM-A network inference toolbox for genome-wide mechanistic modeling.

    Directory of Open Access Journals (Sweden)

    Rasmus Magnusson

    2017-06-01

    Full Text Available Recent technological advancements have made time-resolved, quantitative, multi-omics data available for many model systems, which could be integrated for systems pharmacokinetic use. Here, we present large-scale simulation modeling (LASSIM, which is a novel mathematical tool for performing large-scale inference using mechanistically defined ordinary differential equations (ODE for gene regulatory networks (GRNs. LASSIM integrates structural knowledge about regulatory interactions and non-linear equations with multiple steady state and dynamic response expression datasets. The rationale behind LASSIM is that biological GRNs can be simplified using a limited subset of core genes that are assumed to regulate all other gene transcription events in the network. The LASSIM method is implemented as a general-purpose toolbox using the PyGMO Python package to make the most of multicore computers and high performance clusters, and is available at https://gitlab.com/Gustafsson-lab/lassim. As a method, LASSIM works in two steps, where it first infers a non-linear ODE system of the pre-specified core gene expression. Second, LASSIM in parallel optimizes the parameters that model the regulation of peripheral genes by core system genes. We showed the usefulness of this method by applying LASSIM to infer a large-scale non-linear model of naïve Th2 cell differentiation, made possible by integrating Th2 specific bindings, time-series together with six public and six novel siRNA-mediated knock-down experiments. ChIP-seq showed significant overlap for all tested transcription factors. Next, we performed novel time-series measurements of total T-cells during differentiation towards Th2 and verified that our LASSIM model could monitor those data significantly better than comparable models that used the same Th2 bindings. In summary, the LASSIM toolbox opens the door to a new type of model-based data analysis that combines the strengths of reliable mechanistic models

  6. Exploring the pros and cons of mechanistic case diagrams for problem-based learning

    Directory of Open Access Journals (Sweden)

    Minjeong Kim

    2017-09-01

    Full Text Available Purpose Mechanistic case diagram (MCD was recommended for increasing the depth of understanding of disease, but with few articles on its specific methods. We address the experience of making MCD in the fullest depth to identify the pros and cons of using MCDs in such ways. Methods During problem-based learning, we gave guidelines of MCD for its mechanistic exploration from subcellular processes to clinical features, being laid out in as much detail as possible. To understand the students’ attitudes and depth of study using MCDs, we analyzed the results of a questionnaire in an open format about experiencing MCDs and examined the resulting products. Results Through the responses to questionnaire, we found several favorable outcomes, major of which was deeper insight and comprehensive understanding of disease facilitated by the process of making well-organized diagram. The main disadvantages of these guidelines were the feeling of too much workload and difficulty of finding mechanisms. Students gave suggestions to overcome these problems: cautious reading of comprehensive texts, additional guidance from staff about depth and focus of mechanisms, and cooperative group work. From the analysis of maps, we recognized there should be allowance of diversities in the appearance of maps and many hypothetical connections, which could be related to an insufficient understanding of mechanisms in nature. Conclusion The more detailed an MCD task is, the better students can become acquainted with deep knowledges. However, this advantage should be balanced by the results that there are many ensuing difficulties for the work and deliberate help plans should be prepared.

  7. Modeling Bird Migration under Climate Change: A Mechanistic Approach

    Science.gov (United States)

    Smith, James A.

    2009-01-01

    How will migrating birds respond to changes in the environment under climate change? What are the implications for migratory success under the various accelerated climate change scenarios as forecast by the Intergovernmental Panel on Climate Change? How will reductions or increased variability in the number or quality of wetland stop-over sites affect migratory bird species? The answers to these questions have important ramifications for conservation biology and wildlife management. Here, we describe the use of continental scale simulation modeling to explore how spatio-temporal changes along migratory flyways affect en-route migration success. We use an individually based, biophysical, mechanistic, bird migration model to simulate the movement of shorebirds in North America as a tool to study how such factors as drought and wetland loss may impact migratory success and modify migration patterns. Our model is driven by remote sensing and climate data and incorporates important landscape variables. The energy budget components of the model include resting, foraging, and flight, but presently predation is ignored. Results/Conclusions We illustrate our model by studying the spring migration of sandpipers through the Great Plains to their Arctic breeding grounds. Why many species of shorebirds have shown significant declines remains a puzzle. Shorebirds are sensitive to stop-over quality and spacing because of their need for frequent refueling stops and their opportunistic feeding patterns. We predict bird "hydrographs that is, stop-over frequency with latitude, that are in agreement with the literature. Mean stop-over durations predicted from our model for nominal cases also are consistent with the limited, but available data. For the shorebird species simulated, our model predicts that shorebirds exhibit significant plasticity and are able to shift their migration patterns in response to changing drought conditions. However, the question remains as to whether this

  8. On the antibacterial effects of manuka honey: mechanistic insights

    Directory of Open Access Journals (Sweden)

    Roberts AEL

    2015-10-01

    Full Text Available Aled Edward Lloyd Roberts,* Helen Louise Brown,* Rowena Eleri Jenkins Department of Biomedical Sciences, Cardiff Metropolitan University, Cardiff, Wales, UK *These authors contributed equally to this work Abstract: Antimicrobial resistance (AMR is an increasing clinical problem precipitated by the inappropriate use of antibiotics in the later parts of the 20th Century. This problem, coupled with the lack of novel therapeutics in the development pipeline, means AMR is reaching crisis point, with an expected annual death rate of ten million people worldwide by 2050. To reduce, and to potentially remedy this problem, many researchers are looking into natural compounds with antimicrobial and/or antivirulence activity. Manuka honey is an ancient antimicrobial remedy with a good track record against a wide range of nosocomial pathogens that have increased AMR. Its inhibitory effects are the result of its constituent components, which add varying degrees of antimicrobial efficacy to the overall activity of manuka honey. The antimicrobial efficacy of manuka honey and some of its constituent components (such as methylglyoxal and leptosperin are known to bestow some degree of antimicrobial efficacy to manuka honey. Despite growing in vitro evidence of its antimicrobial efficacy, the in vivo use of manuka honey (especially in a clinical environment has been unexpectedly slow, partly due to the lack of mechanistic data. The mechanism by which manuka honey achieves its inhibitory efficacy has recently been identified against Staphylococcus aureus and Pseudomonas aeruginosa, with both of these contrasting organisms being inhibited through different mechanisms. Manuka honey inhibits S. aureus by interfering with the cell division process, whereas P. aeruginosa cells lyse in its presence due to the reduction of a key structural protein. In addition to these inhibitory effects, manuka honey is known to reduce virulence, motility, and biofilm formation. With this

  9. Isoflurane is a suitable alternative to ether for anesthetizing rats prior to euthanasia for gene expression analysis.

    Science.gov (United States)

    Nakatsu, Noriyuki; Igarashi, Yoshinobu; Aoshi, Taiki; Hamaguchi, Isao; Saito, Masumichi; Mizukami, Takuo; Momose, Haruka; Ishii, Ken J; Yamada, Hiroshi

    2017-01-01

    Diethyl ether (ether) had been widely used in Japan for anesthesia, despite its explosive properties and toxicity to both humans and animals. We also had used ether as an anesthetic for euthanizing rats for research in the Toxicogenomics Project (TGP). Because the use of ether for these purposes will likely cease, it is required to select an alternative anesthetic which is validated for consistency with existing TGP data acquired under ether anesthesia. We therefore compared two alternative anesthetic candidates, isoflurane and pentobarbital, with ether in terms of hematological findings, serum biochemical parameters, and gene expressions. As a result, few differences among the three agents were observed. In hematological and serum biochemistry analysis, no significant changes were found. In gene expression analysis, four known genes were extracted as differentially expressed genes in the liver of rats anesthetized with ether, isoflurane, or pentobarbital. However, no significant relationships were detected using gene ontology, pathway, or gene enrichment analyses by DAVID and TargetMine. Surprisingly, although it was expected that the lung would be affected by administration via inhalation, only one differentially expressed gene was extracted in the lung. Taken together, our data indicate that there are no significant differences among ether, isoflurane, and pentobarbital with respect to effects on hematological parameters, serum biochemistry parameters, and gene expression. Based on its smallest affect to existing data and its safety profile for humans and animals, we suggest isoflurane as a suitable alternative anesthetic for use in rat euthanasia in toxicogenomics analysis.

  10. Mechanistic insight into neurotoxicity induced by developmental insults

    International Nuclear Information System (INIS)

    Tamm, Christoffer; Ceccatelli, Sandra

    2017-01-01

    Epidemiological and/or experimental studies have shown that unfavorable prenatal environmental factors, such as stress or exposure to certain neurotoxic environmental contaminants, may have adverse consequences for neurodevelopment. Alterations in neurogenesis can have harmful effects not only for the developing nervous system, but also for the adult brain where neurogenesis is believed to play a role in learning, memory, and even in depression. Many recent advances in the understanding of the complex process of nervous system development can be integrated into the field of neurotoxicology. In the past 15 years we have been using cultured neural stem or progenitor cells to investigate the effects of neurotoxic stimuli on cell survival, proliferation and differentiation, with special focus on heritable effects. This is an overview of the work performed by our group in the attempt to elucidate the mechanisms of developmental neurotoxicity and possibly provide relevant information for the understanding of the etiopathogenesis of complex brain disorders. - Highlights: • The developing nervous system is highly sensitive to toxic insults. • Neural stem cells are relevant models for mechanistic studies as well as for identifying heritable effects due to epigenetic changes. • Depending on the dose, the outcome of exposure to neurotoxicants ranges from altered proliferation and differentiation to cell death. • The elucidation of neurotoxicity mechanisms is relevant for understanding the etiopathogenesis of developmental and adult nervous system disorders.

  11. Mechanistic modeling of aberrant energy metabolism in human disease

    Directory of Open Access Journals (Sweden)

    Vineet eSangar

    2012-10-01

    Full Text Available Dysfunction in energy metabolism—including in pathways localized to the mitochondria—has been implicated in the pathogenesis of a wide array of disorders, ranging from cancer to neurodegenerative diseases to type II diabetes. The inherent complexities of energy and mitochondrial metabolism present a significant obstacle in the effort to understand the role that these molecular processes play in the development of disease. To help unravel these complexities, systems biology methods have been applied to develop an array of computational metabolic models, ranging from mitochondria-specific processes to genome-scale cellular networks. These constraint-based models can efficiently simulate aspects of normal and aberrant metabolism in various genetic and environmental conditions. Development of these models leverages—and also provides a powerful means to integrate and interpret—information from a wide range of sources including genomics, proteomics, metabolomics, and enzyme kinetics. Here, we review a variety of mechanistic modeling studies that explore metabolic functions, deficiency disorders, and aberrant biochemical pathways in mitochondria and related regions in the cell.

  12. Ancient Chinese medicine and mechanistic evidence of acupuncture physiology.

    Science.gov (United States)

    Yang, Edward S; Li, Pei-Wen; Nilius, Bernd; Li, Geng

    2011-11-01

    Acupuncture has been widely used in China for three millennia as an art of healing. Yet, its physiology is not yet understood. The current interest in acupuncture started in 1971. Soon afterward, extensive research led to the concept of neural signaling with possible involvement of opioid peptides, glutamate, adenosine and identifying responsive parts in the central nervous system. In the last decade scientists began investigating the subject with anatomical and molecular imaging. It was found that mechanical movements of the needle, ignored in the past, appear to be central to the method and intracellular calcium ions may play a pivotal role. In this review, we trace the technique of clinical treatment from the first written record about 2,200 years ago to the modern time. The ancient texts have been used to introduce the concepts of yin, yang, qi, de qi, and meridians, the traditional foundation of acupuncture. We explore the sequence of the physiological process, from the turning of the needle, the mechanical wave activation of calcium ion channel to beta-endorphin secretion. By using modern terminology to re-interpret the ancient texts, we have found that the 2nd century B.C.: physiologists were meticulous investigators and their explanation fits well with the mechanistic model derived from magnetic resonance imaging (MRI) and confocal microscopy. In conclusion, the ancient model appears to have withstood the test of time surprisingly well confirming the popular axiom that the old wine is better than the new.

  13. Mechanistic Perspectives of Maslinic Acid in Targeting Inflammation

    Directory of Open Access Journals (Sweden)

    Wei Hsum Yap

    2015-01-01

    Full Text Available Chronic inflammation drives the development of various pathological diseases such as rheumatoid arthritis, atherosclerosis, multiple sclerosis, and cancer. The arachidonic acid pathway represents one of the major mechanisms for inflammation. Prostaglandins (PGs are lipid products generated from arachidonic acid by the action of cyclooxygenase (COX enzymes and their activity is blocked by nonsteroidal anti-inflammatory drugs (NSAIDS. The use of natural compounds in regulation of COX activity/prostaglandins production is receiving increasing attention. In Mediterranean diet, olive oil and table olives contain significant dietary sources of maslinic acid. Maslinic acid is arising as a safe and novel natural pentacyclic triterpene which has protective effects against chronic inflammatory diseases in various in vivo and in vitro experimental models. Understanding the anti-inflammatory mechanism of maslinic acid is crucial for its development as a potential dietary nutraceutical. This review focuses on the mechanistic action of maslinic acid in regulating the inflammation pathways through modulation of the arachidonic acid metabolism including the nuclear factor-kappa B (NF-κB/COX-2 expression, upstream protein kinase signaling, and phospholipase A2 enzyme activity. Further investigations may provide insight into the mechanism of maslinic acid in regulating the molecular targets and their associated pathways in response to specific inflammatory stimuli.

  14. Diffusion theory in biology: a relic of mechanistic materialism.

    Science.gov (United States)

    Agutter, P S; Malone, P C; Wheatley, D N

    2000-01-01

    Diffusion theory explains in physical terms how materials move through a medium, e.g. water or a biological fluid. There are strong and widely acknowledged grounds for doubting the applicability of this theory in biology, although it continues to be accepted almost uncritically and taught as a basis of both biology and medicine. Our principal aim is to explore how this situation arose and has been allowed to continue seemingly unchallenged for more than 150 years. The main shortcomings of diffusion theory will be briefly reviewed to show that the entrenchment of this theory in the corpus of biological knowledge needs to be explained, especially as there are equally valid historical grounds for presuming that bulk fluid movement powered by the energy of cell metabolism plays a prominent note in the transport of molecules in the living body. First, the theory's evolution, notably from its origins in connection with the mechanistic materialist philosophy of mid nineteenth century physiology, is discussed. Following this, the entrenchment of the theory in twentieth century biology is analyzed in relation to three situations: the mechanism of oxygen transport between air and mammalian tissues; the structure and function of cell membranes; and the nature of the intermediary metalbolism, with its implicit presumptions about the intracellular organization and the movement of molecules within it. In our final section, we consider several historically based alternatives to diffusion theory, all of which have their precursors in nineteenth and twentieth century philosophy of science.

  15. A mechanistic compartmental model for total antibody uptake in tumors.

    Science.gov (United States)

    Thurber, Greg M; Dane Wittrup, K

    2012-12-07

    Antibodies are under development to treat a variety of cancers, such as lymphomas, colon, and breast cancer. A major limitation to greater efficacy for this class of drugs is poor distribution in vivo. Localization of antibodies occurs slowly, often in insufficient therapeutic amounts, and distributes heterogeneously throughout the tumor. While the microdistribution around individual vessels is important for many therapies, the total amount of antibody localized in the tumor is paramount for many applications such as imaging, determining the therapeutic index with antibody drug conjugates, and dosing in radioimmunotherapy. With imaging and pretargeted therapeutic strategies, the time course of uptake is critical in determining when to take an image or deliver a secondary reagent. We present here a simple mechanistic model of antibody uptake and retention that captures the major rates that determine the time course of antibody concentration within a tumor including dose, affinity, plasma clearance, target expression, internalization, permeability, and vascularization. Since many of the parameters are known or can be estimated in vitro, this model can approximate the time course of antibody concentration in tumors to aid in experimental design, data interpretation, and strategies to improve localization. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. Mechanistic studies of ethylene biosynthesis in higher plants

    International Nuclear Information System (INIS)

    McGeehan, G.M.

    1986-01-01

    Ethylene is a plant hormone that elicits a wide variety of responses in plant tissue. Among these responses are the hastening of abscission, ripening and senescence. In 1979 it was discovered that 1-amino-1-cyclopropane carboxylic acid is the immediate biosynthetic precursor to ethylene. Given the obvious economic significance of ethylene production the authors concentrated their studies on the conversion of ACC to ethylene. They delved into mechanistic aspects of ACC oxidation and they studied potential inhibitors of ethylene forming enzyme (EFE). They synthesized various analogs of ACC and found that EFE shows good stereodiscrimination among alkyl substituted ACC analogs with the 1R, 2S stereoisomer being processed nine times faster than the 1S, 2R isomer in the MeACC series. They also synthesized 2-cyclopropyl ACC which is a good competitive inhibitor of EFE. This compound also causes time dependent loss of EFE activity leading us to believe it is an irreversible inhibitor of ethylene formation. The synthesis of these analogs has also allowed them to develop a spectroscopic technique to assign the relative stereochemistry of alkyl groups. 13 C NMR allows them to assign the alkyl stereochemistry based upon gamma-shielding effects on the carbonyl resonance. Lastly, they measured kinetic isotope effects on the oxidation of ACC in vivo and in vitro and found that ACC is oxidized by a rate-determining 1-electron removal from nitrogen in close accord with mechanisms for the oxidation of other alkyl amines

  17. Enzymatic Halogenation and Dehalogenation Reactions: Pervasive and Mechanistically Diverse.

    Science.gov (United States)

    Agarwal, Vinayak; Miles, Zachary D; Winter, Jaclyn M; Eustáquio, Alessandra S; El Gamal, Abrahim A; Moore, Bradley S

    2017-04-26

    Naturally produced halogenated compounds are ubiquitous across all domains of life where they perform a multitude of biological functions and adopt a diversity of chemical structures. Accordingly, a diverse collection of enzyme catalysts to install and remove halogens from organic scaffolds has evolved in nature. Accounting for the different chemical properties of the four halogen atoms (fluorine, chlorine, bromine, and iodine) and the diversity and chemical reactivity of their organic substrates, enzymes performing biosynthetic and degradative halogenation chemistry utilize numerous mechanistic strategies involving oxidation, reduction, and substitution. Biosynthetic halogenation reactions range from simple aromatic substitutions to stereoselective C-H functionalizations on remote carbon centers and can initiate the formation of simple to complex ring structures. Dehalogenating enzymes, on the other hand, are best known for removing halogen atoms from man-made organohalogens, yet also function naturally, albeit rarely, in metabolic pathways. This review details the scope and mechanism of nature's halogenation and dehalogenation enzymatic strategies, highlights gaps in our understanding, and posits where new advances in the field might arise in the near future.

  18. Refined pipe theory for mechanistic modeling of wood development.

    Science.gov (United States)

    Deckmyn, Gaby; Evans, Sam P; Randle, Tim J

    2006-06-01

    We present a mechanistic model of wood tissue development in response to changes in competition, management and climate. The model is based on a refinement of the pipe theory, where the constant ratio between sapwood and leaf area (pipe theory) is replaced by a ratio between pipe conductivity and leaf area. Simulated pipe conductivity changes with age, stand density and climate in response to changes in allocation or pipe radius, or both. The central equation of the model, which calculates the ratio of carbon (C) allocated to leaves and pipes, can be parameterized to describe the contrasting stem conductivity behavior of different tree species: from constant stem conductivity (functional homeostasis hypothesis) to height-related reduction in stem conductivity with age (hydraulic limitation hypothesis). The model simulates the daily growth of pipes (vessels or tracheids), fibers and parenchyma as well as vessel size and simulates the wood density profile and the earlywood to latewood ratio from these data. Initial runs indicate the model yields realistic seasonal changes in pipe radius (decreasing pipe radius from spring to autumn) and wood density, as well as realistic differences associated with the competitive status of trees (denser wood in suppressed trees).

  19. Mechanistic understanding of monosaccharide-air flow battery electrochemistry

    Science.gov (United States)

    Scott, Daniel M.; Tsang, Tsz Ho; Chetty, Leticia; Aloi, Sekotilani; Liaw, Bor Yann

    Recently, an inexpensive monosaccharide-air flow battery configuration has been demonstrated to utilize a strong base and a mediator redox dye to harness electrical power from the partial oxidation of glucose. Here the mechanistic understanding of glucose oxidation in this unique glucose-air power source is further explored by acid-base titration experiments, 13C NMR, and comparison of results from chemically different redox mediators (indigo carmine vs. methyl viologen) and sugars (fructose vs. glucose) via studies using electrochemical techniques. Titration results indicate that gluconic acid is the main product of the cell reaction, as supported by evidence in the 13C NMR spectra. Using indigo carmine as the mediator dye and fructose as the energy source, an abiotic cell configuration generates a power density of 1.66 mW cm -2, which is greater than that produced from glucose under similar conditions (ca. 1.28 mW cm -2). A faster transition from fructose into the ene-diol intermediate than from glucose likely contributed to this difference in power density.

  20. Four Mechanistic Models of Peer Influence on Adolescent Cannabis Use.

    Science.gov (United States)

    Caouette, Justin D; Feldstein Ewing, Sarah W

    2017-06-01

    Most adolescents begin exploring cannabis in peer contexts, but the neural mechanisms that underlie peer influence on adolescent cannabis use are still unknown. This theoretical overview elucidates the intersecting roles of neural function and peer factors in cannabis use in adolescents. Novel paradigms using functional magnetic resonance imaging (fMRI) in adolescents have identified distinct neural mechanisms of risk decision-making and incentive processing in peer contexts, centered on reward-motivation and affect regulatory neural networks; these findings inform a theoretical model of peer-driven cannabis use decisions in adolescents. We propose four "mechanistic profiles" of social facilitation of cannabis use in adolescents: (1) peer influence as the primary driver of use; (2) cannabis exploration as the primary driver, which may be enhanced in peer contexts; (3) social anxiety; and (4) negative peer experiences. Identification of "neural targets" involved in motivating cannabis use may inform clinicians about which treatment strategies work best in adolescents with cannabis use problems, and via which social and neurocognitive processes.

  1. Mechanistic modeling of insecticide risks to breeding birds in ...

    Science.gov (United States)

    Insecticide usage in the United States is ubiquitous in urban, suburban, and rural environments. In evaluating data for an insecticide registration application and for registration review, scientists at the United States Environmental Protection Agency (USEPA) assess the fate of the insecticide and the risk the insecticide poses to the environment and non-target wildlife. At the present time, current USEPA risk assessments do not include population-level endpoints. In this paper, we present a new mechanistic model, which allows risk assessors to estimate the effects of insecticide exposure on the survival and seasonal productivity of birds known to use agricultural fields during their breeding season. The new model was created from two existing USEPA avian risk assessment models, the Terrestrial Investigation Model (TIM v.3.0) and the Markov Chain Nest Productivity model (MCnest). The integrated TIM/MCnest model has been applied to assess the relative risk of 12 insecticides used to control corn pests on a suite of 31 avian species known to use cornfields in midwestern agroecosystems. The 12 insecticides that were assessed in this study are all used to treat major pests of corn (corn root worm borer, cutworm, and armyworm). After running the integrated TIM/MCnest model, we found extensive differences in risk to birds among insecticides, with chlorpyrifos and malathion (organophosphates) generally posing the greatest risk, and bifenthrin and ë-cyhalothrin (

  2. A mechanistic approach to the generation of sorption databases

    International Nuclear Information System (INIS)

    Bradbury, M.H.; Baeyens, B.

    1992-01-01

    Sorption of radionuclides in the near and far fields of an underground nuclear waste repository is one of the most important processes retarding their release to the environment. In the vast majority of cases sorption data have been presented in terms of empirical parameters such as distribution coefficients and isotherm equations. A consequence of this empirical methodology is that the sorption data are only strictly valid under the experimental conditions at which they were measured. Implicit in this approach is the need to generate large amounts of data and fitting parameters necessary for an empirical description of sorption under all realistically conceivable conditions which may arise in space and time along the migration pathway to Man. An alternative approach to the problem is to try to understand, and develop model descriptions of, underlying retention mechanisms and to identify those systems parameters which essentially determine the extent of sorption. The aim of this work is to see to what extent currently existing mechanistic models, together with their associated data, can be applied to predict sorption data from laboratory experiments on natural systems. This paper describes the current status of this work which is very much in an early stage of development. An example is given whereby model predictions are compared with laboratory results for the sorption of Np at trace concentrations under oxidizing conditions on a series of minerals relevant to granite formations. 31 refs., 11 figs., 5 tabs

  3. MECHANISTIC STUDY OF COLCHICINE’s ELECTROCHEMICAL OXIDATION

    International Nuclear Information System (INIS)

    Bodoki, Ede; Chira, Ruxandra; Zaharia, Valentin; Săndulescu, Robert

    2015-01-01

    Colchicine, as one of the most ancient drugs of human kind, is still in the focal point of the current research due to its multimodal mechanism of action. The elucidation of colchicine’s still unknown redox properties may play an important role in deciphering its beneficial and harmful implications over the human body. Therefore, a systematic mechanistic study of colchicine’s oxidation has been undertaken by electrochemistry coupled to mass spectrometry using two different types of electrolytic cells, in order to clarify the existing inconsistencies with respect to this topic. At around 1 V vs. Pd/H 2 , initiated by a one-electron transfer, the oxidation of colchicine sets off leading to a cation radical, whose further oxidation may evolve on several different pathways. The main product of the anodic electrochemical reaction, regardless of the carrier solution’s pH is represented by a 7-hydroxy derivative of colchicine. At more anodic potentials (above 1.4 V vs. Pd/H 2 ) compounds arising from epoxidation and/or multiple hydroxylation occur. No di- or tridemethylated quinone structures, as previously suggested in the literature for the electrolytic oxidation of colchicine, has been detected in the mass spectra.

  4. Rapid Discrimination Among Putative Mechanistic Models of Biochemical Systems.

    Science.gov (United States)

    Lomnitz, Jason G; Savageau, Michael A

    2016-08-31

    An overarching goal in molecular biology is to gain an understanding of the mechanistic basis underlying biochemical systems. Success is critical if we are to predict effectively the outcome of drug treatments and the development of abnormal phenotypes. However, data from most experimental studies is typically noisy and sparse. This allows multiple potential mechanisms to account for experimental observations, and often devising experiments to test each is not feasible. Here, we introduce a novel strategy that discriminates among putative models based on their repertoire of qualitatively distinct phenotypes, without relying on knowledge of specific values for rate constants and binding constants. As an illustration, we apply this strategy to two synthetic gene circuits exhibiting anomalous behaviors. Our results show that the conventional models, based on their well-characterized components, cannot account for the experimental observations. We examine a total of 40 alternative hypotheses and show that only 5 have the potential to reproduce the experimental data, and one can do so with biologically relevant parameter values.

  5. Multiscale mechanistic modeling in pharmaceutical research and development.

    Science.gov (United States)

    Kuepfer, Lars; Lippert, Jörg; Eissing, Thomas

    2012-01-01

    Discontinuation of drug development projects due to lack of efficacy or adverse events is one of the main cost drivers in pharmaceutical research and development (R&D). Investments have to be written-off and contribute to the total costs of a successful drug candidate receiving marketing authorization and allowing return on invest. A vital risk for pharmaceutical innovator companies is late stage clinical failure since costs for individual clinical trials may exceed the one billion Euro threshold. To guide investment decisions and to safeguard maximum medical benefit and safety for patients recruited in clinical trials, it is therefore essential to understand the clinical consequences of all information and data generated. The complexity of the physiological and pathophysiological processes and the sheer amount of information available overcharge the mental capacity of any human being and prevent a prediction of the success in clinical development. A rigorous integration of knowledge, assumption, and experimental data into computational models promises a significant improvement of the rationalization of decision making in pharmaceutical industry. We here give an overview of the current status of modeling and simulation in pharmaceutical R&D and outline the perspectives of more recent developments in mechanistic modeling. Specific modeling approaches for different biological scales ranging from intracellular processes to whole organism physiology are introduced and an example for integrative multiscale modeling of therapeutic efficiency in clinical oncology trials is showcased.

  6. Confinement effects and mechanistic aspects for montmorillonite nanopores.

    Science.gov (United States)

    Li, Xiong; Zhu, Chang; Jia, Zengqiang; Yang, Gang

    2018-08-01

    Owing to the ubiquity, critical importance and special properties, confined microenvironments have recently triggered overwhelming interest. In this work, all-atom molecular dynamics simulations have been conducted to address the confinement effects and ion-specific effects for electrolyte solutions within montmorillonite nanopores, where the pore widths vary with a wide range. The adsorption number, structure, dynamics and stability of inner- and outer-sphere metal ions are affected by the change of pore widths (confinement effects), while the extents are significantly dependent on the type of adsorbed species. The type of adsorbed species is, however, not altered by the magnitude of confinement effects, and confinement effects are similar for different electrolyte concentrations. Ion-specific effects are pronounced for all magnitudes of confinement effects (from non- to strong confined conditions), and Hofmeister sequences of outer-sphere species are closely associated with the magnitude of confinement effects while those of inner-sphere species remain consistent. In addition, mechanistic aspects of confinement have been posed using the electrical double layer theories, and the results can be generalized to other confined systems that are ubiquitous in biology, chemistry, geology and nanotechnology. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Analytical techniques for mechanistic characterization of EUV photoresists

    Science.gov (United States)

    Grzeskowiak, Steven; Narasimhan, Amrit; Murphy, Michael; Ackerman, Christian; Kaminsky, Jake; Brainard, Robert L.; Denbeaux, Greg

    2017-03-01

    Extreme ultraviolet (EUV, 13.5 nm) lithography is the prospective technology for high volume manufacturing by the microelectronics industry. Significant strides towards achieving adequate EUV source power and availability have been made recently, but a limited rate of improvement in photoresist performance still delays the implementation of EUV. Many fundamental questions remain to be answered about the exposure mechanisms of even the relatively well understood chemically amplified EUV photoresists. Moreover, several groups around the world are developing revolutionary metal-based resists whose EUV exposure mechanisms are even less understood. Here, we describe several evaluation techniques to help elucidate mechanistic details of EUV exposure mechanisms of chemically amplified and metal-based resists. EUV absorption coefficients are determined experimentally by measuring the transmission through a resist coated on a silicon nitride membrane. Photochemistry can be evaluated by monitoring small outgassing reaction products to provide insight into photoacid generator or metal-based resist reactivity. Spectroscopic techniques such as thin-film Fourier transform infrared (FTIR) spectroscopy can measure the chemical state of a photoresist system pre- and post-EUV exposure. Additionally, electrolysis can be used to study the interaction between photoresist components and low energy electrons. Collectively, these techniques improve our current understanding of photomechanisms for several EUV photoresist systems, which is needed to develop new, better performing materials needed for high volume manufacturing.

  8. Mechanistic features of isomerizing alkoxycarbonylation of methyl oleate

    KAUST Repository

    Roesle, Philipp

    2012-10-24

    The weakly coordinated triflate complex [(P̂P)Pd(OTf)] +(OTf)- (1) (P̂P = 1,3-bis(di-tert- butylphosphino)propane) is a suitable reactive precursor for mechanistic studies of the isomerizing alkoxcarbonylation of methyl oleate. Addition of CH 3OH or CD3OD to 1 forms the hydride species [(P ̂P)PdH(CH3OH)]+(OTf)- (2-CH3OH) or the deuteride [(P̂P)PdD(CD 3OD)]+(OTf)- (2D-CD3OD), respectively. Further reaction with pyridine cleanly affords the stable and isolable hydride [(P̂P)PdH(pyridine)]+(OTf) - (2-pyr). This complex yields the hydride fragment free of methanol by abstraction of pyridine with BF3OEt2, and thus provides an entry to mechanistic observations including intermediates reactive toward methanol. Exposure of methyl oleate (100 equiv) to 2D-CD 3OD resulted in rapid isomerization to the thermodynamic isomer distribution, 94.3% of internal olefins, 5.5% of α,β-unsaturated ester and <0.2% of terminal olefin. Reaction of 2-pyr/BF3OEt 2 with a stoichiometric amount of 1-13C-labeled 1-octene at -80 °C yields a 50:50 mixture of the linear alkyls [(P ̂P)Pd13CH2(CH2) 6CH3]+ and [(P̂P)PdCH 2(CH2)6 13CH3] + (4a and 4b). Further reaction with 13CO yields the linear acyls [(P̂P)Pd13C(=O)12/13CH 2(CH2)6 12/13CH3(L)] + (5-L; L = solvent or 13CO). Reaction of 2-pyr/BF 3·OEt2 with a stoichiometric amount of methyl oleate at -80 °C also resulted in fast isomerization to form a linear alkyl species [(P̂P)PdCH2(CH2) 16C(=O)OCH3]+ (6) and a branched alkyl stabilized by coordination of the ester carbonyl group as a four membered chelate [(P̂P)PdCH{(CH2)15CH 3}C(=O)OCH3]+ (7). Addition of carbon monoxide (2.5 equiv) at -80 °C resulted in insertion to form the linear acyl carbonyl [(P̂P)PdC(=O)(CH2)17C(=O)OCH 3(CO)]+ (8-CO) and the five-membered chelate [(P ̂P)PdC(=O)CH{(CH2)15CH3}C(=O) OCH3]+ (9). Exposure of 8-CO and 9 to 13CO at -50 °C results in gradual incorporation of the 13C label. Reversibility of 7 + CO ⇄ 9 is also evidenced by ΔG = -2.9 kcal mol-1 and

  9. The attention schema theory: a mechanistic account of subjective awareness.

    Science.gov (United States)

    Graziano, Michael S A; Webb, Taylor W

    2015-01-01

    We recently proposed the attention schema theory, a novel way to explain the brain basis of subjective awareness in a mechanistic and scientifically testable manner. The theory begins with attention, the process by which signals compete for the brain's limited computing resources. This internal signal competition is partly under a bottom-up influence and partly under top-down control. We propose that the top-down control of attention is improved when the brain has access to a simplified model of attention itself. The brain therefore constructs a schematic model of the process of attention, the 'attention schema,' in much the same way that it constructs a schematic model of the body, the 'body schema.' The content of this internal model leads a brain to conclude that it has a subjective experience. One advantage of this theory is that it explains how awareness and attention can sometimes become dissociated; the brain's internal models are never perfect, and sometimes a model becomes dissociated from the object being modeled. A second advantage of this theory is that it explains how we can be aware of both internal and external events. The brain can apply attention to many types of information including external sensory information and internal information about emotions and cognitive states. If awareness is a model of attention, then this model should pertain to the same domains of information to which attention pertains. A third advantage of this theory is that it provides testable predictions. If awareness is the internal model of attention, used to help control attention, then without awareness, attention should still be possible but should suffer deficits in control. In this article, we review the existing literature on the relationship between attention and awareness, and suggest that at least some of the predictions of the theory are borne out by the evidence.

  10. The attention schema theory: a mechanistic account of subjective awareness

    Directory of Open Access Journals (Sweden)

    Taylor W. Webb

    2015-04-01

    Full Text Available We recently proposed the attention schema theory, a novel way to explain the brain basis of subjective awareness in a mechanistic and scientifically testable manner. The theory begins with attention, the process by which signals compete for the brain’s limited computing resources. This internal signal competition is partly under a bottom-up influence and partly under top-down control. We propose that the top-down control of attention is improved when the brain has access to a simplified model of attention itself. The brain therefore constructs a schematic model of the process of attention, the ‘attention schema’, in much the same way that it constructs a schematic model of the body, the ‘body schema’. The content of this internal model leads a brain to conclude that it has a subjective experience. One advantage of this theory is that it explains how awareness and attention can sometimes become dissociated; the brain’s internal models are never perfect, and sometimes a model becomes dissociated from the object being modeled. A second advantage of this theory is that it explains how we can be aware of both internal and external events. The brain can apply attention to many types of information including external sensory information and internal information about emotions and cognitive states. If awareness is a model of attention, then this model should pertain to the same domains of information to which attention pertains. A third advantage of this theory is that it provides testable predictions. If awareness is the internal model of attention, used to help control attention, then without awareness, attention should still be possible but should suffer deficits in control. In this article, we review the existing literature on the relationship between attention and awareness, and suggest that at least some of the predictions of the theory are borne out by the evidence.

  11. Conceptualising population health: from mechanistic thinking to complexity science

    Directory of Open Access Journals (Sweden)

    Jayasinghe Saroj

    2011-01-01

    Full Text Available Abstract The mechanistic interpretation of reality can be traced to the influential work by René Descartes and Sir Isaac Newton. Their theories were able to accurately predict most physical phenomena relating to motion, optics and gravity. This paradigm had at least three principles and approaches: reductionism, linearity and hierarchy. These ideas appear to have influenced social scientists and the discourse on population health. In contrast, Complexity Science takes a more holistic view of systems. It views natural systems as being 'open', with fuzzy borders, constantly adapting to cope with pressures from the environment. These are called Complex Adaptive Systems (CAS. The sub-systems within it lack stable hierarchies, and the roles of agency keep changing. The interactions with the environment and among sub-systems are non-linear interactions and lead to self-organisation and emergent properties. Theoretical frameworks such as epi+demos+cracy and the ecosocial approach to health have implicitly used some of these concepts of interacting dynamic sub-systems. Using Complexity Science we can view population health outcomes as an emergent property of CAS, which has numerous dynamic non-linear interactions among its interconnected sub-systems or agents. In order to appreciate these sub-systems and determinants, one should acquire a basic knowledge of diverse disciplines and interact with experts from different disciplines. Strategies to improve health should be multi-pronged, and take into account the diversity of actors, determinants and contexts. The dynamic nature of the system requires that the interventions are constantly monitored to provide early feedback to a flexible system that takes quick corrections.

  12. A mechanistic nitrogen limitation model for CLM(ED)

    Science.gov (United States)

    Ali, A. A.; Xu, C.; McDowell, N. G.; Rogers, A.; Wullschleger, S. D.; Fisher, R.; Vrugt, J. A.

    2014-12-01

    Photosynthetic capacity is a key plant trait that determines the rate of photosynthesis; however, in Earth System Models it is either a fixed value or derived from a linear function of leaf nitrogen content. A mechanistic leaf nitrogen allocation model have been developed for a DOE-sponsored Community Land Model coupled to the Ecosystem Demography model (CLM-ED) to predict the photosynthetic capacity [Vc,max25 (μmol CO2 m-2 s-1)] under different environmental conditions at the global scale. We collected more than 800 data points of photosynthetic capacity (Vc,max25) for 124 species from 57 studies with the corresponding leaf nitrogen content and environmental conditions (temperature, radiation, humidity and day length) from literature and the NGEE arctic site (Barrow). Based on the data, we found that environmental control of Vc,max25 is about 4 times stronger than the leaf nitrogen content. Using the Markov-Chain Monte Carlo simulation approach, we fitted the collected data to our newly developed nitrogen allocation model, which predict the leaf nitrogen investment in different components including structure, storage, respiration, light capture, carboxylation and electron transport at different environmental conditions. Our results showed that our nitrogen allocation model explained 52% of variance in observed Vc,max25 and 65% variance in observed Jmax25 using a single set of fitted model parameters for all species. Across the growing season, we found that the modeled Vc,max25 explained 49% of the variability in measured Vc,max25. In the context of future global warming, our model predicts that a temperature increase by 5oC and the doubling of atmospheric carbon dioxide reduced the Vc,max25 by 5%, 11%, respectively.

  13. Conceptualising population health: from mechanistic thinking to complexity science.

    Science.gov (United States)

    Jayasinghe, Saroj

    2011-01-20

    The mechanistic interpretation of reality can be traced to the influential work by René Descartes and Sir Isaac Newton. Their theories were able to accurately predict most physical phenomena relating to motion, optics and gravity. This paradigm had at least three principles and approaches: reductionism, linearity and hierarchy. These ideas appear to have influenced social scientists and the discourse on population health. In contrast, Complexity Science takes a more holistic view of systems. It views natural systems as being 'open', with fuzzy borders, constantly adapting to cope with pressures from the environment. These are called Complex Adaptive Systems (CAS). The sub-systems within it lack stable hierarchies, and the roles of agency keep changing. The interactions with the environment and among sub-systems are non-linear interactions and lead to self-organisation and emergent properties. Theoretical frameworks such as epi+demos+cracy and the ecosocial approach to health have implicitly used some of these concepts of interacting dynamic sub-systems. Using Complexity Science we can view population health outcomes as an emergent property of CAS, which has numerous dynamic non-linear interactions among its interconnected sub-systems or agents. In order to appreciate these sub-systems and determinants, one should acquire a basic knowledge of diverse disciplines and interact with experts from different disciplines. Strategies to improve health should be multi-pronged, and take into account the diversity of actors, determinants and contexts. The dynamic nature of the system requires that the interventions are constantly monitored to provide early feedback to a flexible system that takes quick corrections.

  14. Mechanistic Understanding of Microbial Plugging for Improved Sweep Efficiency

    Energy Technology Data Exchange (ETDEWEB)

    Steven Bryant; Larry Britton

    2008-09-30

    Microbial plugging has been proposed as an effective low cost method of permeability reduction. Yet there is a dearth of information on the fundamental processes of microbial growth in porous media, and there are no suitable data to model the process of microbial plugging as it relates to sweep efficiency. To optimize the field implementation, better mechanistic and volumetric understanding of biofilm growth within a porous medium is needed. In particular, the engineering design hinges upon a quantitative relationship between amount of nutrient consumption, amount of growth, and degree of permeability reduction. In this project experiments were conducted to obtain new data to elucidate this relationship. Experiments in heterogeneous (layered) beadpacks showed that microbes could grow preferentially in the high permeability layer. Ultimately this caused flow to be equally divided between high and low permeability layers, precisely the behavior needed for MEOR. Remarkably, classical models of microbial nutrient uptake in batch experiments do not explain the nutrient consumption by the same microbes in flow experiments. We propose a simple extension of classical kinetics to account for the self-limiting consumption of nutrient observed in our experiments, and we outline a modeling approach based on architecture and behavior of biofilms. Such a model would account for the changing trend of nutrient consumption by bacteria with the increasing biomass and the onset of biofilm formation. However no existing model can explain the microbial preference for growth in high permeability regions, nor is there any obvious extension of the model for this observation. An attractive conjecture is that quorum sensing is involved in the heterogeneous bead packs.

  15. Mechanistic kinetic models of enzymatic cellulose hydrolysis-A review.

    Science.gov (United States)

    Jeoh, Tina; Cardona, Maria J; Karuna, Nardrapee; Mudinoor, Akshata R; Nill, Jennifer

    2017-07-01

    Bioconversion of lignocellulose forms the basis for renewable, advanced biofuels, and bioproducts. Mechanisms of hydrolysis of cellulose by cellulases have been actively studied for nearly 70 years with significant gains in understanding of the cellulolytic enzymes. Yet, a full mechanistic understanding of the hydrolysis reaction has been elusive. We present a review to highlight new insights gained since the most recent comprehensive review of cellulose hydrolysis kinetic models by Bansal et al. (2009) Biotechnol Adv 27:833-848. Recent models have taken a two-pronged approach to tackle the challenge of modeling the complex heterogeneous reaction-an enzyme-centric modeling approach centered on the molecularity of the cellulase-cellulose interactions to examine rate limiting elementary steps and a substrate-centric modeling approach aimed at capturing the limiting property of the insoluble cellulose substrate. Collectively, modeling results suggest that at the molecular-scale, how rapidly cellulases can bind productively (complexation) and release from cellulose (decomplexation) is limiting, while the overall hydrolysis rate is largely insensitive to the catalytic rate constant. The surface area of the insoluble substrate and the degrees of polymerization of the cellulose molecules in the reaction both limit initial hydrolysis rates only. Neither enzyme-centric models nor substrate-centric models can consistently capture hydrolysis time course at extended reaction times. Thus, questions of the true reaction limiting factors at extended reaction times and the role of complexation and decomplexation in rate limitation remain unresolved. Biotechnol. Bioeng. 2017;114: 1369-1385. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

  16. A Mechanistic Link from GABA to Cortical Architecture and Perception.

    Science.gov (United States)

    Kolasinski, James; Logan, John P; Hinson, Emily L; Manners, Daniel; Divanbeighi Zand, Amir P; Makin, Tamar R; Emir, Uzay E; Stagg, Charlotte J

    2017-06-05

    Understanding both the organization of the human cortex and its relation to the performance of distinct functions is fundamental in neuroscience. The primary sensory cortices display topographic organization, whereby receptive fields follow a characteristic pattern, from tonotopy to retinotopy to somatotopy [1]. GABAergic signaling is vital to the maintenance of cortical receptive fields [2]; however, it is unclear how this fine-grain inhibition relates to measurable patterns of perception [3, 4]. Based on perceptual changes following perturbation of the GABAergic system, it is conceivable that the resting level of cortical GABAergic tone directly relates to the spatial specificity of activation in response to a given input [5-7]. The specificity of cortical activation can be considered in terms of cortical tuning: greater cortical tuning yields more localized recruitment of cortical territory in response to a given input. We applied a combination of fMRI, MR spectroscopy, and psychophysics to substantiate the link between the cortical neurochemical milieu, the tuning of cortical activity, and variability in perceptual acuity, using human somatosensory cortex as a model. We provide data that explain human perceptual acuity in terms of both the underlying cellular and metabolic processes. Specifically, higher concentrations of sensorimotor GABA are associated with more selective cortical tuning, which in turn is associated with enhanced perception. These results show anatomical and neurochemical specificity and are replicated in an independent cohort. The mechanistic link from neurochemistry to perception provides a vital step in understanding population variability in sensory behavior, informing metabolic therapeutic interventions to restore perceptual abilities clinically. Copyright © 2017 The Author(s). Published by Elsevier Ltd.. All rights reserved.

  17. Mechanistic basis of infertility of mouse intersubspecific hybrids

    Science.gov (United States)

    Bhattacharyya, Tanmoy; Gregorova, Sona; Mihola, Ondrej; Anger, Martin; Sebestova, Jaroslava; Denny, Paul; Simecek, Petr; Forejt, Jiri

    2013-01-01

    According to the Dobzhansky–Muller model, hybrid sterility is a consequence of the independent evolution of related taxa resulting in incompatible genomic interactions of their hybrids. The model implies that the incompatibilities evolve randomly, unless a particular gene or nongenic sequence diverges much faster than the rest of the genome. Here we propose that asynapsis of heterospecific chromosomes in meiotic prophase provides a recurrently evolving trigger for the meiotic arrest of interspecific F1 hybrids. We observed extensive asynapsis of chromosomes and disturbance of the sex body in >95% of pachynemas of Mus m. musculus × Mus m. domesticus sterile F1 males. Asynapsis was not preceded by a failure of double-strand break induction, and the rate of meiotic crossing over was not affected in synapsed chromosomes. DNA double-strand break repair was delayed or failed in unsynapsed autosomes, and misexpression of chromosome X and chromosome Y genes was detected in single pachynemas and by genome-wide expression profiling. Oocytes of F1 hybrid females showed the same kind of synaptic problems but with the incidence reduced to half. Most of the oocytes with pachytene asynapsis were eliminated before birth. We propose the heterospecific pairing of homologous chromosomes as a preexisting condition of asynapsis in interspecific hybrids. The asynapsis may represent a universal mechanistic basis of F1 hybrid sterility manifested by pachytene arrest. It is tempting to speculate that a fast-evolving subset of the noncoding genomic sequence important for chromosome pairing and synapsis may be the culprit. PMID:23329330

  18. Labor Inhibits Placental Mechanistic Target of Rapamycin Complex 1 Signaling

    Science.gov (United States)

    LAGER, Susanne; AYE, Irving L.M.H.; GACCIOLI, Francesca; RAMIREZ, Vanessa I.; JANSSON, Thomas; POWELL, Theresa L.

    2014-01-01

    Introduction Labor induces a myriad of changes in placental gene expression. These changes may represent a physiological adaptation inhibiting placental cellular processes associated with a high demand for oxygen and energy (e.g., protein synthesis and active transport) thereby promoting oxygen and glucose transfer to the fetus. We hypothesized that mechanistic target of rapamycin complex 1 (mTORC1) signaling, a positive regulator of trophoblast protein synthesis and amino acid transport, is inhibited by labor. Methods Placental tissue was collected from healthy, term pregnancies (n=15 no-labor; n=12 labor). Activation of Caspase-1, IRS1/Akt, STAT, mTOR, and inflammatory signaling pathways was determined by Western blot. NFκB p65 and PPARγ DNA binding activity was measured in isolated nuclei. Results Labor increased Caspase-1 activation and mTOR complex 2 signaling, as measured by phosphorylation of Akt (S473). However, mTORC1 signaling was inhibited in response to labor as evidenced by decreased phosphorylation of mTOR (S2448) and 4EBP1 (T37/46 and T70). Labor also decreased NFκB and PPARγ DNA binding activity, while having no effect on IRS1 or STAT signaling pathway. Discussion and conclusion Several placental signaling pathways are affected by labor, which has implications for experimental design in studies of placental signaling. Inhibition of placental mTORC1 signaling in response to labor may serve to down-regulate protein synthesis and amino acid transport, processes that account for a large share of placental oxygen and glucose consumption. We speculate that this response preserves glucose and oxygen for transfer to the fetus during the stressful events of labor. PMID:25454472

  19. The ecological impacts of nighttime light pollution: a mechanistic appraisal.

    Science.gov (United States)

    Gaston, Kevin J; Bennie, Jonathan; Davies, Thomas W; Hopkins, John

    2013-11-01

    The ecological impacts of nighttime light pollution have been a longstanding source of concern, accentuated by realized and projected growth in electrical lighting. As human communities and lighting technologies develop, artificial light increasingly modifies natural light regimes by encroaching on dark refuges in space, in time, and across wavelengths. A wide variety of ecological implications of artificial light have been identified. However, the primary research to date is largely focused on the disruptive influence of nighttime light on higher vertebrates, and while comprehensive reviews have been compiled along taxonomic lines and within specific research domains, the subject is in need of synthesis within a common mechanistic framework. Here we propose such a framework that focuses on the cross-factoring of the ways in which artificial lighting alters natural light regimes (spatially, temporally, and spectrally), and the ways in which light influences biological systems, particularly the distinction between light as a resource and light as an information source. We review the evidence for each of the combinations of this cross-factoring. As artificial lighting alters natural patterns of light in space, time and across wavelengths, natural patterns of resource use and information flows may be disrupted, with downstream effects to the structure and function of ecosystems. This review highlights: (i) the potential influence of nighttime lighting at all levels of biological organisation (from cell to ecosystem); (ii) the significant impact that even low levels of nighttime light pollution can have; and (iii) the existence of major research gaps, particularly in terms of the impacts of light at population and ecosystem levels, identification of intensity thresholds, and the spatial extent of impacts in the vicinity of artificial lights. © 2013 The Authors. Biological Reviews © 2013 Cambridge Philosophical Society.

  20. "Gum bug, leave my heart alone!"--epidemiologic and mechanistic evidence linking periodontal infections and atherosclerosis.

    Science.gov (United States)

    Kebschull, M; Demmer, R T; Papapanou, P N

    2010-09-01

    Evidence from epidemiologic studies suggests that periodontal infections are independently associated with subclinical and clinical atherosclerotic vascular disease. Although the strength of the reported associations is modest, the consistency of the data across diverse populations and a variety of exposure and outcome variables suggests that the findings are not spurious or attributable only to the effects of confounders. Analysis of limited data from interventional studies suggests that periodontal treatment generally results in favorable effects on subclinical markers of atherosclerosis, although such analysis also indicates considerable heterogeneity in responses. Experimental mechanistic in vitro and in vivo studies have established the plausibility of a link between periodontal infections and atherogenesis, and have identified biological pathways by which these effects may be mediated. However, the utilized models are mostly mono-infections of host cells by a limited number of 'model' periodontal pathogens, and therefore may not adequately portray human periodontitis as a polymicrobial, biofilm-mediated disease. Future research must identify in vivo pathways in humans that may (i) lead to periodontitis-induced atherogenesis, or (ii) result in treatment-induced reduction of atherosclerosis risk. Data from these studies will be essential for determining whether periodontal interventions have a role in the primary or secondary prevention of atherosclerosis.

  1. Validation of mechanistic models for gas precipitation in solids during postirradiation annealing experiments

    Science.gov (United States)

    Rest, J.

    1989-12-01

    A number of different phenomenological models for gas precipitation in solids during postirradiation annealing experiments have been proposed. Validation of such mechanistic models for gas release and swelling is complicated by the use of data containing large systematic errors, and phenomena characterized by synergistic effects as well as uncertainties in materials properties. Statistical regression analysis is recommended for the selection of a reasonably well characterized data base for gas release from irradiated fuel under transient heating conditions. It is demonstrated that an appropriate data selection method is required in order to realistically examine the impact of differing descriptions of the phenomena, and uncertainties in selected materials properties, on the validation results. The results of the analysis show that the kinetics of gas precipitation in solids depend on bubble overpressurization effects and need to be accounted for during the heatup phase of isothermal heating experiments. It is shown that if only the total gas release values (as opposed to time-dependent data) were available, differentiation between different gas precipitation models would be ambiguous. The observed sustained increase in the fractional release curve at relatively high temperatures after the total precipitation of intragranular gas in fission gas bubbles is ascribed to the effects of a grain-growth/grain-boundary sweeping mechanism.

  2. Validation of mechanistic models for gas precipitation in solids during postirradiation annealing experiments

    International Nuclear Information System (INIS)

    Rest, J.

    1989-01-01

    A number of different phenomenological models for gas precipitation in solids during postirradiation annealing experiments have been proposed. Validation of such mechanistic models for gas release and swelling is complicated by the use of data containing large systematic errors, and phenomena characterized by synergistic effects as well as uncertainties in materials properties. Statistical regression analysis is recommended for the selection of a reasonably well characterized data base for gas release from irradiated fuel under transient heating conditions. It is demonstrated that an appropriate data selection method is required in order to realistically examine the impact of differing descriptions of the phenomena, and uncertainties in selected materials properties, on the validation results. The results of the analysis show that the kinetics of gas precipitation in solid depend on bubble overpressurization effects and need to be accounted for during the heatup phase of isothermal heating experiments. It is shown that if only the total gas release values (as opposed to time-dependent data) were available, differentiation between different gas precipitation models would be ambiguous. The observed sustained increase in the fractional release curve at relatively high temperatures after the total precipitation of intragranular gas in fission gas bubbles is ascribed to the effects of a grain-growth/grain-boundary sweeping mechanism. (orig.)

  3. In vitro efficiency and mechanistic role of indocyanine green as photodynamic therapy agent for human melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Mamoon, A.M.; Miller, L.; Gamal-Eldeen, A. M.; Ruppel, M. E.; Smith, R. J.; Tsang, T.; Miller, L. M.

    2009-05-02

    Photodynamic therapy (PDT) is a promising treatment for superficial cancer. However, poor therapeutic results have been reported for melanoma, due to the high melanin content. Indocyanine green (ICG) has near infrared absorption (700-800 nm) and melanins do not absorb strongly in this area. This study explores the efficiency of ICG as a PDT agent for human melanoma, and its mechanistic role in the cell death pathway. Human skin melanoma cells (Sk-Mel-28) were incubated with ICG and exposed to a low power Ti:Sapphire laser. Synchrotron-assisted Fourier transform infrared microspectroscopy and hierarchical cluster analysis were used to assess the cell damage and changes in lipid, protein, and nucleic acids. The cell death pathway was determined by analysis of cell viability and apoptosis and necrosis markers. In the cell death pathway, {sup 1}O{sub 2} generation evoked rapid multiple consequences that trigger apoptosis after laser exposure for only 15min including the release of cytochrome c, the activation of total caspases, caspase-3, and caspase-9, the inhibition of NF-{Kappa}B P65, and the enhancement of DNA fragmentation, and histone acetylation. ICG/PDT can efficiently and rapidly induce apoptosis in human melanoma cells and it can be considered as a new therapeutic approach for topical treatment of melanoma.

  4. [Mechanistic modelling allows to assess pathways of DNA lesion interactions underlying chromosome aberration formation].

    Science.gov (United States)

    Eĭdel'man, Iu A; Slanina, S V; Sal'nikov, I V; Andreev, S G

    2012-12-01

    The knowledge of radiation-induced chromosomal aberration (CA) mechanisms is required in many fields of radiation genetics, radiation biology, biodosimetry, etc. However, these mechanisms are yet to be quantitatively characterised. One of the reasons is that the relationships between primary lesions of DNA/chromatin/chromosomes and dose-response curves for CA are unknown because the pathways of lesion interactions in an interphase nucleus are currently inaccessible for direct experimental observation. This article aims for the comparative analysis of two principally different scenarios of formation of simple and complex interchromosomal exchange aberrations: by lesion interactions at chromosome territories' surface vs. in the whole space of the nucleus. The analysis was based on quantitative mechanistic modelling of different levels of structures and processes involved in CA formation: chromosome structure in an interphase nucleus, induction, repair and interactions of DNA lesions. It was shown that the restricted diffusion of chromosomal loci, predicted by computational modelling of chromosome organization, results in lesion interactions in the whole space of the nucleus being impossible. At the same time, predicted features of subchromosomal dynamics agrees well with in vivo observations and does not contradict the mechanism of CA formation at the surface of chromosome territories. On the other hand, the "surface mechanism" of CA formation, despite having certain qualities, proved to be insufficient to explain high frequency of complex exchange aberrations observed by mFISH technique. The alternative mechanism, CA formation on nuclear centres is expected to be sufficient to explain frequent complex exchanges.

  5. Mechanistic-empirical subgrade design model based on heavy vehicle simulator test results

    CSIR Research Space (South Africa)

    Theyse, HL

    2006-06-01

    Full Text Available Although Accelerated Pavement Testing (APT) is often done with specific objectives, valuable pavement performance data is generated over the long-term that may be used to investigate pavement behaviour in general and calibrate mechanistic...

  6. Use of Gene Expression Changes in Blood to Elucidate Mechanistic Indicators of Childhood Asthma (MICA)

    Science.gov (United States)

    Risk assessment increasingly relies more heavily on mode of action, thus the identification of human bioindicators of disease becomes all the more important. Genomic methods represent a tool for both mode of action determination and bioindicator identification. The Mechanistic In...

  7. INCORPORATION OF MECHANISTIC INFORMATION IN THE ARSENIC PBPK MODEL DEVELOPMENT PROCESS

    Science.gov (United States)

    INCORPORATING MECHANISTIC INSIGHTS IN A PBPK MODEL FOR ARSENICElaina M. Kenyon, Michael F. Hughes, Marina V. Evans, David J. Thomas, U.S. EPA; Miroslav Styblo, University of North Carolina; Michael Easterling, Analytical Sciences, Inc.A physiologically based phar...

  8. Existing pavement input information for the mechanistic-empirical pavement design guide.

    Science.gov (United States)

    2009-02-01

    The objective of this study is to systematically evaluate the Iowa Department of Transportations (DOTs) existing Pavement Management Information System (PMIS) with respect to the input information required for Mechanistic-Empirical Pavement Des...

  9. Cross-study and cross-omics comparisons of three nephrotoxic compounds reveal mechanistic insights and new candidate biomarkers

    International Nuclear Information System (INIS)

    Matheis, Katja A.; Com, Emmanuelle; Gautier, Jean-Charles; Guerreiro, Nelson; Brandenburg, Arnd; Gmuender, Hans; Sposny, Alexandra; Hewitt, Philip; Amberg, Alexander; Boernsen, Olaf; Riefke, Bjoern; Hoffmann, Dana; Mally, Angela; Kalkuhl, Arno; Suter, Laura; Dieterle, Frank; Staedtler, Frank

    2011-01-01

    The European InnoMed-PredTox project was a collaborative effort between 15 pharmaceutical companies, 2 small and mid-sized enterprises, and 3 universities with the goal of delivering deeper insights into the molecular mechanisms of kidney and liver toxicity and to identify mechanism-linked diagnostic or prognostic safety biomarker candidates by combining conventional toxicological parameters with 'omics' data. Mechanistic toxicity studies with 16 different compounds, 2 dose levels, and 3 time points were performed in male Crl: WI(Han) rats. Three of the 16 investigated compounds, BI-3 (FP007SE), Gentamicin (FP009SF), and IMM125 (FP013NO), induced kidney proximal tubule damage (PTD). In addition to histopathology and clinical chemistry, transcriptomics microarray and proteomics 2D-DIGE analysis were performed. Data from the three PTD studies were combined for a cross-study and cross-omics meta-analysis of the target organ. The mechanistic interpretation of kidney PTD-associated deregulated transcripts revealed, in addition to previously described kidney damage transcript biomarkers such as KIM-1, CLU and TIMP-1, a number of additional deregulated pathways congruent with histopathology observations on a single animal basis, including a specific effect on the complement system. The identification of new, more specific biomarker candidates for PTD was most successful when transcriptomics data were used. Combining transcriptomics data with proteomics data added extra value.

  10. Mechanistic species distribution modelling as a link between physiology and conservation.

    Science.gov (United States)

    Evans, Tyler G; Diamond, Sarah E; Kelly, Morgan W

    2015-01-01

    Climate change conservation planning relies heavily on correlative species distribution models that estimate future areas of occupancy based on environmental conditions encountered in present-day ranges. The approach benefits from rapid assessment of vulnerability over a large number of organisms, but can have poor predictive power when transposed to novel environments and reveals little in the way of causal mechanisms that define changes in species distribution or abundance. Having conservation planning rely largely on this single approach also increases the risk of policy failure. Mechanistic models that are parameterized with physiological information are expected to be more robust when extrapolating distributions to future environmental conditions and can identify physiological processes that set range boundaries. Implementation of mechanistic species distribution models requires knowledge of how environmental change influences physiological performance, and because this information is currently restricted to a comparatively small number of well-studied organisms, use of mechanistic modelling in the context of climate change conservation is limited. In this review, we propose that the need to develop mechanistic models that incorporate physiological data presents an opportunity for physiologists to contribute more directly to climate change conservation and advance the field of conservation physiology. We begin by describing the prevalence of species distribution modelling in climate change conservation, highlighting the benefits and drawbacks of both mechanistic and correlative approaches. Next, we emphasize the need to expand mechanistic models and discuss potential metrics of physiological performance suitable for integration into mechanistic models. We conclude by summarizing other factors, such as the need to consider demography, limiting broader application of mechanistic models in climate change conservation. Ideally, modellers, physiologists and

  11. Toward a mechanistic modeling of nitrogen limitation for photosynthesis

    Science.gov (United States)

    Xu, C.; Fisher, R. A.; Travis, B. J.; Wilson, C. J.; McDowell, N. G.

    2011-12-01

    The nitrogen limitation is an important regulator for vegetation growth and global carbon cycle. Most current ecosystem process models simulate nitrogen effects on photosynthesis based on a prescribed relationship between leaf nitrogen and photosynthesis; however, there is a large amount of variability in this relationship with different light, temperature, nitrogen availability and CO2 conditions, which can affect the reliability of photosynthesis prediction under future climate conditions. To account for the variability in nitrogen-photosynthesis relationship under different environmental conditions, in this study, we developed a mechanistic model of nitrogen limitation for photosynthesis based on nitrogen trade-offs among light absorption, electron transport, carboxylization and carbon sink. Our model shows that strategies of nitrogen storage allocation as determined by tradeoff among growth and persistence is a key factor contributing to the variability in relationship between leaf nitrogen and photosynthesis. Nitrogen fertilization substantially increases the proportion of nitrogen in storage for coniferous trees but much less for deciduous trees, suggesting that coniferous trees allocate more nitrogen toward persistence compared to deciduous trees. The CO2 fertilization will cause lower nitrogen allocation for carboxylization but higher nitrogen allocation for storage, which leads to a weaker relationship between leaf nitrogen and maximum photosynthesis rate. Lower radiation will cause higher nitrogen allocation for light absorption and electron transport but less nitrogen allocation for carboxylyzation and storage, which also leads to weaker relationship between leaf nitrogen and maximum photosynthesis rate. At the same time, lower growing temperature will cause higher nitrogen allocation for carboxylyzation but lower allocation for light absorption, electron transport and storage, which leads to a stronger relationship between leaf nitrogen and maximum

  12. Mechanistic, kinetic, and processing aspects of tungsten chemical mechanical polishing

    Science.gov (United States)

    Stein, David

    This dissertation presents an investigation into tungsten chemical mechanical polishing (CMP). CMP is the industrially predominant unit operation that removes excess tungsten after non-selective chemical vapor deposition (CVD) during sub-micron integrated circuit (IC) manufacture. This work explores the CMP process from process engineering and fundamental mechanistic perspectives. The process engineering study optimized an existing CMP process to address issues of polish pad and wafer carrier life. Polish rates, post-CMP metrology of patterned wafers, electrical test data, and synergy with a thermal endpoint technique were used to determine the optimal process. The oxidation rate of tungsten during CMP is significantly lower than the removal rate under identical conditions. Tungsten polished without inhibition during cathodic potentiostatic control. Hertzian indenter model calculations preclude colloids of the size used in tungsten CMP slurries from indenting the tungsten surface. AFM surface topography maps and TEM images of post-CMP tungsten do not show evidence of plow marks or intergranular fracture. Polish rate is dependent on potassium iodate concentration; process temperature is not. The colloid species significantly affects the polish rate and process temperature. Process temperature is not a predictor of polish rate. A process energy balance indicates that the process temperature is predominantly due to shaft work, and that any heat of reaction evolved during the CMP process is negligible. Friction and adhesion between alumina and tungsten were studied using modified AFM techniques. Friction was constant with potassium iodate concentration, but varied with applied pressure. This corroborates the results from the energy balance. Adhesion between the alumina and the tungsten was proportional to the potassium iodate concentration. A heuristic mechanism, which captures the relationship between polish rate, pressure, velocity, and slurry chemistry, is presented

  13. Mechanistic, Mutational, and Structural Evaluation of a Taxus Phenylalanine Aminomutase

    Energy Technology Data Exchange (ETDEWEB)

    Feng, Lei; Wanninayake, Udayanga; Strom, Susan; Geiger, James; Walker, Kevin D. (MSU)

    2014-10-02

    The structure of a phenylalanine aminomutase (TcPAM) from Taxus canadensis has been determined at 2.4 {angstrom} resolution. The active site of the TcPAM contains the signature 4-methylidene-1H-imidazol-5(4H)-one prosthesis, observed in all catalysts of the class I lyase-like family. This catalyst isomerizes (S)-{alpha}-phenylalanine to the (R)-{beta}-isomer by exchange of the NH{sub 2}/H pair. The stereochemistry of the TcPAM reaction product is opposite of the (S)-{beta}-tyrosine made by the mechanistically related tyrosine aminomutase (SgTAM) from Streptomyces globisporus. Since TcPAM and SgTAM share similar tertiary- and quaternary-structures and have several highly conserved aliphatic residues positioned analogously in their active sites for substrate recognition, the divergent product stereochemistries of these catalysts likely cannot be explained by differences in active site architecture. The active site of the TcPAM structure also is in complex with (E)-cinnamate; the latter functions as both a substrate and an intermediate. To account for the distinct (3R)-{beta}-amino acid stereochemistry catalyzed by TcPAM, the cinnamate skeleton must rotate the C{sub 1}-C{sub {alpha}} and C{sub ipso}-C{sub {beta}} bonds 180{sup o} in the active site prior to exchange and rebinding of the NH{sub 2}/H pair to the cinnamate, an event that is not required for the corresponding acrylate intermediate in the SgTAM reaction. Moreover, the aromatic ring of the intermediate makes only one direct hydrophobic interaction with Leu-104. A L104A mutant of TcPAM demonstrated an 1.5-fold increase in k{sub cat} and a decrease in K{sub M} values for sterically demanding 3'-methyl-{alpha}-phenylalanine and styryl-{alpha}-alanine substrates, compared to the kinetic parameters for TcPAM. These parameters did not change significantly for the mutant with 4'-methyl-{alpha}-phenylalanine compared to those for TcPAM.

  14. Isolation, characterization, and mechanistic studies of (-)-alpha-gurjunene synthase from Solidago canadensis.

    Science.gov (United States)

    Schmidt, C O; Bouwmeester, H J; Bülow, N; König, W A

    1999-04-15

    The leaves of the composite Solidago canadensis (goldenrod) were shown to contain (-)-alpha-gurjunene synthase activity. This sesquiterpene is likely to be the precursor for cyclocolorenone, a sesquiterpene ketone present in high amounts in S. canadensis leaves. (-)-alpha-Gurjunene synthase was purified to apparent homogeneity (741-fold) by anion-exchange chromatography (on several matrices), dye ligand chromatography, hydroxylapatite chromatography, and gel filtration. Chromatography on a gel filtration matrix indicated a native molecular mass of 48 kDa, and SDS-PAGE showed the enzyme to be composed of one subunit with a denatured mass of 60 kDa. Its maximum activity was observed at pH 7.8 in the presence of 10 mM Mg2+ and the KM value for the substrate farnesyl diphosphate was 5.5 microM. Over a range of purification steps (-)-alpha-gurjunene and (+)-gamma-gurjunene synthase activities copurified. In addition, the product ratio of the enzyme activity under several different assay conditions was always 91% (-)-alpha-gurjunene and 9% (+)-gamma-gurjunene. This suggests that the formation of these two structurally related products is catalyzed by one enzyme. For further confirmation, we carried out a number of mechanistic studies with (-)-alpha-gurjunene synthase, in which an enzyme preparation was incubated with deuterated substrate analogues. Based on mass spectrometry analysis of the products formed, a cyclization mechanism was postulated which makes it plausible that the synthase catalyzes the formation of both sesquiterpenes. Copyright 1999 Academic Press.

  15. Iterative Systems Biology for Medicine – time for advancing from network signature to mechanistic equations

    KAUST Repository

    Gomez-Cabrero, David

    2017-05-09

    The rise and growth of Systems Biology following the sequencing of the human genome has been astounding. Early on, an iterative wet-dry methodology was formulated which turned out as a successful approach in deciphering biological complexity. Such type of analysis effectively identified and associated molecular network signatures operative in biological processes across different systems. Yet, it has proven difficult to distinguish between causes and consequences, thus making it challenging to attack medical questions where we require precise causative drug targets and disease mechanisms beyond a web of associated markers. Here we review principal advances with regard to identification of structure, dynamics, control, and design of biological systems, following the structure in the visionary review from 2002 by Dr. Kitano. Yet, here we find that the underlying challenge of finding the governing mechanistic system equations enabling precision medicine remains open thus rendering clinical translation of systems biology arduous. However, stunning advances in raw computational power, generation of high-precision multi-faceted biological data, combined with powerful algorithms hold promise to set the stage for data-driven identification of equations implicating a fundamental understanding of living systems during health and disease.

  16. Thermal tides and studies to tune the mechanistic tidal model using UARS observations

    Directory of Open Access Journals (Sweden)

    V. A. Yudin

    1997-09-01

    Full Text Available Monthly simulations of the thermal diurnal and semidiurnal tides are compared to High-Resolution Doppler Imager (HRDI and Wind Imaging Interferometer (WINDII wind and temperature measurements on the Upper-Atmosphere Research Satellite (UARS. There is encouraging agreement between the observations and the linear global mechanistic tidal model results both for the diurnal and semidiurnal components in the equatorial and mid-latitude regions. This gives us the confidence to outline the first steps of an assimilative analysis/interpretation for tides, dissipation, and mean flow using a combination of model results and the global measurements from HRDI and WINDII. The sensitivity of the proposed technique to the initial guess employed to obtain a best fit to the data by tuning model parameters is discussed for the January and March 1993 cases, when the WINDII day and night measurements of the meridional winds between 90 and 110 km are used along with the daytime HRDI measurements. Several examples for the derivation of the tidal variables and decomposition of the measured winds into tidal and mean flow components using this approach are compared with previous tidal estimates and modeling results for the migrating tides. The seasonal cycle of the derived diurnal tidal amplitudes are discussed and compared with radar observation between 80 and 100 km and 40°S and 40°N.

  17. Thermal tides and studies to tune the mechanistic tidal model using UARS observations

    Directory of Open Access Journals (Sweden)

    V. A. Yudin

    Full Text Available Monthly simulations of the thermal diurnal and semidiurnal tides are compared to High-Resolution Doppler Imager (HRDI and Wind Imaging Interferometer (WINDII wind and temperature measurements on the Upper-Atmosphere Research Satellite (UARS. There is encouraging agreement between the observations and the linear global mechanistic tidal model results both for the diurnal and semidiurnal components in the equatorial and mid-latitude regions. This gives us the confidence to outline the first steps of an assimilative analysis/interpretation for tides, dissipation, and mean flow using a combination of model results and the global measurements from HRDI and WINDII. The sensitivity of the proposed technique to the initial guess employed to obtain a best fit to the data by tuning model parameters is discussed for the January and March 1993 cases, when the WINDII day and night measurements of the meridional winds between 90 and 110 km are used along with the daytime HRDI measurements. Several examples for the derivation of the tidal variables and decomposition of the measured winds into tidal and mean flow components using this approach are compared with previous tidal estimates and modeling results for the migrating tides. The seasonal cycle of the derived diurnal tidal amplitudes are discussed and compared with radar observation between 80 and 100 km and 40°S and 40°N.

  18. Towards the development of mechanistically based design rules for corrosion fatigue in ductile steels

    International Nuclear Information System (INIS)

    Johnson, R.; McMinn, A.; Tomkins, B.

    1980-08-01

    Design curves for nuclear pressure vessels and off-shore structures are based on air endurance curves that have had a safety factor applied to account for effects such as corrosive environments, frequency and mean stress. These are supported by a limited number of endurance tests on actual pressure vessels, and on welded joints under service conditions. These data-based rules are limited in their ability to cope with environmental effects and as the time dependencies of fatigue and corrosion processes are so different, no sound basis exists for the extrapolation of data to long component lifetimes. The crack-growth behaviour of materials used in nuclear pressure vessels and off-shore structures is examined with a view to determining how it may be used to re-assess the design curves. Even simple integration of crack-growth laws can be seen to be within reasonable agreement with present design curves; with improved methods of stress analysis, etc. this approach could potentially improve these curves. Mechanistic studies are also seen to offer a means of examining and assessing time-dependent process interactions and so, potentially, to form the basis of new guidelines. Finally the areas where further work would be needed to substantiate any changes in design curves are indicated. (author)

  19. Mechanistic pathways of recognition of a solvent-inaccessible cavity of protein by a ligand

    Science.gov (United States)

    Mondal, Jagannath; Pandit, Subhendu; Dandekar, Bhupendra; Vallurupalli, Pramodh

    One of the puzzling questions in the realm of protein-ligand recognition is how a solvent-inaccessible hydrophobic cavity of a protein gets recognized by a ligand. We address the topic by simulating, for the first time, the complete binding process of benzene from aqueous media to the well-known buried cavity of L99A T4 Lysozyme at an atomistic resolution. Our multiple unbiased microsecond-long trajectories, which were completely blind to the location of target binding site, are able to unequivocally identify the kinetic pathways along which benzene molecule meanders across the solvent and protein and ultimately spontaneously recognizes the deeply buried cavity of L99A T4 Lysozyme at an accurate precision. Our simulation, combined with analysis based on markov state model and free energy calculation, reveals that there are more than one distinct ligand binding pathways. Intriguingly, each of the identified pathways involves the transient opening of a channel of the protein prior to ligand binding. The work will also decipher rich mechanistic details on unbinding kinetics of the ligand as obtained from enhanced sampling techniques.

  20. A Three-Stage Mechanistic Model for Solidification Cracking During Welding of Steel

    Science.gov (United States)

    Aucott, L.; Huang, D.; Dong, H. B.; Wen, S. W.; Marsden, J.; Rack, A.; Cocks, A. C. F.

    2018-03-01

    A three-stage mechanistic model for solidification cracking during TIG welding of steel is proposed from in situ synchrotron X-ray imaging of solidification cracking and subsequent analysis of fracture surfaces. Stage 1—Nucleation of inter-granular hot cracks: cracks nucleate inter-granularly in sub-surface where maximum volumetric strain is localized and volume fraction of liquid is less than 0.1; the crack nuclei occur at solute-enriched liquid pockets which remain trapped in increasingly impermeable semi-solid skeleton. Stage 2—Coalescence of cracks via inter-granular fracture: as the applied strain increases, cracks coalesce through inter-granular fracture; the coalescence path is preferential to the direction of the heat source and propagates through the grain boundaries to solidifying dendrites. Stage 3—Propagation through inter-dendritic hot tearing: inter-dendritic hot tearing occurs along the boundaries between solidifying columnar dendrites with higher liquid fraction. It is recommended that future solidification cracking criterion shall be based on the application of multiphase mechanics and fracture mechanics to the failure of semi-solid materials.

  1. Kinetics and Mechanistic Chemistry of Oxidation of Butacaine Sulfate by Chloramine-B in Acid Medium

    International Nuclear Information System (INIS)

    Shubha, Jayachamarajapura Pranesh; Kotabagi, Vinutha; Puttaswamy

    2012-01-01

    Butacaine sulfate is an ester of p-aminobenzoic acid which has been widely used as a local anaesthetic and it is a long standing agent particularly for spinal anaesthesia. For this reason, a kinetic study of oxidation of butacaine sulfate by sodium N-chlorobenzenesulfonamide (chloramine-B or CAB) has been carried out in HClO 4 medium at 303 K in order to explore this redox system mechanistic chemistry. The rate shows a first-order dependence on both [CAB] o , and [substrate] o , and a fractional-order dependence on acid concentration. Decrease of dielectric constant of the medium, by adding methanol, increases the rate of the reaction. Variation of ionic strength and addition of benzenesulfonamide or NaCl have no significant effect on the rate. The reaction was studied at different temperatures and the activation parameters have been evaluated. The stoichiometry of the reaction has been found to be 1:2 and the oxidation products have been identified by spectral analysis. The observed results have been explained by plausible mechanism and the related rate law has been deduced

  2. Structural, mechanistic and functional insight into gliotoxin bis-thiomethylation in Aspergillus fumigatus.

    Science.gov (United States)

    Dolan, Stephen K; Bock, Tobias; Hering, Vanessa; Owens, Rebecca A; Jones, Gary W; Blankenfeldt, Wulf; Doyle, Sean

    2017-02-01

    Gliotoxin is an epipolythiodioxopiperazine (ETP) class toxin, contains a disulfide bridge that mediates its toxic effects via redox cycling and is produced by the opportunistic fungal pathogen Aspergillus fumigatus Self-resistance against gliotoxin is effected by the gliotoxin oxidase GliT, and attenuation of gliotoxin biosynthesis is catalysed by gliotoxin S -methyltransferase GtmA. Here we describe the X-ray crystal structures of GtmA-apo (1.66 Å), GtmA complexed to S -adenosylhomocysteine (1.33 Å) and GtmA complexed to S -adenosylmethionine (2.28 Å), providing mechanistic insights into this important biotransformation. We further reveal that simultaneous elimination of the ability of A. fumigatus to dissipate highly reactive dithiol gliotoxin, via deletion of GliT and GtmA, results in the most significant hypersensitivity to exogenous gliotoxin observed to date. Indeed, quantitative proteomic analysis of Δ gliT ::Δ gtmA reveals an uncontrolled over-activation of the gli -cluster upon gliotoxin exposure. The data presented herein reveal, for the first time, the extreme risk associated with intracellular dithiol gliotoxin biosynthesis-in the absence of an efficient dismutation capacity. Significantly, a previously concealed protective role for GtmA and functionality of ETP bis -thiomethylation as an ancestral protection strategy against dithiol compounds is now evident. © 2017 The Authors.

  3. Disruption of steroidogenesis: Cell models for mechanistic investigations and as screening tools.

    Science.gov (United States)

    Odermatt, Alex; Strajhar, Petra; Engeli, Roger T

    2016-04-01

    In the modern world, humans are exposed during their whole life to a large number of synthetic chemicals. Some of these chemicals have the potential to disrupt endocrine functions and contribute to the development and/or progression of major diseases. Every year approximately 1000 novel chemicals, used in industrial production, agriculture, consumer products or as pharmaceuticals, are reaching the market, often with limited safety assessment regarding potential endocrine activities. Steroids are essential endocrine hormones, and the importance of the steroidogenesis pathway as a target for endocrine disrupting chemicals (EDCs) has been recognized by leading scientists and authorities. Cell lines have a prominent role in the initial stages of toxicity assessment, i.e. for mechanistic investigations and for the medium to high throughput analysis of chemicals for potential steroidogenesis disrupting activities. Nevertheless, the users have to be aware of the limitations of the existing cell models in order to apply them properly, and there is a great demand for improved cell-based testing systems and protocols. This review intends to provide an overview of the available cell lines for studying effects of chemicals on gonadal and adrenal steroidogenesis, their use and limitations, as well as the need for future improvements of cell-based testing systems and protocols. Copyright © 2016 Elsevier Ltd. All rights reserved.

  4. Rotary ultrasonic machining of CFRP: a mechanistic predictive model for cutting force.

    Science.gov (United States)

    Cong, W L; Pei, Z J; Sun, X; Zhang, C L

    2014-02-01

    Cutting force is one of the most important output variables in rotary ultrasonic machining (RUM) of carbon fiber reinforced plastic (CFRP) composites. Many experimental investigations on cutting force in RUM of CFRP have been reported. However, in the literature, there are no cutting force models for RUM of CFRP. This paper develops a mechanistic predictive model for cutting force in RUM of CFRP. The material removal mechanism of CFRP in RUM has been analyzed first. The model is based on the assumption that brittle fracture is the dominant mode of material removal. CFRP micromechanical analysis has been conducted to represent CFRP as an equivalent homogeneous material to obtain the mechanical properties of CFRP from its components. Based on this model, relationships between input variables (including ultrasonic vibration amplitude, tool rotation speed, feedrate, abrasive size, and abrasive concentration) and cutting force can be predicted. The relationships between input variables and important intermediate variables (indentation depth, effective contact time, and maximum impact force of single abrasive grain) have been investigated to explain predicted trends of cutting force. Experiments are conducted to verify the model, and experimental results agree well with predicted trends from this model. Copyright © 2013 Elsevier B.V. All rights reserved.

  5. Anodic Cyclization Reactions and the Mechanistic Strategies That Enable Optimization.

    Science.gov (United States)

    Feng, Ruozhu; Smith, Jake A; Moeller, Kevin D

    2017-09-19

    Oxidation reactions are powerful tools for synthesis because they allow us to reverse the polarity of electron-rich functional groups, generate highly reactive intermediates, and increase the functionality of molecules. For this reason, oxidation reactions have been and continue to be the subject of intense study. Central to these efforts is the development of mechanism-based strategies that allow us to think about the reactive intermediates that are frequently central to the success of the reactions and the mechanistic pathways that those intermediates trigger. For example, consider oxidative cyclization reactions that are triggered by the removal of an electron from an electron-rich olefin and lead to cyclic products that are functionalized for further elaboration. For these reactions to be successful, the radical cation intermediate must first be generated using conditions that limit its polymerization and then channeled down a productive desired pathway. Following the cyclization, a second oxidation step is necessary for product formation, after which the resulting cation must be quenched in a controlled fashion to avoid undesired elimination reactions. Problems can arise at any one or all of these steps, a fact that frequently complicates reaction optimization and can discourage the development of new transformations. Fortunately, anodic electrochemistry offers an outstanding opportunity to systematically probe the mechanism of oxidative cyclization reactions. The use of electrochemical methods allows for the generation of radical cations under neutral conditions in an environment that helps prevent polymerization of the intermediate. Once the intermediates have been generated, a series of "telltale indicators" can be used to diagnose which step in an oxidative cyclization is problematic for less successful transformation. A set of potential solutions to address each type of problem encountered has been developed. For example, problems with the initial

  6. In silico, experimental, mechanistic model for extended-release felodipine disposition exhibiting complex absorption and a highly variable food interaction.

    Directory of Open Access Journals (Sweden)

    Sean H J Kim

    Full Text Available The objective of this study was to develop and explore new, in silico experimental methods for deciphering complex, highly variable absorption and food interaction pharmacokinetics observed for a modified-release drug product. Toward that aim, we constructed an executable software analog of study participants to whom product was administered orally. The analog is an object- and agent-oriented, discrete event system, which consists of grid spaces and event mechanisms that map abstractly to different physiological features and processes. Analog mechanisms were made sufficiently complicated to achieve prespecified similarity criteria. An equation-based gastrointestinal transit model with nonlinear mixed effects analysis provided a standard for comparison. Subject-specific parameterizations enabled each executed analog's plasma profile to mimic features of the corresponding six individual pairs of subject plasma profiles. All achieved prespecified, quantitative similarity criteria, and outperformed the gastrointestinal transit model estimations. We observed important subject-specific interactions within the simulation and mechanistic differences between the two models. We hypothesize that mechanisms, events, and their causes occurring during simulations had counterparts within the food interaction study: they are working, evolvable, concrete theories of dynamic interactions occurring within individual subjects. The approach presented provides new, experimental strategies for unraveling the mechanistic basis of complex pharmacological interactions and observed variability.

  7. Use of mechanistic simulations as a quantitative risk-ranking tool within the quality by design framework.

    Science.gov (United States)

    Stocker, Elena; Toschkoff, Gregor; Sacher, Stephan; Khinast, Johannes G

    2014-11-20

    The purpose of this study is to evaluate the use of computer simulations for generating quantitative knowledge as a basis for risk ranking and mechanistic process understanding, as required by ICH Q9 on quality risk management systems. In this specific publication, the main focus is the demonstration of a risk assessment workflow, including a computer simulation for the generation of mechanistic understanding of active tablet coating in a pan coater. Process parameter screening studies are statistically planned under consideration of impacts on a potentially critical quality attribute, i.e., coating mass uniformity. Based on computer simulation data the process failure mode and effects analysis of the risk factors is performed. This results in a quantitative criticality assessment of process parameters and the risk priority evaluation of failure modes. The factor for a quantitative reassessment of the criticality and risk priority is the coefficient of variation, which represents the coating mass uniformity. The major conclusion drawn from this work is a successful demonstration of the integration of computer simulation in the risk management workflow leading to an objective and quantitative risk assessment. Copyright © 2014. Published by Elsevier B.V.

  8. Insight into the hydraulics and resilience of Ponderosa pine seedlings using a mechanistic ecohydrologic model

    Science.gov (United States)

    Maneta, M. P.; Simeone, C.; Dobrowski, S.; Holden, Z.; Sapes, G.; Sala, A.; Begueria, S.

    2017-12-01

    In semiarid regions, drought-induced seedling mortality is considered to be caused by failure in the tree hydraulic column. Understanding the mechanisms that cause hydraulic failure and death in seedlings is important, among other things, to diagnose where some tree species may fail to regenerate, triggering demographic imbalances in the forest that could result in climate-driven shifts of tree species. Ponderosa pine is a common lower tree line species in the western US. Seedlings of ponderosa pine are often subject to low soil water potentials, which require lower water potentials in the xylem and leaves to maintain the negative pressure gradient that drives water upward. The resilience of the hydraulic column to hydraulic tension is species dependent, but from greenhouse experiments, we have identified general tension thresholds beyond which loss of xylem conductivity becomes critical, and mortality in Ponderosa pine seedlings start to occur. We describe this hydraulic behavior of plants using a mechanistic soil-vegetation-atmosphere transfer model. Before we use this models to understand water-stress induced seedling mortality at the landscape scale, we perform a modeling analysis of the dynamics of soil moisture, transpiration, leaf water potential and loss of plant water conductivity using detailed data from our green house experiments. The analysis is done using a spatially distributed model that simulates water fluxes, energy exchanges and water potentials in the soil-vegetation-atmosphere continuum. Plant hydraulic and physiological parameters of this model were calibrated using Monte Carlo methods against information on soil moisture, soil hydraulic potential, transpiration, leaf water potential and percent loss of conductivity in the xylem. This analysis permits us to construct a full portrait of the parameter space for Ponderosa pine seedling and generate posterior predictive distributions of tree response to understand the sensitivity of transpiration

  9. Modeling and validation of a mechanistic tool (MEFISTO) for the prediction of critical power in BWR fuel assemblies

    International Nuclear Information System (INIS)

    Adamsson, Carl; Le Corre, Jean-Marie

    2011-01-01

    Highlights: → The MEFISTO code efficiently and accurately predicts the dryout event in a BWR fuel bundle, using a mechanistic model. → A hybrid approach between a fast and robust sub-channel analysis and a three-field two-phase analysis is adopted. → MEFISTO modeling approach, calibration, CPU usage, sensitivity, trend analysis and performance evaluation are presented. → The calibration parameters and process were carefully selected to preserve the mechanistic nature of the code. → The code dryout prediction performance is near the level of fuel-specific empirical dryout correlations. - Abstract: Westinghouse is currently developing the MEFISTO code with the main goal to achieve fast, robust, practical and reliable prediction of steady-state dryout Critical Power in Boiling Water Reactor (BWR) fuel bundle based on a mechanistic approach. A computationally efficient simulation scheme was used to achieve this goal, where the code resolves all relevant field (drop, steam and multi-film) mass balance equations, within the annular flow region, at the sub-channel level while relying on a fast and robust two-phase (liquid/steam) sub-channel solution to provide the cross-flow information. The MEFISTO code can hence provide highly detailed solution of the multi-film flow in BWR fuel bundle while enhancing flexibility and reducing the computer time by an order of magnitude as compared to a standard three-field sub-channel analysis approach. Models for the numerical computation of the one-dimensional field flowrate distributions in an open channel (e.g. a sub-channel), including the numerical treatment of field cross-flows, part-length rods, spacers grids and post-dryout conditions are presented in this paper. The MEFISTO code is then applied to dryout prediction in BWR fuel bundle using VIPRE-W as a fast and robust two-phase sub-channel driver code. The dryout power is numerically predicted by iterating on the bundle power so that the minimum film flowrate in the

  10. Collection and analysis of existing data for waste tank mechanistic analysis. Progress report, December 1990

    Energy Technology Data Exchange (ETDEWEB)

    Allemann, R.T.; Antoniak, Z.I.; Friley, J.R.; Haines, C.E.; Liljegren, L.M.; Somasundaram, S.

    1991-12-01

    Pacific Northwest Laboratory (PNL) is conducting this study for Westinghouse Hanford Company (Westinghouse Hanford), a contractor for the US Department of Energy (DOE). The purpose of the work is to study possible mechanisms and fluid dynamics contributing to the periodic release of gases from the double-shell waste storage tanks at the Hanford Site in Richland, Washington. The waste inside the tank is generating and periodically releasing potentially flammable gases into the tank`s vent system according to observations. Questions scientists are trying to answer are: (1) How are these gases generated? (2) How did these gases become trapped? (3) What causes the periodic gas releases? (4) And, what is the mechanism of the gas releases? To develop a safe mitigation strategy, possible physical mechanisms for the periodic release of flammable gases need to be understood. During initial work, PNL has obtained, correlated, analyzed, and compared data with expected physical properties, defined mechanisms; and prepared initial models of gas formation and retention. This is the second interim report summarizing the status of the work done to data.

  11. Collection and analysis of existing data for waste tank mechanistic analysis

    Energy Technology Data Exchange (ETDEWEB)

    Allemann, R.T.; Antoniak, Z.I.; Friley, J.R.; Haines, C.E.; Liljegren, L.M.; Somasundaram, S.

    1991-12-01

    Pacific Northwest Laboratory (PNL) is conducting this study for Westinghouse Hanford Company (Westinghouse Hanford), a contractor for the US Department of Energy (DOE). The purpose of the work is to study possible mechanisms and fluid dynamics contributing to the periodic release of gases from the double-shell waste storage tanks at the Hanford Site in Richland, Washington. The waste inside the tank is generating and periodically releasing potentially flammable gases into the tank's vent system according to observations. Questions scientists are trying to answer are: (1) How are these gases generated (2) How did these gases become trapped (3) What causes the periodic gas releases (4) And, what is the mechanism of the gas releases To develop a safe mitigation strategy, possible physical mechanisms for the periodic release of flammable gases need to be understood. During initial work, PNL has obtained, correlated, analyzed, and compared data with expected physical properties, defined mechanisms; and prepared initial models of gas formation and retention. This is the second interim report summarizing the status of the work done to data.

  12. Hierarchical modeling of activation mechanisms in the ABL and EGFR kinase domains: thermodynamic and mechanistic catalysts of kinase activation by cancer mutations.

    Directory of Open Access Journals (Sweden)

    Anshuman Dixit

    2009-08-01

    Full Text Available Structural and functional studies of the ABL and EGFR kinase domains have recently suggested a common mechanism of activation by cancer-causing mutations. However, dynamics and mechanistic aspects of kinase activation by cancer mutations that stimulate conformational transitions and thermodynamic stabilization of the constitutively active kinase form remain elusive. We present a large-scale computational investigation of activation mechanisms in the ABL and EGFR kinase domains by a panel of clinically important cancer mutants ABL-T315I, ABL-L387M, EGFR-T790M, and EGFR-L858R. We have also simulated the activating effect of the gatekeeper mutation on conformational dynamics and allosteric interactions in functional states of the ABL-SH2-SH3 regulatory complexes. A comprehensive analysis was conducted using a hierarchy of computational approaches that included homology modeling, molecular dynamics simulations, protein stability analysis, targeted molecular dynamics, and molecular docking. Collectively, the results of this study have revealed thermodynamic and mechanistic catalysts of kinase activation by major cancer-causing mutations in the ABL and EGFR kinase domains. By using multiple crystallographic states of ABL and EGFR, computer simulations have allowed one to map dynamics of conformational fluctuations and transitions in the normal (wild-type and oncogenic kinase forms. A proposed multi-stage mechanistic model of activation involves a series of cooperative transitions between different conformational states, including assembly of the hydrophobic spine, the formation of the Src-like intermediate structure, and a cooperative breakage and formation of characteristic salt bridges, which signify transition to the active kinase form. We suggest that molecular mechanisms of activation by cancer mutations could mimic the activation process of the normal kinase, yet exploiting conserved structural catalysts to accelerate a conformational transition

  13. A preliminary study of mechanistic approach in pavement design to accommodate climate change effects

    Science.gov (United States)

    Harnaeni, S. R.; Pramesti, F. P.; Budiarto, A.; Setyawan, A.

    2018-03-01

    Road damage is caused by some factors, including climate changes, overload, and inappropriate procedure for material and development process. Meanwhile, climate change is a phenomenon which cannot be avoided. The effects observed include air temperature rise, sea level rise, rainfall changes, and the intensity of extreme weather phenomena. Previous studies had shown the impacts of climate changes on road damage. Therefore, several measures to anticipate the damage should be considered during the planning and construction in order to reduce the cost of road maintenance. There are three approaches generally applied in the design of flexible pavement thickness, namely mechanistic approach, mechanistic-empirical (ME) approach and empirical approach. The advantages of applying mechanistic approach or mechanistic-empirical (ME) approaches are its efficiency and reliability in the design of flexible pavement thickness as well as its capacity to accommodate climate changes in compared to empirical approach. However, generally, the design of flexible pavement thickness in Indonesia still applies empirical approach. This preliminary study aimed to emphasize the importance of the shifting towards a mechanistic approach in the design of flexible pavement thickness.

  14. Mechanistic insights into the neutralization of cytotoxic abrin by the monoclonal antibody D6F10.

    Directory of Open Access Journals (Sweden)

    Shradha Bagaria

    Full Text Available Abrin, an A/B toxin obtained from the Abrus precatorius plant is extremely toxic and a potential bio-warfare agent. Till date there is no antidote or vaccine available against this toxin. The only known neutralizing monoclonal antibody against abrin, namely D6F10, has been shown to rescue the toxicity of abrin in cells as well as in mice. The present study focuses on mapping the epitopic region to understand the mechanism of neutralization of abrin by the antibody D6F10. Truncation and mutational analysis of abrin A chain revealed that the amino acids 74-123 of abrin A chain contain the core epitope and the residues Thr112, Gly114 and Arg118 are crucial for binding of the antibody. In silico analysis of the position of the mapped epitope indicated that it is present close to the active site cleft of abrin A chain. Thus, binding of the antibody near the active site blocks the enzymatic activity of abrin A chain, thereby rescuing inhibition of protein synthesis by the toxin in vitro. At 1∶10 molar concentration of abrin:antibody, the antibody D6F10 rescued cells from abrin-mediated inhibition of protein synthesis but did not prevent cell attachment of abrin. Further, internalization of the antibody bound to abrin was observed in cells by confocal microscopy. This is a novel finding which suggests that the antibody might function intracellularly and possibly explains the rescue of abrin's toxicity by the antibody in whole cells and animals. To our knowledge, this study is the first report on a neutralizing epitope for abrin and provides mechanistic insights into the poorly understood mode of action of anti-A chain antibodies against several toxins including ricin.

  15. Requirements on mechanistic NPP models used in CSS for diagnostics and predictions

    International Nuclear Information System (INIS)

    Juslin, K.

    1996-01-01

    Mechanistic models have for several years with good experience been used for operators' support in electric power dispatching centres. Some models of limited scope have already been in use at nuclear power plants. It is considered that also advanced mechanistic models in combination with present computer technology with preference could be used in Computerized Support Systems (CSS) for the assistance of Nuclear Power Plant (NPP) operators. Requirements with respect to accuracy, validity range, speed flexibility and level of detail on the models used for such purposes are discussed. Quality Assurance, Verification and Validation efforts are considered. A long term commitment in the field of mechanistic modelling and real time simulation is considered as the key to successful implementations. The Advanced PROcess Simulation (APROS) code system and simulation environment developed at the Technical Research Centre of Finland (VTT) is intended also for CSS applications in NPP control rooms. (author). 4 refs

  16. The use of mechanistic descriptions of algal growth and zooplankton grazing in an estuarine eutrophication model

    Science.gov (United States)

    Baird, M. E.; Walker, S. J.; Wallace, B. B.; Webster, I. T.; Parslow, J. S.

    2003-03-01

    A simple model of estuarine eutrophication is built on biomechanical (or mechanistic) descriptions of a number of the key ecological processes in estuaries. Mechanistically described processes include the nutrient uptake and light capture of planktonic and benthic autotrophs, and the encounter rates of planktonic predators and prey. Other more complex processes, such as sediment biogeochemistry, detrital processes and phosphate dynamics, are modelled using empirical descriptions from the Port Phillip Bay Environmental Study (PPBES) ecological model. A comparison is made between the mechanistically determined rates of ecological processes and the analogous empirically determined rates in the PPBES ecological model. The rates generally agree, with a few significant exceptions. Model simulations were run at a range of estuarine depths and nutrient loads, with outputs presented as the annually averaged biomass of autotrophs. The simulations followed a simple conceptual model of eutrophication, suggesting a simple biomechanical understanding of estuarine processes can provide a predictive tool for ecological processes in a wide range of estuarine ecosystems.

  17. Mechanistic Models for Process Development and Optimization of Fed-batch Fermentation Systems

    DEFF Research Database (Denmark)

    Mears, Lisa; Stocks, Stuart M.; Albæk, Mads O.

    2016-01-01

    This work discusses the application of mechanistic models to pilot scale filamentous fungal fermentation systems operated at Novozymes A/S. For on-line applications, a state estimator model is developed based on a stoichiometric balance in order to predict the biomass and product concentration....... This is based on on-line gas measurements and ammonia addition flow rate measurements. Additionally, a mechanistic model is applied offline as a tool for batch planning, based on definition of the process back pressure, aeration rate and stirrer speed. This allows the batch starting fill to be planned, taking...... into account the oxygen transfer conditions, as well as the evaporation rates of the system. Mechanistic models are valuable tools which are applicable for both process development and optimization. The state estimator described will be a valuable tool for future work as part of control strategy development...

  18. Toxicogenomic investigation of Tetrahymena thermophila exposed to dichlorodiphenyltrichloroethane (DDT), tributyltin (TBT), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD).

    Science.gov (United States)

    Chang, Yue; Feng, LiFang; Miao, Wei

    2011-07-01

    Dichlorodiphenyltrichloroethane (DDT), tributyltin (TBT), and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) are persistent in the environment and cause continuous toxic effects in humans and aquatic life. Tetrahymena thermophila has the potential for use as a model for research regarding toxicants. In this study, this organism was used to analyze a genome-wide microarray generated from cells exposed to DDT, TBT and TCDD. To accomplish this, genes differentially expressed when treated with each toxicant were identified, after which their functions were categorized using GO enrichment analysis. The results suggested that the responses of T. thermophila were similar to those of multicellular organisms. Additionally, the context likelihood of relatedness method (CLR) was applied to construct a TCDD-relevant network. The T-shaped network obtained could be functionally divided into two subnetworks. The general functions of both subnetworks were related to the epigenetic mechanism of TCDD. Based on analysis of the networks, a model of the TCDD effect on T. thermophila was inferred. Thus, Tetrahymena has the potential to be a good unicellular eukaryotic model for toxic mechanism research at the genome level.

  19. Pulmonary response to surface‐coated nanotitanium dioxide particles includes induction of acute phase response genes, inflammatory cascades, and changes in microRNAs: A toxicogenomic study

    DEFF Research Database (Denmark)

    Halappanavar, Sabina; Jackson, Petra; Williams, Andrew

    2011-01-01

    with acute phase, inflammation and immune response 5 days post exposure with concomitant changes in several miRNAs. The role of these miRNAs in pulmonary response to inhaled particles is unknown and warrants further research. Environ. Mol. Mutagen., 2011. © 2011 Wiley‐Liss, Inc....... in increased levels of mRNA for acute phase markers serum amyloid A‐1 (Saa1) and serum amyloid A‐3 (Saa3), several C‐X‐C and C‐C motif chemokines, and cytokine tumor necrosis factor genes. Protein analysis of Saa1 and 3 showed selective upregulation of Saa3 in lung tissues. Sixteen miRNAs were induced by more...... than 1.2‐fold (adjusted P‐value changes in the expression of genes associated...

  20. The value of mechanistic biophysical information for systems-level understanding of complex biological processes such as cytokinesis.

    Science.gov (United States)

    Pollard, Thomas D

    2014-12-02

    This review illustrates the value of quantitative information including concentrations, kinetic constants and equilibrium constants in modeling and simulating complex biological processes. Although much has been learned about some biological systems without these parameter values, they greatly strengthen mechanistic accounts of dynamical systems. The analysis of muscle contraction is a classic example of the value of combining an inventory of the molecules, atomic structures of the molecules, kinetic constants for the reactions, reconstitutions with purified proteins and theoretical modeling to account for the contraction of whole muscles. A similar strategy is now being used to understand the mechanism of cytokinesis using fission yeast as a favorable model system. Copyright © 2014 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  1. A mechanistic model for long-term nuclear waste glass dissolution integrating chemical affinity and interfacial diffusion barrier

    Energy Technology Data Exchange (ETDEWEB)

    Ma, Teqi [Northwest Institute of Nuclear Technology, No.28 Pingyu Road, Baqiao District, Xi' an,Shaanxi, 710024 (China); Mechanics and Physics of Solids Research Group, Modelling and Simulation Centre, The University of Manchester, Oxford Road, Manchester, M13 9PL (United Kingdom); Jivkov, Andrey P., E-mail: andrey.jivkov@manchester.ac.uk [Mechanics and Physics of Solids Research Group, Modelling and Simulation Centre, The University of Manchester, Oxford Road, Manchester, M13 9PL (United Kingdom); Li, Weiping; Liang, Wei; Wang, Yu; Xu, Hui [Northwest Institute of Nuclear Technology, No.28 Pingyu Road, Baqiao District, Xi' an,Shaanxi, 710024 (China); Han, Xiaoyuan, E-mail: xyhan_nint@sina.cn [Northwest Institute of Nuclear Technology, No.28 Pingyu Road, Baqiao District, Xi' an,Shaanxi, 710024 (China)

    2017-04-01

    Understanding the alteration of nuclear waste glass in geological repository conditions is critical element of the analysis of repository retention function. Experimental observations of glass alterations provide a general agreement on the following regimes: inter-diffusion, hydrolysis process, rate drop, residual rate and, under very particular conditions, resumption of alteration. Of these, the mechanisms controlling the rate drop and the residual rate remain a subject of dispute. This paper offers a critical review of the two most competitive models related to these regimes: affinity–limited dissolution and diffusion barrier. The limitations of these models are highlighted by comparison of their predictions with available experimental evidence. Based on the comprehensive discussion of the existing models, a new mechanistic model is proposed as a combination of the chemical affinity and diffusion barrier concepts. It is demonstrated how the model can explain experimental phenomena and data, for which the existing models are shown to be not fully adequate.

  2. Flow regimes and mechanistic modeling of critical heat flux under subcooled flow boiling conditions

    Science.gov (United States)

    Le Corre, Jean-Marie

    Thermal performance of heat flux controlled boiling heat exchangers are usually limited by the Critical Heat Flux (CHF) above which the heat transfer degrades quickly, possibly leading to heater overheating and destruction. In an effort to better understand the phenomena, a literature review of CHF experimental visualizations under subcooled flow boiling conditions was performed and systematically analyzed. Three major types of CHF flow regimes were identified (bubbly, vapor clot and slug flow regime) and a CHF flow regime map was developed, based on a dimensional analysis of the phenomena and available data. It was found that for similar geometric characteristics and pressure, a Weber number (We)/thermodynamic quality (x) map can be used to predict the CHF flow regime. Based on the experimental observations and the review of the available CHF mechanistic models under subcooled flow boiling conditions, hypothetical CHF mechanisms were selected for each CHF flow regime, all based on a concept of wall dry spot overheating, rewetting prevention and subsequent dry spot spreading. It is postulated that a high local wall superheat occurs locally in a dry area of the heated wall, due to a cyclical event inherent to the considered CHF two-phase flow regime, preventing rewetting (Leidenfrost effect). The selected modeling concept has the potential to span the CHF conditions from highly subcooled bubbly flow to early stage of annular flow. A numerical model using a two-dimensional transient thermal analysis of the heater undergoing nucleation was developed to mechanistically predict CHF in the case of a bubbly flow regime. In this type of CHF two-phase flow regime, the high local wall superheat occurs underneath a nucleating bubble at the time of bubble departure. The model simulates the spatial and temporal heater temperature variations during nucleation at the wall, accounting for the stochastic nature of the boiling phenomena. The model has also the potential to evaluate

  3. Protective Effects of Dihydromyricetin against •OH-Induced Mesenchymal Stem Cells Damage and Mechanistic Chemistry

    Directory of Open Access Journals (Sweden)

    Xican Li

    2016-05-01

    Full Text Available As a natural flavonoid in Ampelopsis grossedentata, dihydromyricetin (DHM, 2R,3R-3,5,7,3′,4′,5′-hexahydroxy-2,3-dihydroflavonol was observed to increase the viability of •OH-treated mesenchymal stem cells using a MTT [3-(4,5-dimethylthiazol-2-yl-2,5-diphenyl] assay and flow cytometry analysis. This protective effect indicates DHM may be a beneficial agent for cell transplantation therapy. Mechanistic chemistry studies indicated that compared with myricetin, DHM was less effective at ABTS+• (2,2′-azino-bis(3-ethylbenzothiazoline-6-sulfonic acid radical scavenging and reducing Cu2+, and had higher •O2− and DPPH• (1,1-diphenyl-2-picrylhydrazyl radical scavenging activities. Additionally, DHM could also chelate Fe2+ to give an absorption maximum at 589 nm. Hence, such protective effect of DHM may arise from its antioxidant activities which are thought to occur via direct radical-scavenging and Fe2+-chelation. Direct radical-scavenging involves an electron transfer (ET pathway. The hydrogenation of the 2,3-double bond is hypothesized to reduce the ET process by blocking the formation of a larger π-π conjugative system. The glycosidation of the 3–OH in myricitrin is assumed to sterically hinder atom transfer in the •O2− and DPPH• radical-scavenging processes. In DHM, the Fe2+-chelating effect can actually be attributed to the 5,3′,4′,5′–OH and 4–C=O groups, and the 3–OH group itself can neither scavenge radicals nor chelate metal.

  4. Mechanistic investigation on microbial toxicity of nano hydroxyapatite on implant associated pathogens

    Energy Technology Data Exchange (ETDEWEB)

    Baskar, K. [Department of Biotechnology, University of Madras, Guindy Campus, Chennai, Tamil Nadu (India); Anusuya, T. [Department of Nanotechnology, SRM University, Kattankulathur, Tamil Nadu (India); Devanand Venkatasubbu, G., E-mail: gdevanandvenkatasubbu@gmail.com [Department of Nanotechnology, SRM University, Kattankulathur, Tamil Nadu (India)

    2017-04-01

    The use of atomic scale inorganic nanoparticles (NPs) to fight against pathogenic microorganisms is a recent trend in biomedical area which overcomes the limitations of organic compounds in terms of stability, shelf life and bioactivity. One such Calcium phosphate based biomaterial is hydroxyapatite (HA), considered as potential bioactive compound with excellent biocompatibility, osteointegrity and biodegradability. Osteomyelitis, the implant associated infection, is the major problem worldwide responsible for the majority of implant failure cases. Since HA is used as a coating material of implants, only few reports were available on its antimicrobial activity and cytotoxicity whereas no reports on its possible antimicrobial mechanism. In this present study, the HA-NPs were synthesized by wet chemical precipitation and were characterized using X-ray diffraction (XRD), Transmission Electron Microscopy (TEM) and Fourier transform infrared spectroscopy (FTIR). The synthesized HA-NPs were evaluated for antimicrobial activity against implant associated bacterial pathogens. The study also explores the mechanistic action of HA-NPs in killing of bacteria by determining the reactive oxygen species (ROS) generation, DNA fragmentation, Lactate dehydrogenase (LDH) leakage and cellular interaction. In addition the cytotoxicity of HA-NPs was determined by MTT assay and Fluorescence Microscopic analysis. The results revealed that, the synthesized HA-NPs showed good antibacterial activity for tested bacterial species and the possible antibacterial mechanism were due to the lack of membrane integrity and cytotoxic studies shows the concentration dependent changes in cell viability. - Highlights: • Antibacterial activity against Gram − ve bacterium • Mechanism of antibacterial activity is analyzed. • DNA fragmentation, growth curve, LDH, ROS are analyzed. • The mechanism is by damaging cell membrane. • Hydroxyapatite is biocompatible.

  5. A mechanistic understanding of allosteric immune escape pathways in the HIV-1 envelope glycoprotein.

    Directory of Open Access Journals (Sweden)

    Anurag Sethi

    Full Text Available The HIV-1 envelope (Env spike, which consists of a compact, heterodimeric trimer of the glycoproteins gp120 and gp41, is the target of neutralizing antibodies. However, the high mutation rate of HIV-1 and plasticity of Env facilitates viral evasion from neutralizing antibodies through various mechanisms. Mutations that are distant from the antibody binding site can lead to escape, probably by changing the conformation or dynamics of Env; however, these changes are difficult to identify and define mechanistically. Here we describe a network analysis-based approach to identify potential allosteric immune evasion mechanisms using three known HIV-1 Env gp120 protein structures from two different clades, B and C. First, correlation and principal component analyses of molecular dynamics (MD simulations identified a high degree of long-distance coupled motions that exist between functionally distant regions within the intrinsic dynamics of the gp120 core, supporting the presence of long-distance communication in the protein. Then, by integrating MD simulations with network theory, we identified the optimal and suboptimal communication pathways and modules within the gp120 core. The results unveil both strain-dependent and -independent characteristics of the communication pathways in gp120. We show that within the context of three structurally homologous gp120 cores, the optimal pathway for communication is sequence sensitive, i.e. a suboptimal pathway in one strain becomes the optimal pathway in another strain. Yet the identification of conserved elements within these communication pathways, termed inter-modular hotspots, could present a new opportunity for immunogen design, as this could be an additional mechanism that HIV-1 uses to shield vulnerable antibody targets in Env that induce neutralizing antibody breadth.

  6. Mechanistic background and clinical applications of indocyanine green fluorescence imaging of hepatocellular carcinoma.

    Science.gov (United States)

    Ishizawa, Takeaki; Masuda, Koichi; Urano, Yasuteru; Kawaguchi, Yoshikuni; Satou, Shouichi; Kaneko, Junichi; Hasegawa, Kiyoshi; Shibahara, Junji; Fukayama, Masashi; Tsuji, Shingo; Midorikawa, Yutaka; Aburatani, Hiroyuki; Kokudo, Norihiro

    2014-02-01

    Although clinical applications of intraoperative fluorescence imaging of liver cancer using indocyanine green (ICG) have begun, the mechanistic background of ICG accumulation in the cancerous tissues remains unclear. In 170 patients with hepatocellular carcinoma cells (HCC), the liver surfaces and resected specimens were intraoperatively examined by using a near-infrared fluorescence imaging system after preoperative administration of ICG (0.5 mg/kg i.v.). Microscopic examinations, gene expression profile analysis, and immunohistochemical staining were performed for HCCs, which showed ICG fluorescence in the cancerous tissues (cancerous-type fluorescence), and HCCs showed fluorescence only in the surrounding non-cancerous liver parenchyma (rim-type fluorescence). ICG fluorescence imaging enabled identification of 273 of 276 (99%) HCCs in the resected specimens. HCCs showed that cancerous-type fluorescence was associated with higher cancer cell differentiation as compared with rim-type HCCs (P Fluorescence microscopy identified the presence of ICG in the canalicular side of the cancer cell cytoplasm, and pseudoglands of the HCCs showed a cancerous-type fluorescence pattern. The ratio of the gene and protein expression levels in the cancerous to non-cancerous tissues for Na(+)/taurocholate cotransporting polypeptide (NTCP) and organic anion-transporting polypeptide 8 (OATP8), which are associated with portal uptake of ICG by hepatocytes that tended to be higher in the HCCs that showed cancerous-type fluorescence than in those that showed rim-type fluorescence. Preserved portal uptake of ICG in differentiated HCC cells by NTCP and OATP8 with concomitant biliary excretion disorders causes accumulation of ICG in the cancerous tissues after preoperative intravenous administration. This enables highly sensitive identification of HCC by intraoperative ICG fluorescence imaging.

  7. Heterogeneity of pulmonary perfusion as a mechanistic image-based phenotype in emphysema susceptible smokers.

    Science.gov (United States)

    Alford, Sara K; van Beek, Edwin J R; McLennan, Geoffrey; Hoffman, Eric A

    2010-04-20

    Recent evidence suggests that endothelial dysfunction and pathology of pulmonary vascular responses may serve as a precursor to smoking-associated emphysema. Although it is known that emphysematous destruction leads to vasculature changes, less is known about early regional vascular dysfunction which may contribute to and precede emphysematous changes. We sought to test the hypothesis, via multidetector row CT (MDCT) perfusion imaging, that smokers showing early signs of emphysema susceptibility have a greater heterogeneity in regional perfusion parameters than emphysema-free smokers and persons who had never smoked (NS). Assuming that all smokers have a consistent inflammatory response, increased perfusion heterogeneity in emphysema-susceptible smokers would be consistent with the notion that these subjects may have the inability to block hypoxic vasoconstriction in patchy, small regions of inflammation. Dynamic ECG-gated MDCT perfusion scans with a central bolus injection of contrast were acquired in 17 NS, 12 smokers with normal CT imaging studies (SNI), and 12 smokers with subtle CT findings of centrilobular emphysema (SCE). All subjects had normal spirometry. Quantitative image analysis determined regional perfusion parameters, pulmonary blood flow (PBF), and mean transit time (MTT). Mean and coefficient of variation were calculated, and statistical differences were assessed with one-way ANOVA. MDCT-based MTT and PBF measurements demonstrate globally increased heterogeneity in SCE subjects compared with NS and SNI subjects but demonstrate similarity between NS and SNI subjects. These findings demonstrate a functional lung-imaging measure that provides a more mechanistically oriented phenotype that differentiates smokers with and without evidence of emphysema susceptibility.

  8. Mechanistic Mathematical Modeling Tests Hypotheses of the Neurovascular Coupling in fMRI.

    Directory of Open Access Journals (Sweden)

    Karin Lundengård

    2016-06-01

    Full Text Available Functional magnetic resonance imaging (fMRI measures brain activity by detecting the blood-oxygen-level dependent (BOLD response to neural activity. The BOLD response depends on the neurovascular coupling, which connects cerebral blood flow, cerebral blood volume, and deoxyhemoglobin level to neuronal activity. The exact mechanisms behind this neurovascular coupling are not yet fully investigated. There are at least three different ways in which these mechanisms are being discussed. Firstly, mathematical models involving the so-called Balloon model describes the relation between oxygen metabolism, cerebral blood volume, and cerebral blood flow. However, the Balloon model does not describe cellular and biochemical mechanisms. Secondly, the metabolic feedback hypothesis, which is based on experimental findings on metabolism associated with brain activation, and thirdly, the neurotransmitter feed-forward hypothesis which describes intracellular pathways leading to vasoactive substance release. Both the metabolic feedback and the neurotransmitter feed-forward hypotheses have been extensively studied, but only experimentally. These two hypotheses have never been implemented as mathematical models. Here we investigate these two hypotheses by mechanistic mathematical modeling using a systems biology approach; these methods have been used in biological research for many years but never been applied to the BOLD response in fMRI. In the current work, model structures describing the metabolic feedback and the neurotransmitter feed-forward hypotheses were applied to measured BOLD responses in the visual cortex of 12 healthy volunteers. Evaluating each hypothesis separately shows that neither hypothesis alone can describe the data in a biologically plausible way. However, by adding metabolism to the neurotransmitter feed-forward model structure, we obtained a new model structure which is able to fit the estimation data and successfully predict new

  9. Lynx web services for annotations and systems analysis of multi-gene disorders.

    Science.gov (United States)

    Sulakhe, Dinanath; Taylor, Andrew; Balasubramanian, Sandhya; Feng, Bo; Xie, Bingqing; Börnigen, Daniela; Dave, Utpal J; Foster, Ian T; Gilliam, T Conrad; Maltsev, Natalia

    2014-07-01

    Lynx is a web-based integrated systems biology platform that supports annotation and analysis of experimental data and generation of weighted hypotheses on molecular mechanisms contributing to human phenotypes and disorders of interest. Lynx has integrated multiple classes of biomedical data (genomic, proteomic, pathways, phenotypic, toxicogenomic, contextual and others) from various public databases as well as manually curated data from our group and collaborators (LynxKB). Lynx provides tools for gene list enrichment analysis using multiple functional annotations and network-based gene prioritization. Lynx provides access to the integrated database and the analytical tools via REST based Web Services (http://lynx.ci.uchicago.edu/webservices.html). This comprises data retrieval services for specific functional annotations, services to search across the complete LynxKB (powered by Lucene), and services to access the analytical tools built within the Lynx platform. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

  10. Applying Mechanistic Dam Breach Models to Historic Levee Breaches

    OpenAIRE

    Risher Paul; Gibson Stanford

    2016-01-01

    Hurricane Katrina elevated levee risk in the US national consciousness, motivating agencies to assess and improve their levee risk assessment methodology. Accurate computation of the flood flow magnitude and timing associated with a levee breach remains one of the most difficult and uncertain components of levee risk analysis. Contemporary methods are largely empirical and approximate, introducing substantial uncertainty to the damage and life loss models. Levee breach progressions are often ...

  11. Intestinal toxicity evaluation of TiO2 degraded surface-treated nanoparticles: a combined physico-chemical and toxicogenomics approach in caco-2 cells

    Directory of Open Access Journals (Sweden)

    Fisichella Matthieu

    2012-05-01

    Full Text Available Abstract Background Titanium dioxide (TiO2 nanoparticles (NPs are widely used due to their specific properties, like UV filters in sunscreen. In that particular case TiO2 NPs are surface modified to avoid photocatalytic effects. These surface-treated nanoparticles (STNPs spread in the environment and might release NPs as degradation residues. Indeed, degradation by the environment (exposure to UV, water and air contact … will occur and could profoundly alter the physicochemical properties of STNPs such as chemistry, size, shape, surface structure and dispersion that are important parameters for toxicity. Although the toxicity of surface unmodified TiO2 NPs has been documented, nothing was done about degraded TiO2 STNPs which are the most likely to be encountered in environment. The superoxide production by aged STNPs suspensions was tested and compared to surface unmodified TiO2 NPs. We investigated the possible toxicity of commercialized STNPs, degraded by environmental conditions, on human intestinal epithelial cells. STNPs sizes and shape were characterized and viability tests were performed on Caco-2 cells exposed to STNPs. The exposed cells were imaged with SEM and STNPs internalization was researched by TEM. Gene expression microarray analyses were performed to look for potential changes in cellular functions. Results The production of reactive oxygen species was detected with surface unmodified TiO2 NPs but not with STNPs or their residues. Through three different toxicity assays, the STNPs tested, which have a strong tendency to aggregate in complex media, showed no toxic effect in Caco-2 cells after exposures to STNPs up to 100 μg/mL over 4 h, 24 h and 72 h. The cell morphology remained intact, attested by SEM, and internalization of STNPs was not seen by TEM. Moreover gene expression analysis using pangenomic oligomicroarrays (4x 44000 genes did not show any change versus unexposed cells after exposure to 10 μg/ mL, which

  12. Corrigendum: Free Will and Punishment: A Mechanistic View of Human Nature Reduces Retribution.

    Science.gov (United States)

    2018-02-01

    Original article: Shariff, A. F., Greene, J. D., Karremans, J. C., Luguri, J. B., Clark, C. J., Schooler, J. W., . . . Vohs, K. D. (2014). Free will and punishment: A mechanistic view of human nature reduces retribution. Psychological Science, 25, 1563-1570. doi:10.1177/0956797614534693.

  13. Corrigendum: Free will and punishment: A mechanistic view of human nature reduces retribution

    NARCIS (Netherlands)

    Shariff, A.F.; Greene, J.D.; Karremans, J.C.T.M.; Luguri, J.B.; Clark, C.J.; Schooler, J.W.; Baumeister, R.F.; Vohs, K.D.

    2018-01-01

    Original article: Shariff, A. F., Greene, J. D., Karremans, J. C., Luguri, J. B., Clark, C. J., Schooler, J. W., . . . Vohs, K. D. (2014). Free will and punishment: A mechanistic view of human nature reduces retribution. Psychological Science, 25, 1563-1570. doi:10.1177/0956797614534693

  14. Mechanistic-Empirical (M-E) Design Implementation & Monitoring for Flexible Pavements : 2018 PROJECT SUMMARY

    Science.gov (United States)

    2018-06-01

    This document is a summary of the tasks performed for Project ICT-R27-149-1. Mechanistic-empirical (M-E)based flexible pavement design concepts and procedures were previously developed in Illinois Cooperative Highway Research Program projects IHR-...

  15. A Mechanistic Study of Arsenic (III) Rejection by Reverse Osmosis and Nanofiltration Membranes

    Science.gov (United States)

    Suzuki, Tasuma

    2009-01-01

    Reverse osmosis/nanofiltration (RO/NF) membranes are capable to provide an effective barrier for a wide range of contaminants (including disinfection by-products precursors) in a single treatment step. However, solute rejection mechanisms by RO/NF membranes are not well understood. The lack of mechanistic information arises from experimental…

  16. Atomization of bismuthane in a dielectric barrier discharge: A mechanistic study

    Czech Academy of Sciences Publication Activity Database

    Kratzer, Jan; Zelina, Ondřej; Svoboda, Milan; Sturgeon, R. E.; Mester, Z.; Dědina, Jiří

    2016-01-01

    Roč. 88, č. 3 (2016), s. 1804-1811 ISSN 0003-2700 R&D Projects: GA ČR GA14-23532S Grant - others:GA AV ČR(CZ) M200311202 Institutional support: RVO:68081715 Keywords : dielectric barrier discharge * hydride generation * mechanistic study Subject RIV: CB - Analytical Chemistry, Separation Impact factor: 6.320, year: 2016

  17. Productivity of "Collisions Generate Heat" for Reconciling an Energy Model with Mechanistic Reasoning: A Case Study

    Science.gov (United States)

    Scherr, Rachel E.; Robertson, Amy D.

    2015-01-01

    We observe teachers in professional development courses about energy constructing mechanistic accounts of energy transformations. We analyze a case in which teachers investigating adiabatic compression develop a model of the transformation of kinetic energy to thermal energy. Among their ideas is the idea that thermal energy is generated as a…

  18. Growth and lipid production of Umbelopsis isabellina on a solid substrate - Mechanistic modeling and validation

    NARCIS (Netherlands)

    Meeuwse, P.; Klok, A.J.; Haemers, S.; Tramper, J.; Rinzema, A.

    2012-01-01

    Microbial lipids are an interesting feedstock for biodiesel. Their production from agricultural waste streams by fungi cultivated in solid-state fermentation may be attractive, but the yield of this process is still quite low. In this article, a mechanistic model is presented that describes growth,

  19. A mechanistic model for electricity consumption on dairy farms: Definition, validation, and demonstration

    NARCIS (Netherlands)

    Upton, J.R.; Murphy, M.; Shallo, L.; Groot Koerkamp, P.W.G.; Boer, de I.J.M.

    2014-01-01

    Our objective was to define and demonstrate a mechanistic model that enables dairy farmers to explore the impact of a technical or managerial innovation on electricity consumption, associated CO2 emissions, and electricity costs. We, therefore, (1) defined a model for electricity consumption on

  20. Atomization of bismuthane in a dielectric barrier discharge: A mechanistic study

    Czech Academy of Sciences Publication Activity Database

    Kratzer, Jan; Zelina, Ondřej; Svoboda, Milan; Sturgeon, R. E.; Mester, Z.; Dědina, Jiří

    2016-01-01

    Roč. 88, č. 3 (2016), s. 1804-1811 ISSN 0003-2700 R&D Projects: GA ČR GA14-23532S Grant - others:GA AV ČR(CZ) M200311202 Institutional support: RVO:68081715 Keywords : dielectric barrier discharge * hydride generation * mechanistic study Subject RIV: CB - Analytical Chemistry , Separation Impact factor: 6.320, year: 2016

  1. Permanent deformation testing for a new South African mechanistic pavement design method

    CSIR Research Space (South Africa)

    Anochie-Boateng, Joseph

    2012-01-01

    Full Text Available The South Africa National Road Agency Limited together with the CSIR are undertaking a research and development project to support the revision of the South African mechanistic-empirical pavement design method. An important part of this project...

  2. Mechanistic applicability domain classification of a local lymph node assay dataset for skin sensitization.

    Science.gov (United States)

    Roberts, David W; Patlewicz, Grace; Kern, Petra S; Gerberick, Frank; Kimber, Ian; Dearman, Rebecca J; Ryan, Cindy A; Basketter, David A; Aptula, Aynur O

    2007-07-01

    The goal of eliminating animal testing in the predictive identification of chemicals with the intrinsic ability to cause skin sensitization is an important target, the attainment of which has recently been brought into even sharper relief by the EU Cosmetics Directive and the requirements of the REACH legislation. Development of alternative methods requires that the chemicals used to evaluate and validate novel approaches comprise not only confirmed skin sensitizers and non-sensitizers but also substances that span the full chemical mechanistic spectrum associated with skin sensitization. To this end, a recently published database of more than 200 chemicals tested in the mouse local lymph node assay (LLNA) has been examined in relation to various chemical reaction mechanistic domains known to be associated with sensitization. It is demonstrated here that the dataset does cover the main reaction mechanistic domains. In addition, it is shown that assignment to a reaction mechanistic domain is a critical first step in a strategic approach to understanding, ultimately on a quantitative basis, how chemical properties influence the potency of skin sensitizing chemicals. This understanding is necessary if reliable non-animal approaches, including (quantitative) structure-activity relationships (Q)SARs, read-across, and experimental chemistry based models, are to be developed.

  3. Assessing Metal Levels in Children from the Mechanistic Indicators of Childhood Asthma(MICA) study

    Science.gov (United States)

    Toxic and essential metals levels can be used as health indicators. Here, we quantitatively compare and contrast toxic and essential metals levels in vacuum dust, urine, and fingernail samples of 109 children in Detroit, Michigan as part of The Mechanistic Indicators of Childhood...

  4. Mechanistic investigation on the oxidation of kinetin by Ag(III)

    Indian Academy of Sciences (India)

    Home; Journals; Journal of Chemical Sciences; Volume 122; Issue 6. Mechanistic investigation on the oxidation of kinetin by Ag(III) periodate complex in aqueous alkaline media: A kinetic approach. S D Lamani A M Tatagar S T Nandibewoor. Full Papers Volume 122 Issue 6 November 2010 pp 891-900 ...

  5. Ruthenium-Catalyzed Transformations of Alcohols: Mechanistic Investigations and Methodology Development

    DEFF Research Database (Denmark)

    Makarov, Ilya; Madsen, Robert; Fristrup, Peter

    with dimethoxyisopropylidene and pyridilidene ligands could be more active than RuCl2(IiPr)(p-cymene) used in the mechanistic investigation. Two analogs of the calculated complexes were synthesized but were not isolated in a pure form. The amidation reaction catalyzed by a mixture containing the N-ethyl pyridilidene...

  6. Mechanistic and kinetic aspects of pentose dehydration towards furfural in aqueous media employing homogeneous catalysis

    NARCIS (Netherlands)

    Danon, B.; Marcotullio, G.; De Jong, W.

    2013-01-01

    In this paper both the mechanistic and kinetic aspects of furfural formation from pentoses in aqueous acidic media have been reviewed. Based on the reviewed literature, a comprehensive reaction mechanism has been proposed consisting of more than one route, all starting from acyclic xylose, and

  7. Lipids, adiposity and tendinopathy : is there a mechanistic link? Critical review

    NARCIS (Netherlands)

    Scott, Alex; Zwerver, Johannes; Grewal, Navi; de Sa, Agnetha; Alktebi, Thuraya; Granville, David J.; Hart, David A.

    Being overweight or obese is associated with an elevated risk of tendon pathology. However, for sportspeople the epidemiological data linking weight or adiposity on one hand, and risk of tendon pathology on the other, are less consistent. Indeed, the mechanistic links between diet, adiposity and

  8. Mechanistic assessment of hillslope transpiration controls of diel subsurface flow: a steady-state irrigation approach

    Science.gov (United States)

    H.R. Barnard; C.B. Graham; W.J. van Verseveld; J.R. Brooks; B.J. Bond; J.J. McDonnell

    2010-01-01

    Mechanistic assessment of how transpiration influences subsurface flow is necessary to advance understanding of catchment hydrology. We conducted a 24-day, steady-state irrigation experiment to quantify the relationships among soil moisture, transpiration and hillslope subsurface flow. Our objectives were to: (1) examine the time lag between maximum transpiration and...

  9. A MECHANISTIC STUDY OF RHODIUM TRI(ORTHO-TERT-BUTYLPHENYL)PHOSPHITE COMPLEXES AS HYDROFORMYLATION CATALYSTS

    NARCIS (Netherlands)

    JONGSMA, T; CHALLA, G; VANLEEUWEN, PWNM

    1991-01-01

    A mechanistic study of the hydroformylation cycle with a rhodium tri(o-t-butylphenyl)phosphite complex as catalyst is presented. Spectroscopic experiments prove that under hydroformylation conditions this complex is coordinated by only one phosphite. The complex has a high activity in the

  10. An Emphasis on Perception: Teaching Image Formation Using a Mechanistic Model of Vision.

    Science.gov (United States)

    Allen, Sue; And Others

    An effective way to teach the concept of image is to give students a model of human vision which incorporates a simple mechanism of depth perception. In this study two almost identical versions of a curriculum in geometrical optics were created. One used a mechanistic, interpretive eye model, and in the other the eye was modeled as a passive,…

  11. From Source to Sink: Mechanistic Reasoning Using the Electron-Pushing Formalism

    Science.gov (United States)

    Bhattacharyya, Gautam

    2013-01-01

    Since the introduction of Morrison and Boyd's textbook in organic chemistry over 50 years ago, reaction mechanisms and mechanistic reasoning using the electron-pushing formalism (EPF) have become a mainstay of organic chemistry courses. In recent years there have even been several papers in this Journal and others detailing research on how…

  12. Students' Interpretations of Mechanistic Language in Organic Chemistry before Learning Reactions

    Science.gov (United States)

    Galloway, Kelli R.; Stoyanovich, Carlee; Flynn, Alison B.

    2017-01-01

    Research on mechanistic thinking in organic chemistry has shown that students attribute little meaning to the electron-pushing (i.e., curved arrow) formalism. At the University of Ottawa, a new curriculum has been developed in which students are taught the electron-pushing formalism prior to instruction on specific reactions--this formalism is…

  13. Reprogramming of B cells into macrophages: mechanistic insights

    OpenAIRE

    Di Tullio, Alessandro, 1982-

    2012-01-01

    Our earlier work has shown that pre-B cells can be converted into macrophages by the transcription factor C/EBPα at very high frequencies and also that a clonal pre-B cell line with an inducible form of C/EBPα can be converted into macrophage-like cells. Using these systems we have performed a systematic analysis of the questions whether during transdifferentiation the cells retrodifferentiate to a precursor cell state and whether cell cycle is required for reprogramming. As for the first ...

  14. Mechanistic studies of the alkaline degradation of cellulose in cement

    International Nuclear Information System (INIS)

    Greenfield, B.F.; Robertson, G.P.; Spindler, M.W.; Harrison, W.N.; Somers, P.J.

    1993-07-01

    The alkaline degradation of cellulose-based materials under conditions simulating those of a deep underground radioactive waste repository has been investigated. A number of key degradation products, of which 2-C-(hydroxymethyl)-3-deoxy-D-pentonic acid (isosaccharinic acid) is the most important, have been synthesised, and the solubilities of their plutonium complexes have been determined. Analysis of leachates of anaerobically degraded cellulose has shown concentrations of organic acids which are broadly consistent with the enhanced plutonium solubilities found in these leachates. Reaction mechanisms have been identified that can lead to isosaccharinic acid production by non-oxidative transformations, which may be catalysed by some divalent cations. (Author)

  15. Mechanistic Study of Oxygen Atom Transfer Catalyzed by Rhenium Compounds

    Energy Technology Data Exchange (ETDEWEB)

    Shan, Xiaopeng [Iowa State Univ., Ames, IA (United States)

    2003-01-01

    Two ionic and one neutral methyl(oxo)rhenium(V) compounds were synthesized and structurally characterized. They were compared in reactivity towards the ligands triphenylphosphane, pyridines, pyridine N-oxides. Assistance from Broensted bases was found on ligand displacement of ionic rhenium compounds as well as nucleophile assistance on oxidation of all compounds. From the kinetic data, crystal structures, and an analysis of the intermediates, a structural formula of PicH+3- and mechanisms of ligand displacement and oxidation were proposed.

  16. A mechanistic approach to safe igniter implementation for hydrogen mitigation

    International Nuclear Information System (INIS)

    Breitung, W.; Dorofeev, S.B.; Travis, J.R.

    1997-01-01

    A new methodology for safe igniter implementation in a full-scale 3-d containment is described. The method consists of the following steps: determination of bounding H 2 /steam sources; high-resolution analysis of the 3-d transport and mixing processes; evaluation of the detonation potential at the time of ignition; optimization of the igniter system such that only early ignition and nonenergetic combustion occurs; and modelling of the continuous deflagration processes during H 2 -release. The method was implemented into the GASFLOW code. The principle and the feasibility is demonstrated for a single room geometry. A full-scale 3-d reactor case is analyzed without and with deliberate ignition, assuming a severe dry H 2 release sequence (1200 kg). In the unmitigated case significant DDT potential in the whole containment develops, including the possibility of global detonations. The analysis with igniters in different positions predicted deflagration or detonation in the break compartment, depending on the igniter location. Igniter positions were found which lead to early ignition, effective H 2 -removal, and negligible pressure loads. The approach can be used to determine number, position and frequency of a safe igniter system for a given large dry containment. (author)

  17. Synthesis, characterization and mechanistic insights of mycogenic iron oxide nanoparticles

    Energy Technology Data Exchange (ETDEWEB)

    Bhargava, Arpit; Jain, Navin; Manju Barathi L [Birla Institute of Technology and Science, Centre for Biotechnology, Department of Biological Sciences (India); Akhtar, Mohd Sayeed [Jimma University, Department of Applied Microbiology, College of Natural Sciences (Ethiopia); Yun, Yeoung-Sang [Chonbuk National University, Division of Environmental and Chemical Engineering (Korea, Republic of); Panwar, Jitendra, E-mail: drjitendrapanwar@yahoo.co.in [Birla Institute of Technology and Science, Centre for Biotechnology, Department of Biological Sciences (India)

    2013-11-15

    In the present study, extracellular synthesis of iron oxide nanoparticles (IONPs) was achieved using Aspergillus japonicus isolate AJP01. The isolate demonstrated its ability to hydrolyze the precursor salt solution, a mixture of iron cyanide complexes, under ambient conditions. Hydrolysis of these complexes released ferric and ferrous ions, which underwent protein-mediated coprecipitation and controlled nucleation resulting in the formation of IONPs. Transmission electron microscopy, selected area electron diffraction pattern, energy dispersive spectroscopy and grazing incidence X-ray diffraction analysis confirmed the mycosynthesis of IONPs. The synthesized particles were cubic in shape with a size range of 60–70 nm with crystal structure corresponding to magnetite. Scanning electron microscopy analysis revealed the absence of IONPs on fungal biomass surface, indicating the extracellular nature of synthesis. Fourier transform infrared spectroscopy confirmed the presence of proteins on as-synthesised IONPs, which may confer their stability. Preliminary investigation indicated the role of proteins in the synthesis and stabilization of IONPs. On the basis of present findings, a probable mechanism for synthesis of IONPs is suggested. The simplicity and versatility of the present approach can be utilized for the synthesis of other nanomaterials.

  18. Optical coherence tomography assessment of the mechanistic effects of rotational and orbital atherectomy in severely calcified coronary lesions.

    Science.gov (United States)

    Kini, Annapoorna S; Vengrenyuk, Yuliya; Pena, Jacobo; Motoyama, Sadako; Feig, Jonathan E; Meelu, Omar A; Rajamanickam, Anitha; Bhat, Arjun M; Panwar, Sadik; Baber, Usman; Sharma, Samin K

    2015-11-15

    This study sought to assess the mechanistic effect of rotational atherectomy (RA) and orbital atherectomy (OA) on heavily calcified coronary lesions and subsequent stent placement using optical coherence tomography (OCT). RA and OA are two main approaches to ablate coronary calcium. While small case reports have described the mechanistic effect of RA in calcified coronary lesions, there has been no imaging study to assess the effect of OA on coronary artery architecture and/or compare the effects of two atherectomy devices. This study analyzed 20 consecutive patients with OCT imaging performed after atherectomy and after stent implantation, RA (n = 10) and OA (n = 10). Postatherectomy OCT analysis identified tissue modification with deep dissections in around a third of lesions after RA and OA; however, post OA dissections ("lacunae") were significantly deeper (1.14 vs. 0.82 mm, P = 0.048). Post OA/RA lesions with dissections had significantly higher percentage of lipid rich plaques and smaller calcification arcs as compared to plaques without dissections. Stents after OA were associated with a significantly lower percent of stent strut malapposition than post RA stents (4.36 vs. 8.02%, P = 0.038). Although the incidence of dissections was comparable between RA and OA cases, OA resulted in deeper tissue modifications (lacunae) as shown by OCT imaging. The finding might provide an explanation for a better stent apposition after OA as compared to RA. Their impact on long-term outcome needs to be determined. © 2015 Wiley Periodicals, Inc.

  19. A Mechanistic Model of Waterfall Plunge Pool Erosion into Bedrock

    Science.gov (United States)

    Scheingross, Joel S.; Lamb, Michael P.

    2017-11-01

    Landscapes often respond to changes in climate and tectonics through the formation and upstream propagation of knickzones composed of waterfalls. Little work has been done on the mechanics of waterfall erosion, and instead most landscape-scale models neglect waterfalls or use rules for river erosion, such as stream power, that may not be applicable to waterfalls. Here we develop a physically based model to predict waterfall plunge pool erosion into rock by abrasion from particle impacts and test the model against flume experiments. Both the model and experiments show that evolving plunge pools have initially high vertical erosion rates due to energetic particle impacts, and erosion slows and eventually ceases as pools deepen and deposition protects the pool floor from further erosion. Lateral erosion can continue after deposition on the pool floor, but it occurs at slow rates that become negligible as pools widen. Our work points to the importance of vertical drilling of successive plunge pools to drive upstream knickzone propagation in homogenous rock, rather than the classic mechanism of headwall undercutting. For a series of vertically drilling waterfalls, we find that upstream knickzone propagation is faster under higher combined water and sediment fluxes and for knickzones composed of many waterfalls that are closely spaced. Our model differs significantly from stream-power-based erosion rules in that steeper knickzones can retreat faster or more slowly depending on the number and spacing of waterfalls within a knickzone, which has implications for interpreting climatic and tectonic history through analysis of river longitudinal profiles.

  20. Mechanistic Processes Controlling Gas Sorption in Shale Reservoirs

    Science.gov (United States)

    Schaef, T.; Loring, J.; Ilton, E. S.; Davidson, C. L.; Owen, T.; Hoyt, D.; Glezakou, V. A.; McGrail, B. P.; Thompson, C.

    2014-12-01

    Utilization of CO2 to stimulate natural gas production in previously fractured shale-dominated reservoirs where CO2 remains in place for long-term storage may be an attractive new strategy for reducing the cost of managing anthropogenic CO2. A preliminary analysis of capacities and potential revenues in US shale plays suggests nearly 390 tcf in additional gas recovery may be possible via CO2 driven enhanced gas recovery. However, reservoir transmissivity properties, optimum gas recovery rates, and ultimate fate of CO2 vary among reservoirs, potentially increasing operational costs and environmental risks. In this paper, we identify key mechanisms controlling the sorption of CH4 and CO2 onto phyllosilicates and processes occurring in mixed gas systems that have the potential of impacting fluid transfer and CO2 storage in shale dominated formations. Through a unique set of in situ experimental techniques coupled with molecular-level simulations, we identify structural transformations occurring to clay minerals, optimal CO2/CH4 gas exchange conditions, and distinguish between adsorbed and intercalated gases in a mixed gas system. For example, based on in situ measurements with magic angle spinning NMR, intercalation of CO2 within the montmorillonite structure occurs in CH4/CO2 gas mixtures containing low concentrations (hydrocarbon recovery processes.

  1. RITA Mimics: Synthesis and Mechanistic Evaluation of Asymmetric Linked Trithiazoles.

    Science.gov (United States)

    Pietkiewicz, Adrian L; Zhang, Yuqi; Rahimi, Marwa N; Stramandinoli, Michael; Teusner, Matthew; McAlpine, Shelli R

    2017-04-13

    The established cytotoxic agent RITA contains a thiophene-furan-thiophene backbone and two terminal alcohol groups. Herein we investigate the effect of using thiazoles as the backbone in RITA-like molecules and modifying the terminal groups of these trithiazoles, thereby generating 41 unique structures. Incorporating side chains with varied steric bulk allowed us to investigate how size and a stereocenter impacted biological activity. Subjecting compounds to growth inhibition assays on HCT-116 cells showed that the most potent compounds 7d , 7e , and 7h had GI 50 values of 4.4, 4.4, and 3.4 μM, respectively, versus RITA (GI 50 of 800 nM). Analysis of these compounds in apoptosis assays proved that 7d , 7e , and 7h were as effective as RITA at inducing apoptosis. Evaluating the impact of 7h on proteins targeted by RITA (p53, c-Myc, and Mcl-1) indicated that it acts via a different mechanism of action to that of RITA. RITA suppressed Mcl-1 protein via p53, whereas compound 7h suppressed Mcl-1 expression via an alternative mechanism independent of p53.

  2. Mechanistic Effects of Porosity on Structural Composite Materials

    Science.gov (United States)

    Siver, Andrew

    As fiber reinforced composites continue to gain popularity as primary structures in aerospace, automotive, and powersports industries, quality control becomes an extremely important aspect of materials and mechanical engineering. The ability to recognize and control manufacturing induced defects can greatly reduce the likelihood of unexpected catastrophic failure. Porosity is the result of trapped volatiles or air bubbles during the layup process and can significantly compromise the strength of fiber reinforced composites. A comprehensive study was performed on an AS4C-UF3352 TCR carbon fiber-epoxy prepreg system to determine the effect of porosity on flexural, shear, low-velocity impact, and damage residual strength properties. Autoclave cure pressure was controlled to induce varying levels of porosity to construct six laminates with porosity concentrations between 0-40%. Porosity concentrations were measured using several destructive and nondestructive techniques including resin burnoff, sectioning and optical analysis, and X-ray computed tomography (CT) scanning. Ultrasonic transmission, thermography, and CT scanning provided nondestructive imaging to evaluate impact damage. A bilinear relationship accurately characterizes the change in mechanical properties with increasing porosity. Strength properties are relatively unaffected when porosity concentrations are below approximately 2.25% and decrease linearly by up to 40% in high porosity specimens.

  3. A Mechanistic Study of Wetting Superhydrophobic Porous 3D Meshes

    Science.gov (United States)

    Yohe, Stefan T.; Freedman, Jonathan D.; Falde, Eric J.; Colson, Yolonda L.; Grinstaff, Mark W.

    2014-01-01

    Superhydrophobic, porous, 3D materials composed of poly( ε -caprolactone) (PCL) and the hydrophobic polymer dopant poly(glycerol monostearate-co- ε -caprolactone) (PGC-C18) are fabricated using the electrospinning technique. These 3D materials are distinct from 2D superhydrophobic surfaces, with maintenance of air at the surface as well as within the bulk of the material. These superhydrophobic materials float in water, and when held underwater and pressed, an air bubble is released and will rise to the surface. By changing the PGC-C18 doping concentration in the meshes and/or the fiber size from the micro- to nanoscale, the long-term stability of the entrapped air layer is controlled. The rate of water infiltration into the meshes, and the resulting displacement of the entrapped air, is quantitatively measured using X-ray computed tomography. The properties of the meshes are further probed using surfactants and solvents of different surface tensions. Finally, the application of hydraulic pressure is used to quantify the breakthrough pressure to wet the meshes. The tools for fabrication and analysis of these superhydrophobic materials as well as the ability to control the robustness of the entrapped air layer are highly desirable for a number of existing and emerging applications. PMID:25309305

  4. Mechanistic aspects of radioprotection by todralazine hydrochloride, a hematopoietic stem cell expanding agent

    International Nuclear Information System (INIS)

    Dimri, Manali; Joshi, Jaidev; Jain, Sanjoli; Ghosh, Subhajit; Srivastva, Nitisha; Prem Kumar, Indracanti; Chakrabarti, Rina

    2014-01-01

    Previously, we have reported todralazine hydrochloride, an antihypertensive drug, as a radioprotector and hematopoietic stem cell (HSC) expanding agent. The present study aims at unraveling mechanistic aspects of its radioprotective and HSC expanding potential. Zebrafish Tg (cmyb:GFP) embryos treated with 5 μM todralazine from 24-36 hours post fertilization (hpf), increased the number of HSCs (∼ 2 folds) at aorta gonad mesonephros (AGM) region. Similarly, the expression of HSC marker genes, runx1 (3.3 folds) and cMyb (1.4 folds) were also found to be increased. Further, todralazine also accelerated hematopoietic lineage production, erythropoiesis, as evaluated in chemical induced anemic model in zebrafish. Genome wide expression changes in todralazine treated embryos (from 24-36 hpf) using microarray, revealed up and down regulation of 645 and 429 genes respectively. Pathway analysis using DAVID database strongly suggested up regulation of wnt pathway (p<0.019253), which is known to involve in HSC expansion, in todralazine pre-treated embryos. NOS1, known to have its role in HSC expansion through wnt pathway, has been significantly upregulated (1.54 folds; q PCR) by todralazine treatment (from 24-36 hpf). Todralazine treatment (∼30 minutes; 20 Gy) led to a significant upregulation of antioxidant genes (SOD, catalase), DNA damage response genes (p53, p21, GADD45) and nucleotide excision repair genes (XPC, XPA, XPF, XPD) when compared to irradiated control. Immunohistochemical analysis of DNA damage marker (γH2AX) (30 minutes post irradiation), further supported radiation induced DNA damage and protection by todralazine pre-treatment. Corroborating these results, pre-irradiation treatment of todralazine reduced radiation induced apoptosis (caspase 3 assay). Overall, the results suggest that, todralazine protects zebrafish from radiation induced damages by upregulating antioxidant defense system, DNA damage recognition, DNA repair machinery and by reducing cell

  5. Mechanistic study of the rubber-brass adhesion interphase

    Science.gov (United States)

    Ashirgade, Akshay

    Brass-plated steel tire cords form an essential strengthening component of a radial automobile tire. Adhesion between rubber compound and brass-plated steel tire cord is crucial in governing the overall performance of tires. The rubber-brass interfacial adhesion is influenced by the chemical composition and thickness of the interfacial layer. It has been shown that the interfacial layer consists mainly of sulfides and oxides of copper and zinc. This thesis discusses the effect of changes in the chemical composition and the structure of the interfacial layers due to addition of adhesion promoter resins. Grazing incidence X-Ray Diffraction (GIXRD) experiments were run on sulfidized polished brass coupons previously bonded to six experimental rubber compounds. It was confirmed that heat and humidity conditions lead to physical and chemical changes of the rubber-steel tire cord interfacial layer, closely related to the degree of rubber-brass adhesion. Morphological transformation of the interfacial layer led to loss of adhesion after aging. The adhesion promoter resins inhibit unfavorable morphological changes in the interfacial layer thus stabilizing it during aging and prolonging failure. Tire cord adhesion tests illustrated that the one-component resins improved adhesion after aging using a rubber compound with lower cobalt loading. Based on the acquired diffraction profiles, these resins were also found to impede crystallization of the sulfide layer after aging leading to improved adhesion. Secondary Ion Mass Spectrometry (SIMS) depth profiles, SEM micrographs and AFM images strongly corroborated the findings from GIXRD. FTIR was utilized in a novel way to understand the degradation mechanism due to aging. A model for rubber and interfacial layer degradation is proposed to illustrate the effect of aging and the one-component resins. This interfacial analysis adds valuable new information to our understanding of the complex nature of the rubber-brass bonding

  6. Biocide leaching from CBA treated wood — A mechanistic interpretation

    International Nuclear Information System (INIS)

    Lupsea, Maria; Mathies, Helena; Schoknecht, Ute; Tiruta-Barna, Ligia; Schiopu, Nicoleta

    2013-01-01

    Treated wood is frequently used for construction. However, there is a need to ensure that biocides used for the treatment are not a threat for people or environment. The paper focused on Pinus sylvestris treated with copper–boron–azole (CBA), containing tebuconazole as organic biocide and monoethanolamine (Mea). This study investigates chemical mechanisms of fixation and mobilisation involved in the leaching process of the used inorganic and organic biocides in CBA. A pH dependent leaching test was performed, followed by a set of complementary analysis methods in order to identify and quantify the species released from wood. The main findings of this study are: -Organic compounds are released from untreated and treated wood; the quantity of released total organic carbon, carboxylic and phenolic functions increasing with the pH. -Nitrogen containing compounds, i.e. mainly Mea and its reaction products with extractives, are released in important quantities from CBA treated wood, especially at low pH. -The release of copper is the result of competitive reactions: fixation via complexation reactions and complexation with extractives in the liquid phase. The specific pH dependency of Cu leaching is explained by the competition of ligands for protonation and complexation. -Tebuconazole is released to a lesser extent relative to its initial content. Its fixation on solid wood structure seems to be influenced by pH, suggesting interactions with -OH groups on wood. Boron release appears to be pH independent and very high. This confirms its weak fixation on wood and also no or weak interaction with the extractives. - Highlights: ► A pH dependent leaching mechanism for CBA treated wood is described. ► The fixation and mobilisation of inorganic and organic biocides was investigated. ► Extractives' quantity and nature depend on pH. ► Competition of ligands for protonation and complexation explains Cu behaviour. ► Tebuconazole seems to interact with -OH groups on

  7. Similarity queries for temporal toxicogenomic expression profiles.

    Directory of Open Access Journals (Sweden)

    Adam A Smith

    2008-07-01

    Full Text Available We present an approach for answering similarity queries about gene expression time series that is motivated by the task of characterizing the potential toxicity of various chemicals. Our approach involves two key aspects. First, our method employs a novel alignment algorithm based on time warping. Our time warping algorithm has several advantages over previous approaches. It allows the user to impose fairly strong biases on the form that the alignments can take, and it permits a type of local alignment in which the entirety of only one series has to be aligned. Second, our method employs a relaxed spline interpolation to predict expression responses for unmeasured time points, such that the spline does not necessarily exactly fit every observed point. We evaluate our approach using expression time series from the Edge toxicology database. Our experiments show the value of using spline representations for sparse time series. More significantly, they show that our time warping method provides more accurate alignments and classifications than previous standard alignment methods for time series.

  8. Biocide leaching from CBA treated wood — A mechanistic interpretation

    Energy Technology Data Exchange (ETDEWEB)

    Lupsea, Maria [University of Toulouse, INSA, UPS, INP, LISBP, 135 Avenue de Rangueil, F-31077 Toulouse (France); INRA, UMR 792, F-31400 Toulouse (France); CNRS, UMR 5504, F-31400 Toulouse (France); Paris-Est University, CSTB — Scientific and Technical Centre for the Building Industry, ESE/Environment, 24 rue Joseph Fourier, F-38400 Saint Martin d' Hères (France); Mathies, Helena; Schoknecht, Ute [BAM — Federal Institute for Materials Research and Testing, Division 4.1, Unter den Eichen 87, 12205 Berlin (Germany); Tiruta-Barna, Ligia, E-mail: ligia.barna@insa-toulouse.fr [University of Toulouse, INSA, UPS, INP, LISBP, 135 Avenue de Rangueil, F-31077 Toulouse (France); INRA, UMR 792, F-31400 Toulouse (France); CNRS, UMR 5504, F-31400 Toulouse (France); Schiopu, Nicoleta [Paris-Est University, CSTB — Scientific and Technical Centre for the Building Industry, ESE/Environment, 24 rue Joseph Fourier, F-38400 Saint Martin d' Hères (France)

    2013-02-01

    Treated wood is frequently used for construction. However, there is a need to ensure that biocides used for the treatment are not a threat for people or environment. The paper focused on Pinus sylvestris treated with copper–boron–azole (CBA), containing tebuconazole as organic biocide and monoethanolamine (Mea). This study investigates chemical mechanisms of fixation and mobilisation involved in the leaching process of the used inorganic and organic biocides in CBA. A pH dependent leaching test was performed, followed by a set of complementary analysis methods in order to identify and quantify the species released from wood. The main findings of this study are: -Organic compounds are released from untreated and treated wood; the quantity of released total organic carbon, carboxylic and phenolic functions increasing with the pH. -Nitrogen containing compounds, i.e. mainly Mea and its reaction products with extractives, are released in important quantities from CBA treated wood, especially at low pH. -The release of copper is the result of competitive reactions: fixation via complexation reactions and complexation with extractives in the liquid phase. The specific pH dependency of Cu leaching is explained by the competition of ligands for protonation and complexation. -Tebuconazole is released to a lesser extent relative to its initial content. Its fixation on solid wood structure seems to be influenced by pH, suggesting interactions with -OH groups on wood. Boron release appears to be pH independent and very high. This confirms its weak fixation on wood and also no or weak interaction with the extractives. - Highlights: ► A pH dependent leaching mechanism for CBA treated wood is described. ► The fixation and mobilisation of inorganic and organic biocides was investigated. ► Extractives' quantity and nature depend on pH. ► Competition of ligands for protonation and complexation explains Cu behaviour. ► Tebuconazole seems to interact with -OH groups

  9. Using a Mechanistic Reactive Transport Model to Represent Soil Organic Matter Dynamics and Climate Sensitivity

    Science.gov (United States)

    Guerry, N.; Riley, W. J.; Maggi, F.; Torn, M. S.; Kleber, M.

    2011-12-01

    The nature of long term Soil Organic Matter (SOM) dynamics is uncertain and the mechanisms involved are crudely represented in site, regional, and global models. Recent work challenging the paradigm that SOM is stabilized because of its sequential transformations to more intrinsically recalcitrant compounds motivated us to develop a mechanistic modeling framework that can be used to test hypotheses of SOM dynamics. We developed our C cycling model in TOUGHREACT, an established 3-dimensional reactive transport solver that accounts for multiple phases (aqueous, gaseous, sorbed), multiple species, advection and diffusion, and multiple microbial populations. Energy and mass exchange through the soil boundaries are accounted for via ground heat flux, rainfall, C sources (e.g., exudation, woody, leaf, root litter) and C losses (e.g., CO2 emissions and DOC deep percolation). SOM is categorized according to the various types of compounds commonly found in the above mentioned C sources and microbial byproducts, including poly- and monosaccharides, lignin, amino compounds, organic acids, nucleic acids, lipids, and phenols. Each of these compounds is accounted for by one or more representative species in the model. A reaction network was developed to describe the microbially-mediated processes and chemical interactions of these species, including depolymerization, microbial assimilation, respiration and deposition of byproducts, and incorporation of dead biomass into SOM stocks. Enzymatic reactions are characterized by Michaelis-Menten kinetics, with maximum reaction rates determined by the species' O/C ratio. Microbial activity is further regulated by soil moisture content, O2 availability, pH, and temperature. For the initial set of simulations, literature values were used to constrain microbial Monod parameters, Michaelis-Menten parameters, sorption parameters, physical protection, partitioning of microbial byproducts, and partitioning of litter inputs, although there is

  10. Mechanistic characterization and molecular modeling of hepatitis B virus polymerase resistance to entecavir.

    Science.gov (United States)

    Walsh, Ann W; Langley, David R; Colonno, Richard J; Tenney, Daniel J

    2010-02-12

    Entecavir (ETV) is a deoxyguanosine analog competitive inhibitor of hepatitis B virus (HBV) polymerase that exhibits delayed chain termination of HBV DNA. A high barrier to entecavir-resistance (ETVr) is observed clinically, likely due to its potency and a requirement for multiple resistance changes to overcome suppression. Changes in the HBV polymerase reverse-transcriptase (RT) domain involve lamivudine-resistance (LVDr) substitutions in the conserved YMDD motif (M204V/I +/- L180M), plus an additional ETV-specific change at residues T184, S202 or M250. These substitutions surround the putative dNTP binding site or primer grip regions of the HBV RT. To determine the mechanistic basis for ETVr, wildtype, lamivudine-resistant (M204V, L180M) and ETVr HBVs were studied using in vitro RT enzyme and cell culture assays, as well as molecular modeling. Resistance substitutions significantly reduced ETV incorporation and chain termination in HBV DNA and increased the ETV-TP inhibition constant (K(i)) for HBV RT. Resistant HBVs exhibited impaired replication in culture and reduced enzyme activity (k(cat)) in vitro. Molecular modeling of the HBV RT suggested that ETVr residue T184 was adjacent to and stabilized S202 within the LVDr YMDD loop. ETVr arose through steric changes at T184 or S202 or by disruption of hydrogen-bonding between the two, both of which repositioned the loop and reduced the ETV-triphosphate (ETV-TP) binding pocket. In contrast to T184 and S202 changes, ETVr at primer grip residue M250 was observed during RNA-directed DNA synthesis only. Experimentally, M250 changes also impacted the dNTP-binding site. Modeling suggested a novel mechanism for M250 resistance, whereby repositioning of the primer-template component of the dNTP-binding site shifted the ETV-TP binding pocket. No structural data are available to confirm the HBV RT modeling, however, results were consistent with phenotypic analysis of comprehensive substitutions of each ETVr position

  11. Mechanistic characterization and molecular modeling of hepatitis B virus polymerase resistance to entecavir.

    Directory of Open Access Journals (Sweden)

    Ann W Walsh

    Full Text Available BACKGROUND: Entecavir (ETV is a deoxyguanosine analog competitive inhibitor of hepatitis B virus (HBV polymerase that exhibits delayed chain termination of HBV DNA. A high barrier to entecavir-resistance (ETVr is observed clinically, likely due to its potency and a requirement for multiple resistance changes to overcome suppression. Changes in the HBV polymerase reverse-transcriptase (RT domain involve lamivudine-resistance (LVDr substitutions in the conserved YMDD motif (M204V/I +/- L180M, plus an additional ETV-specific change at residues T184, S202 or M250. These substitutions surround the putative dNTP binding site or primer grip regions of the HBV RT. METHODS/PRINCIPAL FINDINGS: To determine the mechanistic basis for ETVr, wildtype, lamivudine-resistant (M204V, L180M and ETVr HBVs were studied using in vitro RT enzyme and cell culture assays, as well as molecular modeling. Resistance substitutions significantly reduced ETV incorporation and chain termination in HBV DNA and increased the ETV-TP inhibition constant (K(i for HBV RT. Resistant HBVs exhibited impaired replication in culture and reduced enzyme activity (k(cat in vitro. Molecular modeling of the HBV RT suggested that ETVr residue T184 was adjacent to and stabilized S202 within the LVDr YMDD loop. ETVr arose through steric changes at T184 or S202 or by disruption of hydrogen-bonding between the two, both of which repositioned the loop and reduced the ETV-triphosphate (ETV-TP binding pocket. In contrast to T184 and S202 changes, ETVr at primer grip residue M250 was observed during RNA-directed DNA synthesis only. Experimentally, M250 changes also impacted the dNTP-binding site. Modeling suggested a novel mechanism for M250 resistance, whereby repositioning of the primer-template component of the dNTP-binding site shifted the ETV-TP binding pocket. No structural data are available to confirm the HBV RT modeling, however, results were consistent with phenotypic analysis of

  12. Mechanistic modelling of Middle Eocene atmospheric carbon dioxide using fossil plant material

    Science.gov (United States)

    Grein, Michaela; Roth-Nebelsick, Anita; Wilde, Volker; Konrad, Wilfried; Utescher, Torsten

    2010-05-01

    Various proxies (such as pedogenic carbonates, boron isotopes or phytoplankton) and geochemical models were applied in order to reconstruct palaeoatmospheric carbon dioxide, partially providing conflicting results. Another promising proxy is the frequency of stomata (pores on the leaf surface used for gaseous exchange). In this project, fossil plant material from the Messel Pit (Hesse, Germany) is used to reconstruct atmospheric carbon dioxide concentration in the Middle Eocene by analyzing stomatal density. We applied the novel mechanistic-theoretical approach of Konrad et al. (2008) which provides a quantitative derivation of the stomatal density response (number of stomata per leaf area) to varying atmospheric carbon dioxide concentration. The model couples 1) C3-photosynthesis, 2) the process of diffusion and 3) an optimisation principle providing maximum photosynthesis (via carbon dioxide uptake) and minimum water loss (via stomatal transpiration). These three sub-models also include data of the palaeoenvironment (temperature, water availability, wind velocity, atmospheric humidity, precipitation) and anatomy of leaf and stoma (depth, length and width of stomatal porus, thickness of assimilation tissue, leaf length). In order to calculate curves of stomatal density as a function of atmospheric carbon dioxide concentration, various biochemical parameters have to be borrowed from extant representatives. The necessary palaeoclimate data are reconstructed from the whole Messel flora using Leaf Margin Analysis (LMA) and the Coexistence Approach (CA). In order to obtain a significant result, we selected three species from which a large number of well-preserved leaves is available (at least 20 leaves per species). Palaeoclimate calculations for the Middle Eocene Messel Pit indicate a warm and humid climate with mean annual temperature of approximately 22°C, up to 2540 mm mean annual precipitation and the absence of extended periods of drought. Mean relative air

  13. Mechanistic modelling of cancer: some reflections from software engineering and philosophy of science.

    Science.gov (United States)

    Cañete-Valdeón, José M; Wieringa, Roel; Smallbone, Kieran

    2012-12-01

    There is a growing interest in mathematical mechanistic modelling as a promising strategy for understanding tumour progression. This approach is accompanied by a methodological change of making research, in which models help to actively generate hypotheses instead of waiting for general principles to become apparent once sufficient data are accumulated. This paper applies recent research from philosophy of science to uncover three important problems of mechanistic modelling which may compromise its mainstream application, namely: the dilemma of formal and informal descriptions, the need to express degrees of confidence and the need of an argumentation framework. We report experience and research on similar problems from software engineering and provide evidence that the solutions adopted there can be transferred to the biological domain. We hope this paper can provoke new opportunities for further and profitable interdisciplinary research in the field.

  14. Mechanistic models for the evaluation of biocatalytic reaction conditions and biosensor design optimization

    DEFF Research Database (Denmark)

    Semenova, Daria

    . In the first case study a mechanistic model was developed to describe the enzymatic reaction of glucose oxidase and glucose in the presence of catalase inside a commercial microfluidic platform with integrated oxygen sensor spots. The simplicity of the proposed model allowed an easy calibration of the reaction...... the microfluidic device. In the second case study the flexible microfluidic platform with integrated amperometric glucose biosensors was developed for continuous monitoring of glucose consumption rates. The integration of the mixing chamber inside the platform allowed performing sample dilutions which subsequently......BRs. In the third case study the mechanistic model of the cyclic voltammetry response of the first generation glucose biosensors was developed and applied for the biosensor design optimization. Furthermore the obtained qualitative and quantitative dependencies between the model output and experimental results were...

  15. An improved mechanistic critical heat flux model for subcooled flow boiling

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Young Min [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of); Chang, Soon Heung [Korea Advanced Institute of Science and Technology, Taejon (Korea, Republic of)

    1997-12-31

    Based on the bubble coalescence adjacent to the heated wall as a flow structure for CHF condition, Chang and Lee developed a mechanistic critical heat flux (CHF) model for subcooled flow boiling. In this paper, improvements of Chang-Lee model are implemented with more solid theoretical bases for subcooled and low-quality flow boiling in tubes. Nedderman-Shearer`s equations for the skin friction factor and universal velocity profile models are employed. Slip effect of movable bubbly layer is implemented to improve the predictability of low mass flow. Also, mechanistic subcooled flow boiling model is used to predict the flow quality and void fraction. The performance of the present model is verified using the KAIST CHF database of water in uniformly heated tubes. It is found that the present model can give a satisfactory agreement with experimental data within less than 9% RMS error. 9 refs., 5 figs. (Author)

  16. An improved mechanistic critical heat flux model for subcooled flow boiling

    Energy Technology Data Exchange (ETDEWEB)

    Kwon, Young Min [Korea Atomic Energy Research Institute, Taejon (Korea, Republic of); Chang, Soon Heung [Korea Advanced Institute of Science and Technology, Taejon (Korea, Republic of)

    1998-12-31

    Based on the bubble coalescence adjacent to the heated wall as a flow structure for CHF condition, Chang and Lee developed a mechanistic critical heat flux (CHF) model for subcooled flow boiling. In this paper, improvements of Chang-Lee model are implemented with more solid theoretical bases for subcooled and low-quality flow boiling in tubes. Nedderman-Shearer`s equations for the skin friction factor and universal velocity profile models are employed. Slip effect of movable bubbly layer is implemented to improve the predictability of low mass flow. Also, mechanistic subcooled flow boiling model is used to predict the flow quality and void fraction. The performance of the present model is verified using the KAIST CHF database of water in uniformly heated tubes. It is found that the present model can give a satisfactory agreement with experimental data within less than 9% RMS error. 9 refs., 5 figs. (Author)

  17. FOAM3D: A numerical simulator for mechanistic prediciton of foam displacement in multidimensions

    Energy Technology Data Exchange (ETDEWEB)

    Kovscek, A.R.; Patzek, T.W. [Lawrence Berkeley Laboratory, Berkeley, CA (United States); Radke, C.J. [Univ. of California, Berkeley, CA (United States)

    1995-03-01

    Field application of foam is a technically viable enhanced oil recovery process (EOR) as demonstrated by recent steam-foam field studies. Traditional gas-displacement processes, such as steam drive, are improved substantially by controlling gas mobility and thereby improving volumetric displacement efficiency. For instance, Patzek and Koinis showed major oil-recovery response after about two years of foam injection in two different pilot studies at the Kern River field. They report increased production of 5.5 to 14% of the original oil in place over a five year period. Because reservoir-scale simulation is a vital component of the engineering and economic evaluation of any EOR project, efficient application of foam as a displacement fluid requires a predictive numerical model of foam displacement. A mechanistic model would also expedite scale-up of the process from the laboratory to the field scale. No general, mechanistic, field-scale model for foam displacement is currently in use.

  18. How phenyl makes a difference: mechanistic insights into the ruthenium( ii )-catalysed isomerisation of allylic alcohols

    KAUST Repository

    Manzini, Simone

    2013-10-16

    [RuCl(η5-3-phenylindenyl)(PPh3)2] (1) has been shown to be a highly active catalyst for the isomerisation of allylic alcohols to the corresponding ketones. A variety of substrates undergo the transformation, typically with 0.25-0.5 mol% of catalyst at room temperature, outperforming commonly-used complexes such as [RuCl(Cp)(PPh3) 2] and [RuCl(η5-indenyl)(PPh3) 2]. Mechanistic experiments and density functional theory have been employed to investigate the mechanism and understand the effect of catalyst structure on reactivity. These investigations suggest a oxo-π-allyl mechanism is in operation, avoiding intermediate ruthenium hydride complexes and leading to a characteristic 1,3-deuterium shift. Important mechanistic insights from DFT and experiments also allowed for the design of a protocol that expands the scope of the transformation to include primary allylic alcohols. © 2013 The Royal Society of Chemistry.

  19. How phenyl makes a difference: mechanistic insights into the ruthenium( ii )-catalysed isomerisation of allylic alcohols

    KAUST Repository

    Manzini, Simone; Poater, Albert; Nelson, David J.; Cavallo, Luigi; Nolan, Steven P.

    2013-01-01

    [RuCl(η5-3-phenylindenyl)(PPh3)2] (1) has been shown to be a highly active catalyst for the isomerisation of allylic alcohols to the corresponding ketones. A variety of substrates undergo the transformation, typically with 0.25-0.5 mol% of catalyst at room temperature, outperforming commonly-used complexes such as [RuCl(Cp)(PPh3) 2] and [RuCl(η5-indenyl)(PPh3) 2]. Mechanistic experiments and density functional theory have been employed to investigate the mechanism and understand the effect of catalyst structure on reactivity. These investigations suggest a oxo-π-allyl mechanism is in operation, avoiding intermediate ruthenium hydride complexes and leading to a characteristic 1,3-deuterium shift. Important mechanistic insights from DFT and experiments also allowed for the design of a protocol that expands the scope of the transformation to include primary allylic alcohols. © 2013 The Royal Society of Chemistry.

  20. Protection by caffeine against oxic radiation damage and chemical carcinogens : mechanistic considerations

    International Nuclear Information System (INIS)

    Kesavan, P.C.

    1992-01-01

    There is little doubt that caffeine administered after exposure to UV light enhances the damage to cells and organisms by inhibiting photoreactivation, excision and/or recombinational repair. However, when already present in the system, it affords remarkable protection not only against O 2 -dependent component of radiation damage, but also against chemical carcinogens that require metabolic activation. Possible mechanistic aspects are discussed briefly. (author). 81 refs

  1. A mechanistic model for electricity consumption on dairy farms: Definition, validation, and demonstration

    OpenAIRE

    Upton, J.R.; Murphy, M.; Shallo, L.; Groot Koerkamp, P.W.G.; Boer, de, I.J.M.

    2014-01-01

    Our objective was to define and demonstrate a mechanistic model that enables dairy farmers to explore the impact of a technical or managerial innovation on electricity consumption, associated CO2 emissions, and electricity costs. We, therefore, (1) defined a model for electricity consumption on dairy farms (MECD) capable of simulating total electricity consumption along with related CO2 emissions and electricity costs on dairy farms on a monthly basis; (2) validated the MECD using empirical d...

  2. Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation: Report of an FDA Public Workshop.

    Science.gov (United States)

    Zhang, X; Duan, J; Kesisoglou, F; Novakovic, J; Amidon, G L; Jamei, M; Lukacova, V; Eissing, T; Tsakalozou, E; Zhao, L; Lionberger, R

    2017-08-01

    On May 19, 2016, the US Food and Drug Administration (FDA) hosted a public workshop, entitled "Mechanistic Oral Absorption Modeling and Simulation for Formulation Development and Bioequivalence Evaluation." The topic of mechanistic oral absorption modeling, which is one of the major applications of physiologically based pharmacokinetic (PBPK) modeling and simulation, focuses on predicting oral absorption by mechanistically integrating gastrointestinal transit, dissolution, and permeation processes, incorporating systems, active pharmaceutical ingredient (API), and the drug product information, into a systemic mathematical whole-body framework. © 2017 The Authors CPT: Pharmacometrics & Systems Pharmacology published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  3. Mechanistic and "natural" body metaphors and their effects on attitudes to hormonal contraception.

    Science.gov (United States)

    Walker, Susan

    2012-01-01

    A small, self-selected convenience sample of male and female contraceptive users in the United Kingdom (n = 34) were interviewed between 2006 and 2008 concerning their feelings about the body and their contraceptive attitudes and experiences. The interviewees were a sub-sample of respondents (n = 188) who completed a paper-based questionnaire on similar topics, who were recruited through a poster placed in a family planning clinic, web-based advertisements on workplace and university websites, and through direct approaches to social groups. The bodily metaphors used when discussing contraception were analyzed using an interpretative phenomenological analytical approach facilitated by Atlas.ti software. The dominant bodily metaphor was mechanistic (i.e.,"body as machine"). A subordinate but influential bodily metaphor was the "natural" body, which had connotations of connection to nature and a quasi-sacred bodily order. Interviewees drew upon this "natural" metaphorical image in the context of discussing their anxieties about hormonal contraception. Drawing upon a "natural," non-mechanistic body image in the context of contraceptive decision-making contributed to reluctance to use a hormonal form of contraception. This research suggests that clinicians could improve communication and advice about contraception by recognizing that some users may draw upon non-mechanistic body imagery.

  4. INTEGRATION OF QSAR AND SAR METHODS FOR THE MECHANISTIC INTERPRETATION OF PREDICTIVE MODELS FOR CARCINOGENICITY

    Directory of Open Access Journals (Sweden)

    Natalja Fjodorova

    2012-07-01

    Full Text Available The knowledge-based Toxtree expert system (SAR approach was integrated with the statistically based counter propagation artificial neural network (CP ANN model (QSAR approach to contribute to a better mechanistic understanding of a carcinogenicity model for non-congeneric chemicals using Dragon descriptors and carcinogenic potency for rats as a response. The transparency of the CP ANN algorithm was demonstrated using intrinsic mapping technique specifically Kohonen maps. Chemical structures were represented by Dragon descriptors that express the structural and electronic features of molecules such as their shape and electronic surrounding related to reactivity of molecules. It was illustrated how the descriptors are correlated with particular structural alerts (SAs for carcinogenicity with recognized mechanistic link to carcinogenic activity. Moreover, the Kohonen mapping technique enables one to examine the separation of carcinogens and non-carcinogens (for rats within a family of chemicals with a particular SA for carcinogenicity. The mechanistic interpretation of models is important for the evaluation of safety of chemicals.

  5. Mechanistic effect modeling for ecological risk assessment: where to go from here?

    Science.gov (United States)

    Grimm, Volker; Martin, Benjamin T

    2013-07-01

    Mechanistic effect models (MEMs) consider the mechanisms of how chemicals affect individuals and ecological systems such as populations and communities. There is an increasing awareness that MEMs have high potential to make risk assessment of chemicals more ecologically relevant than current standard practice. Here we discuss what kinds of MEMs are needed to improve scientific and regulatory aspects of risk assessment. To make valid predictions for a wide range of environmental conditions, MEMs need to include a sufficient amount of emergence, for example, population dynamics emerging from what individual organisms do. We present 1 example where the life cycle of individuals is described using Dynamic Energy Budget theory. The resulting individual-based population model is thus parameterized at the individual level but correctly predicts multiple patterns at the population level. This is the case for both control and treated populations. We conclude that the state-of-the-art in mechanistic effect modeling has reached a level where MEMs are robust and predictive enough to be used in regulatory risk assessment. Mechanistic effect models will thus be used to advance the scientific basis of current standard practice and will, if their development follows Good Modeling Practice, be included in a standardized way in future regulatory risk assessments. Copyright © 2013 SETAC.

  6. Mechanistic model of mass-specific basal metabolic rate: evaluation in healthy young adults.

    Science.gov (United States)

    Wang, Z; Bosy-Westphal, A; Schautz, B; Müller, M

    2011-12-01

    Mass-specific basal metabolic rate (mass-specific BMR), defined as the resting energy expenditure per unit body mass per day, is an important parameter in energy metabolism research. However, a mechanistic explanation for magnitude of mass-specific BMR remains lacking. The objective of the present study was to validate the applicability of a proposed mass-specific BMR model in healthy adults. A mechanistic model was developed at the organ-tissue level, mass-specific BMR = Σ( K i × F i ), where Fi is the fraction of body mass as individual organs and tissues, and K i is the specific resting metabolic rate of major organs and tissues. The Fi values were measured by multiple MRI scans and the K i values were suggested by Elia in 1992. A database of healthy non-elderly non-obese adults (age 20 - 49 yrs, BMI BMR of all subjects was 21.6 ± 1.9 (mean ± SD) and 21.7 ± 1.6 kcal/kg per day, respectively. The measured mass-specific BMR was correlated with the predicted mass-specific BMR (r = 0.82, P BMR, versus the average of measured and predicted mass-specific BMR. In conclusion, the proposed mechanistic model was validated in non-elderly non-obese adults and can help to understand the inherent relationship between mass-specific BMR and body composition.

  7. Electrochemical processes and mechanistic aspects of field-effect sensors for biomolecules

    Science.gov (United States)

    Huang, Weiguo; Diallo, Abdou Karim; Dailey, Jennifer L.; Besar, Kalpana

    2017-01-01

    Electronic biosensing is a leading technology for determining concentrations of biomolecules. In some cases, the presence of an analyte molecule induces a measured change in current flow, while in other cases, a new potential difference is established. In the particular case of a field effect biosensor, the potential difference is monitored as a change in conductance elsewhere in the device, such as across a film of an underlying semiconductor. Often, the mechanisms that lead to these responses are not specifically determined. Because improved understanding of these mechanisms will lead to improved performance, it is important to highlight those studies where various mechanistic possibilities are investigated. This review explores a range of possible mechanistic contributions to field-effect biosensor signals. First, we define the field-effect biosensor and the chemical interactions that lead to the field effect, followed by a section on theoretical and mechanistic background. We then discuss materials used in field-effect biosensors and approaches to improving signals from field-effect biosensors. We specifically cover the biomolecule interactions that produce local electric fields, structures and processes at interfaces between bioanalyte solutions and electronic materials, semiconductors used in biochemical sensors, dielectric layers used in top-gated sensors, and mechanisms for converting the surface voltage change to higher signal/noise outputs in circuits. PMID:29238595

  8. Mechanistic Systems Modeling to Improve Understanding and Prediction of Cardiotoxicity Caused by Targeted Cancer Therapeutics

    Directory of Open Access Journals (Sweden)

    Jaehee V. Shim

    2017-09-01

    Full Text Available Tyrosine kinase inhibitors (TKIs are highly potent cancer therapeutics that have been linked with serious cardiotoxicity, including left ventricular dysfunction, heart failure, and QT prolongation. TKI-induced cardiotoxicity is thought to result from interference with tyrosine kinase activity in cardiomyocytes, where these signaling pathways help to control critical processes such as survival signaling, energy homeostasis, and excitation–contraction coupling. However, mechanistic understanding is limited at present due to the complexities of tyrosine kinase signaling, and the wide range of targets inhibited by TKIs. Here, we review the use of TKIs in cancer and the cardiotoxicities that have been reported, discuss potential mechanisms underlying cardiotoxicity, and describe recent progress in achieving a more systematic understanding of cardiotoxicity via the use of mechanistic models. In particular, we argue that future advances are likely to be enabled by studies that combine large-scale experimental measurements with Quantitative Systems Pharmacology (QSP models describing biological mechanisms and dynamics. As such approaches have proven extremely valuable for understanding and predicting other drug toxicities, it is likely that QSP modeling can be successfully applied to cardiotoxicity induced by TKIs. We conclude by discussing a potential strategy for integrating genome-wide expression measurements with models, illustrate initial advances in applying this approach to cardiotoxicity, and describe challenges that must be overcome to truly develop a mechanistic and systematic understanding of cardiotoxicity caused by TKIs.

  9. Incorporation of lysosomal sequestration in the mechanistic model for prediction of tissue distribution of basic drugs.

    Science.gov (United States)

    Assmus, Frauke; Houston, J Brian; Galetin, Aleksandra

    2017-11-15

    The prediction of tissue-to-plasma water partition coefficients (Kpu) from in vitro and in silico data using the tissue-composition based model (Rodgers & Rowland, J Pharm Sci. 2005, 94(6):1237-48.) is well established. However, distribution of basic drugs, in particular into lysosome-rich lung tissue, tends to be under-predicted by this approach. The aim of this study was to develop an extended mechanistic model for the prediction of Kpu which accounts for lysosomal sequestration and the contribution of different cell types in the tissue of interest. The extended model is based on compound-specific physicochemical properties and tissue composition data to describe drug ionization, distribution into tissue water and drug binding to neutral lipids, neutral phospholipids and acidic phospholipids in tissues, including lysosomes. Physiological data on the types of cells contributing to lung, kidney and liver, their lysosomal content and lysosomal pH were collated from the literature. The predictive power of the extended mechanistic model was evaluated using a dataset of 28 basic drugs (pK a ≥7.8, 17 β-blockers, 11 structurally diverse drugs) for which experimentally determined Kpu data in rat tissue have been reported. Accounting for the lysosomal sequestration in the extended mechanistic model improved the accuracy of Kpu predictions in lung compared to the original Rodgers model (56% drugs within 2-fold or 88% within 3-fold of observed values). Reduction in the extent of Kpu under-prediction was also evident in liver and kidney. However, consideration of lysosomal sequestration increased the occurrence of over-predictions, yielding overall comparable model performances for kidney and liver, with 68% and 54% of Kpu values within 2-fold error, respectively. High lysosomal concentration ratios relative to cytosol (>1000-fold) were predicted for the drugs investigated; the extent differed depending on the lysosomal pH and concentration of acidic phospholipids among

  10. Meditative Movement, Energetic, and Physical Analyses of Three Qigong Exercises: Unification of Eastern and Western Mechanistic Exercise Theory.

    Science.gov (United States)

    Klein, Penelope; Picard, George; Baumgarden, Joseph; Schneider, Roger

    2017-09-23

    Abstract : Qigong is the meditative movement and therapeutic exercise of Eastern medicine. A growing body of evidence is validating its health benefits leading to mechanistic questions of how it works. The purpose of this article is to explore mechanisms of action related to Qigong, with the intent of unifying Eastern and Western exercise theory and to present a model for Qigong exercise analysis. Three exercises from a standardized Qigong form: 'Plucking the Stars', 'Lotus Leaves Rustle in the Wind', and 'Pacing Forwards and Backwards' were selected for meditative, energetic, and physical analyses. Meditative aspects include relaxation response, interoception and exteroception. Energetic aspects include stimulation of meridians through mental intent, acupressure, and self-massage. Physical aspects include flexibility, strength, articular stimulation, neuro-integration, respiratory effect, fascial stretch, visceral massage, balance challenge CranioSacral pump, lymphatic and venous return and glandular stimulation, and physiologic response to relaxation. Knowledge of mechanisms of action for specific Qigong exercises can guide operational definition of Qigong, selection of outcomes assessment in future research, inform prescriptive practice addressing clinical health issues, and advance adoption of Qigong practice within integrative health care. The model of analysis demonstrated in this discussion may assist in these endeavors.

  11. Mechanistic Studies of Hafnium-Pyridyl Amido-Catalyzed 1-Octene Polymerization and Chain Transfer Using Quench-Labeling Methods.

    Science.gov (United States)

    Cueny, Eric S; Johnson, Heather C; Anding, Bernie J; Landis, Clark R

    2017-08-30

    Chromophore quench-labeling applied to 1-octene polymerization as catalyzed by hafnium-pyridyl amido precursors enables quantification of the amount of active catalyst and observation of the molecular weight distribution (MWD) of Hf-bound polymers via UV-GPC analysis. Comparison of the UV-detected MWD with the MWD of the "bulk" (all polymers, from RI-GPC analysis) provides important mechanistic information. The time evolution of the dual-detection GPC data, concentration of active catalyst, and monomer consumption suggests optimal activation conditions for the Hf pre-catalyst in the presence of the activator [Ph 3 C][B(C 6 F 5 ) 4 ]. The chromophore quench-labeling agents do not react with the chain-transfer agent ZnEt 2 under the reaction conditions. Thus, Hf-bound polymeryls are selectively labeled in the presence of zinc-polymeryls. Quench-labeling studies in the presence of ZnEt 2 reveal that ZnEt 2 does not influence the rate of propagation at the Hf center, and chain transfer of Hf-bound polymers to ZnEt 2 is fast and quasi-irreversible. The quench-label techniques represent a means to study commercial polymerization catalysts that operate with high efficiency at low catalyst concentrations without the need for specialized equipment.

  12. Establishing appropriate inputs when using the mechanistic-empirical pavement design guide to design rigid pavements in Pennsylvania.

    Science.gov (United States)

    2011-03-01

    Each design input in the Mechanistic-Empirical Design Guide (MEPDG) required for the design of Jointed Plain Concrete : Pavements (JPCPs) is introduced and discussed in this report. Best values for Pennsylvania conditions were established and : recom...

  13. Geomaterial characterizations of full scale pavement test sections for mechanistic analysis and design

    CSIR Research Space (South Africa)

    Kwon, J

    2007-02-01

    Full Text Available roller compactor. The compaction effort was monitored with nuclear density gauge and DCP measurements taken from each pavement test section. As-built density of each subgrade lift obtained using the nuclear gauge satisfied a minimum relative density... was monitored with a nuclear gauge to maintain a minimum 95% relative compaction in the field. 0 100 200 300 400 500 0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 CBR (%) Pe n et ra tio n (m m ) Pe n et ra tio n (m m ) Figure 2...

  14. Analysis of the efficacy of SGLT2 inhibitors using semi-mechanistic model

    Science.gov (United States)

    Demin, Oleg; Yakovleva, Tatiana; Kolobkov, Dmitry; Demin, Oleg

    2014-01-01

    The Renal sodium-dependent glucose co-transporter 2 (SGLT2) is one of the most promising targets for the treatment of type 2 diabetes. Two SGLT2 inhibitors, dapagliflozin, and canagliflozin, have already been approved for use in USA and Europe; several additional compounds are also being developed for this purpose. Based on the in vitro IC50 values and plasma concentration of dapagliflozin measured in clinical trials, the marketed dosage of the drug was expected to almost completely inhibit SGLT2 function and reduce glucose reabsorption by 90%. However, the administration of dapagliflozin resulted in only 30–50% inhibition of reabsorption. This study was aimed at investigating the mechanism underlying the discrepancy between the expected and observed levels of glucose reabsorption. To this end, systems pharmacology models were developed to analyze the time profile of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin in the plasma and urine; their filtration and active secretion from the blood to the renal proximal tubules; reverse reabsorption; urinary excretion; and their inhibitory effect on SGLT2. The model shows that concentration levels of tofogliflozin, ipragliflozin, and empagliflozin are higher than levels of other inhibitors following administration of marketed SGLT2 inhibitors at labeled doses and non-marketed SGLT2 inhibitors at maximal doses (approved for phase 2/3 studies). All the compounds exhibited almost 100% inhibition of SGLT2. Based on the results of our model, two explanations for the observed low efficacy of SGLT2 inhibitors were supported: (1) the site of action of SGLT2 inhibitors is not in the lumen of the kidney's proximal tubules, but elsewhere (e.g., the kidneys proximal tubule cells); and (2) there are other transporters that could facilitate glucose reabsorption under the conditions of SGLT2 inhibition (e.g., other transporters of SGLT family). PMID:25352807

  15. Analysis of efficacy of SGLT2 inhibitors using semi-mechanistic model

    Directory of Open Access Journals (Sweden)

    Oleg eDemin Jr

    2014-10-01

    Full Text Available Renal sodium-dependent glucose co-transporter 2 (SGLT2 is one of the most promising targets for the treatment of type 2 diabetes. Two SGLT2 inhibitors, dapagliflozin and canagliflozin, have already been approved for use in USA and Europe; several additional compounds are also being developed for this purpose. Based on the in vitro IC50 values and plasma concentration of dapagliflozin measured in clinical trials, the marketed dosage of the drug was expected to almost completely inhibit SGLT2 function and reduce glucose reabsorption by 90%. However, the administration of dapagliflozin resulted in only 30–50% inhibition of reabsorption. This study was aimed at investigating the mechanism underlying the discrepancy between the expected and observed levels of glucose reabsorption. To this end, systems pharmacology models were developed to analyze the time profile of dapagliflozin, canagliflozin, ipragliflozin, empagliflozin, and tofogliflozin in the plasma and urine; their filtration and active secretion from the blood to the renal proximal tubules; reverse reabsorption; urinary excretion; and their inhibitory effect on SGLT2. The model shows that concentration levels of tofogliflozin, ipragliflozin, and empagliflozin are higher than levels of other inhibitors following administration of marketed SGLT2 inhibitors at labeled doses and non-marketed SGLT2 inhibitors at maximal doses (approved for phase 2/3 studies. All the compounds exhibited almost 100% inhibition of SGLT2. Based on the results of our model, two explanations for the observed low efficacy of SGLT2 inhibitors were supported: 1 the site of action of SGLT2 inhibitors is not in the lumen of the kidney’s proximal tubules, but elsewhere (e.g., the kidneys proximal tubule cells; and 2 there are other transporters that could facilitate glucose reabsorption under the conditions of SGLT2 inhibition (e.g., other transporters of SGLT family.

  16. Computational Modelling Approaches on Epigenetic Factors in Neurodegenerative and Autoimmune Diseases and Their Mechanistic Analysis

    Directory of Open Access Journals (Sweden)

    Afroza Khanam Irin

    2015-01-01

    Full Text Available Neurodegenerative as well as autoimmune diseases have unclear aetiologies, but an increasing number of evidences report for a combination of genetic and epigenetic alterations that predispose for the development of disease. This review examines the major milestones in epigenetics research in the context of diseases and various computational approaches developed in the last decades to unravel new epigenetic modifications. However, there are limited studies that systematically link genetic and epigenetic alterations of DNA to the aetiology of diseases. In this work, we demonstrate how disease-related epigenetic knowledge can be systematically captured and integrated with heterogeneous information into a functional context using Biological Expression Language (BEL. This novel methodology, based on BEL, enables us to integrate epigenetic modifications such as DNA methylation or acetylation of histones into a specific disease network. As an example, we depict the integration of epigenetic and genetic factors in a functional context specific to Parkinson’s disease (PD and Multiple Sclerosis (MS.

  17. Predicting Residential Exposure to Phthalate Plasticizer Emitted from Vinyl Flooring - A Mechanistic Analysis

    Science.gov (United States)

    A two-room model is developed to estimate the emission rate of di-2-ethylhexyl phthalate (DEHP) from vinyl flooring and the evolving gas-phase and adsorbed surface concentrations in a realistic indoor environment. Adsorption isotherms for phthalates and plasticizers on interior ...

  18. Mechanistic analysis of double-shell tank gas release. Progress report, November 1990

    Energy Technology Data Exchange (ETDEWEB)

    Allemann, R.T.; Antoniak, Z.I.; Friley, J.R.; Haines, C.E.; Liljegren, L.M.; Somasundaram, S.

    1991-12-01

    Pacific Northwest Laboratory (PNL) is studying possible mechanisms and fluid dynamics contributing to the periodic release of gases from the double-shell waste storage tanks at Hanford. This study is being conducted for Westinghouse Hanford Company (WHC), a contractor for the US Department of Energy (DOE). This interim report discusses the work done through November 1990. Safe management of the wastes at Hanford depends on an understanding of the chemical and physical mechanisms that take place in the waste tanks. An example of the need to understand these mechanisms is tank 101-SY. The waste in this tank is generating and periodically releasing potentially flammable gases into the tank vent system according to observations of the tank. How these gases are generated and become trapped, the causes of periodic release, and the mechanism of the release are not known in detail. In order to develop a safe mitigation strategy, possible physical mechanisms for the periodic release of flammable gases need to be understood.

  19. Mechanistic analysis of Zein nanoparticles/PLGA triblock in situ forming implants for glimepiride

    Directory of Open Access Journals (Sweden)

    Ahmed OAA

    2016-02-01

    Full Text Available Osama Abdelhakim Aly Ahmed,1,2 Ahmed Samir Zidan,1,3 Maan Khayat4 1Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia; 2Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Minia University, Minia, Egypt; 3Department of Pharmaceutics and Industrial Pharmacy, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt; 4Department of Pharmaceutical Chemistry, Faculty of Pharmacy, King Abdulaziz University, Jeddah, Saudi Arabia Objectives: The study aims at applying pharmaceutical nanotechnology and D-optimal fractional factorial design to screen and optimize the high-risk variables affecting the performance of a complex drug delivery system consisting of glimepiride–Zein nanoparticles and inclusion of the optimized formula with thermoresponsive triblock copolymers in in situ gel. Methods: Sixteen nanoparticle formulations were prepared by liquid–liquid phase separation method according to the D-optimal fractional factorial design encompassing five variables at two levels. The responses investigated were glimepiride entrapment capacity (EC, particle size and size distribution, zeta potential, and in vitro drug release from the prepared nanoparticles. Furthermore, the feasibility of embedding the optimized Zein-based glimepiride nanoparticles within thermoresponsive triblock copolymers poly(lactide-co-glycolide-block-poly(ethylene glycol-block-poly(lactide-co-glycolide in in situ gel was evaluated for controlling glimepiride release rate. Results: Through the systematic optimization phase, improvement of glimepiride EC of 33.6%, nanoparticle size of 120.9 nm with a skewness value of 0.2, zeta potential of 11.1 mV, and sustained release features of 3.3% and 17.3% drug released after 2 and 24 hours, respectively, were obtained. These desirability functions were obtained at Zein and glimepiride loadings of 50 and 75 mg, respectively, utilizing didodecyldimethylammonium bromide as a stabilizer at 0.1% and 90% ethanol as a common solvent. Moreover, incorporating this optimized formulation in triblock copolymers-based in situ gel demonstrated pseudoplastic behavior with reduction of drug release rate as the concentration of polymer increased. Conclusion: This approach to control the release of glimepiride using Zein nanoparticles/triblock copolymers-based in situ gel forming intramuscular implants could be useful for improving diabetes treatment effectiveness. Keywords: glimepiride, Zein, nanoparticles, quality by design, in situ implants

  20. Structural and mechanistic analysis of trans-3-chloroacrylic acid dehalogenase activity

    Energy Technology Data Exchange (ETDEWEB)

    Pegan, Scott D., E-mail: pegan@uic.edu [Center of Pharmaceutical Biotechnology and the Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago (United States); Serrano, Hector; Whitman, Christian P. [Division of Medicinal Chemistry, College of Pharmacy, The University of Texas, Austin (United States); Mesecar, Andrew D., E-mail: pegan@uic.edu [Center of Pharmaceutical Biotechnology and the Department of Medicinal Chemistry and Pharmacognosy, University of Illinois, Chicago (United States)

    2008-12-01

    The X-ray structure of a noncovalently modified trans-3-chloroacrylic acid dehalogenase with a substrate-homolog acetate bound in the active site has been determined to 1.7 Å resolution. Elucidation of catalytically important water is reported and multiple conformations of the catalytic residue αGlu52 are observed. Trans-3-chloroacrylic acid dehalogenase (CaaD) is a critical enzyme in the trans-1, 3-dichloropropene (DCP) degradation pathway in Pseudomonas pavonaceae 170. This enzyme allows bacteria to use trans-DCP, a common component in commercially produced fumigants, as a carbon source. CaaD specifically catalyzes the fourth step of the pathway by cofactor-independent dehalogenation of a vinyl carbon–halogen bond. Previous studies have reported an X-ray structure of CaaD under acidic conditions with a covalent modification of the catalytic βPro1 residue. Here, the 1.7 Å resolution X-ray structure of CaaD under neutral (pH 6.5) conditions is reported without the presence of the covalent adduct. In this new structure, a substrate-like acetate molecule is bound within the active site in a position analogous to the putative substrate-binding site. Additionally, a catalytically important water molecule was identified, consistent with previously proposed reaction schemes. Finally, flexibility of the catalytically relevant side chain αGlu52 is observed in the structure, supporting its role in the catalytic mechanism.

  1. The Cardiopulmonary Effects of Ambient Air Pollution and Mechanistic Pathways: A Comparative Hierarchical Pathway Analysis

    Science.gov (United States)

    Thomas, Duncan C.; Zhang, Junfeng; Kipen, Howard M.; Rich, David Q.; Zhu, Tong; Huang, Wei; Hu, Min; Wang, Guangfa; Wang, Yuedan; Zhu, Ping; Lu, Shou-En; Ohman-Strickland, Pamela; Diehl, Scott R.; Eckel, Sandrah P.

    2014-01-01

    Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001) and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005). These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours) and the hemostasis pathway responds gradually over a 2–3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system. PMID:25502951

  2. Review Of Mechanistic Understanding And Modeling And Uncertainty Analysis Methods For Predicting Cementitious Barrier Performance

    International Nuclear Information System (INIS)

    Langton, C.; Kosson, D.

    2009-01-01

    Cementitious barriers for nuclear applications are one of the primary controls for preventing or limiting radionuclide release into the environment. At the present time, performance and risk assessments do not fully incorporate the effectiveness of engineered barriers because the processes that influence performance are coupled and complicated. Better understanding the behavior of cementitious barriers is necessary to evaluate and improve the design of materials and structures used for radioactive waste containment, life extension of current nuclear facilities, and design of future nuclear facilities, including those needed for nuclear fuel storage and processing, nuclear power production and waste management. The focus of the Cementitious Barriers Partnership (CBP) literature review is to document the current level of knowledge with respect to: (1) mechanisms and processes that directly influence the performance of cementitious materials (2) methodologies for modeling the performance of these mechanisms and processes and (3) approaches to addressing and quantifying uncertainties associated with performance predictions. This will serve as an important reference document for the professional community responsible for the design and performance assessment of cementitious materials in nuclear applications. This review also provides a multi-disciplinary foundation for identification, research, development and demonstration of improvements in conceptual understanding, measurements and performance modeling that would be lead to significant reductions in the uncertainties and improved confidence in the estimating the long-term performance of cementitious materials in nuclear applications. This report identifies: (1) technology gaps that may be filled by the CBP project and also (2) information and computational methods that are in currently being applied in related fields but have not yet been incorporated into performance assessments of cementitious barriers. The various chapters contain both a description of the mechanism or and a discussion of the current approaches to modeling the phenomena.

  3. REVIEW OF MECHANISTIC UNDERSTANDING AND MODELING AND UNCERTAINTY ANALYSIS METHODS FOR PREDICTING CEMENTITIOUS BARRIER PERFORMANCE

    Energy Technology Data Exchange (ETDEWEB)

    Langton, C.; Kosson, D.

    2009-11-30

    Cementitious barriers for nuclear applications are one of the primary controls for preventing or limiting radionuclide release into the environment. At the present time, performance and risk assessments do not fully incorporate the effectiveness of engineered barriers because the processes that influence performance are coupled and complicated. Better understanding the behavior of cementitious barriers is necessary to evaluate and improve the design of materials and structures used for radioactive waste containment, life extension of current nuclear facilities, and design of future nuclear facilities, including those needed for nuclear fuel storage and processing, nuclear power production and waste management. The focus of the Cementitious Barriers Partnership (CBP) literature review is to document the current level of knowledge with respect to: (1) mechanisms and processes that directly influence the performance of cementitious materials (2) methodologies for modeling the performance of these mechanisms and processes and (3) approaches to addressing and quantifying uncertainties associated with performance predictions. This will serve as an important reference document for the professional community responsible for the design and performance assessment of cementitious materials in nuclear applications. This review also provides a multi-disciplinary foundation for identification, research, development and demonstration of improvements in conceptual understanding, measurements and performance modeling that would be lead to significant reductions in the uncertainties and improved confidence in the estimating the long-term performance of cementitious materials in nuclear applications. This report identifies: (1) technology gaps that may be filled by the CBP project and also (2) information and computational methods that are in currently being applied in related fields but have not yet been incorporated into performance assessments of cementitious barriers. The various chapters contain both a description of the mechanism or and a discussion of the current approaches to modeling the phenomena.

  4. Identification and Mechanistic Analysis of a Novel Tick-Derived Inhibitor of Thrombin

    Czech Academy of Sciences Publication Activity Database

    Jablonka, W.; Kotsyfakis, Michalis; Mizurini, D.M.; Monteiro, R.Q.; Lukszo, J.; Drake, S.K.; Ribeiro, J.M.C.; Andersen, J. F.

    2015-01-01

    Roč. 10, č. 8 (2015), e0133991 E-ISSN 1932-6203 R&D Projects: GA ČR GAP502/12/2409 Institutional support: RVO:60077344 Keywords : Haemaphysalis longicornis * binding inhibitor * crystal structure Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 3.057, year: 2015

  5. The cardiopulmonary effects of ambient air pollution and mechanistic pathways: a comparative hierarchical pathway analysis.

    Directory of Open Access Journals (Sweden)

    Ananya Roy

    Full Text Available Previous studies have investigated the associations between exposure to ambient air pollution and biomarkers of physiological pathways, yet little has been done on the comparison across biomarkers of different pathways to establish the temporal pattern of biological response. In the current study, we aim to compare the relative temporal patterns in responses of candidate pathways to different pollutants. Four biomarkers of pulmonary inflammation and oxidative stress, five biomarkers of systemic inflammation and oxidative stress, ten parameters of autonomic function, and three biomarkers of hemostasis were repeatedly measured in 125 young adults, along with daily concentrations of ambient CO, PM2.5, NO2, SO2, EC, OC, and sulfate, before, during, and after the Beijing Olympics. We used a two-stage modeling approach, including Stage I models to estimate the association between each biomarker and pollutant over each of 7 lags, and Stage II mixed-effect models to describe temporal patterns in the associations when grouping the biomarkers into the four physiological pathways. Our results show that candidate pathway groupings of biomarkers explained a significant amount of variation in the associations for each pollutant, and the temporal patterns of the biomarker-pollutant-lag associations varied across candidate pathways (p<0.0001 and were not linear (from lag 0 to lag 3: p = 0.0629, from lag 3 to lag 6: p = 0.0005. These findings suggest that, among this healthy young adult population, the pulmonary inflammation and oxidative stress pathway is the first to respond to ambient air pollution exposure (within 24 hours and the hemostasis pathway responds gradually over a 2-3 day period. The initial pulmonary response may contribute to the more gradual systemic changes that likely ultimately involve the cardiovascular system.

  6. Numerical analysis of reflood simulation based on a mechanistic, best-estimate, approach by KREWET code

    International Nuclear Information System (INIS)

    Chun, Moon-Hyun; Jeong, Eun-Soo

    1983-01-01

    A new computer code entitled KREWET has been developed in an effort to improve the accuracy and applicability of the existing reflood heat transfer simulation computer code. Sample calculations for temperature histories and heat transfer coefficient are made using KREWET code and the results are compared with the predictions of REFLUX, QUEN1D, and the PWR-FLECHT data for various conditions. These show favourable agreement in terms of clad temperature versus time. For high flooding rates (5-15cm/sec) and high pressure (∼413 Kpa), reflood predictions are reasonably well predicted by KREWET code as well as with other codes. For low flooding rates (less than ∼4cm/sec) and low pressure (∼138Kpa), predictions show considerable error in evaluating the rewet position versus time. This observation is common to all the codes examined in the present work

  7. Numerical analysis for reflood simulation based on a mechanistic, best-estimate, approach by KREWET code

    International Nuclear Information System (INIS)

    Chun, M.-H.; Jeong, E.-S.

    1983-01-01

    A new computer code entitled KREWET has been developed in an effort to improve the accuracy and applicability of the existing reflood heat transfer simulation computer code. Sample calculations for temperature histories and heat transfer coefficient are made using KREWET code and the results are compared with the predictions of REFLUX, QUENID, and the PWR-FLECHT data for various conditions. These show favorable agreement in terms of clad temperature versus time. For high flooding rates (5-15cm/sec) and high pressure (approx. =413 Kpa), reflood predictions are reasonably well predicted by KREWET code as well as with other codes. For low flooding rates (less than approx. =4cm/sec) and low pressure (approx. =138 Kpa), predictions show considerable error in evaluating the rewet position versus time. This observation is common to all the codes examined in the present work

  8. Characterization of cementitiously stabilized subgrades for mechanistic-empirical pavement design

    Science.gov (United States)

    Solanki, Pranshoo

    Pavements are vulnerable to subgrade layer performance because it acts as a foundation. Due to increase in the truck traffic, pavement engineers are challenged to build more strong and long-lasting pavements. To increase the load-bearing capacity of pavements, subgrade layer is often stabilized with cementitious additives. Thus, an overall characterization of stabilized subgrade layer is important for enhanced short- and long-term pavement performance. In this study, the effect of type and amount of additive on the short-term performance in terms of material properties recommended by the new Mechanistic-Empirical Pavement Design Guide (MEPDG) is examined. A total of four soils commonly encountered as subgrades in Oklahoma are utilized. Results show that the changes in the Mr, ME and UCS values stabilized specimens depend on the soil type and properties of additives. The long-term performance (or durability) of stabilized soil specimens is investigated by conducting freeze-thaw (F-T) cycling, vacuum saturation and tube suction tests on 7-day cured P-, K- and C-soil specimens stabilized with 6% lime, 10% CFA and 10% CKD. This study is motivated by the fact that during the service life of pavement stabilized layers are subjected to F-T cycles and moisture variations. It is found that that UCS value of all the stabilized specimens decreased with increase in the number of F-T cycles. A strong correlation was observed between UCS values retained after vacuum saturation and F-T cycles indicating that vacuum saturation could be used as a time-efficient and inexpensive method for evaluating durability of stabilized soils. In this study, short- and long-term observations from stabilization of sulfate bearing soil with locally available low (CFA), moderate (CKD) and high (lime) calcium-based stabilizers are determined to evaluate and compare the effect of additive type on the phenomenon of sulfate-induced heave. The impact of different factors on the development of the

  9. Regulatory Technology Development Plan Sodium Fast Reactor. Mechanistic Source Term Development

    Energy Technology Data Exchange (ETDEWEB)

    Grabaskas, David S. [Argonne National Lab. (ANL), Argonne, IL (United States); Brunett, Acacia Joann [Argonne National Lab. (ANL), Argonne, IL (United States); Bucknor, Matthew D. [Argonne National Lab. (ANL), Argonne, IL (United States); Sienicki, James J. [Argonne National Lab. (ANL), Argonne, IL (United States); Sofu, Tanju [Argonne National Lab. (ANL), Argonne, IL (United States)

    2015-02-28

    Construction and operation of a nuclear power installation in the U.S. requires licensing by the U.S. Nuclear Regulatory Commission (NRC). A vital part of this licensing process and integrated safety assessment entails the analysis of a source term (or source terms) that represents the release of radionuclides during normal operation and accident sequences. Historically, nuclear plant source term analyses have utilized deterministic, bounding assessments of the radionuclides released to the environment. Significant advancements in technical capabilities and the knowledge state have enabled the development of more realistic analyses such that a mechanistic source term (MST) assessment is now expected to be a requirement of advanced reactor licensing. This report focuses on the state of development of an MST for a sodium fast reactor (SFR), with the intent of aiding in the process of MST definition by qualitatively identifying and characterizing the major sources and transport processes of radionuclides. Due to common design characteristics among current U.S. SFR vendor designs, a metal-fuel, pool-type SFR has been selected as the reference design for this work, with all phenomenological discussions geared toward this specific reactor configuration. This works also aims to identify the key gaps and uncertainties in the current knowledge state that must be addressed for SFR MST development. It is anticipated that this knowledge state assessment can enable the coordination of technology and analysis tool development discussions such that any knowledge gaps may be addressed. Sources of radionuclides considered in this report include releases originating both in-vessel and ex-vessel, including in-core fuel, primary sodium and cover gas cleanup systems, and spent fuel movement and handling. Transport phenomena affecting various release groups are identified and qualitatively discussed, including fuel pin and primary coolant retention, and behavior in the cover gas and

  10. Development and Implementation of Mechanistic Terry Turbine Models in RELAP-7 to Simulate RCIC Normal Operation Conditions

    Energy Technology Data Exchange (ETDEWEB)

    Zhao, Haihua [Idaho National Lab. (INL), Idaho Falls, ID (United States); Zou, Ling [Idaho National Lab. (INL), Idaho Falls, ID (United States); Zhang, Hongbin [Idaho National Lab. (INL), Idaho Falls, ID (United States); O' Brien, James Edward [Idaho National Lab. (INL), Idaho Falls, ID (United States)

    2016-09-01

    As part of the efforts to understand the unexpected “self-regulating” mode of the RCIC (Reactor Core Isolation Cooling) systems in Fukushima accidents and extend BWR RCIC and PWR AFW (Auxiliary Feed Water) operational range and flexibility, mechanistic models for the Terry turbine, based on Sandia’s original work [1], have been developed and implemented in the RELAP-7 code to simulate the RCIC system. In 2016, our effort has been focused on normal working conditions of the RCIC system. More complex off-design conditions will be pursued in later years when more data are available. In the Sandia model, the turbine stator inlet velocity is provided according to a reduced-order model which was obtained from a large number of CFD (computational fluid dynamics) simulations. In this work, we propose an alternative method, using an under-expanded jet model to obtain the velocity and thermodynamic conditions for the turbine stator inlet. The models include both an adiabatic expansion process inside the nozzle and a free expansion process outside of the nozzle to ambient pressure. The combined models are able to predict the steam mass flow rate and supersonic velocity to the Terry turbine bucket entrance, which are the necessary input information for the Terry turbine rotor model. The analytical models for the nozzle were validated with experimental data and benchmarked with CFD simulations. The analytical models generally agree well with the experimental data and CFD simulations. The analytical models are suitable for implementation into a reactor system analysis code or severe accident code as part of mechanistic and dynamical models to understand the RCIC behaviors. The newly developed nozzle models and modified turbine rotor model according to the Sandia’s original work have been implemented into RELAP-7, along with the original Sandia Terry turbine model. A new pump model has also been developed and implemented to couple with the Terry turbine model. An input

  11. A metabonomic approach for mechanistic exploration of pre-clinical toxicology.

    Science.gov (United States)

    Coen, Muireann

    2010-12-30

    Metabonomics involves the application of advanced analytical tools to profile the diverse metabolic complement of a given biofluid or tissue. Subsequent statistical modelling of the complex multivariate spectral profiles enables discrimination between phenotypes of interest and identifies panels of discriminatory metabolites that represent candidate biomarkers. This review article presents an overview of recent developments in the field of metabonomics with a focus on application to pre-clinical toxicology studies. Recent research investigations carried out as part of the international COMET 2 consortium project on the hepatotoxic action of the aminosugar, galactosamine (galN) are presented. The application of advanced, high-field NMR spectroscopy is demonstrated, together with complementary application of a targeted mass spectrometry platform coupled with ultra-performance liquid chromatography. Much novel mechanistic information has been gleaned on both the mechanism of galN hepatotoxicity in multiple biofluids and tissues, and on the protection afforded by co-administration of glycine and uridine. The simultaneous identification of both the metabolic fate of galN and its associated endogenous consequences in spectral profiles is demonstrated. Furthermore, metabonomic assessment of inter-animal variability in response to galN presents enhanced mechanistic insight on variable response phentoypes and is relevant to understanding wider aspects of individual variability in drug response. This exemplar highlights the analytical and statistical tools commonly applied in metabonomic studies and notably, the approach is applicable to the study of any toxin/drug or intervention of interest. The metabonomic approach holds considerable promise and potential to significantly advance our understanding of the mechanistic bases for adverse drug reactions. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  12. ReactionPredictor: prediction of complex chemical reactions at the mechanistic level using machine learning.

    Science.gov (United States)

    Kayala, Matthew A; Baldi, Pierre

    2012-10-22

    Proposing reasonable mechanisms and predicting the course of chemical reactions is important to the practice of organic chemistry. Approaches to reaction prediction have historically used obfuscating representations and manually encoded patterns or rules. Here we present ReactionPredictor, a machine learning approach to reaction prediction that models elementary, mechanistic reactions as interactions between approximate molecular orbitals (MOs). A training data set of productive reactions known to occur at reasonable rates and yields and verified by inclusion in the literature or textbooks is derived from an existing rule-based system and expanded upon with manual curation from graduate level textbooks. Using this training data set of complex polar, hypervalent, radical, and pericyclic reactions, a two-stage machine learning prediction framework is trained and validated. In the first stage, filtering models trained at the level of individual MOs are used to reduce the space of possible reactions to consider. In the second stage, ranking models over the filtered space of possible reactions are used to order the reactions such that the productive reactions are the top ranked. The resulting model, ReactionPredictor, perfectly ranks polar reactions 78.1% of the time and recovers all productive reactions 95.7% of the time when allowing for small numbers of errors. Pericyclic and radical reactions are perfectly ranked 85.8% and 77.0% of the time, respectively, rising to >93% recovery for both reaction types with a small number of allowed errors. Decisions about which of the polar, pericyclic, or radical reaction type ranking models to use can be made with >99% accuracy. Finally, for multistep reaction pathways, we implement the first mechanistic pathway predictor using constrained tree-search to discover a set of reasonable mechanistic steps from given reactants to given products. Webserver implementations of both the single step and pathway versions of Reaction

  13. A dynamic and mechanistic model of PCB bioaccumulation in the European hake ( Merluccius merluccius)

    Science.gov (United States)

    Bodiguel, Xavier; Maury, Olivier; Mellon-Duval, Capucine; Roupsard, François; Le Guellec, Anne-Marie; Loizeau, Véronique

    2009-08-01

    Bioaccumulation is difficult to document because responses differ among chemical compounds, with environmental conditions, and physiological processes characteristic of each species. We use a mechanistic model, based on the Dynamic Energy Budget (DEB) theory, to take into account this complexity and study factors impacting accumulation of organic pollutants in fish through ontogeny. The bioaccumulation model proposed is a comprehensive approach that relates evolution of hake PCB contamination to physiological information about the fish, such as diet, metabolism, reserve and reproduction status. The species studied is the European hake ( Merluccius merluccius, L. 1758). The model is applied to study the total concentration and the lipid normalised concentration of 4 PCB congeners in male and female hakes from the Gulf of Lions (NW Mediterranean sea) and the Bay of Biscay (NE Atlantic ocean). Outputs of the model compare consistently to measurements over the life span of fish. Simulation results clearly demonstrate the relative effects of food contamination, growth and reproduction on the PCB bioaccumulation in hake. The same species living in different habitats and exposed to different PCB prey concentrations exhibit marked difference in the body accumulation of PCBs. At the adult stage, female hakes have a lower PCB concentration compared to males for a given length. We successfully simulated these sex-specific PCB concentrations by considering two mechanisms: a higher energy allocation to growth for females and a transfer of PCBs from the female to its eggs when allocating lipids from reserve to eggs. Finally, by its mechanistic description of physiological processes, the model is relevant for other species and sets the stage for a mechanistic understanding of toxicity and ecological effects of organic contaminants in marine organisms.

  14. A mechanistic model of an upper bound on oceanic carbon export as a function of mixed layer depth and temperature

    Directory of Open Access Journals (Sweden)

    Z. Li

    2017-11-01

    Full Text Available Export production reflects the amount of organic matter transferred from the ocean surface to depth through biological processes. This export is in large part controlled by nutrient and light availability, which are conditioned by mixed layer depth (MLD. In this study, building on Sverdrup's critical depth hypothesis, we derive a mechanistic model of an upper bound on carbon export based on the metabolic balance between photosynthesis and respiration as a function of MLD and temperature. We find that the upper bound is a positively skewed bell-shaped function of MLD. Specifically, the upper bound increases with deepening mixed layers down to a critical depth, beyond which a long tail of decreasing carbon export is associated with increasing heterotrophic activity and decreasing light availability. We also show that in cold regions the upper bound on carbon export decreases with increasing temperature when mixed layers are deep, but increases with temperature when mixed layers are shallow. A meta-analysis shows that our model envelopes field estimates of carbon export from the mixed layer. When compared to satellite export production estimates, our model indicates that export production in some regions of the Southern Ocean, particularly the subantarctic zone, is likely limited by light for a significant portion of the growing season.

  15. Mechanistic insight into ultrasound induced enhancement of simultaneous saccharification and fermentation of Parthenium hysterophorus for ethanol production.

    Science.gov (United States)

    Singh, Shuchi; Agarwal, Mayank; Sarma, Shyamali; Goyal, Arun; Moholkar, Vijayanand S

    2015-09-01

    This paper presents investigations into mechanism of ultrasound assisted bioethanol synthesis using Parthenium hysterophorus biomass through simultaneous saccharification and fermentation (SSF) mode. Approach of coupling experimental results to mathematical model for SSF using Genetic Algorithm based optimization has been adopted. Comparison of model parameters for experiments with mechanical shaking and sonication (10% duty cycle) give an interesting mechanistic account of influence of ultrasound on SSF system. A 4-fold rise in ethanol and cell mass productivity is seen with ultrasound. The analysis reveals following facets of influence of ultrasound on SSF: increase in Monod constant for glucose for cell growth, maximal specific growth rate and inhibition constant of cell growth by glucose and reduction in specific cell death rate. Values of inhibition constant of cell growth by ethanol (K3E), and constants for growth associated (a) and non-growth associated (b) ethanol production remained unaltered with sonication. Beneficial effects of ultrasound are attributed to enhanced cellulose hydrolysis, enhanced trans-membrane transport of substrate and products as well as dilution of the toxic substances due to micro-convection induced by ultrasound. Intrinsic physiological functioning of cells remained unaffected by ultrasound as indicated by unaltered values of K3E, a and b. Copyright © 2015 Elsevier B.V. All rights reserved.

  16. Cationic Pd(II-catalyzed C–H activation/cross-coupling reactions at room temperature: synthetic and mechanistic studies

    Directory of Open Access Journals (Sweden)

    Takashi Nishikata

    2016-05-01

    Full Text Available Cationic palladium(II complexes have been found to be highly reactive towards aromatic C–H activation of arylureas at room temperature. A commercially available catalyst [Pd(MeCN4](BF42 or a nitrile-free cationic palladium(II complex generated in situ from the reaction of Pd(OAc2 and HBF4, effectively catalyzes C–H activation/cross-coupling reactions between aryl iodides, arylboronic acids and acrylates under milder conditions than those previously reported. The nature of the directing group was found to be critical for achieving room temperature conditions, with the urea moiety the most effective in promoting facile coupling reactions at an ortho C–H position. This methodology has been utilized in a streamlined and efficient synthesis of boscalid, an agent produced on the kiloton scale annually and used to control a range of plant pathogens in broadacre and horticultural crops. Mechanistic investigations led to a proposed catalytic cycle involving three steps: (1 C–H activation to generate a cationic palladacycle; (2 reaction of the cationic palladacycle with an aryl iodide, arylboronic acid or acrylate, and (3 regeneration of the active cationic palladium catalyst. The reaction between a cationic palladium(II complex and arylurea allowed the formation and isolation of the corresponding palladacycle intermediate, characterized by X-ray analysis. Roles of various additives in the stepwise process have also been studied.

  17. Mechanistic Drifting Forecast Model for A Small Semi-Submersible Drifter Under Tide-Wind-Wave Conditions

    Science.gov (United States)

    Zhang, Wei-Na; Huang, Hui-ming; Wang, Yi-gang; Chen, Da-ke; Zhang, lin

    2018-03-01

    Understanding the drifting motion of a small semi-submersible drifter is of vital importance regarding monitoring surface currents and the floating pollutants in coastal regions. This work addresses this issue by establishing a mechanistic drifting forecast model based on kinetic analysis. Taking tide-wind-wave into consideration, the forecast model is validated against in situ drifting experiment in the Radial Sand Ridges. Model results show good performance with respect to the measured drifting features, characterized by migrating back and forth twice a day with daily downwind displacements. Trajectory models are used to evaluate the influence of the individual hydrodynamic forcing. The tidal current is the fundamental dynamic condition in the Radial Sand Ridges and has the greatest impact on the drifting distance. However, it loses its leading position in the field of the daily displacement of the used drifter. The simulations reveal that different hydrodynamic forces dominate the daily displacement of the used drifter at different wind scales. The wave-induced mass transport has the greatest influence on the daily displacement at Beaufort wind scale 5-6; while wind drag contributes mostly at wind scale 2-4.

  18. Synthesis, Photoluminescence Behavior of Green Light Emitting Tb(III) Complexes and Mechanistic Investigation of Energy Transfer Process.

    Science.gov (United States)

    Bala, Manju; Kumar, Satish; Devi, Rekha; Khatkar, Avni; Taxak, V B; Boora, Priti; Khatkar, S P

    2018-06-04

    A series of five new terbium(III) ion complexes with 4,4-difluoro-1-phenylbutane-1,3-dione (HDPBD) and anciliary ligands was synthesized. The composition and properties of complexes were analyzed by elemental analysis, IR, NMR, powder X-ray diffaraction, TG-DTG and photoluminescence spectroscopy. These complexes exhibited ligand sensitized green emission at 546 nm associated with 5 D 4  →  7 F 5 transitions of terbium ion in the emission spectra. The photoluminescence study manifested that the organic ligands act as antenna and facilitate the absorbed energy to emitting levels of Tb(III) ion efficiently. The enhanced luminescence intensity and decay time of ternary C2-C5 complexes observed due to synergistic effect of anciliary ligands. The CIE color coordinates of complexes came under the green region of chromaticity diagram. The mechanistic investigation of intramolecular energy transfer in the complexes was discussed in detail. These terbium(III) complexes can be thrivingly used as one of the green component in light emitting material and in display devices. Graphical Abstract Illustrate the sensitization process of the Tb ion and intramolecular energy transfer process in the Tb 3+ complex.

  19. A Mechanistic Model of Onset of Flow Instability Due to Mergence of Bubble Layers in a Vertical Narrow Rectangular Channel

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Juh Yung; Chang, Soon Heung; Jeong, Yong [KAIST, Daejeon (Korea, Republic of)

    2016-05-15

    The onset of flow instability (OFI) is the one of important boiling phenomena since it may induce the premature critical heat flux (CHF) at the lowest heat flux level due to sudden flow excursion in a single channel of multichannel configuration. Especially prediction of OFI for narrow rectangular channel is very crucial in relevant to thermal-hydraulic design and safety analysis of open pool-type research reactors (RRs) using plate-type fuels. Based on high speed video (HSV) technique, the authors observed and determined that OFI and the minimum premature CHF in a narrow rectangular channel are induced by abrupt pressure drop fluctuation due to the mergence of facing bubble boundary layers (BLs) on opposite boiling surfaces. In this study, new mechanistic OFI model for narrow rectangular channel heated on both sides has been derived, which satisfies with the real triggering phenomena. Force balance approach was used for modeling of the maximum BLT since the quantity is comparable to the bubble departure diameter. From the validation with OFI database, it was shown that the new model fairly well predicts OFI heat flux for wide range of conditions.

  20. Revisiting the mechanistic basis of the French Paradox: red wine inhibits the activity of protein disulfide isomerase in vitro

    Science.gov (United States)

    Galinski, Christine N.; Zwicker, Jeffrey I.; Kennedy, Daniel R.

    2015-01-01

    Introduction Although epidemiologic evidence points to cardioprotective activity of red wine, the mechanistic basis for antithrombotic activity has not been established. Quercetin and related flavonoids are present in high concentrations in red but not white wine. Quercetin-glycosides were recently shown to prevent thrombosis in animal models through the inhibition of extracellular protein disulfide isomerase (PDI). We evaluated whether red or white wine inhibited PDI activity in vitro. Methods Quercetin levels in red and white wines were measured by HPLC analysis. Inhibition of PDI activity by red and white wines was assessed by an insulin reduction turbidity assay at various concentrations of wine. PDI inhibition was confirmed using a reduced peptide that contained a disulfide containing peptide as a substrate. The inhibition of PDI related thiol isomerases ERp5 and ERp57 was also assessed. Results We observed a dose-dependent decrease of PDI activity for a variety of red but not white wines. Red wine diluted to 3% final concentration resulted in over 80% inhibition of PDI activity by insulin reductase assay for all varieties tested. This inhibition was also observed in the peptide based assay. Red grape juice yielded similar results but ethanol alone did not affect PDI activity. Interestingly, red wine also inhibited the PDI related thiol isomerases ERp5 and ERp57, albeit to a lesser degree than PDI. Conclusions PDI activity is inhibited by red wine and grape juice, identifying a potentially novel mechanism underlying the cardiovascular benefits attributed to wine consumption. PMID:26585763

  1. Mechanistic model coupling gas exchange dynamics and Listeria monocytogenes growth in modified atmosphere packaging of non respiring food.

    Science.gov (United States)

    Chaix, E; Broyart, B; Couvert, O; Guillaume, C; Gontard, N; Guillard, V

    2015-10-01

    A mechanistic model coupling O2 and CO2 mass transfer (namely diffusion and solubilisation in the food itself and permeation through the packaging material) to microbial growth models was developed aiming at predicting the shelf life of modified atmosphere packaging (MAP) systems. It was experimentally validated on a non-respiring food by investigating concomitantly the O2/CO2 partial pressure in packaging headspace and the growth of Listeria monocytogenes (average microbial count) within the food sample. A sensitivity analysis has revealed that the reliability of the prediction by this "super-parametrized" model (no less than 47 parameters were required for running one simulation) was strongly dependent on the accuracy of the microbial input parameters. Once validated, this model was used to decipher the role of O2/CO2 mass transfer on microbial growth and as a MAP design tool: an example of MAP dimensioning was provided in this paper as a proof of concept. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Mechanistic approach for the kinetics of the decomposition of nitrous oxide over calcined hydrotalcites

    Energy Technology Data Exchange (ETDEWEB)

    Dandl, H.; Emig, G. [Lehrstuhl fuer Technische Chemie I, Erlangen (Germany)

    1998-03-27

    A highly active catalyst for the decomposition of N{sub 2}O was prepared by the thermal treatment of CoLaAl-hydrotalcite. For this catalyst the reaction rate was determined at various partial pressures of N{sub 2}O, O{sub 2} and H{sub 2}O in a temperature range from 573K to 823K. The kinetic simulation resulted in a mechanistic model. The energies of activation and rate coefficients are estimated for the main steps of the reaction

  3. Mechanistic differences between methanol and dimethyl ether carbonylation in side pockets and large channels of mordenite.

    Science.gov (United States)

    Boronat, Mercedes; Martínez, Cristina; Corma, Avelino

    2011-02-21

    The activity and selectivity towards carbonylation presented by Brønsted acid sites located inside the 8MR pockets or in the main 12MR channels of mordenite is studied by means of quantum-chemical calculations, and the mechanistic differences between methanol and DME carbonylation are investigated. The selectivity towards carbonylation is higher inside the 8MR pockets, where the competitive formation of DME and hydrocarbons that finally leads to catalyst deactivation is sterically impeded. Moreover, inclusion of dispersion interactions in the calculations leads to agreement between the calculated activation barriers for the rate determining step and the experimentally observed higher reactivity of methoxy groups located inside the 8MR channels.

  4. Bird Migration Under Climate Change - A Mechanistic Approach Using Remote Sensing

    Science.gov (United States)

    Smith, James A.; Blattner, Tim; Messmer, Peter

    2010-01-01

    The broad-scale reductions and shifts that may be expected under climate change in the availability and quality of stopover habitat for long-distance migrants is an area of increasing concern for conservation biologists. Researchers generally have taken two broad approaches to the modeling of migration behaviour to understand the impact of these changes on migratory bird populations. These include models based on causal processes and their response to environmental stimulation, "mechanistic models", or models that primarily are based on observed animal distribution patterns and the correlation of these patterns with environmental variables, i.e. "data driven" models. Investigators have applied the latter technique to forecast changes in migration patterns with changes in the environment, for example, as might be expected under climate change, by forecasting how the underlying environmental data layers upon which the relationships are built will change over time. The learned geostatstical correlations are then applied to the modified data layers.. However, this is problematic. Even if the projections of how the underlying data layers will change are correct, it is not evident that the statistical relationships will remain the same, i.e. that the animal organism may not adapt its' behaviour to the changing conditions. Mechanistic models that explicitly take into account the physical, biological, and behaviour responses of an organism as well as the underlying changes in the landscape offer an alternative to address these shortcomings. The availability of satellite remote sensing observations at multiple spatial and temporal scales, coupled with advances in climate modeling and information technologies enable the application of the mechanistic models to predict how continental bird migration patterns may change in response to environmental change. In earlier work, we simulated the impact of effects of wetland loss and inter-annual variability on the fitness of

  5. Mechanistic modeling of reactive soil nitrogen emissions across agricultural management practices

    Science.gov (United States)

    Rasool, Q. Z.; Miller, D. J.; Bash, J. O.; Venterea, R. T.; Cooter, E. J.; Hastings, M. G.; Cohan, D. S.

    2017-12-01

    The global reactive nitrogen (N) budget has increased by a factor of 2-3 from pre-industrial levels. This increase is especially pronounced in highly N fertilized agricultural regions in summer. The reactive N emissions from soil to atmosphere can be in reduced (NH3) or oxidized (NO, HONO, N2O) forms, depending on complex biogeochemical transformations of soil N reservoirs. Air quality models like CMAQ typically neglect soil emissions of HONO and N2O. Previously, soil NO emissions estimated by models like CMAQ remained parametric and inconsistent with soil NH3 emissions. Thus, there is a need to more mechanistically and consistently represent the soil N processes that lead to reactive N emissions to the atmosphere. Our updated approach estimates soil NO, HONO and N2O emissions by incorporating detailed agricultural fertilizer inputs from EPIC, and CMAQ-modeled N deposition, into the soil N pool. EPIC addresses the nitrification, denitrification and volatilization rates along with soil N pools for agricultural soils. Suitable updates to account for factors like nitrite (NO2-) accumulation not addressed in EPIC, will also be made. The NO and N2O emissions from nitrification and denitrification are computed mechanistically using the N sub-model of DAYCENT. These mechanistic definitions use soil water content, temperature, NH4+ and NO3- concentrations, gas diffusivity and labile C availability as dependent parameters at various soil layers. Soil HONO emissions found to be most probable under high NO2- availability will be based on observed ratios of HONO to NO emissions under different soil moistures, pH and soil types. The updated scheme will utilize field-specific soil properties and N inputs across differing manure management practices such as tillage. Comparison of the modeled soil NO emission rates from the new mechanistic and existing schemes against field measurements will be discussed. Our updated framework will help to predict the diurnal and daily variability

  6. The Cycloaddition of the Benzimidazolium Ylides with Alkynes: New Mechanistic Insights.

    Directory of Open Access Journals (Sweden)

    Costel Moldoveanu

    Full Text Available New insights concerning the reaction mechanism in the cycloaddition reaction of benzimidazolium ylides to activated alkynes are presented. The proposed pathway leading both to 2-(1H-pyrrol-1-ylanilines and to pyrrolo[1,2-a]quinoxalin-4(5H-ones involves an opening of the imidazole ring from the cycloaddition product, followed by a nucleophilic attack of the aminic nitrogen to a proximal carbonyl group and the elimination of a leaving group. The mechanistic considerations are fully supported by experimental data, including the XRD resolved structure of the key reaction intermediate.

  7. The Cycloaddition of the Benzimidazolium Ylides with Alkynes: New Mechanistic Insights.

    Science.gov (United States)

    Moldoveanu, Costel; Zbancioc, Gheorghita; Mantu, Dorina; Maftei, Dan; Mangalagiu, Ionel

    2016-01-01

    New insights concerning the reaction mechanism in the cycloaddition reaction of benzimidazolium ylides to activated alkynes are presented. The proposed pathway leading both to 2-(1H-pyrrol-1-yl)anilines and to pyrrolo[1,2-a]quinoxalin-4(5H)-ones involves an opening of the imidazole ring from the cycloaddition product, followed by a nucleophilic attack of the aminic nitrogen to a proximal carbonyl group and the elimination of a leaving group. The mechanistic considerations are fully supported by experimental data, including the XRD resolved structure of the key reaction intermediate.

  8. Development of a mechanistically based computer simulation of nitrogen oxide absorption in packed towers

    International Nuclear Information System (INIS)

    Counce, R.M.

    1981-01-01

    A computer simulation for nitrogen oxide (NO/sub x/) scrubbing in packed towers was developed for use in process design and process control. This simulation implements a mechanistically based mathematical model, which was formulated from (1) an exhaustive literature review; (2) previous NO/sub x/ scrubbing experience with sieve-plate towers; and (3) comparisons of sequential sets of experiments. Nitrogen oxide scrubbing is characterized by simultaneous absorption and desorption phenomena: the model development is based on experiments designed to feature these two phenomena. The model was then successfully tested in experiments designed to put it in jeopardy

  9. Arsenic Exposure and Type 2 Diabetes: MicroRNAs as Mechanistic Links?

    OpenAIRE

    Beck, Rowan; Styblo, Miroslav; Sethupathy, Praveen

    2017-01-01

    Purpose of Review The goal of this review is to delineate the following: (1) the primary means of inorganic arsenic (iAs) exposure for human populations, (2) the adverse public health outcomes associated with chronic iAs exposure, (3) the pathophysiological connection between arsenic and type 2 diabetes (T2D), and (4) the incipient evidence for microRNAs as candidate mechanistic links between iAs exposure and T2D. Recent Findings Exposure to iAs in animal models has been associated with the d...

  10. Problems in mechanistic theoretical models for cell transformation by ionizing radiation

    International Nuclear Information System (INIS)

    Chatterjee, Aloke; Holley, W.R.

    1992-01-01

    A mechanistic model based on yields of double strand breaks has been developed to determine the dose response curves for cell transformation frequencies. At its present stage the model is applicable to immortal cell lines and to various qualities (X-rays, Neon and Iron) of ionizing radiation. Presently, we have considered four types of processes which can lead to activation phenomena: (i) point mutation events on a regulatory segment of selected oncogenes, (ii) inactivation of suppressor genes, through point mutation, (iii) deletion of a suppressor gene by a single track, and (iv) deletion of a suppressor gene by two tracks. (author)

  11. Comparative approaches from empirical to mechanistic simulation modelling in Land Evaluation studies

    Science.gov (United States)

    Manna, P.; Basile, A.; Bonfante, A.; Terribile, F.

    2009-04-01

    The Land Evaluation (LE) comprise the evaluation procedures to asses the attitudes of the land to a generic or specific use (e.g. biomass production). From local to regional and national scale the approach to the land use planning should requires a deep knowledge of the processes that drive the functioning of the soil-plant-atmosphere system. According to the classical approaches the assessment of attitudes is the result of a qualitative comparison between the land/soil physical properties and the land use requirements. These approaches have a quick and inexpensive applicability; however, they are based on empirical and qualitative models with a basic knowledge structure specifically built for a specific landscape and for the specific object of the evaluation (e.g. crop). The outcome from this situation is the huge difficulties in the spatial extrapolation of the LE results and the rigidity of the system. Modern techniques instead, rely on the application of mechanistic and quantitative simulation modelling that allow a dynamic characterisation of the interrelated physical and chemical processes taking place in the soil landscape. Moreover, the insertion of physical based rules in the LE procedure may make it less difficult in terms of both extending spatially the results and changing the object (e.g. crop species, nitrate dynamics, etc.) of the evaluation. On the other side these modern approaches require high quality and quantity of input data that cause a significant increase in costs. In this scenario nowadays the LE expert is asked to choose the best LE methodology considering costs, complexity of the procedure and benefits in handling a specific land evaluation. In this work we performed a forage maize land suitability study by comparing 9 different methods having increasing complexity and costs. The study area, of about 2000 ha, is located in North Italy in the Lodi plain (Po valley). The range of the 9 employed methods ranged from standard LE approaches to

  12. Application of response surface methodology and semi-mechanistic model to optimize fluoride removal using crushed concrete in a fixed-bed column.

    Science.gov (United States)

    Gu, Bon-Wun; Lee, Chang-Gu; Park, Seong-Jik

    2018-03-01

    The aim of this study was to investigate the removal of fluoride from aqueous solutions by using crushed concrete fines as a filter medium under varying conditions of pH 3-7, flow rate of 0.3-0.7 mL/min, and filter depth of 10-20 cm. The performance of fixed-bed columns was evaluated on the basis of the removal ratio (Re), uptake capacity (qe), degree of sorbent used (DoSU), and sorbent usage rate (SUR) obtained from breakthrough curves (BTCs). Three widely used semi-mechanistic models, that is, Bohart-Adams, Thomas, and Yoon-Nelson models, were applied to simulate the BTCs and to derive the design parameters. The Box-Behnken design of response surface methodology (RSM) was used to elucidate the individual and interactive effects of the three operational parameters on the column performance and to optimize these parameters. The results demonstrated that pH is the most important factor in the performance of fluoride removal by a fixed-bed column. The flow rate had a significant negative influence on Re and DoSU, and the effect of filter depth was observed only in the regression model for DoSU. Statistical analysis indicated that the model attained from the RSM study is suitable for describing the semi-mechanistic model parameters.

  13. Hidden Hydride Transfer as a Decisive Mechanistic Step in the Reactions of the Unligated Gold Carbide [AuC]+ with Methane under Ambient Conditions.

    Science.gov (United States)

    Li, Jilai; Zhou, Shaodong; Schlangen, Maria; Weiske, Thomas; Schwarz, Helmut

    2016-10-10

    The reactivity of the cationic gold carbide [AuC] + (bearing an electrophilic carbon atom) towards methane has been studied using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR-MS). The product pairs generated, that is, Au + /C 2 H 4 , [Au(C 2 H 2 )] + /H 2 , and [C 2 H 3 ] + /AuH, point to the breaking and making of C-H, C-C, and H-H bonds under single-collision conditions. The mechanisms of these rather efficient reactions have been elucidated by high-level quantum-chemical calculations. As a major result, based on molecular orbital and NBO-based charge analysis, an unprecedented hydride transfer from methane to the carbon atom of [AuC] + has been identified as a key step. Also, the origin of this novel mechanistic scenario has been addressed. The mechanistic insights derived from this study may provide guidance for the rational design of carbon-based catalysts. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  14. Life at the Common Denominator: Mechanistic and Quantitative Biology for the Earth and Space Sciences

    Science.gov (United States)

    Hoehler, Tori M.

    2010-01-01

    The remarkable challenges and possibilities of the coming few decades will compel the biogeochemical and astrobiological sciences to characterize the interactions between biology and its environment in a fundamental, mechanistic, and quantitative fashion. The clear need for integrative and scalable biology-environment models is exemplified in the Earth sciences by the challenge of effectively addressing anthropogenic global change, and in the space sciences by the challenge of mounting a well-constrained yet sufficiently adaptive and inclusive search for life beyond Earth. Our understanding of the life-planet interaction is still, however, largely empirical. A variety of approaches seek to move from empirical to mechanistic descriptions. One approach focuses on the relationship between biology and energy, which is at once universal (all life requires energy), unique (life manages energy flow in a fashion not seen in abiotic systems), and amenable to characterization and quantification in thermodynamic terms. Simultaneously, a focus on energy flow addresses a critical point of interface between life and its geological, chemical, and physical environment. Characterizing and quantifying this relationship for life on Earth will support the development of integrative and predictive models for biology-environment dynamics. Understanding this relationship at its most fundamental level holds potential for developing concepts of habitability and biosignatures that can optimize astrobiological exploration strategies and are extensible to all life.

  15. Evolutionary and mechanistic drivers of laterality: A review and new synthesis.

    Science.gov (United States)

    Wiper, Mallory L

    2017-11-01

    Laterality, best understood as asymmetries of bilateral structures or biases in behaviour, has been demonstrated in species from all major vertebrate classes, and in many invertebrates, showing a large degree of evolutionary conservation across vertebrate groups. Despite the establishment of this phenomenon in so many species, however, the evolutionary and mechanistic study of laterality is uneven with numerous areas in this field requiring greater attention. Here, I present a partial review of how far the study of laterality has come, outlining previous pioneering work, I discuss the hypothesized costs and benefits of a lateralized brain and the suggested path of the evolution of laterality for populations and individuals. I propose an expansion of laterality research into areas that have been touched upon in the past but require stronger evidence from which the field will greatly benefit. Namely, I suggest a continuation of the phylogenetic approach to investigating laterality to better understand its evolutionary path; and a further focus on mechanistic drivers, with special attention to genetic and environmental effects. Putting together the puzzle of laterality using as many pieces as possible will provide a stronger understanding of this field, allowing us to continue to expand the field in novel ways.

  16. Mechanistic Insight into the Dehydro-Diels-Alder Reaction of Styrene-Ynes.

    Science.gov (United States)

    Kocsis, Laura S; Kagalwala, Husain N; Mutto, Sharlene; Godugu, Bhaskar; Bernhard, Stefan; Tantillo, Dean J; Brummond, Kay M

    2015-12-04

    The Diels-Alder reaction represents one of the most thoroughly studied and well-understood synthetic transformations for the assembly of six-membered rings. Although intramolecular dehydro-Diels-Alder (IMDDA) reactions have previously been employed for the preparation of naphthalene and dihydronaphthalene substrates, low yields and product mixtures have reduced the impact and scope of this reaction. Through the mechanistic studies described within, we have confirmed that the thermal IMDDA reaction of styrene-ynes produces a naphthalene product via loss of hydrogen gas from the initially formed cycloadduct, a tetraenyl intermediate. Alternatively, the dihydronaphthalene product is afforded from the same tetraenyl intermediate via a radical isomerization process. Moreover, we have identified conditions that can be used to achieve efficient, high-yielding, and selective IMDDA reactions of styrene-ynes to form either naphthalene or dihydronaphthalene products. The operational simplicity and retrosynthetic orthogonality of this method for the preparation of naphthalenes and dihydronaphthalenes makes this transformation appealing for the synthesis of medicinal and material targets. The mechanistic studies within may impact the development of other thermal transformations.

  17. A tissue-engineered gastric cancer model for mechanistic study of anti-tumor drugs

    International Nuclear Information System (INIS)

    Gao, Ming; Cai, Yiting; Wu, Wei; Shi, Yazhou; Fei, Zhewei

    2013-01-01

    The use of the traditional xenograft subcutaneous tumor model has been contested because of its limitations, such as a slow tumorigenesis, inconsistent chemotherapeutic results, etc. In light of these challenges, we aim to revamp the traditional model by employing an electrospun scaffold composed of polydioxanone, gelatin and elastin to boost the tumorigenesis. The scaffold featured a highly porous microstructure and successfully supported the growth of tumor cells in vitro without provoking apoptosis. In vivo studies showed that in the scaffold model the tumor volume increased by 43.27% and the weight by 75.58%, respectively, within a 12-week period. In addition, the scaffold model saw an increase of CD24 + and CD44 + cells in the tumor mass by 42% and 313%, respectively. The scaffolding materials did not lead to phenotypic changes during the tumorigenesis. Thereafter, in the scaffold model, we found that the chemotherapeutic regimen of docetaxel, cisplatin and fluorouracil unleashed a stronger capability than the regimen comprising cisplatin and fluorouracil to deplete the CD44 + subpopulation. This discovery sheds mechanistic lights on the role of docetaxel for its future chemotherapeutic applications. This revamped model affords cancer scientists a convenient and reliable platform to mechanistically investigate the chemotherapeutic drugs on gastric cancer stem cells. (paper)

  18. Simulating the Risk of Liver Fluke Infection using a Mechanistic Hydro-epidemiological Model

    Science.gov (United States)

    Beltrame, Ludovica; Dunne, Toby; Rose, Hannah; Walker, Josephine; Morgan, Eric; Vickerman, Peter; Wagener, Thorsten

    2016-04-01

    Liver Fluke (Fasciola hepatica) is a common parasite found in livestock and responsible for considerable economic losses throughout the world. Risk of infection is strongly influenced by climatic and hydrological conditions, which characterise the host environment for parasite development and transmission. Despite on-going control efforts, increases in fluke outbreaks have been reported in recent years in the UK, and have been often attributed to climate change. Currently used fluke risk models are based on empirical relationships derived between historical climate and incidence data. However, hydro-climate conditions are becoming increasingly non-stationary due to climate change and direct anthropogenic impacts such as land use change, making empirical models unsuitable for simulating future risk. In this study we introduce a mechanistic hydro-epidemiological model for Liver Fluke, which explicitly simulates habitat suitability for disease development in space and time, representing the parasite life cycle in connection with key environmental conditions. The model is used to assess patterns of Liver Fluke risk for two catchments in the UK under current and potential future climate conditions. Comparisons are made with a widely used empirical model employing different datasets, including data from regional veterinary laboratories. Results suggest that mechanistic models can achieve adequate predictive ability and support adaptive fluke control strategies under climate change scenarios.

  19. Mechanistic aspects of the metal catalyzed alternating copolymerization of epoxides and carbon monoxide.

    Science.gov (United States)

    Allmendinger, Markus; Molnar, Ferenc; Zintl, Manuela; Luinstra, Gerrit A; Preishuber-Pflügl, Peter; Rieger, Bernhard

    2005-09-05

    The cobalt-catalyzed alternating copolymerization of epoxides and CO is a novel, direct approach to aliphatic polyesters, such as poly(hydroxybutyrate) (PHB). This reaction was found to be catalyzed by Ph3Si[Co(CO)4] (4) and pyridine affording in a first step the stable mono-insertion product Ph3Si-O-CH(CH3)-CH2-CO-Co(CO)4 (5). However, a profound mechanistic understanding, especially of the role of pyridine as the key component for the polymerization reaction was missing. ATR-IR online monitoring under catalytic conditions and DFT calculations were used to show that an acylpyridinium cation is formed by cleavage of the cobalt-acyl bond of 5 in the presence of pyridine. The Lewis acid thus generated activates the next incoming epoxide monomer for ring opening through [Co(CO)4]-. The catalytic cycle is completed by a subsequent CO insertion in the new cobalt-alkyl bond. The calculations are used to explore the energetic hypersurface of the polymerization reaction and are complemented by extended experimental investigations that also support the mechanistic hypotheses.

  20. Comparative ecophysiology of two sympatric lizards. Laying the groundwork for mechanistic distribution models

    Directory of Open Access Journals (Sweden)

    Enrique García-Muñoz

    2013-12-01

    Full Text Available Distribution modelling usually makes inferences correlating species presence and environmental variables but does not take biotic relations into account. Alternative approaches based on a mechanistic understanding of biological processes are now being applied. Regarding lacertid lizards, physiological traits such as preferred body temperature (Tp are well known to correlate with several physiological optima. Much less is known about their water ecology although body temperature and evaporative water loss (Wl may trade-off. Two saxicolous lacertids, Algyroides marchi and Podarcis hispanica ss are sympatric in the Subbetic Mountains (SE Spain were they can be found in syntopy. Previous distribution modelling indicates the first species is associated with mountains, low temperatures; high precipitation and forest cover whereas the second one is more generalistic. Here, we perform two ecophysiological tests with both species: a Tp experiment in thermal gradient and a Wl experiment in sealed chambers. Although both species attained similar body temperatures, A. marchi lost more water and more uniformly in time than P. hispanica ss that displayed an apparent response to dehydration. These results suggest that water loss rather temperature is crucial to explain the distribution patterns of A. marchi in relation to P. hispanica ss, the former risking dehydration in dry areas no matter what temperature is. Ecophysiological traits represent a promising tool to build future mechanistic models for (lacertid lizards. Additionally, the implications for their biogeography and conservation are discussed.

  1. SITE-94. Adaptation of mechanistic sorption models for performance assessment calculations

    International Nuclear Information System (INIS)

    Arthur, R.C.

    1996-10-01

    Sorption is considered in most predictive models of radionuclide transport in geologic systems. Most models simulate the effects of sorption in terms of empirical parameters, which however can be criticized because the data are only strictly valid under the experimental conditions at which they were measured. An alternative is to adopt a more mechanistic modeling framework based on recent advances in understanding the electrical properties of oxide mineral-water interfaces. It has recently been proposed that these 'surface-complexation' models may be directly applicable to natural systems. A possible approach for adapting mechanistic sorption models for use in performance assessments, using this 'surface-film' concept, is described in this report. Surface-acidity parameters in the Generalized Two-Layer surface complexation model are combined with surface-complexation constants for Np(V) sorption ob hydrous ferric oxide to derive an analytical model enabling direct calculation of corresponding intrinsic distribution coefficients as a function of pH, and Ca 2+ , Cl - , and HCO 3 - concentrations. The surface film concept is then used to calculate whole-rock distribution coefficients for Np(V) sorption by altered granitic rocks coexisting with a hypothetical, oxidized Aespoe groundwater. The calculated results suggest that the distribution coefficients for Np adsorption on these rocks could range from 10 to 100 ml/g. Independent estimates of K d for Np sorption in similar systems, based on an extensive review of experimental data, are consistent, though slightly conservative, with respect to the calculated values. 31 refs

  2. Physiologically induced color-pattern changes in butterfly wings: mechanistic and evolutionary implications.

    Science.gov (United States)

    Otaki, Joji M

    2008-07-01

    A mechanistic understanding of the butterfly wing color-pattern determination can be facilitated by experimental pattern changes. Here I review physiologically induced color-pattern changes in nymphalid butterflies and their mechanistic and evolutionary implications. A type of color-pattern change can be elicited by elemental changes in size and position throughout the wing, as suggested by the nymphalid groundplan. These changes of pattern elements are bi-directional and bi-sided dislocation toward or away from eyespot foci and in both proximal and distal sides of the foci. The peripheral elements are dislocated even in the eyespot-less compartments. Anterior spots are more severely modified, suggesting the existence of an anterior-posterior gradient. In one species, eyespots are transformed into white spots with remnant-like orange scales, and such patterns emerge even at the eyespot-less "imaginary" foci. A series of these color-pattern modifications probably reveal "snap-shots" of a dynamic morphogenic signal due to heterochronic uncoupling between the signaling and reception steps. The conventional gradient model can be revised to account for these observed color-pattern changes.

  3. Productivity of "collisions generate heat" for reconciling an energy model with mechanistic reasoning: A case study

    Science.gov (United States)

    Scherr, Rachel E.; Robertson, Amy D.

    2015-06-01

    We observe teachers in professional development courses about energy constructing mechanistic accounts of energy transformations. We analyze a case in which teachers investigating adiabatic compression develop a model of the transformation of kinetic energy to thermal energy. Among their ideas is the idea that thermal energy is generated as a byproduct of individual particle collisions, which is represented in science education research literature as an obstacle to learning. We demonstrate that in this instructional context, the idea that individual particle collisions generate thermal energy is not an obstacle to learning, but instead is productive: it initiates intellectual progress. Specifically, this idea initiates the reconciliation of the teachers' energy model with mechanistic reasoning about adiabatic compression, and leads to a canonically correct model of the transformation of kinetic energy into thermal energy. We claim that the idea's productivity is influenced by features of our particular instructional context, including the instructional goals of the course, the culture of collaborative sense making, and the use of certain representations of energy.

  4. Comparison of Two-Phase Pipe Flow in OpenFOAM with a Mechanistic Model

    International Nuclear Information System (INIS)

    Shuard, Adrian M; Mahmud, Hisham B; King, Andrew J

    2016-01-01

    Two-phase pipe flow is a common occurrence in many industrial applications such as power generation and oil and gas transportation. Accurate prediction of liquid holdup and pressure drop is of vast importance to ensure effective design and operation of fluid transport systems. In this paper, a Computational Fluid Dynamics (CFD) study of a two-phase flow of air and water is performed using OpenFOAM. The two-phase solver, interFoam is used to identify flow patterns and generate values of liquid holdup and pressure drop, which are compared to results obtained from a two-phase mechanistic model developed by Petalas and Aziz (2002). A total of 60 simulations have been performed at three separate pipe inclinations of 0°, +10° and -10° respectively. A three dimensional, 0.052m diameter pipe of 4m length is used with the Shear Stress Transport (SST) k - ω turbulence model to solve the turbulent mixtures of air and water. Results show that the flow pattern behaviour and numerical values of liquid holdup and pressure drop compare reasonably well to the mechanistic model. (paper)

  5. Comparison of Two-Phase Pipe Flow in OpenFOAM with a Mechanistic Model

    Science.gov (United States)

    Shuard, Adrian M.; Mahmud, Hisham B.; King, Andrew J.

    2016-03-01

    Two-phase pipe flow is a common occurrence in many industrial applications such as power generation and oil and gas transportation. Accurate prediction of liquid holdup and pressure drop is of vast importance to ensure effective design and operation of fluid transport systems. In this paper, a Computational Fluid Dynamics (CFD) study of a two-phase flow of air and water is performed using OpenFOAM. The two-phase solver, interFoam is used to identify flow patterns and generate values of liquid holdup and pressure drop, which are compared to results obtained from a two-phase mechanistic model developed by Petalas and Aziz (2002). A total of 60 simulations have been performed at three separate pipe inclinations of 0°, +10° and -10° respectively. A three dimensional, 0.052m diameter pipe of 4m length is used with the Shear Stress Transport (SST) k - ɷ turbulence model to solve the turbulent mixtures of air and water. Results show that the flow pattern behaviour and numerical values of liquid holdup and pressure drop compare reasonably well to the mechanistic model.

  6. Prediction of warfarin maintenance dose in Han Chinese patients using a mechanistic model based on genetic and non-genetic factors.

    Science.gov (United States)

    Lu, Yuan; Yang, Jinbo; Zhang, Haiyan; Yang, Jin

    2013-07-01

    Many attempts have been made to predict the warfarin maintenance dose in patients beginning warfarin therapy using a descriptive model based on multiple linear regression. Here we report the first attempt to develop a comprehensive mechanistic model integrating in vitro-in vivo extrapolation (IVIVE) with a pharmacokinetic-pharmacodynamic model to predict the warfarin maintenance dose in Han Chinese patients. The model incorporates demographic factors [sex, age, body weight (BW)] and the genetic polymorphisms of cytochrome P450 (CYP) 2C9 (CYP2C9) and vitamin K epoxide reductase complex subunit 1 (VKORC1). Information on the various factors, mean warfarin daily dose and International Normalized Ratio (INR) was available for a cohort of 197 Han Chinese patients. Based on in vitro enzyme kinetic parameters for S-warfarin metabolism, demographic data for Han Chinese and some scaling factors, the S-warfarin clearance (CL) was predicted for patients in the cohort with different CYP2C9 genotypes using IVIVE. The plasma concentration of S-warfarin after a single oral dose was simulated using a one-compartment pharmacokinetic model with first-order absorption and a lag time and was combined with a mechanistic coagulation model to simulate the INR response. The warfarin maintenance dose was then predicted based on the demographic data and genotypes of CYP2C9 and VKORC1 for each patient and using the observed steady-state INR (INRss) as a target value. Finally, sensitivity analysis was carried out to determine which factor(s) affect the warfarin maintenance dose most strongly. The predictive performance of this mechanistic model is not inferior to that of our previous descriptive model. There were significant differences in the mean warfarin daily dose in patients with different CYP2C9 and VKORC1 genotypes. Using IVIVE, the predicted mean CL of S-warfarin for patients with CYP2C9*1/*3 (0.092 l/h, n = 11) was 57 % less than for those with wild-type *1/*1 (0.215 l/h, n

  7. Mechanistic insights on the cycloisomerization of polyunsaturated precursors catalyzed by platinum and gold complexes.

    Science.gov (United States)

    Soriano, Elena; Marco-Contelles, José

    2009-08-18

    Organometallic chemistry provides powerful tools for the stereocontrolled synthesis of heterocycles and carbocycles. The electrophilic transition metals Pt(II) and Au(I, III) are efficient catalysts in these transitions and promote a variety of organic transformations of unsaturated precursors. These reactions produce functionalized cyclic and acyclic scaffolds for the synthesis of natural and non-natural products efficiently, under mild conditions, and with excellent chemoselectivity. Because these transformations are strongly substrate-dependent, they are versatile and may yield diverse molecular scaffolds. Therefore, synthetic chemists need a mechanistic interpretation to optimize this reaction process and design a new generation of catalysts. However, so far, no intermediate species has been isolated or characterized, so the formulated mechanistic hypotheses have been primarily based on labeling studies or trapping reactions. Recently, theoretical DFT studies have become a useful tool in our research, giving us insights into the key intermediates and into a variety of plausible reaction pathways. In this Account, we present a comprehensive mechanistic overview of transformations promoted by Pt and Au in a non-nucleophilic medium based on quantum-mechanical studies. The calculations are consistent with the experimental observations and provide fundamental insights into the versatility of these reaction processes. The reactivity of these metals results from their peculiar Lewis acid properties: the alkynophilic character of these soft metals and the pi-acid activation of unsaturated groups promotes the intra- or intermolecular attack of a nucleophile. 1,n-Enynes (n = 3-8) are particularly important precursors, and their transformation may yield a variety of cycloadducts depending on the molecular structure. However, the calculations suggest that these different cyclizations would have closely related reaction mechanisms, and we propose a unified mechanistic

  8. Mechanistic Studies at the Interface Between Organometallic Chemistry and Homogeneous Catalysis

    Energy Technology Data Exchange (ETDEWEB)

    Casey, Charles P

    2012-11-14

    Mechanistic Studies at the Interface Between Organometallic Chemistry and Homogeneous Catalysis Charles P. Casey, Principal Investigator Department of Chemistry, University of Wisconsin - Madison, Madison, Wisconsin 53706 Phone 608-262-0584 FAX: 608-262-7144 Email: casey@chem.wisc.edu http://www.chem.wisc.edu/main/people/faculty/casey.html Executive Summary. Our goal was to learn the intimate mechanistic details of reactions involved in homogeneous catalysis and to use the insight we gain to develop new and improved catalysts. Our work centered on the hydrogenation of polar functional groups such as aldehydes and ketones and on hydroformylation. Specifically, we concentrated on catalysts capable of simultaneously transferring hydride from a metal center and a proton from an acidic oxygen or nitrogen center to an aldehyde or ketone. An economical iron based catalyst was developed and patented. Better understanding of fundamental organometallic reactions and catalytic processes enabled design of energy and material efficient chemical processes. Our work contributed to the development of catalysts for the selective and mild hydrogenation of ketones and aldehydes; this will provide a modern green alternative to reductions by LiAlH4 and NaBH4, which require extensive work-up procedures and produce waste streams. (C5R4OH)Ru(CO)2H Hydrogenation Catalysts. Youval Shvo described a remarkable catalytic system in which the key intermediate (C5R4OH)Ru(CO)2H (1) has an electronically coupled acidic OH unit and a hydridic RuH unit. Our efforts centered on understanding and improving upon this important catalyst for reduction of aldehydes and ketones. Our mechanistic studies established that the reduction of aldehydes by 1 to produce alcohols and a diruthenium bridging hydride species occurs much more rapidly than regeneration of the ruthenium hydride from the diruthenium bridging hydride species. Our mechanistic studies require simultaneous transfer of hydride from ruthenium to

  9. Simulation and mechanistic investigation of the arrhythmogenic role of the late sodium current in human heart failure.

    Directory of Open Access Journals (Sweden)

    Beatriz Trenor

    Full Text Available Heart failure constitutes a major public health problem worldwide. The electrophysiological remodeling of failing hearts sets the stage for malignant arrhythmias, in which the role of the late Na(+ current (I(NaL is relevant and is currently under investigation. In this study we examined the role of I(NaL in the electrophysiological phenotype of ventricular myocytes, and its proarrhythmic effects in the failing heart. A model for cellular heart failure was proposed using a modified version of Grandi et al. model for human ventricular action potential that incorporates the formulation of I(NaL. A sensitivity analysis of the model was performed and simulations of the pathological electrical activity of the cell were conducted. The proposed model for the human I(NaL and the electrophysiological remodeling of myocytes from failing hearts accurately reproduce experimental observations. The sensitivity analysis of the modulation of electrophysiological parameters of myocytes from failing hearts due to ion channels remodeling, revealed a role for I(NaL in the prolongation of action potential duration (APD, triangulation of the shape of the AP, and changes in Ca(2+ transient. A mechanistic investigation of intracellular Na(+ accumulation and APD shortening with increasing frequency of stimulation of failing myocytes revealed a role for the Na(+/K(+ pump, the Na(+/Ca(2+ exchanger and I(NaL. The results of the simulations also showed that in failing myocytes, the enhancement of I(NaL increased the reverse rate-dependent APD prolongation and the probability of initiating early afterdepolarizations. The electrophysiological remodeling of failing hearts and especially the enhancement of the I(NaL prolong APD and alter Ca(2+ transient facilitating the development of early afterdepolarizations. An enhanced I(NaL appears to be an important contributor to the electrophysiological phenotype and to the dysregulation of [Ca(2+](i homeostasis of failing myocytes.

  10. Organophotocatalysis: Insights into the Mechanistic Aspects of Thiourea-Mediated Intermolecular [2+2] Photocycloadditions.

    Science.gov (United States)

    Vallavoju, Nandini; Selvakumar, Sermadurai; Pemberton, Barry C; Jockusch, Steffen; Sibi, Mukund P; Sivaguru, Jayaraman

    2016-04-25

    Mechanistic investigations of the intermolecular [2+2] photocycloaddition of coumarin with tetramethylethylene mediated by thiourea catalysts reveal that the reaction is enabled by a combination of minimized aggregation, enhanced intersystem crossing, and altered excited-state lifetime(s). These results clarify how the excited-state reactivity can be manipulated through catalyst-substrate interactions and reveal a third mechanistic pathway for thiourea-mediated organo-photocatalysis. © 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  11. Combining Solvent Isotope Effects with Substrate Isotope Effects in Mechanistic Studies of Alcohol and Amine Oxidation by Enzymes*

    Science.gov (United States)

    Fitzpatrick, Paul F.

    2014-01-01

    Oxidation of alcohols and amines is catalyzed by multiple families of flavin-and pyridine nucleotide-dependent enzymes. Measurement of solvent isotope effects provides a unique mechanistic probe of the timing of the cleavage of the OH and NH bonds, necessary information for a complete description of the catalytic mechanism. The inherent ambiguities in interpretation of solvent isotope effects can be significantly decreased if isotope effects arising from isotopically labeled substrates are measured in combination with solvent isotope effects. The application of combined solvent and substrate (mainly deuterium) isotope effects to multiple enzymes is described here to illustrate the range of mechanistic insights that such an approach can provide. PMID:25448013

  12. Mechanistic kinetic modeling generates system-independent P-glycoprotein mediated transport elementary rate constants for inhibition and, in combination with 3D SIM microscopy, elucidates the importance of microvilli morphology on P-glycoprotein mediated efflux activity.

    Science.gov (United States)

    Ellens, Harma; Meng, Zhou; Le Marchand, Sylvain J; Bentz, Joe

    2018-06-01

    In vitro transporter kinetics are typically analyzed by steady-state Michaelis-Menten approximations. However, no clear evidence exists that these approximations, applied to multiple transporters in biological membranes, yield system-independent mechanistic parameters needed for reliable in vivo hypothesis generation and testing. Areas covered: The classical mass action model has been developed for P-glycoprotein (P-gp) mediated transport across confluent polarized cell monolayers. Numerical integration of the mass action equations for transport using a stable global optimization program yields fitted elementary rate constants that are system-independent. The efflux active P-gp was defined by the rate at which P-gp delivers drugs to the apical chamber, since as much as 90% of drugs effluxed by P-gp partition back into nearby microvilli prior to reaching the apical chamber. The efflux active P-gp concentration was 10-fold smaller than the total expressed P-gp for Caco-2 cells, due to their microvilli membrane morphology. The mechanistic insights from this analysis are readily extrapolated to P-gp mediated transport in vivo. Expert opinion: In vitro system-independent elementary rate constants for transporters are essential for the generation and validation of robust mechanistic PBPK models. Our modeling approach and programs have broad application potential. They can be used for any drug transporter with minor adaptations.

  13. Unification and mechanistic detail as drivers of model construction: models of networks in economics and sociology.

    Science.gov (United States)

    Kuorikoski, Jaakko; Marchionni, Caterina

    2014-12-01

    We examine the diversity of strategies of modelling networks in (micro) economics and (analytical) sociology. Field-specific conceptions of what explaining (with) networks amounts to or systematic preference for certain kinds of explanatory factors are not sufficient to account for differences in modelling methodologies. We argue that network models in both sociology and economics are abstract models of network mechanisms and that differences in their modelling strategies derive to a large extent from field-specific conceptions of the way in which a good model should be a general one. Whereas the economics models aim at unification, the sociological models aim at a set of mechanism schemas that are extrapolatable to the extent that the underlying psychological mechanisms are general. These conceptions of generality induce specific biases in mechanistic explanation and are related to different views of when knowledge from different fields should be seen as relevant.

  14. Mechanistic Basis for Plant Responses to Drought Stress : Regulatory Mechanism of Abscisic Acid Signaling

    Science.gov (United States)

    Miyakawa, Takuya; Tanokura, Masaru

    The phytohormone abscisic acid (ABA) plays a key role in the rapid adaptation of plants to environmental stresses such as drought and high salinity. Accumulated ABA in plant cells promotes stomatal closure in guard cells and transcription of stress-tolerant genes. Our understanding of ABA responses dramatically improved by the discovery of both PYR/PYL/RCAR as a soluble ABA receptor and inhibitory complex of a protein phospatase PP2C and a protein kinase SnRK2. Moreover, several structural analyses of PYR/PYL/RCAR revealed the mechanistic basis for the regulatory mechanism of ABA signaling, which provides a rational framework for the design of alternative agonists in future.

  15. Pathophysiology of white-nose syndrome in bats: a mechanistic model linking wing damage to mortality.

    Science.gov (United States)

    Warnecke, Lisa; Turner, James M; Bollinger, Trent K; Misra, Vikram; Cryan, Paul M; Blehert, David S; Wibbelt, Gudrun; Willis, Craig K R

    2013-08-23

    White-nose syndrome is devastating North American bat populations but we lack basic information on disease mechanisms. Altered blood physiology owing to epidermal invasion by the fungal pathogen Geomyces destructans (Gd) has been hypothesized as a cause of disrupted torpor patterns of affected hibernating bats, leading to mortality. Here, we present data on blood electrolyte concentration, haematology and acid-base balance of hibernating little brown bats, Myotis lucifugus, following experimental inoculation with Gd. Compared with controls, infected bats showed electrolyte depletion (i.e. lower plasma sodium), changes in haematology (i.e. increased haematocrit and decreased glucose) and disrupted acid-base balance (i.e. lower CO2 partial pressure and bicarbonate). These findings indicate hypotonic dehydration, hypovolaemia and metabolic acidosis. We propose a mechanistic model linking tissue damage to altered homeostasis and morbidity/mortality.

  16. Mechanistic study of fuel freezing, channel plugging, and continued coolability during fast reactor overpower excursions

    International Nuclear Information System (INIS)

    Wong, K.W.; Catton, I.; Kastenberg, W.E.

    1977-07-01

    A mechanistic model is presented which describes events following fuel pin failure which may lead to in-channel fuel plate-out. The thermal and hydraulic effects of the plate-out fuel are also evaluated. Given the amount and particle size of the fuel injected into the coolant channel during fuel pin failure, and the initial conditions of the interaction zone, the physical states of the fuel particles and the coolant in the interaction zone can be determined. The trajectories of the fuel particles in the coolant channel are determined by assuming a slip factor between the local tangential velocities of the coolant and the fuel particles. The time and distance after which a fuel particle hits a wire wrap are then determined and the impact stresses induced in the thin solid fuel crust can be evaluated

  17. Combating Pathogenic Microorganisms Using Plant-Derived Antimicrobials: A Minireview of the Mechanistic Basis

    Directory of Open Access Journals (Sweden)

    Abhinav Upadhyay

    2014-01-01

    Full Text Available The emergence of antibiotic resistance in pathogenic bacteria has led to renewed interest in exploring the potential of plant-derived antimicrobials (PDAs as an alternative therapeutic strategy to combat microbial infections. Historically, plant extracts have been used as a safe, effective, and natural remedy for ailments and diseases in traditional medicine. Extensive research in the last two decades has identified a plethora of PDAs with a wide spectrum of activity against a variety of fungal and bacterial pathogens causing infections in humans and animals. Active components of many plant extracts have been characterized and are commercially available; however, research delineating the mechanistic basis of their antimicrobial action is scanty. This review highlights the potential of various plant-derived compounds to control pathogenic bacteria, especially the diverse effects exerted by plant compounds on various virulence factors that are critical for pathogenicity inside the host. In addition, the potential effect of PDAs on gut microbiota is discussed.

  18. Assessing first-order emulator inference for physical parameters in nonlinear mechanistic models

    Science.gov (United States)

    Hooten, Mevin B.; Leeds, William B.; Fiechter, Jerome; Wikle, Christopher K.

    2011-01-01

    We present an approach for estimating physical parameters in nonlinear models that relies on an approximation to the mechanistic model itself for computational efficiency. The proposed methodology is validated and applied in two different modeling scenarios: (a) Simulation and (b) lower trophic level ocean ecosystem model. The approach we develop relies on the ability to predict right singular vectors (resulting from a decomposition of computer model experimental output) based on the computer model input and an experimental set of parameters. Critically, we model the right singular vectors in terms of the model parameters via a nonlinear statistical model. Specifically, we focus our attention on first-order models of these right singular vectors rather than the second-order (covariance) structure.

  19. REM sleep behaviour disorder: prodromal and mechanistic insights for Parkinson's disease.

    Science.gov (United States)

    Tekriwal, Anand; Kern, Drew S; Tsai, Jean; Ince, Nuri F; Wu, Jianping; Thompson, John A; Abosch, Aviva

    2017-05-01

    Rapid eye movement (REM) sleep behaviour disorder (RBD) is characterised by complex motor enactment of dreams and is a potential prodromal marker of Parkinson's disease (PD). Of note, patients with PD observed during RBD episodes exhibit improved motor function, relative to baseline states during wake periods. Here, we review recent epidemiological and mechanistic findings supporting the prodromal value of RBD for PD, incorporating clinical and electrophysiological studies. Explanations for the improved motor function during RBD episodes are evaluated in light of recent publications. In addition, we present preliminary findings describing changes in the activity of the basal ganglia across the sleep-wake cycle that contribute to our understanding of RBD. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/.

  20. Mechanistic studies related to the safety of Li/SOCl2 cells

    Science.gov (United States)

    Carter, B. J.; Williams, R. M.; Tsay, F. D.; Rodriguez, A.; Kim, S.; Evans, M. M.; Frank, H.

    1985-01-01

    Mechanistic studies of the reactions in Li-SOCl2 cells have been undertaken to improve understanding of the safety problems of these cells. The electrochemical reduction of 1.5M LiAlCl4/SOCl2 has been investigated using gas chromatography, electron spin resonance spectroscopy, and infrared spectroscopy. Cl2 and S2Cl2 have been identified as intermediates in the reduction of SOCl2, along with a radical species (g/xx/ = 2.004, g/yy/ = 2.016, g/zz/ = 2.008) and the proposed triplet ground-state dimer of this radical. SO2 and sulfur have been identified as products. Based upon these findings, a mechanism for the electrochemical reduction of 1.5M LiAlCl4/SOCl2 has been proposed, and its implications for safety of Li-SOCl2 cells during discharge to +0.5V at 25-30 C are discussed.

  1. Blood-brain barrier disruption: mechanistic links between Western diet consumption and dementia

    Directory of Open Access Journals (Sweden)

    Ted Menghsiung Hsu

    2014-05-01

    Full Text Available Both obesity and Alzheimer’s disease are major health burdens in Western societies. While commonly viewed as having separate etiologies, this review highlights data suggesting that intake of Western diets, diets high in saturated fatty acids and simple carbohydrates, may pose a common environmental risk factor contributing to the development of both of these adverse pathologies. We discuss the effects of Western Diet intake on learning and memory processes that are dependent on the hippocampus, as well as the importance of this brain region in both obesity development and the onset of Alzheimer’s and other dementias. A putative mechanism is discussed that mechanistically links Western diet consumption, blood brain barrier degradation, and subsequent hippocampal damage and dementia pathology.

  2. Mechanistic studies of copper(I)-catalyzed 1,3-halogen migration.

    Science.gov (United States)

    Van Hoveln, Ryan; Hudson, Brandi M; Wedler, Henry B; Bates, Desiree M; Le Gros, Gabriel; Tantillo, Dean J; Schomaker, Jennifer M

    2015-04-29

    An ongoing challenge in modern catalysis is to identify and understand new modes of reactivity promoted by earth-abundant and inexpensive first-row transition metals. Herein, we report a mechanistic study of an unusual copper(I)-catalyzed 1,3-migration of 2-bromostyrenes that reincorporates the bromine activating group into the final product with concomitant borylation of the aryl halide bond. A combination of experimental and computational studies indicated this reaction does not involve any oxidation state changes at copper; rather, migration occurs through a series of formal sigmatropic shifts. Insight provided from these studies will be used to expand the utility of aryl copper species in synthesis and develop new ligands for enantioselective copper-catalyzed halogenation.

  3. Study of n-Butyl Acrylate Self-Initiation Reaction Experimentally and via Macroscopic Mechanistic Modeling

    Directory of Open Access Journals (Sweden)

    Ahmad Arabi Shamsabadi

    2016-04-01

    Full Text Available This paper presents an experimental study of the self-initiation reaction of n-butyl acrylate (n-BA in free-radical polymerization. For the first time, the frequency factor and activation energy of the monomer self-initiation reaction are estimated from measurements of n-BA conversion in free-radical homo-polymerization initiated only by the monomer. The estimation was carried out using a macroscopic mechanistic mathematical model of the reactor. In addition to already-known reactions that contribute to the polymerization, the model considers a n-BA self-initiation reaction mechanism that is based on our previous electronic-level first-principles theoretical study of the self-initiation reaction. Reaction rate equations are derived using the method of moments. The reaction-rate parameter estimates obtained from conversion measurements agree well with estimates obtained via our purely-theoretical quantum chemical calculations.

  4. Mechanistic modelling of the corrosion behaviour of copper nuclear fuel waste containers

    Energy Technology Data Exchange (ETDEWEB)

    King, F; Kolar, M

    1996-10-01

    A mechanistic model has been developed to predict the long-term corrosion behaviour of copper nuclear fuel waste containers in a Canadian disposal vault. The model is based on a detailed description of the electrochemical, chemical, adsorption and mass-transport processes involved in the uniform corrosion of copper, developed from the results of an extensive experimental program. Predictions from the model are compared with the results of some of these experiments and with observations from a bronze cannon submerged in seawater saturated clay sediments. Quantitative comparisons are made between the observed and predicted corrosion potential, corrosion rate and copper concentration profiles adjacent to the corroding surface, as a way of validating the long-term model predictions. (author). 12 refs., 5 figs.

  5. Mechanistic study on spraying of blended biodiesel using phase Doppler anemometry

    International Nuclear Information System (INIS)

    Kamrak, Juthamas; Kongsombut, Benjapol; Grehan, Gerard; Saengkaew, Sawitree; Kim, Kyo-Seon; Charinpanitkul, Tawatchai

    2009-01-01

    Droplet size and dynamics of blended palm oil-based fatty acid methyl ester (FAME) and diesel oil spray were mechanistically investigated using a phase Doppler anemometry. A two-fluid atomizer was applied for dispersing viscous blends of blended biodiesel oil with designated flow rates. It was experimentally found that the atomizer could generate a spray with large droplets with Sauter mean diameters of ca. 30 μm at low air injection pressure. Such large droplets traveled with a low velocity along their trajectory after emerging from the nozzle tip. The viscosity of blended biodiesel could significantly affect the atomizing process, resulting in the controlled droplet size distribution. Blended biodiesel with a certain fraction of palm oil-based FAME would be consistently atomized owing to its low viscosity. However, the viscosity could exert only a small effect on the droplet velocity profile with the air injection pressure higher than 0.2 MPa.

  6. Mechanistic study on spraying of blended biodiesel using phase Doppler anemometry

    Energy Technology Data Exchange (ETDEWEB)

    Kamrak, Juthamas; Kongsombut, Benjapol; Charinpanitkul, Tawatchai [Center of Excellence in Particle Technology, Department of Chemical Engineering, Faculty of Engineering, Chulalongkorn University, Payathai Road, Patumwan, Bangkok 10330 (Thailand); Grehan, Gerard; Saengkaew, Sawitree [LESP/UMR CNRS6614/INSA et Universite de Rouen, BP 12, avenue de l' universite, 76801, Saint Etienne du Rouvray (France); Kim, Kyo-Seon [Department of Chemical Engineering, Faculty of Engineering, Kangwon National University, Chuncheon (Korea)

    2009-10-15

    Droplet size and dynamics of blended palm oil-based fatty acid methyl ester (FAME) and diesel oil spray were mechanistically investigated using a phase Doppler anemometry. A two-fluid atomizer was applied for dispersing viscous blends of blended biodiesel oil with designated flow rates. It was experimentally found that the atomizer could generate a spray with large droplets with Sauter mean diameters of ca. 30 {mu}m at low air injection pressure. Such large droplets traveled with a low velocity along their trajectory after emerging from the nozzle tip. The viscosity of blended biodiesel could significantly affect the atomizing process, resulting in the controlled droplet size distribution. Blended biodiesel with a certain fraction of palm oil-based FAME would be consistently atomized owing to its low viscosity. However, the viscosity could exert only a small effect on the droplet velocity profile with the air injection pressure higher than 0.2 MPa. (author)

  7. A new mechanistic and engineering fission gas release model for a uranium dioxide fuel

    International Nuclear Information System (INIS)

    Lee, Chan Bock; Yang, Yong Sik; Kim, Dae Ho; Kim, Sun Ki; Bang, Je Geun

    2008-01-01

    A mechanistic and engineering fission gas release model (MEGA) for uranium dioxide (UO 2 ) fuel was developed. It was based upon the diffusional release of fission gases from inside the grain to the grain boundary and the release of fission gases from the grain boundary to the external surface by the interconnection of the fission gas bubbles in the grain boundary. The capability of the MEGA model was validated by a comparison with the fission gas release data base and the sensitivity analyses of the parameters. It was found that the MEGA model correctly predicts the fission gas release in the broad range of fuel burnups up to 98 MWd/kgU. Especially, the enhancement of fission gas release in a high-burnup fuel, and the reduction of fission gas release at a high burnup by increasing the UO 2 grain size were found to be correctly predicted by the MEGA model without using any artificial factor. (author)

  8. Structural and mechanistic basis of differentiated inhibitors of the acute pancreatitis target kynurenine-3-monooxygenase

    Science.gov (United States)

    Hutchinson, Jonathan P.; Rowland, Paul; Taylor, Mark R. D.; Christodoulou, Erica M.; Haslam, Carl; Hobbs, Clare I.; Holmes, Duncan S.; Homes, Paul; Liddle, John; Mole, Damian J.; Uings, Iain; Walker, Ann L.; Webster, Scott P.; Mowat, Christopher G.; Chung, Chun-Wa

    2017-06-01

    Kynurenine-3-monooxygenase (KMO) is a key FAD-dependent enzyme of tryptophan metabolism. In animal models, KMO inhibition has shown benefit in neurodegenerative diseases such as Huntington's and Alzheimer's. Most recently it has been identified as a target for acute pancreatitis multiple organ dysfunction syndrome (AP-MODS); a devastating inflammatory condition with a mortality rate in excess of 20%. Here we report and dissect the molecular mechanism of action of three classes of KMO inhibitors with differentiated binding modes and kinetics. Two novel inhibitor classes trap the catalytic flavin in a previously unobserved tilting conformation. This correlates with picomolar affinities, increased residence times and an absence of the peroxide production seen with previous substrate site inhibitors. These structural and mechanistic insights culminated in GSK065(C1) and GSK366(C2), molecules suitable for preclinical evaluation. Moreover, revising the repertoire of flavin dynamics in this enzyme class offers exciting new opportunities for inhibitor design.

  9. On the closed form mechanistic modeling of milling: Specific cutting energy, torque, and power

    Science.gov (United States)

    Bayoumi, A. E.; Yücesan, G.; Hutton, D. V.

    1994-02-01

    Specific energy in metal cutting, defined as the energy expended in removing a unit volume of workpiece material, is formulated and determined using a previously developed closed form mechanistic force model for milling operations. Cutting power is computed from the cutting torque, cutting force, kinematics of the cutter, and the volumetric material removal rate. Closed form expressions for specific cutting energy were formulated and found to be functions of the process parameters: pressure and friction for both rake and flank surfaces and chip flow angle at the rake face of the tool. Friction is found to play a very important role in cutting torque and power. Experiments were carried out to determine the effects of feedrate, cutting speed, workpiece material, and flank wear land width on specific cutting energy. It was found that the specific cutting energy increases with a decrease in the chip thickness and with an increase in flank wear land.

  10. Exposure factors for marine eutrophication impacts assessment based on a mechanistic biological model

    DEFF Research Database (Denmark)

    Cosme, Nuno Miguel Dias; Koski, Marja; Hauschild, Michael Zwicky

    2015-01-01

    marine ecosystem (LME), five climate zones, and site-generic. The XFs obtained range from 0.45 (Central Arctic Ocean) to 15.9kgO2kgN-1 (Baltic Sea). While LME resolution is recommended, aggregated PE or XF per climate zone can be adopted, but not global aggregation due to high variability. The XF......Emissions of nitrogen (N) from anthropogenic sources enrich marine waters and promote planktonic growth. This newly synthesised organic carbon is eventually exported to benthic waters where aerobic respiration by heterotrophic bacteria results in the consumption of dissolved oxygen (DO......). This pathway is typical of marine eutrophication. A model is proposed to mechanistically estimate the response of coastal marine ecosystems to N inputs. It addresses the biological processes of nutrient-limited primary production (PP), metazoan consumption, and bacterial degradation, in four distinct sinking...

  11. Antimalarial benzoheterocyclic 4-aminoquinolines: Structure-activity relationship, in vivo evaluation, mechanistic and bioactivation studies.

    Science.gov (United States)

    Ongarora, Dennis S B; Strydom, Natasha; Wicht, Kathryn; Njoroge, Mathew; Wiesner, Lubbe; Egan, Timothy J; Wittlin, Sergio; Jurva, Ulrik; Masimirembwa, Collen M; Chibale, Kelly

    2015-09-01

    A novel class of benzoheterocyclic analogues of amodiaquine designed to avoid toxic reactive metabolite formation was synthesized and evaluated for antiplasmodial activity against K1 (multidrug resistant) and NF54 (sensitive) strains of the malaria parasite Plasmodium falciparum. Structure-activity relationship studies led to the identification of highly promising analogues, the most potent of which had IC50s in the nanomolar range against both strains. The compounds further demonstrated good in vitro microsomal metabolic stability while those subjected to in vivo pharmacokinetic studies had desirable pharmacokinetic profiles. In vivo antimalarial efficacy in Plasmodium berghei infected mice was evaluated for four compounds, all of which showed good activity following oral administration. In particular, compound 19 completely cured treated mice at a low multiple dose of 4×10mg/kg. Mechanistic and bioactivation studies suggest hemozoin formation inhibition and a low likelihood of forming quinone-imine reactive metabolites, respectively. Copyright © 2015 Elsevier Ltd. All rights reserved.

  12. A holistic approach to anesthesia-induced neurotoxicity and its implications for future mechanistic studies.

    Science.gov (United States)

    Zanghi, Christine N; Jevtovic-Todorovic, Vesna

    The year 2016 marked the 15th anniversary since anesthesia-induced developmental neurotoxicity and its resulting cognitive dysfunction were first described. Since that time, multiple scientific studies have supported these original findings and investigated possible mechanisms behind anesthesia-induced neurotoxicity. This paper reviews the existing mechanistic literature on anesthesia-induced neurotoxicity in the context of a holistic approach that emphasizes the importance of both neuronal and non-neuronal cells during early postnatal development. Sections are divided into key stages in early neural development; apoptosis, neurogenesis, migration, differentiation, synaptogenesis, gliogenesis, myelination and blood brain barrier/cerebrovasculature. In addition, the authors combine the established literature in the field of anesthesia-induced neurotoxicity with literature from other related scientific fields to speculate on the potential role of non-neuronal cells and to generate new future hypotheses for understanding anesthetic toxicity and its application to the practice of pediatric anesthesia. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Determining environmental causes of biological effects: the need for a mechanistic physiological dimension in conservation biology.

    Science.gov (United States)

    Seebacher, Frank; Franklin, Craig E

    2012-06-19

    The emerging field of Conservation Physiology links environmental change and ecological success by the application of physiological theory, approaches and tools to elucidate and address conservation problems. Human activity has changed the natural environment to a point where the viability of many ecosystems is now under threat. There are already many descriptions of how changes in biological patterns are correlated with environmental changes. The next important step is to determine the causative relationship between environmental variability and biological systems. Physiology provides the mechanistic link between environmental change and ecological patterns. Physiological research, therefore, should be integrated into conservation to predict the biological consequences of human activity, and to identify those species or populations that are most vulnerable.

  14. Improving Predictive Modeling in Pediatric Drug Development: Pharmacokinetics, Pharmacodynamics, and Mechanistic Modeling

    Energy Technology Data Exchange (ETDEWEB)

    Slikker, William; Young, John F.; Corley, Rick A.; Dorman, David C.; Conolly, Rory B.; Knudsen, Thomas; Erstad, Brian L.; Luecke, Richard H.; Faustman, Elaine M.; Timchalk, Chuck; Mattison, Donald R.

    2005-07-26

    A workshop was conducted on November 18?19, 2004, to address the issue of improving predictive models for drug delivery to developing humans. Although considerable progress has been made for adult humans, large gaps remain for predicting pharmacokinetic/pharmacodynamic (PK/PD) outcome in children because most adult models have not been tested during development. The goals of the meeting included a description of when, during development, infants/children become adultlike in handling drugs. The issue of incorporating the most recent advances into the predictive models was also addressed: both the use of imaging approaches and genomic information were considered. Disease state, as exemplified by obesity, was addressed as a modifier of drug pharmacokinetics and pharmacodynamics during development. Issues addressed in this workshop should be considered in the development of new predictive and mechanistic models of drug kinetics and dynamics in the developing human.

  15. Mechanistic Studies on the Copper-Catalyzed N-Arylation of Amides

    Science.gov (United States)

    Strieter, Eric R.; Bhayana, Brijesh; Buchwald, Stephen L.

    2009-01-01

    The copper-catalyzed N-arylation of amides, i.e., the Goldberg reaction, is an efficient method for the construction of products relevant to both industry and academic settings. Herein, we present mechanistic details concerning the catalytic and stoichiometric N-arylation of amides. In the context of the catalytic reaction, our findings reveal the importance of chelating diamine ligands in controlling the concentration of the active catalytic species. The consistency between the catalytic and stoichiometric results suggest that the activation of aryl halides occurs through a 1,2-diamine-ligated copper(I) amidate complex. Kinetic studies on the stoichiometric N-arylation of aryl iodides using 1,2-diamine ligated Cu(I) amidates also provide insights into the mechanism of aryl halide activation. PMID:19072233

  16. A semi-mechanistic approach to calculate the probability of fuel defects

    International Nuclear Information System (INIS)

    Tayal, M.; Millen, E.; Sejnoha, R.

    1992-10-01

    In this paper the authors describe the status of a semi-mechanistic approach to the calculation of the probability of fuel defects. This approach expresses the defect probability in terms of fundamental parameters such as local stresses, local strains, and fission product concentration. The calculations of defect probability continue to reflect the influences of the conventional parameters like power ramp, burnup and CANLUB. In addition, the new approach provides a mechanism to account for the impacts of additional factors involving detailed fuel design and reactor operation, for example pellet density, pellet shape and size, sheath diameter and thickness, pellet/sheath clearance, and coolant temperature and pressure. The approach has been validated against a previous empirical correlation. AN illustrative example shows how the defect thresholds are influenced by changes in the internal design of the element and in the coolant pressure. (Author) (7 figs., tab., 12 refs.)

  17. Mechanistic basis of an epistatic interaction reducing age at onset in hereditary spastic paraplegia.

    Science.gov (United States)

    Newton, Timothy; Allison, Rachel; Edgar, James R; Lumb, Jennifer H; Rodger, Catherine E; Manna, Paul T; Rizo, Tania; Kohl, Zacharias; Nygren, Anders O H; Arning, Larissa; Schüle, Rebecca; Depienne, Christel; Goldberg, Lisa; Frahm, Christiane; Stevanin, Giovanni; Durr, Alexandra; Schöls, Ludger; Winner, Beate; Beetz, Christian; Reid, Evan

    2018-05-01

    Many genetic neurological disorders exhibit variable expression within affected families, often exemplified by variations in disease age at onset. Epistatic effects (i.e. effects of modifier genes on the disease gene) may underlie this variation, but the mechanistic basis for such epistatic interactions is rarely understood. Here we report a novel epistatic interaction between SPAST and the contiguous gene DPY30, which modifies age at onset in hereditary spastic paraplegia, a genetic axonopathy. We found that patients with hereditary spastic paraplegia caused by genomic deletions of SPAST that extended into DPY30 had a significantly younger age at onset. We show that, like spastin, the protein encoded by SPAST, the DPY30 protein controls endosomal tubule fission, traffic of mannose 6-phosphate receptors from endosomes to the Golgi, and lysosomal ultrastructural morphology. We propose that additive effects on this pathway explain the reduced age at onset of hereditary spastic paraplegia in patients who are haploinsufficient for both genes.

  18. Mechanistic origin of dragon-kings in a population of competing agents

    Science.gov (United States)

    Johnson, N.; Tivnan, B.

    2012-05-01

    We analyze the mechanistic origins of the extreme behaviors that arise in an idealized model of a population of competing agents, such as traders in a market. These extreme behaviors exhibit the defining characteristics of `dragon-kings'. Our model comprises heterogeneous agents who repeatedly compete for some limited resource, making binary choices based on the strategies that they have in their possession. It generalizes the well-known Minority Game by allowing agents whose strategies have not made accurate recent predictions, to step out of the competition until their strategies improve. This generates a complex dynamical interplay between the number V of active agents (mimicking market volume) and the imbalance D between the decisions made (mimicking excess demand). The wide spectrum of extreme behaviors which emerge, helps to explain why no unique relationship has been identified between the price and volume during real market crashes and rallies.

  19. DFT Mechanistic Study of the Selective Terminal C-H Activation of n-Pentane with a Tungsten Allyl Nitrosyl Complex

    KAUST Repository

    Lee, Richmond

    2017-01-17

    Mechanistic insights into the selective C-H terminal activation of n-pentane with tungsten allyl nitrosyl complex reported by Legzdins were gained by employing density functional theory with B3LYP hybrid functional. Using Bader’s atom in molecules (AIM) analysis on the elementary steps of the hydrogen transfer process, TS1 and TS2, it was observed that the calculated H-transfer models were closely similar to Hall’s metal-assisted σ-bond metathesis through bond critical point (BCP) comparisons. One distinguishable feature was the fact that the formal oxidation state of the W changed in the concerted H-transfer process. To better differentiate, we term these processes as ‘Formal Reductive Hydrogen Transfer’ (FRHT) for TS1 and ‘Formal Oxidative Hydrogen Transfer’ (FOHT) for TS2.

  20. DFT Mechanistic Study of the Selective Terminal C-H Activation of n-Pentane with a Tungsten Allyl Nitrosyl Complex

    KAUST Repository

    Lee, Richmond; Tan, Davin; Liu, Chaoli; Li, Huaifeng; Guo, Hao; Shyue, Jing-Jong; Huang, Kuo-Wei

    2017-01-01

    Mechanistic insights into the selective C-H terminal activation of n-pentane with tungsten allyl nitrosyl complex reported by Legzdins were gained by employing density functional theory with B3LYP hybrid functional. Using Bader’s atom in molecules (AIM) analysis on the elementary steps of the hydrogen transfer process, TS1 and TS2, it was observed that the calculated H-transfer models were closely similar to Hall’s metal-assisted σ-bond metathesis through bond critical point (BCP) comparisons. One distinguishable feature was the fact that the formal oxidation state of the W changed in the concerted H-transfer process. To better differentiate, we term these processes as ‘Formal Reductive Hydrogen Transfer’ (FRHT) for TS1 and ‘Formal Oxidative Hydrogen Transfer’ (FOHT) for TS2.

  1. Exploring BSEP Inhibition-Mediated Toxicity with a Mechanistic Model of Drug-Induced Liver Injury

    Directory of Open Access Journals (Sweden)

    Jeffrey L Woodhead

    2014-11-01

    Full Text Available Inhibition of the bile salt export pump (BSEP has been linked to incidence of drug-induced liver injury (DILI, presumably by the accumulation of toxic bile acids in the liver. We have previously constructed and validated a model of bile acid disposition within DILIsym®, a mechanistic model of DILI. In this paper, we use DILIsym® to simulate the DILI response of the hepatotoxic BSEP inhibitors bosentan and CP-724,714 and the non-hepatotoxic BSEP inhibitor telmisartan in humans in order to explore whether we can predict that hepatotoxic BSEP inhibitors can cause bile acid accumulation to reach toxic levels. We also simulate bosentan in rats in order to illuminate potential reasons behind the lack of toxicity in rats compared to the toxicity observed in humans. DILIsym® predicts that bosentan, but not telmisartan, will cause mild hepatocellular ATP decline and serum ALT elevation in a simulated population of humans. The difference in hepatotoxic potential between bosentan and telmisartan is consistent with clinical observations. However, DILIsym® underpredicts the incidence of bosentan toxicity. DILIsym® also predicts that bosentan will not cause toxicity in a simulated population of rats, and that the difference between the response to bosentan in rats and in humans is primarily due to the less toxic bile acid pool in rats. Our simulations also suggest a potential synergistic role for bile acid accumulation and mitochondrial electron transport chain inhibition in producing the observed toxicity in CP-724,714, and suggest that CP-724,714 metabolites may also play a role in the observed toxicity. Our work also compares the impact of competitive and noncompetitive BSEP inhibition for CP-724,714 and demonstrates that noncompetitive inhibition leads to much greater bile acid accumulation and potential toxicity. Our research demonstrates the potential for mechanistic modeling to contribute to the understanding of how bile acid transport inhibitors

  2. Regulatory Technology Development Plan - Sodium Fast Reactor. Mechanistic Source Term - Metal Fuel Radionuclide Release

    International Nuclear Information System (INIS)

    Grabaskas, David; Bucknor, Matthew; Jerden, James

    2016-01-01

    The development of an accurate and defensible mechanistic source term will be vital for the future licensing efforts of metal fuel, pool-type sodium fast reactors. To assist in the creation of a comprehensive mechanistic source term, the current effort sought to estimate the release fraction of radionuclides from metal fuel pins to the primary sodium coolant during fuel pin failures at a variety of temperature conditions. These release estimates were based on the findings of an extensive literature search, which reviewed past experimentation and reactor fuel damage accidents. Data sources for each radionuclide of interest were reviewed to establish release fractions, along with possible release dependencies, and the corresponding uncertainty levels. Although the current knowledge base is substantial, and radionuclide release fractions were established for the elements deemed important for the determination of offsite consequences following a reactor accident, gaps were found pertaining to several radionuclides. First, there is uncertainty regarding the transport behavior of several radionuclides (iodine, barium, strontium, tellurium, and europium) during metal fuel irradiation to high burnup levels. The migration of these radionuclides within the fuel matrix and bond sodium region can greatly affect their release during pin failure incidents. Post-irradiation examination of existing high burnup metal fuel can likely resolve this knowledge gap. Second, data regarding the radionuclide release from molten high burnup metal fuel in sodium is sparse, which makes the assessment of radionuclide release from fuel melting accidents at high fuel burnup levels difficult. This gap could be addressed through fuel melting experimentation with samples from the existing high burnup metal fuel inventory.

  3. Ionizing radiation induced cataracts: Recent biological and mechanistic developments and perspectives for future research.

    Science.gov (United States)

    Ainsbury, Elizabeth A; Barnard, Stephen; Bright, Scott; Dalke, Claudia; Jarrin, Miguel; Kunze, Sarah; Tanner, Rick; Dynlacht, Joseph R; Quinlan, Roy A; Graw, Jochen; Kadhim, Munira; Hamada, Nobuyuki

    The lens of the eye has long been considered as a radiosensitive tissue, but recent research has suggested that the radiosensitivity is even greater than previously thought. The 2012 recommendation of the International Commission on Radiological Protection (ICRP) to substantially reduce the annual occupational equivalent dose limit for the ocular lens has now been adopted in the European Union and is under consideration around the rest of the world. However, ICRP clearly states that the recommendations are chiefly based on epidemiological evidence because there are a very small number of studies that provide explicit biological, mechanistic evidence at doses <2Gy. This paper aims to present a review of recently published information on the biological and mechanistic aspects of cataracts induced by exposure to ionizing radiation (IR). The data were compiled by assessing the pertinent literature in several distinct areas which contribute to the understanding of IR induced cataracts, information regarding lens biology and general processes of cataractogenesis. Results from cellular and tissue level studies and animal models, and relevant human studies, were examined. The main focus was the biological effects of low linear energy transfer IR, but dosimetry issues and a number of other confounding factors were also considered. The results of this review clearly highlight a number of gaps in current knowledge. Overall, while there have been a number of recent advances in understanding, it remains unknown exactly how IR exposure contributes to opacification. A fuller understanding of how exposure to relatively low doses of IR promotes induction and/or progression of IR-induced cataracts will have important implications for prevention and treatment of this disease, as well as for the field of radiation protection. Crown Copyright © 2016. Published by Elsevier B.V. All rights reserved.

  4. Regulatory Technology Development Plan - Sodium Fast Reactor. Mechanistic Source Term - Metal Fuel Radionuclide Release

    Energy Technology Data Exchange (ETDEWEB)

    Grabaskas, David [Argonne National Lab. (ANL), Argonne, IL (United States); Bucknor, Matthew [Argonne National Lab. (ANL), Argonne, IL (United States); Jerden, James [Argonne National Lab. (ANL), Argonne, IL (United States)

    2016-02-01

    The development of an accurate and defensible mechanistic source term will be vital for the future licensing efforts of metal fuel, pool-type sodium fast reactors. To assist in the creation of a comprehensive mechanistic source term, the current effort sought to estimate the release fraction of radionuclides from metal fuel pins to the primary sodium coolant during fuel pin failures at a variety of temperature conditions. These release estimates were based on the findings of an extensive literature search, which reviewed past experimentation and reactor fuel damage accidents. Data sources for each radionuclide of interest were reviewed to establish release fractions, along with possible release dependencies, and the corresponding uncertainty levels. Although the current knowledge base is substantial, and radionuclide release fractions were established for the elements deemed important for the determination of offsite consequences following a reactor accident, gaps were found pertaining to several radionuclides. First, there is uncertainty regarding the transport behavior of several radionuclides (iodine, barium, strontium, tellurium, and europium) during metal fuel irradiation to high burnup levels. The migration of these radionuclides within the fuel matrix and bond sodium region can greatly affect their release during pin failure incidents. Post-irradiation examination of existing high burnup metal fuel can likely resolve this knowledge gap. Second, data regarding the radionuclide release from molten high burnup metal fuel in sodium is sparse, which makes the assessment of radionuclide release from fuel melting accidents at high fuel burnup levels difficult. This gap could be addressed through fuel melting experimentation with samples from the existing high burnup metal fuel inventory.

  5. A dynamic, mechanistic model of metabolism in adipose tissue of lactating dairy cattle.

    Science.gov (United States)

    McNamara, J P; Huber, K; Kenéz, A

    2016-07-01

    Research in dairy cattle biology has resulted in a large body of knowledge on nutrition and metabolism in support of milk production and efficiency. This quantitative knowledge has been compiled in several model systems to balance and evaluate rations and predict requirements. There are also systems models for metabolism and reproduction in the cow that can be used to support research programs. Adipose tissue plays a significant role in the success and efficiency of lactation, and recent research has resulted in several data sets on genomic differences and changes in gene transcription of adipose tissue in dairy cattle. To fully use this knowledge, we need to build and expand mechanistic, dynamic models that integrate control of metabolism and production. Therefore, we constructed a second-generation dynamic, mechanistic model of adipose tissue metabolism of dairy cattle. The model describes the biochemical interconversions of glucose, acetate, β-hydroxybutyrate (BHB), glycerol, C16 fatty acids, and triacylglycerols. Data gathered from our own research and published references were used to set equation forms and parameter values. Acetate, glucose, BHB, and fatty acids are taken up from blood. The fatty acids are activated to the acyl coenzyme A moieties. Enzymatically catalyzed reactions are explicitly described with parameters including maximal velocity and substrate sensitivity. The control of enzyme activity is partially carried out by insulin and norepinephrine, portraying control in the cow. Model behavior was adequate, with sensitive responses to changing substrates and hormones. Increased nutrient uptake and increased insulin stimulate triacylglycerol synthesis, whereas a reduction in nutrient availability or increase in norepinephrine increases triacylglycerol hydrolysis and free fatty acid release to blood. This model can form a basis for more sophisticated integration of existing knowledge and future studies on metabolic efficiency of dairy cattle

  6. Development of mechanistic sorption model and treatment of uncertainties for Ni sorption on montmorillonite/bentonite