WorldWideScience

Sample records for exposure pathways models

  1. Multi-pathway exposure modelling of chemicals in cosmetics ...

    Science.gov (United States)

    We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quantified based on the chemical mass originally applied via a product, multiplied by the product intake fractions (PiF, the fraction of a chemical in a product that is taken in by exposed persons) to yield intake rates. The average PiFs for the evaluated chemicals in shampoo ranged from 3 × 10− 4 up to 0.3 for rapidly absorbed ingredients. Average intake rates ranged between nano- and micrograms per kilogram bodyweight per day; the order of chemical prioritization was strongly affected by the ingredient concentration in shampoo. Dermal intake and inhalation (for 20% of the evaluated chemicals) during use dominated exposure, while the skin permeation coefficient dominated the estimated uncertainties. The fraction of chemical taken in by a shampoo user often exceeded, by orders of magnitude, the aggregated fraction taken in by the population through post-use environmental emissions. Chemicals with relatively high octanol-water partitioning and/or volatility, and low molecular weight tended to have higher use stage exposure. Chemicals with low intakes during use (< 1%) and subsequent high post-use emissions, however, may yield comparable intake for a member of the general population. The pre

  2. Model framework for integrating multiple exposure pathways to chemicals in household cleaning products.

    Science.gov (United States)

    Shin, H-M; McKone, T E; Bennett, D H

    2017-07-01

    We present a screening-level exposure-assessment method which integrates exposure from all plausible exposure pathways as a result of indoor residential use of cleaning products. The exposure pathways we considered are (i) exposure to a user during product use via inhalation and dermal, (ii) exposure to chemical residues left on clothing, (iii) exposure to all occupants from the portion released indoors during use via inhalation and dermal, and (iv) exposure to the general population due to down-the-drain disposal via inhalation and ingestion. We use consumer product volatilization models to account for the chemical fractions volatilized to air (fvolatilized ) and disposed down the drain (fdown-the-drain ) during product use. For each exposure pathway, we use a fate and exposure model to estimate intake rates (iR) in mg/kg/d. Overall, the contribution of the four exposure pathways to the total exposure varies by the type of cleaning activities and with chemical properties. By providing a more comprehensive exposure model and by capturing additional exposures from often-overlooked exposure pathways, our method allows us to compare the relative contribution of various exposure routes and could improve high-throughput exposure assessment for chemicals in cleaning products. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. Multi-pathway exposure modelling of chemicals in cosmetics with application to shampoo

    Science.gov (United States)

    We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quant...

  4. Multi-pathway exposure modelling of chemicals in cosmetics with application to shampoo

    DEFF Research Database (Denmark)

    Ernstoff, Alexi S.; Fantke, Peter; Csiszar, Susan A.

    2016-01-01

    We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quantified based...... the skin permeation coefficient dominated the estimated uncertainties. The fraction of chemical taken in by a shampoo user often exceeded, by orders of magnitude, the aggregated fraction taken in by the population through post-use environmental emissions. Chemicals with relatively high octanol...... and critical advancement for life cycle assessments and high-throughput exposure screening of chemicals in cosmetic products demonstrating the importance of consistent consideration of near- and far-field multi-pathway exposures....

  5. Review of the chronic exposure pathways models in MACCS (MELCOR Accident Consequence Code System) and several other well-known probabilistic risk assessment models

    Energy Technology Data Exchange (ETDEWEB)

    Tveten, U. (Institutt for Energiteknikk, Kjeller (Norway))

    1990-06-01

    The purpose of this report is to document the results of the work performed by the author in connection with the following task, performed for US Nuclear Regulatory Commission, (USNRC) Office of Nuclear Regulatory Research, Division of Systems Research: MACCS Chronic Exposure Pathway Models: Review the chronic exposure pathway models implemented in the MELCOR Accident Consequence Code System (MACCS) and compare those models to the chronic exposure pathway models implemented in similar codes developed in countries that are members of the OECD. The chronic exposures concerned are via: the terrestrial food pathways, the water pathways, the long-term groundshine pathway, and the inhalation of resuspended radionuclides pathway. The USNRC has indicated during discussions of the task that the major effort should be spent on the terrestrial food pathways. There is one chapter for each of the categories of chronic exposure pathways listed above.

  6. Multimedia Environmental Pollutant Assessment System (MEPAS{reg_sign}): Exposure pathway and human health impact assessment models

    Energy Technology Data Exchange (ETDEWEB)

    Strenge, D.L.; Chamberlain, P.J.

    1995-05-01

    The Multimedia Environmental Pollutant Assessment System (MEPAS) provides physics-based models for human health risk assessment for radioactive and hazardous pollutants. MEPAS analyzes pollutant behavior in various media (air, soil, groundwater and surface water) and estimates transport through and between media and exposure and impacts to the environment, to the maximum individual, and to populations. MEPAS includes 25 exposure pathway models, a database with information on more than 650 contaminants, and a sensitivity module that allows for uncertainty analysis. Four major transport pathways are considered in MEPAS: groundwater, overland, surface water, and atmospheric. This report describes the exposure pathway and health impact assessment component of MEPAS, which provides an estimate of health impacts to selected individuals and populations from exposure to pollutants. The exposure pathway analysis starts with pollutant concentration in a transport medium and estimates the average daily dose to exposed individuals from contact with the transport medium or a secondary medium contaminated by the transport medium. The average daily dose is then used to estimate a measure of health impact appropriate to the type of pollutant considered. Discussions of the exposure pathway models include the assumptions and equations used to convert the transport medium concentrations to exposure medium concentrations. The discussion for a given exposure pathway defines the transport pathways leading to the exposure, the special processes considered in determining the pollutant concentration in the exposure medium, and the exposure model used to estimate the average daily dose. Models for the exposure pathway and health impact assessments require definition of several parameters. A summary of the notation used for these parameters is provided.

  7. Multi-pathway exposure modeling of chemicals in cosmetics with application to shampoo.

    Science.gov (United States)

    Ernstoff, Alexi S; Fantke, Peter; Csiszar, Susan A; Henderson, Andrew D; Chung, Susie; Jolliet, Olivier

    2016-01-01

    We present a novel multi-pathway, mass balance based, fate and exposure model compatible with life cycle and high-throughput screening assessments of chemicals in cosmetic products. The exposures through product use as well as post-use emissions and environmental media were quantified based on the chemical mass originally applied via a product, multiplied by the product intake fractions (PiF, the fraction of a chemical in a product that is taken in by exposed persons) to yield intake rates. The average PiFs for the evaluated chemicals in shampoo ranged from 3×10(-4) up to 0.3 for rapidly absorbed ingredients. Average intake rates ranged between nano- and micrograms per kilogram bodyweight per day; the order of chemical prioritization was strongly affected by the ingredient concentration in shampoo. Dermal intake and inhalation (for 20% of the evaluated chemicals) during use dominated exposure, while the skin permeation coefficient dominated the estimated uncertainties. The fraction of chemical taken in by a shampoo user often exceeded, by orders of magnitude, the aggregated fraction taken in by the population through post-use environmental emissions. Chemicals with relatively high octanol-water partitioning and/or volatility, and low molecular weight tended to have higher use stage exposure. Chemicals with low intakes during use (<1%) and subsequent high post-use emissions, however, may yield comparable intake for a member of the general population. The presented PiF based framework offers a novel and critical advancement for life cycle assessments and high-throughput exposure screening of chemicals in cosmetic products demonstrating the importance of consistent consideration of near- and far-field multi-pathway exposures. Copyright © 2016 Elsevier Ltd. All rights reserved.

  8. A review of models for near-field exposure pathways of chemicals in consumer products

    DEFF Research Database (Denmark)

    Huang, Lei; Ernstoff, Alexi; Fantke, Peter

    2017-01-01

    Exposure to chemicals in consumer products has been gaining increasing attention, with multiple studies showing that near-field exposures from products is high compared to far-field exposures. Regarding the numerous chemical-product combinations, there is a need for an overarching review of models...

  9. Parsing the effects violence exposure in early childhood: modeling developmental pathways.

    Science.gov (United States)

    Briggs-Gowan, Margaret J; Carter, Alice S; Ford, Julian D

    2012-01-01

    To prospectively examine pathways from early childhood violence exposure and trauma-related symptoms to school-age emotional health. A longitudinal, birth cohort (N = 437) was assessed with parent reports of lifetime violence exposure and trauma-related symptoms at 3 years of age and later, internalizing and externalizing symptoms, and social competence at school age. Early family and neighborhood violence correlated significantly with early trauma-related symptoms and also significantly predicted school-age internalizing and externalizing symptoms and poorer competence, independent of sociodemographic risk and past-year violence exposure. Longitudinal pathways were significantly mediated by arousal and avoidance symptoms at 3 years of age, which increased risk for clinically significant emotional problems and lower competence at school age (adjusted odds ratios = 3.1-6.1, p violence exposure to later emotional health. Interventions that prevent or reduce early trauma-related symptoms may ameliorate the long-term deleterious impact of violence exposure.

  10. Aggregate Exposure Pathway Workshop

    Science.gov (United States)

    Recognizing the growing demands for conducting rapid, cost-effective, and reliable exposure assessment on the thousands of chemicals in commerce, a committee convened by the National Research Council (NRC) developed its vision for exposure science in the 21st century. A necessary...

  11. Children, computer exposure and musculoskeletal outcomes: the development of pathway models for school and home computer-related musculoskeletal outcomes.

    Science.gov (United States)

    Harris, Courtenay; Straker, Leon; Pollock, Clare; Smith, Anne

    2015-01-01

    Children's computer use is rapidly growing, together with reports of related musculoskeletal outcomes. Models and theories of adult-related risk factors demonstrate multivariate risk factors associated with computer use. Children's use of computers is different from adult's computer use at work. This study developed and tested a child-specific model demonstrating multivariate relationships between musculoskeletal outcomes, computer exposure and child factors. Using pathway modelling, factors such as gender, age, television exposure, computer anxiety, sustained attention (flow), socio-economic status and somatic complaints (headache and stomach pain) were found to have effects on children's reports of musculoskeletal symptoms. The potential for children's computer exposure to follow a dose-response relationship was also evident. Developing a child-related model can assist in understanding risk factors for children's computer use and support the development of recommendations to encourage children to use this valuable resource in educational, recreational and communication environments in a safe and productive manner. Computer use is an important part of children's school and home life. Application of this developed model, that encapsulates related risk factors, enables practitioners, researchers, teachers and parents to develop strategies that assist young people to use information technology for school, home and leisure in a safe and productive manner.

  12. Pathway modeling of microarray data: A case study of pathway activity changes in the testis following in utero exposure to dibutyl phthalate (DBP)

    Energy Technology Data Exchange (ETDEWEB)

    Ovacik, Meric A. [Chemical and Biochemical Engineering Department, Rutgers University, Piscataway, NJ 08854 (United States); Sen, Banalata [National Center for Environmental Assessment, U.S. Environmental Protection Agency, Research Triangle Park, NC 27709 (United States); Euling, Susan Y. [National Center for Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, Washington, DC 20460 (United States); Gaido, Kevin W. [U.S. Food and Drug Administration, Center for Veterinary Medicine, Office of New Animal Drug Evaluation, Division of Human Food Safety, Rockville, MD 20855 (United States); Ierapetritou, Marianthi G. [Chemical and Biochemical Engineering Department, Rutgers University, Piscataway, NJ 08854 (United States); Androulakis, Ioannis P., E-mail: yannis@rci.rutgers.edu [Chemical and Biochemical Engineering Department, Rutgers University, Piscataway, NJ 08854 (United States); Biomedical Engineering Department, Rutgers University, NJ 08854 (United States)

    2013-09-15

    Pathway activity level analysis, the approach pursued in this study, focuses on all genes that are known to be members of metabolic and signaling pathways as defined by the KEGG database. The pathway activity level analysis entails singular value decomposition (SVD) of the expression data of the genes constituting a given pathway. We explore an extension of the pathway activity methodology for application to time-course microarray data. We show that pathway analysis enhances our ability to detect biologically relevant changes in pathway activity using synthetic data. As a case study, we apply the pathway activity level formulation coupled with significance analysis to microarray data from two different rat testes exposed in utero to Dibutyl Phthalate (DBP). In utero DBP exposure in the rat results in developmental toxicity of a number of male reproductive organs, including the testes. One well-characterized mode of action for DBP and the male reproductive developmental effects is the repression of expression of genes involved in cholesterol transport, steroid biosynthesis and testosterone synthesis that lead to a decreased fetal testicular testosterone. Previous analyses of DBP testes microarray data focused on either individual gene expression changes or changes in the expression of specific genes that are hypothesized, or known, to be important in testicular development and testosterone synthesis. However, a pathway analysis may inform whether there are additional affected pathways that could inform additional modes of action linked to DBP developmental toxicity. We show that Pathway activity analysis may be considered for a more comprehensive analysis of microarray data.

  13. Pathways of inhalation exposure to manganese in children living near a ferromanganese refinery: A structural equation modeling approach

    Science.gov (United States)

    Manganese (Mn) is both essential element and neurotoxicant. Exposure to Mn can occur from various sources and routes. Structural equation modeling was used to examine routes of exposure to Mn among children residing near a ferromanganese refinery in Marietta, Ohio. An inhalation ...

  14. Pathways of inhalation exposure to manganese in children ...

    Science.gov (United States)

    Manganese (Mn) is both essential element and neurotoxicant. Exposure to Mn can occur from various sources and routes. Structural equation modeling was used to examine routes of exposure to Mn among children residing near a ferromanganese refinery in Marietta, Ohio. An inhalation pathway model to ambient air Mn was hypothesized. Data for model evaluation were obtained from participants in the Communities Actively Researching Exposure Study (CARES). These data were collected in 2009 and included levels of Mn in residential soil and dust, levels of Mn in children's hair, information on the amount of time the child spent outside, heat and air conditioning in the home and level of parent education. Hair Mn concentration was the primary endogenous variable used to assess the theoretical inhalation exposure pathways. The model indicated that household dust Mn was a significant contributor to child hair Mn (0.37). Annual ambient air Mn concentration (0.26), time children spent outside (0.24) and soil Mn (0.24) significantly contributed to the amount of Mn in household dust. These results provide a potential framework for understanding the inhalation exposure pathway for children exposed to ambient air Mn who live in proximity to an industrial emission source. The purpose of this study was to use a structural equations modeling approach combined with exposure estimates derived from air-dispersion modeling to assess potential inhalation exposure pathways for children to a

  15. Significance of environmental exposure pathways for technetium

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, F.O.; Gardner, R.H.; Bartell, S.M.

    1984-01-01

    Numerical simulation techniques are used to produce a probable range of predicted values from estimates of uncertainty assigned to the parameters of radiological assessment models. This range is used to indicate the uncertainty in the model's prediction. The importance of individual parameters and exposure pathways is determined by their relative contribution to this simulated uncertainty index. The major pathways of exposure to humans resulting from the airborne emissions of /sup 99/Tc involve the consumption of vegetables, vegetable products, and poultry eggs. The most important model parameters are related to the mobility of /sup 99/Tc in soil, the incorporation of /sup 99/Tc into the edible portions of crops, its transfer from vegetation to poultry eggs, and its atmospheric deposition. Uncertainty in the dose for individuals exposed to /sup 99/Tc-contaminated liquid discharges is dominated by the bioaccumulation of this isotope in aquatic food chains and by the possibility that contaminated surface water will be used as a source of drinking water. Results suggest that future reductions in the present estimates of uncertainty will lead to the dismissal of /sup 99/Tc as an environmentally important radionuclide, provided that de minimis dose levels are eventually adopted and releases of /sup 99/Tc from individual nuclear fuel cycle facilities will not be substantially larger than 1 Ci/year to the atmosphere and 100 Ci/year to the aquatic environment. These conclusions do not account for the possibility of a large long-term accumulation and remobilization of /sup 99/Tc in aquatic sediment and/or surface soils. 32 references, 9 tables.

  16. Merging Models and Biomonitoring Data to Characterize Sources andPathways of Human Exposure to Organophosphorous Pesticides in the SalinasValley of California

    Energy Technology Data Exchange (ETDEWEB)

    McKone, Thomas E.; Castorina, Rosemary; Kuwabara, Yu; Harnly,Martha E.; Eskenazi, Brenda; Bradman, Asa

    2006-06-01

    By drawing on human biomonitoring data and limited environmental samples together with outputs from the CalTOX multimedia, multipathway source-to-dose model, we characterize cumulative intake of organophosphorous (OP) pesticides in an agricultural region of California. We assemble regional OP pesticide use, environmental sampling, and biological tissue monitoring data for a large and geographically dispersed population cohort of 592 pregnant Latina women in California (the CHAMACOS cohort). We then use CalTOX with regional pesticide usage data to estimate the magnitude and uncertainty of exposure and intake from local sources. We combine model estimates of intake from local sources with food intake based on national residue data to estimate for the CHAMACOS cohort cumulative median OP intake, which corresponds to expected levels of urinary dialkylphosphate (DAP) metabolite excretion for this cohort. From these results we develop premises about relative contributions from different sources and pathways of exposure. We evaluate these premises by comparing the magnitude and variation of DAPs in the CHAMACOS cohort with the whole U.S. population using data from the National Health and Nutrition Evaluation Survey (NHANES). This comparison supports the premise that in both populations diet is the common and dominant exposure pathway. Both the model results and biomarker comparison supports the observation that the CHAMACOS population has a statistically significant higher intake of OP pesticides that appears as an almost constant additional dose among all participants. We attribute the magnitude and small variance of this intake to non-dietary exposure in residences from local sources.

  17. The application of equilibrium models to incidence situations using the example of the exposure pathway human milk

    Energy Technology Data Exchange (ETDEWEB)

    Steiner, Martin; Karcher, Klaus; Nosske, Dietmar [Bundesamt fuer Strahlenschutz, Oberschleissheim (Germany)

    2012-06-15

    The radiation exposure after a short-term release of radioactive substances is often calculated assuming equilibrium conditions. An example is that of the German Incident Calculation Bases for nuclear power plants with pressurized water reactors. Here, the contamination of human milk is calculated using transfer factors. Applying this equilibrium model to incident situations raises the question whether baby's radiation exposure is adequately assessed. This contribution shows that compliance with the relevant dose limits of paragraph 49 of the German Radiation Protection Ordinance is ensured for design basis accidents on the assumption that the hypothetical breastfeeding period starts at the beginning of the activity release. Comparative analyses were performed against the biokinetic models applied by ICRP for radiation protection purposes, taking the reference nuclides {sup 137}Cs, {sup 90}Sr, {sup 131}I, {sup 241}Am and long-lived plutonium isotopes as examples. (orig.)

  18. Tracking the luminal exposure and lymphatic drainage pathways of intravaginal and intrarectal inocula used in nonhuman primate models of HIV transmission.

    Directory of Open Access Journals (Sweden)

    Jeremy Smedley

    Full Text Available Over 80% of sexual HIV-1 transmissions originate from a single viral variant, but the underlying basis for this transmission bottleneck remains to be elucidated. Nonhuman primate models of mucosal virus transmission allow opportunities to gain insight into the basis of this mucosal bottleneck. We used simulated inocula consisting of either non-infectious vital dye or contrast dye with non-invasive magnetic resonance imaging (MRI to visualize mucosal exposure and passive lymphatic drainage patterns following vaginal and rectal exposures in Indian origin rhesus macaques. Results revealed a limited overall distance of dye coverage from the anal verge following 1 ml (n = 8 intrarectally administered, which greatly increased with a 3 ml (n = 8 volume. Intravaginal dye exposure using 2 ml revealed complete coverage of the mucosa of the vagina and ectocervix, however dye was not detectable in the endocervix, uterus, fallopian tubes or ovaries in nuliparous sexually mature rhesus macaques (n = 9. In addition, following submucosal and intranodal injections of vital dye or MRI contrast dye in the rectum (n = 9, or distal and proximal vagina (n = 4, the lymphatic drainage pathways were identified as first the internal then common iliac chain followed by para-aortic lymph nodes. Drainage from the distal descending colon (n = 8 was via the para-colonic lymph nodes followed by the inferior mesenteric and para-aortic lymph nodes. Analysis after vaginal challenge with infectious SIVmac239 followed by euthanasia at day 3 revealed a pattern of viral dissemination consistent with the imaging results. These results provide insights into potential patterns of viral dissemination that can help guide efforts to better elucidate the earliest events of virus transmission and potential intervention strategies.

  19. ECO Exposure Assessment Tools by Exposure Pathways - References

    Science.gov (United States)

    Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

  20. Multiple pathway asbestos exposure assessment for a Superfund community.

    Science.gov (United States)

    Noonan, Curtis W; Conway, Kathrene; Landguth, Erin L; McNew, Tracy; Linker, Laura; Pfau, Jean; Black, Brad; Szeinuk, Jaime; Flores, Raja

    2015-01-01

    Libby, MT, USA, was the home to workers at a historical vermiculite mining facility and served as the processing and distribution center for this industrial product that was contaminated with amphibole asbestos. Several pathways of environmental asbestos exposure to the general population have been identified. The local clinic and health screening program collects data from participants on past occupational and environmental exposures to vermiculite and asbestos. Health studies among this population have demonstrated associations between amphibole exposure and health outcomes, but critical questions regarding the nature and level of exposure associated with specific outcomes remain unanswered. The objective of this study was to develop a comprehensive exposure assessment approach that integrates information on individuals' contact frequency with multiple exposure pathways. For 3031 participants, we describe cumulative exposure metrics for environmental exposures, occupational exposures, and residents' contact with carry-home asbestos from household workers. As expected, cumulative exposures for all three occupational categories were higher among men compared with women, and cumulative exposures for household contact and environmental pathways were higher among women. The comprehensive exposure assessment strategies will advance health studies and risk assessment approaches in this population with a complex history of both occupational and environmental asbestos exposure.

  1. Protecting Critical Infrastructure by Identifying Pathways of Exposure to Risk

    Directory of Open Access Journals (Sweden)

    Philip O’Neill

    2013-08-01

    Full Text Available Increasingly, our critical infrastructure is managed and controlled by computers and the information networks that connect them. Cyber-terrorists and other malicious actors understand the economic and social impact that a successful attack on these systems could have. While it is imperative that we defend against such attacks, it is equally imperative that we realize how best to react to them. This article presents the strongest-path method of analyzing all potential pathways of exposure to risk – no matter how indirect or circuitous they may be – in a network model of infrastructure and operations. The method makes direct use of expert knowledge about entities and dependency relationships without the need for any simulation or any other models. By using path analysis in a directed graph model of critical infrastructure, planners can model and assess the effects of a potential attack and develop resilient responses.

  2. Breastfeeding as an Exposure Pathway for Perfluorinated Alkylates

    DEFF Research Database (Denmark)

    Mogensen, Ulla B; Grandjean, Philippe; Nielsen, Flemming

    2015-01-01

    increases during partial breast-feeding. In contrast to this main pattern, perfluorohexanesulfonate was not affected by breast-feeding. After cessation of breastfeeding, all serum concentrations decreased. This finding supports the evidence of breastfeeding being an important exposure pathway to some PFASs......Perfluorinated alkylate substances (PFASs) are widely used and have resulted in human exposures worldwide. PFASs occur in breast milk, and the duration of breastfeeding is associated with serum-PFAS concentrations in children. To determine the time-dependent impact of this exposure pathway, we...

  3. Sampling strategy for estimating human exposure pathways to consumer chemicals

    Directory of Open Access Journals (Sweden)

    Eleni Papadopoulou

    2016-03-01

    Full Text Available Human exposure to consumer chemicals has become a worldwide concern. In this work, a comprehensive sampling strategy is presented, to our knowledge being the first to study all relevant exposure pathways in a single cohort using multiple methods for assessment of exposure from each exposure pathway. The selected groups of chemicals to be studied are consumer chemicals whose production and use are currently in a state of transition and are; per- and polyfluorinated alkyl substances (PFASs, traditional and “emerging” brominated flame retardants (BFRs and EBFRs, organophosphate esters (OPEs and phthalate esters (PEs. Information about human exposure to these contaminants is needed due to existing data gaps on human exposure intakes from multiple exposure pathways and relationships between internal and external exposure. Indoor environment, food and biological samples were collected from 61 participants and their households in the Oslo area (Norway on two consecutive days, during winter 2013-14. Air, dust, hand wipes, and duplicate diet (food and drink samples were collected as indicators of external exposure, and blood, urine, blood spots, hair, nails and saliva as indicators of internal exposure. A food diary, food frequency questionnaire (FFQ and indoor environment questionnaire were also implemented. Approximately 2000 samples were collected in total and participant views on their experiences of this campaign were collected via questionnaire. While 91% of our participants were positive about future participation in a similar project, some tasks were viewed as problematic. Completing the food diary and collection of duplicate food/drink portions were the tasks most frequent reported as “hard”/”very hard”. Nevertheless, a strong positive correlation between the reported total mass of food/drinks in the food record and the total weight of the food/drinks in the collection bottles was observed, being an indication of accurate performance

  4. Lead in the Dutch environment ; a review of exposure pathways and dispersion models. A pilot study for an integrated chain model

    NARCIS (Netherlands)

    Eggink GJ; Uijt de Haag PAM

    1993-01-01

    Prognoses of possible effects and risks of chemical emissions into the environment and calculation of the effects of countermeasures are often produced using mathematical models. Most models are developed to describe a part of the total source-to-effect chain or to give results for specific

  5. SVOC exposure indoors: fresh look at dermal pathways

    DEFF Research Database (Denmark)

    Weschler, Charles J.; Nazaroff, W. W.

    2012-01-01

    Abstract This paper critically examines indoor exposure to semivolatile organic compounds (SVOCs) via dermal pathways. First, it demonstrates that - in central tendency - an SVOC's abundance on indoor surfaces and in handwipes can be predicted reasonably well from gas-phase concentrations, assumi...

  6. Gene Expression Profiling of Biological Pathway Alterations by Radiation Exposure

    Directory of Open Access Journals (Sweden)

    Kuei-Fang Lee

    2014-01-01

    Full Text Available Though damage caused by radiation has been the focus of rigorous research, the mechanisms through which radiation exerts harmful effects on cells are complex and not well-understood. In particular, the influence of low dose radiation exposure on the regulation of genes and pathways remains unclear. In an attempt to investigate the molecular alterations induced by varying doses of radiation, a genome-wide expression analysis was conducted. Peripheral blood mononuclear cells were collected from five participants and each sample was subjected to 0.5 Gy, 1 Gy, 2.5 Gy, and 5 Gy of cobalt 60 radiation, followed by array-based expression profiling. Gene set enrichment analysis indicated that the immune system and cancer development pathways appeared to be the major affected targets by radiation exposure. Therefore, 1 Gy radioactive exposure seemed to be a critical threshold dosage. In fact, after 1 Gy radiation exposure, expression levels of several genes including FADD, TNFRSF10B, TNFRSF8, TNFRSF10A, TNFSF10, TNFSF8, CASP1, and CASP4 that are associated with carcinogenesis and metabolic disorders showed significant alterations. Our results suggest that exposure to low-dose radiation may elicit changes in metabolic and immune pathways, potentially increasing the risk of immune dysfunctions and metabolic disorders.

  7. Characterization of Changes in Gene Expression and Biochemical Pathways at Low Levels of Benzene Exposure

    Science.gov (United States)

    Thomas, Reuben; Hubbard, Alan E.; McHale, Cliona M.; Zhang, Luoping; Rappaport, Stephen M.; Lan, Qing; Rothman, Nathaniel; Vermeulen, Roel; Guyton, Kathryn Z.; Jinot, Jennifer; Sonawane, Babasaheb R.; Smith, Martyn T.

    2014-01-01

    Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from 10 ppm) compared with 42 subjects with non-workplace ambient exposure levels. Here, we further characterize these dose-dependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel non-parametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response-representative genes (identified by clustering) exhibited similar apparent supra-linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings. PMID:24786086

  8. Characterization of changes in gene expression and biochemical pathways at low levels of benzene exposure.

    Directory of Open Access Journals (Sweden)

    Reuben Thomas

    Full Text Available Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML. Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC, we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across four airborne concentration ranges (from 10 ppm compared with 42 subjects with non-workplace ambient exposure levels. Here, we further characterize these dose-dependent effects with continuous benzene exposure in all 125 study subjects. We estimated air benzene exposure levels in the 42 environmentally-exposed subjects from their unmetabolized urinary benzene levels. We used a novel non-parametric, data-adaptive model selection method to estimate the change with dose in the expression of each gene. We describe non-parametric approaches to model pathway responses and used these to estimate the dose responses of the AML pathway and 4 other pathways of interest. The response patterns of majority of genes as captured by mean estimates of the first and second principal components of the dose-response for the five pathways and the profiles of 6 AML pathway response-representative genes (identified by clustering exhibited similar apparent supra-linear responses. Responses at or below 0.1 ppm benzene were observed for altered expression of AML pathway genes and CYP2E1. Together, these data show that benzene alters disease-relevant pathways and genes in a dose-dependent manner, with effects apparent at doses as low as 100 ppb in air. Studies with extensive exposure assessment of subjects exposed in the low-dose range between 10 ppb and 1 ppm are needed to confirm these findings.

  9. Framework for Multi-Pathway Cumulative Exposure for Comparative Assessments

    DEFF Research Database (Denmark)

    McKone, Tom; Fantke, Peter

    2016-01-01

    to global) environment with information about larger scale populations rather than specific individuals or vulnerable subgroups. Although there can be large uncertainties in this approach, it provides insight on how chemical properties and use patterns map onto population-scale metrics of exposure......-cycle impacts and chemical alternatives. We present a regional case study for pesticide alternatives in an agricultural valley of California to assess the opportunities and future prospects for the multi-pathway cumulative framework in LCA and CAA. This case reveals that the relative contributions to cumulative...... pollutant intake via different exposure pathways depend on (a) persistence of chemicals at different levels of integration (regional, urban-scale, food-web, indoors), (b) basic chemical properties, (c) the retention of chemicals in food webs, and (d) the retention of chemicals by indoor surfaces....

  10. Exposure pathways of anticoagulant rodenticides to nontarget wildlife.

    Science.gov (United States)

    Elliott, John E; Hindmarch, Sofi; Albert, Courtney A; Emery, Jason; Mineau, Pierre; Maisonneuve, France

    2014-02-01

    Second-generation anticoagulant rodenticides are widely reported to contaminate and poison nontarget wildlife, primarily predatory birds and mammals. Exposure pathways, however, have not been well defined. Here, we examined potential movement of rodenticides from deployment of bait to exposure of small mammals and other biota. At two adjacent working farms, we placed baits containing either brodifacoum or bromadiolone. We monitored movement of those compounds to the surrounding environment by collecting small mammals, birds, and invertebrates. Similar collections were made at a third agricultural setting without active bait deployment, but located among intensive livestock production and regular rodenticide use by farmers. Livers and whole invertebrate samples were analyzed for rodenticides using a sensitive LC-MSMS method. Norway rats (Rattus norvegicus) from both baited and non-baited farms had residues of brodifacoum or bromadiolone, implicating rats as an important exposure pathway to wildlife. Among 35 analyzed nontarget small mammals, a single vole had high hepatic residues (18.6 μ/g), providing some indication of a small mammal pathway. One song sparrow (Melospiza melodia) sample from a baited farm contained 0.073 μg/g of brodifacoum in liver, while 0.39 μg/g of diphacinone was measured in a pool of carrion beetles (Dermestes spp.) from the non-baited farm area, implicating avian and invertebrate components in exposure pathways. Regurgitated pellets of barn owl (Tyto alba) selected randomly from baited farms contained no detectable rodenticide residues, while 90% of owl pellets collected from a variety of farms, and selected for the presence of rat fur, contained detectable anticoagulant residues. We recorded behavior of a captive sample of a representative songbird, the house sparrow (Passer domesticus); they readily entered bait stations and fed on (unloaded) bait.

  11. Postulating a dermal pathway for exposure to anti-neoplastic drugs among hospital workers. Applying a conceptual model to the results of three workplace surveys

    NARCIS (Netherlands)

    Kromhout, H.; Hoek, F.; Uitterhoeve, R.; Huijbers, R.; Overmars, R.F.; Anzion, R.; Vermeulen, R.

    2000-01-01

    Dermal exposure to anti-neoplastic drugs has been suggested as a potentially important route of exposure of hospital workers. Three small-scale workplace surveys were carried out in several hospitals focusing on contamination by leakage from IV infusion systems; contamination by spilled urine of

  12. Mathematical modeling of inhalation exposure

    Science.gov (United States)

    Fiserova-Bergerova, V.

    1976-01-01

    The paper presents a mathematical model of inhalation exposure in which uptake, distribution and excretion are described by exponential functions, while rate constants are determined by tissue volumes, blood perfusion and by the solubility of vapors (partition coefficients). In the model, tissues are grouped into four pharmokinetic compartments. The model is used to study continuous and interrupted chronic exposures and is applied to the inhalation of Forane and methylene chloride.

  13. Modeled population exposures to ozone

    Data.gov (United States)

    U.S. Environmental Protection Agency — Population exposures to ozone from APEX modeling for combinations of potential future air quality and demographic change scenarios. This dataset is not publicly...

  14. Soil is an important pathway of human lead exposure.

    OpenAIRE

    Mielke, H W; Reagan, P L

    1998-01-01

    This review shows the equal or greater importance of leaded gasoline-contaminated dust compared to lead-based paint to the child lead problem, and that soil lead, resulting from leaded gasoline and pulverized lead-based paint, is at least or more important than lead-based paint (intact and not pulverized) as a pathway of human lead exposure. Because lead-based paint is a high-dose source, the biologically relevant dosage is similar to lead in soil. Both lead-based paint and soil lead are asso...

  15. Refining the quantitative pathway of the Pathways to Mathematics model.

    Science.gov (United States)

    Sowinski, Carla; LeFevre, Jo-Anne; Skwarchuk, Sheri-Lynn; Kamawar, Deepthi; Bisanz, Jeffrey; Smith-Chant, Brenda

    2015-03-01

    In the current study, we adopted the Pathways to Mathematics model of LeFevre et al. (2010). In this model, there are three cognitive domains--labeled as the quantitative, linguistic, and working memory pathways--that make unique contributions to children's mathematical development. We attempted to refine the quantitative pathway by combining children's (N=141 in Grades 2 and 3) subitizing, counting, and symbolic magnitude comparison skills using principal components analysis. The quantitative pathway was examined in relation to dependent numerical measures (backward counting, arithmetic fluency, calculation, and number system knowledge) and a dependent reading measure, while simultaneously accounting for linguistic and working memory skills. Analyses controlled for processing speed, parental education, and gender. We hypothesized that the quantitative, linguistic, and working memory pathways would account for unique variance in the numerical outcomes; this was the case for backward counting and arithmetic fluency. However, only the quantitative and linguistic pathways (not working memory) accounted for unique variance in calculation and number system knowledge. Not surprisingly, only the linguistic pathway accounted for unique variance in the reading measure. These findings suggest that the relative contributions of quantitative, linguistic, and working memory skills vary depending on the specific cognitive task. Copyright © 2014 Elsevier Inc. All rights reserved.

  16. Use of international data sets to evaluate and validate pathway assessment models applicable to exposure and dose reconstruction at DOE facilities. Monthly progress reports and final report, October--December 1994

    Energy Technology Data Exchange (ETDEWEB)

    Hoffman, F.O. [Senes Oak Ridge, Inc., TN (United States). Center for Risk Analysis

    1995-04-01

    The objective of Task 7.lD was to (1) establish a collaborative US-USSR effort to improve and validate our methods of forecasting doses and dose commitments from the direct contamination of food sources, and (2) perform experiments and validation studies to improve our ability to predict rapidly and accurately the long-term internal dose from the contamination of agricultural soil. At early times following an accident, the direct contamination of pasture and food stuffs, particularly leafy vegetation and grain, can be of great importance. This situation has been modeled extensively. However, models employed then to predict the deposition, retention and transport of radionuclides in terrestrial environments employed concepts and data bases that were more than a decade old. The extent to which these models have been tested with independent data sets was limited. The data gathered in the former-USSR (and elsewhere throughout the Northern Hemisphere) offered a unique opportunity to test model predictions of wet and dry deposition, agricultural foodchain bioaccumulation, and short- and long-term retention, redistribution, and resuspension of radionuclides from a variety of natural and artificial surfaces. The current objective of this project is to evaluate and validate pathway-assessment models applicable to exposure and dose reconstruction at DOE facilities through use of international data sets. This project incorporates the activity of Task 7.lD into a multinational effort to evaluate models and data used for the prediction of radionuclide transfer through agricultural and aquatic systems to humans. It also includes participation in two studies, BIOMOVS (BIOspheric MOdel Validation Study) with the Swedish National Institute for Radiation Protection and VAMP (VAlidation of Model Predictions) with the International Atomic Energy Agency, that address testing the performance of models of radionuclide transport through foodchains.

  17. Modelling exposure opportunities

    DEFF Research Database (Denmark)

    Sabel, Clive E.; Gatrell, Anthony C.; Löytönen, Markku

    2000-01-01

    boundaries.We use kernel estimation to model space-time patterns. Raised relative risk is assessed by adopting appropriate adjustments for the underlying population at risk, with the use of controls. Significance of the results is assessed using Monte Carlo simulation, and comparisons are made with results...... are considered. No prior assumptions about the aetiology of MND are adopted. By using methods for the analysis of point processes, which preserve the continuous nature of the data, we resolve some of the problems of analysis that are often based on arbitrary areal units, such as postcode boundaries, or political...... obtained from Openshaw's geographical analysis machine (GAM).Our results demonstrate the utility of kernel estimation as a visualisation tool. Small areas of elevated risk are identified, which need to be more closely examined before any firm conclusions can be drawn. We highlight a number of issues...

  18. Noise Exposure Model (MOD 4)

    Science.gov (United States)

    1971-08-01

    The purpose of this report is threefold: : 1. To record the results of efforts at the Transportaiton Systems Center to refine and expand the Noise Exposure Model, which have specifically resulted in the MOD 4 ver described herein; : 2. To serve as an...

  19. Mercury in Arctic Marine Ecosystems: Sources, Pathways, and Exposure

    Science.gov (United States)

    Kirk, Jane L.; Lehnherr, Igor; Andersson, Maria; Braune, Birgit M.; Chan, Laurie; Dastoor, Ashu P.; Durnford, Dorothy; Gleason, Amber L.; Loseto, Lisa L.; Steffen, Alexandra; St. Louis, Vincent L.

    2014-01-01

    Mercury in the Arctic is an important environmental and human health issue. The reliance of Northern Peoples on traditional foods, such as marine mammals, for subsistence means that they are particularly at risk from mercury exposure. The cycling of mercury in Arctic marine systems is reviewed here, with emphasis placed on the key sources, pathways and processes which regulate mercury levels in marine food webs and ultimately the exposure of human populations to this contaminant. While many knowledge gaps exist limiting our ability to make strong conclusions, it appears that the long range transport of mercury from Asian emissions is an important source of atmospheric Hg to the Arctic and that mercury methylation resulting in monomethylmercury production (an organic form of mercury which is both toxic and bioaccumulated) in Arctic marine waters is the principal source of mercury incorporated into food webs. Mercury concentrations in biological organisms have increased since the onset of the industrial age and are controlled by a combination of abiotic factors (e.g., monomethylmercury supply), food web dynamics and structure, and animal behavior (e.g., habitat selection and feeding behavior). Finally, although some Northern Peoples have high mercury concentrations of mercury in their blood and hair, harvesting and consuming traditional foods has many nutritional, social, cultural and physical health benefits which must be considered in risk management and communication. PMID:23102902

  20. Pathways to health risk exposure in adult film performers.

    Science.gov (United States)

    Grudzen, Corita R; Ryan, Gery; Margold, William; Torres, Jacqueline; Gelberg, Lillian

    2009-01-01

    Despite being part of a large and legal industry in Los Angeles, little is known about adult film performers' exposure to health risks and when and how these risks might occur. The objective was to identify exposure to physical, mental, and social health risks and the pathways to such risks among adult film performers and to determine how risks differ between different types of performers, such as men and women. Semi-structured in-depth interviews were conducted with 18 female and ten male performers as well as two key informants from the industry. Performers and key informants were recruited through Protecting Adult Welfare, adult film venues, and snowball sampling. Performers engaged in risky health behaviors that included high-risk sexual acts that are unprotected, substance abuse, and body enhancement. They are exposed to physical trauma on the film set. Many entered and left the industry with financial insecurity and suffered from mental health problems. Women were more likely than men to be exposed to health risks. Adult film performers, especially women, are exposed to health risks that accumulate over time and that are not limited to sexually transmitted diseases.

  1. Completing the Link between Exposure Science and Toxicology for Improved Environmental Health Decision Making: The Aggregate Exposure Pathway Framework

    Energy Technology Data Exchange (ETDEWEB)

    Teeguarden, Justin G.; Tan, Yu-Mei; Edwards, Stephen W.; Leonard, Jeremy A.; Anderson, Kim A.; Corley, Richard A.; Kile, Molly L.; Simonich, Staci M.; Stone, David; Tanguay, Robert L.; Waters, Katrina M.; Harper, Stacey L.; Williams, David E.

    2016-05-03

    Driven by major scientific advances in analytical methods, biomonitoring, and computational exposure assessment, and a newly articulated vision for a greater impact in public health, the field of exposure science is undergoing a rapid transition from a field of observation to a field of prediction. Deployment of an organizational and predictive framework for exposure science analogous to the computationally enabled “systems approaches” used in the biological sciences is a necessary step in this evolution. Here we propose the aggregate exposure pathway (AEP) concept as the natural and complementary companion in the exposure sciences to the adverse outcome pathway (AOP) concept in the toxicological sciences. The AEP framework offers an intuitive approach to successful organization of exposure science data within individual units of prediction common to the field, setting the stage for exposure forecasting. Looking farther ahead, we envision direct linkages between aggregate exposure pathway and adverse outcome pathways, completing the source to outcome continuum and setting the stage for more efficient integration of exposure science and toxicity testing information. Together these frameworks form and inform a decision making framework with the flexibility for risk-based, hazard-based or exposure-based decisions.

  2. EPA EcoBox Tools by Exposure Pathways - Food Chains

    Science.gov (United States)

    Eco-Box is a toolbox for exposure assessors. Its purpose is to provide a compendium of exposure assessment and risk characterization tools that will present comprehensive step-by-step guidance and links to relevant exposure assessment data bases

  3. Using meta-regression models to systematically evaluate data in the published literature: relative contributions of agricultural drift, para-occupational, and residential use exposure pathways to house dust pesticide concentrations

    Science.gov (United States)

    Background: Data reported in the published literature have been used qualitatively to aid exposure assessment activities in epidemiologic studies. Analyzing these data in computational models presents statistical challenges because these data are often reported as summary statist...

  4. Modeling cancer progression via pathway dependencies.

    Directory of Open Access Journals (Sweden)

    Elena J Edelman

    2008-02-01

    Full Text Available Cancer is a heterogeneous disease often requiring a complexity of alterations to drive a normal cell to a malignancy and ultimately to a metastatic state. Certain genetic perturbations have been implicated for initiation and progression. However, to a great extent, underlying mechanisms often remain elusive. These genetic perturbations are most likely reflected by the altered expression of sets of genes or pathways, rather than individual genes, thus creating a need for models of deregulation of pathways to help provide an understanding of the mechanisms of tumorigenesis. We introduce an integrative hierarchical analysis of tumor progression that discovers which a priori defined pathways are relevant either throughout or in particular steps of progression. Pathway interaction networks are inferred for these relevant pathways over the steps in progression. This is followed by the refinement of the relevant pathways to those genes most differentially expressed in particular disease stages. The final analysis infers a gene interaction network for these refined pathways. We apply this approach to model progression in prostate cancer and melanoma, resulting in a deeper understanding of the mechanisms of tumorigenesis. Our analysis supports previous findings for the deregulation of several pathways involved in cell cycle control and proliferation in both cancer types. A novel finding of our analysis is a connection between ErbB4 and primary prostate cancer.

  5. Children's Exposure to Violence: Exploring Developmental Pathways to Diverse Outcomes

    Science.gov (United States)

    Margolin, Gayla

    2005-01-01

    Identifying mechanisms that explain the children's differential vulnerability to violence exposure is an important research focus. Developmentally sensitive theories and methods are recommended to better understand children's risk and resilience to violence exposure. Examples are provided of promising research that links violence exposure to…

  6. Exploring consumer exposure pathways and patterns of use for chemicals in the environment

    Directory of Open Access Journals (Sweden)

    Kathie L. Dionisio

    Full Text Available •To assign use-related information to chemicals to help prioritize which will be given more scrutiny relative to human exposure potential.•Categorical chemical use and functional information are presented through the Chemical/Product Categories Database (CPCat.•CPCat contains information on >43,000 unique chemicals mapped to ∼800 terms categorizing their usage or function.•The CPCat database is useful for modeling and prioritizing human chemical exposures.Humans are exposed to thousands of chemicals in the workplace, home, and via air, water, food, and soil. A major challenge in estimating chemical exposures is to understand which chemicals are present in these media and microenvironments. Here we describe the Chemical/Product Categories Database (CPCat, a new, publically available (http://actor.epa.gov/cpcat database of information on chemicals mapped to “use categories” describing the usage or function of the chemical. CPCat was created by combining multiple and diverse sources of data on consumer- and industrial-process based chemical uses from regulatory agencies, manufacturers, and retailers in various countries. The database uses a controlled vocabulary of 833 terms and a novel nomenclature to capture and streamline descriptors of chemical use for 43,596 chemicals from the various sources. Examples of potential applications of CPCat are provided, including identifying chemicals to which children may be exposed and to support prioritization of chemicals for toxicity screening. CPCat is expected to be a valuable resource for regulators, risk assessors, and exposure scientists to identify potential sources of human exposures and exposure pathways, particularly for use in high-throughput chemical exposure assessment. keywords: ACToR,Aggregated Computational Toxicology Resource,AICS,Australian Inventory of Chemical Substances,CAS RN,Chemical Abstracts Service Registry Number,CDR,Chemical Data Reporting Rule

  7. Characterization of changes in gene expression and biochemical pathways at low levels of benzene exposure

    NARCIS (Netherlands)

    Thomas, Reuben; Hubbard, Alan E.; McHale, Cliona M.; Zhang, Luoping; Rappaport, Stephen M.; Lan, Qing; Rothman, Nathaniel; Vermeulen, Roel|info:eu-repo/dai/nl/216532620; Guyton, Kathryn Z.; Jinot, Jennifer; Sonawane, Babasaheb R.; Smith, Martyn T.

    2014-01-01

    Benzene, a ubiquitous environmental pollutant, causes acute myeloid leukemia (AML). Recently, through transcriptome profiling of peripheral blood mononuclear cells (PBMC), we reported dose-dependent effects of benzene exposure on gene expression and biochemical pathways in 83 workers exposed across

  8. Radium in the environment: exposure pathways and health effects.

    Science.gov (United States)

    Brugge, Doug; Buchner, Virginia

    2012-01-01

    Radium is a naturally occurring radioactive element in the environment that can exist as several isotopes. Little information is available on the acute (short-term) non-cancer effects in humans. Radium exposure has resulted in acute leukopenia, anemia, necrosis of the jaw, and other effects. Cancer is the major effect of concern. Radium, via oral exposure, is known to cause bone, head, and nasal passage tumors in humans. The US Environmental Protection Agency has not classified radium for carcinogenicity.

  9. A Pathway Idea for Model Building

    Science.gov (United States)

    Mathai, A.M.; Moschopoulos, Panagis

    2013-01-01

    Models, mathematical or stochastic, which move from one functional form to another through pathway parameters, so that in between stages can be captured, are examined in this article. Models which move from generalized type-1 beta family to type-2 beta family, to generalized gamma family to generalized Mittag-Leffler family to Lévy distributions are examined here. It is known that one can likely find an approximate model for the data at hand whether the data are coming from biological, physical, engineering, social sciences or other areas. Different families of functions are connected through the pathway parameters and hence one will find a suitable member from within one of the families or in between stages of two families. Graphs are provided to show the movement of the different models showing thicker tails, thinner tails, right tail cut off etc. PMID:24883223

  10. Modelling and Decision Support of Clinical Pathways

    Science.gov (United States)

    Gabriel, Roland; Lux, Thomas

    The German health care market is under a rapid rate of change, forcing especially hospitals to provide high-quality services at low costs. Appropriate measures for more effective and efficient service provision are process orientation and decision support by information technology of clinical pathway of a patient. The essential requirements are adequate modelling of clinical pathways as well as usage of adequate systems, which are capable of assisting the complete path of a patient within a hospital, and preferably also outside of it, in a digital way. To fulfil these specifications the authors present a suitable concept, which meets the challenges of well-structured clinical pathways as well as rather poorly structured diagnostic and therapeutic decisions, by interplay of process-oriented and knowledge-based hospital information systems.

  11. A Review of Non-occupational Pathways for Pesticide Exposure in Women Living in Agricultural Areas

    Science.gov (United States)

    Women living in agricultural areas may experience relatively high pesticide exposures compared to women in urban or suburban areas due to their proximity to farm activities. However, exposure pathways in these women are not well-characterized. We reviewed the evidence for the con...

  12. A Pathway Idea in Model Building

    Science.gov (United States)

    Mathai, A. M.; Haubold, H. J.

    2014-01-01

    The pathway idea is a way of going from one family of functions to another family of functions and yet another family of functions through a parameter in the mode l so that a switching mechanism is introduced into the model through a parameter. The advantage of the idea is that the model can cover the ideal or stable situation in a physical situation as well as cover the unstable neighborhoods or move from unstable neighborhoods to the stable situation. The basic idea is illustrated for the real scalar case here and its connections to topics in astrophysics and non-extens ive statistical mechanics, namely superstatistics and Tsallis statistics, Mittag-Leffler models, hypergeometric functions and generalized special functions such as the H-function etc are pointed out. The pathway idea is available for the real and complex rectangular matrix variate cases but only the real scalar case is illustrated here.

  13. Mathematical modeling of the Phoenix Rising pathway.

    Directory of Open Access Journals (Sweden)

    Chad Liu

    2014-02-01

    Full Text Available Apoptosis is a tightly controlled process in mammalian cells. It is important for embryogenesis, tissue homoeostasis, and cancer treatment. Apoptosis not only induces cell death, but also leads to the release of signals that promote rapid proliferation of surrounding cells through the Phoenix Rising (PR pathway. To quantitatively understand the kinetics of interactions of different molecules in this pathway, we developed a mathematical model to simulate the effects of various changes in the PR pathway on the secretion of prostaglandin E2 (PGE2, a key factor for promoting cell proliferation. These changes include activation of caspase 3 (C3, caspase 7 (C7, and nuclear factor κB (NFκB. In addition, we simulated the effects of cyclooxygenase-2 (COX2 inhibition and C3 knockout on the level of secreted PGE2. The model predictions on PGE2 in MEF and 4T1 cells at 48 hours after 10-Gray radiation were quantitatively consistent with the experimental data in the literature. Compared to C7, the model predicted that C3 activation was more critical for PGE2 production. The model also predicted that PGE2 production could be significantly reduced when COX2 expression was blocked via either NFκB inactivation or treatment of cells with exogenous COX2 inhibitors, which led to a decrease in the rate of conversion from arachidonic acid to prostaglandin H2 in the PR pathway. In conclusion, the mathematical model developed in this study yielded new insights into the process of tissue regrowth stimulated by signals from apoptotic cells. In future studies, the model can be used for experimental data analysis and assisting development of novel strategies/drugs for improving cancer treatment or normal tissue regeneration.

  14. Aquatic pathways model to predict the fate of phenolic compounds

    Energy Technology Data Exchange (ETDEWEB)

    Aaberg, R.L.; Peloquin, R.A.; Strenge, D.L.; Mellinger, P.J.

    1983-04-01

    Organic materials released from energy-related activities could affect human health and the environment. To better assess possible impacts, we developed a model to predict the fate of spills or discharges of pollutants into flowing or static bodies of fresh water. A computer code, Aquatic Pathways Model (APM), was written to implement the model. The computer programs use compartmental analysis to simulate aquatic ecosystems. The APM estimates the concentrations of chemicals in fish tissue, water and sediment, and is therefore useful for assessing exposure to humans through aquatic pathways. The APM will consider any aquatic pathway for which the user has transport data. Additionally, APM will estimate transport rates from physical and chemical properties of chemicals between several key compartments. The major pathways considered are biodegradation, fish and sediment uptake, photolysis, and evaporation. The model has been implemented with parameters for distribution of phenols, an important class of compounds found in the water-soluble fractions of coal liquids. Current modeling efforts show that, in comparison with many pesticides and polyaromatic hydrocarbons (PAH), the lighter phenolics (the cresols) are not persistent in the environment. The properties of heavier molecular weight phenolics (indanols, naphthols) are not well enough understood at this time to make similar judgements. For the twelve phenolics studied, biodegradation appears to be the major pathway for elimination from aquatic environments. A pond system simulation (using APM) of a spill of solvent refined coal (SRC-II) materials indicates that phenol, cresols, and other single cyclic phenolics are degraded to 16 to 25 percent of their original concentrations within 30 hours. Adsorption of these compounds into sediments and accumulation by fish was minor.

  15. Frameworks for organizing exposure and toxicity data - the Aggregate Exposure Pathway (AEP) and the Adverse Outcome Pathway (AOP)

    Science.gov (United States)

    The Adverse Outcome Pathway (AOP) framework organizes existing knowledge regarding a series of biological events, starting with a molecular initiating event (MIE) and ending at an adverse outcome. The AOP framework provides a biological context to interpret in vitro toxicity dat...

  16. MAPK pathway activation by chronic lead-exposure increases vascular reactivity through oxidative stress/cyclooxygenase-2-dependent pathways

    Energy Technology Data Exchange (ETDEWEB)

    Simões, Maylla Ronacher, E-mail: yllars@hotmail.com [Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091 (Brazil); Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain); Aguado, Andrea [Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain); Fiorim, Jonaína; Silveira, Edna Aparecida; Azevedo, Bruna Fernandes; Toscano, Cindy Medice [Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091 (Brazil); Zhenyukh, Olha; Briones, Ana María [Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain); Alonso, María Jesús [Dept. of Biochemistry, Physiology and Molecular Genetics, Universidad Rey Juan Carlos, Alcorcón (Spain); Vassallo, Dalton Valentim [Dept. of Physiological Sciences, Federal University of Espirito Santo, Vitória, ES CEP 29040-091 (Brazil); Health Science Center of Vitória-EMESCAM, Vitória, ES CEP 29045-402 (Brazil); Salaices, Mercedes, E-mail: mercedes.salaices@uam.es [Department of Pharmacology, Universidad Autonoma de Madrid, Instituto de Investigación Hospital Universitario La Paz (IdiPAZ), Madrid (Spain)

    2015-03-01

    Chronic exposure to low lead concentration produces hypertension; however, the underlying mechanisms remain unclear. We analyzed the role of oxidative stress, cyclooxygenase-2-dependent pathways and MAPK in the vascular alterations induced by chronic lead exposure. Aortas from lead-treated Wistar rats (1st dose: 10 μg/100 g; subsequent doses: 0.125 μg/100 g, intramuscular, 30 days) and cultured aortic vascular smooth muscle cells (VSMCs) from Sprague Dawley rats stimulated with lead (20 μg/dL) were used. Lead blood levels of treated rats attained 21.7 ± 2.38 μg/dL. Lead exposure increased systolic blood pressure and aortic ring contractile response to phenylephrine, reduced acetylcholine-induced relaxation and did not affect sodium nitroprusside relaxation. Endothelium removal and L-NAME left-shifted the response to phenylephrine more in untreated than in lead-treated rats. Apocynin and indomethacin decreased more the response to phenylephrine in treated than in untreated rats. Aortic protein expression of gp91(phox), Cu/Zn-SOD, Mn-SOD and COX-2 increased after lead exposure. In cultured VSMCs lead 1) increased superoxide anion production, NADPH oxidase activity and gene and/or protein levels of NOX-1, NOX-4, Mn-SOD, EC-SOD and COX-2 and 2) activated ERK1/2 and p38 MAPK. Both antioxidants and COX-2 inhibitors normalized superoxide anion production, NADPH oxidase activity and mRNA levels of NOX-1, NOX-4 and COX-2. Blockade of the ERK1/2 and p38 signaling pathways abolished lead-induced NOX-1, NOX-4 and COX-2 expression. Results show that lead activation of the MAPK signaling pathways activates inflammatory proteins such as NADPH oxidase and COX-2, suggesting a reciprocal interplay and contribution to vascular dysfunction as an underlying mechanisms for lead-induced hypertension. - Highlights: • Lead-exposure increases oxidative stress, COX-2 expression and vascular reactivity. • Lead exposure activates MAPK signaling pathway. • ROS and COX-2 activation by

  17. SIGNALING PATHWAYS ASSOCIATED WITH VX EXPOSURE IN MESENCHYMAL STEM CELLS

    Science.gov (United States)

    2017-09-01

    respiratory arrest and death (2–4) in severe cases. In addition to toxic effects to the nervous system, low-level exposures to OP compounds can cause...acute situations, this hyperstimulation can cause respiratory failure and eventual death . Although AChE is conventionally known for this signaling role...expressed as the mean ± standard error of the mean of the normalized CI (i.e., n ≥ 8 for each experimental condition). ▲ ( Black ) media control

  18. Signal transduction pathway(s) in guard cells after prolonged exposure to low vapour pressure deficit

    NARCIS (Netherlands)

    Ali Niaei Fard, S.

    2014-01-01

    Keywords: Abscisic acid, Arabidopsis thaliana, calcium, CYP707As, desiccation, environmental factors, guard cells’ signalling pathway, hydrogen peroxide, natural variation, nitric oxide, photosystem II efficiency, RD29A, relative water content, secondary messengers, stomata, vapour pressure

  19. Bioreactor Transient Exposure Activates Specific Neurotrophic Pathway in Cortical Neurons

    Science.gov (United States)

    Zimmitti, V.; Benedetti, E.; Caracciolo, V.; Sebastiani, P.; Di Loreto, S.

    2010-02-01

    Altered gravity forces might influence neuroplasticity and can provoke changes in biochemical mechanisms. In this contest, neurotrophins have a pivotal role, particularly nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF). A suspension of dissociated cortical cells from rat embryos was exposed to 24 h of microgravity before plating in normal adherent culture system. Expression and transductional signalling pathways of NGF and BDNF were assessed at the end of maturational process (8-10 days in vitro). Rotating wall vessel bioreactor (RWV) pre-exposition did not induce changes in NGF expression and its high affinity receptor TrkA. On the contrary both BDNF expression and its high affinity receptor TrkB were strongly up-regulated, inducing Erk-5, but not Erk-1/2 activation and, in turn, MEF2C over-expression and activation. According to our previous and present results, we postulate that relatively short microgravitational stimuli, applied to neural cells during the developmental stage, exert a long time activation of specific neurotrophic pathways.

  20. Exposure pathways and biological receptors: baseline data for the canyon uranium mine, Coconino County, Arizona

    Science.gov (United States)

    Hinck, Jo E.; Linder, Greg L.; Darrah, Abigail J.; Drost, Charles A.; Duniway, Michael C.; Johnson, Matthew J.; Méndez-Harclerode, Francisca M.; Nowak, Erika M.; Valdez, Ernest W.; van Riper, Charles; Wolff, S.W.

    2014-01-01

    Recent restrictions on uranium mining within the Grand Canyon watershed have drawn attention to scientific data gaps in evaluating the possible effects of ore extraction to human populations as well as wildlife communities in the area. Tissue contaminant concentrations, one of the most basic data requirements to determine exposure, are not available for biota from any historical or active uranium mines in the region. The Canyon Uranium Mine is under development, providing a unique opportunity to characterize concentrations of uranium and other trace elements, as well as radiation levels in biota, found in the vicinity of the mine before ore extraction begins. Our study objectives were to identify contaminants of potential concern and critical contaminant exposure pathways for ecological receptors; conduct biological surveys to understand the local food web and refine the list of target species (ecological receptors) for contaminant analysis; and collect target species for contaminant analysis prior to the initiation of active mining. Contaminants of potential concern were identified as arsenic, cadmium, chromium, copper, lead, mercury, nickel, selenium, thallium, uranium, and zinc for chemical toxicity and uranium and associated radionuclides for radiation. The conceptual exposure model identified ingestion, inhalation, absorption, and dietary transfer (bioaccumulation or bioconcentration) as critical contaminant exposure pathways. The biological survey of plants, invertebrates, amphibians, reptiles, birds, and small mammals is the first to document and provide ecological information on .200 species in and around the mine site; this study also provides critical baseline information about the local food web. Most of the species documented at the mine are common to ponderosa pine Pinus ponderosa and pinyon–juniper Pinus–Juniperus spp. forests in northern Arizona and are not considered to have special conservation status by state or federal agencies; exceptions

  1. Testing Pathways Linking Exposure to Community Violence and Sexual Behaviors Among African American Youth

    Science.gov (United States)

    Hotton, Anna L.; Neilands, Torsten B.

    2014-01-01

    Exposure to community violence and HIV sexual risks are two major public health concerns among youth. This study tests various pathways linking exposure to community violence and sexual behaviors among African American adolescents. Using a sample of 563 (61 % females) African American youth attending high school we examined whether problematic psychological symptoms, low school engagement, and/or negative perceptions of peer norms about safer sex functioned as pathways linking exposure to community violence and sexual behaviors. Major findings indicated that, for boys, the relationship between exposure to community violence and sexual début and sexual risk behaviors were linked by aggression. In addition, the relationship between exposure to community violence and sexual risk behaviors were linked by negative perceptions of peer attitudes about safer sex. For girls, the relationship between exposure to community violence and sexual début was linked by aggression and negative perceptions of peer attitudes about safer sex. These findings provide support for pathways linking exposure to community violence to sexual behaviors. PMID:24327295

  2. Testing pathways linking exposure to community violence and sexual behaviors among African American youth.

    Science.gov (United States)

    Voisin, Dexter R; Hotton, Anna L; Neilands, Torsten B

    2014-09-01

    Exposure to community violence and HIV sexual risks are two major public health concerns among youth. This study tests various pathways linking exposure to community violence and sexual behaviors among African American adolescents. Using a sample of 563 (61% females) African American youth attending high school we examined whether problematic psychological symptoms, low school engagement, and/or negative perceptions of peer norms about safer sex functioned as pathways linking exposure to community violence and sexual behaviors. Major findings indicated that, for boys, the relationship between exposure to community violence and sexual début and sexual risk behaviors were linked by aggression. In addition, the relationship between exposure to community violence and sexual risk behaviors were linked by negative perceptions of peer attitudes about safer sex. For girls, the relationship between exposure to community violence and sexual début was linked by aggression and negative perceptions of peer attitudes about safer sex. These findings provide support for pathways linking exposure to community violence to sexual behaviors.

  3. Pathways to adolescent sexual risk behaviors: Effects of prenatal cocaine exposure.

    Science.gov (United States)

    Min, Meeyoung O; Minnes, Sonia; Lang, Adelaide; Albert, Jeffrey M; Kim, June-Yung; Singer, Lynn T

    2016-04-01

    To assess the impact of prenatal cocaine exposure (PCE) on adolescent sexual risk behaviors. Externalizing behavior, teen substance use, and early sexual intercourse were examined as pathways mediating the effects of PCE on sexual risk behaviors. Adolescents (N=364; 185 PCE, 179 non-cocaine exposure (NCE); 205 girls, 159 boys), primarily African-American and of low socioeconomic status, were prospectively enrolled in a longitudinal study at birth. Risky sexual behaviors were assessed at ages 15 and 17. Externalizing behavior at 12 years was assessed with the Youth Self-Report. Substance use, via self-report and biologic assays, and early (before age 15) sexual intercourse were assessed at age 15. Path analyses with the weighted least squares estimator with mean and variance adjustments were performed. The final structural equation model-based path model, χ(2)=31.97 (df=27), p=.23, CFI=.99, TLI=.99, RMSEA=.021, WRMR=.695, indicated a direct effect of PCE on sexual risk behavior (β=.16, p=.02). Although PCE was related to greater externalizing behavior (β=.14, p=.009), which in turn, predicted early sexual intercourse (β=.16, p=.03), leading to sexual risk behavior (β=.44, peffect (β=.01, p>.10). Substance use was correlated with early sexual intercourse (r=.60, psexual risk behavior by age 17 (β=.31, p=.01). Prenatal cocaine exposure was related to more engagement in sexual risk behaviors, suggesting the importance of reducing substance use among pregnant women as a means of prevention of offspring substance use and sexual risk behavior. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  4. Wall Paint Exposure Assessment Model (WPEM)

    Science.gov (United States)

    WPEM uses mathematical models developed from small chamber data to estimate the emissions of chemicals from oil-based (alkyd) and latex wall paint which is then combined with detailed use, workload and occupancy data to estimate user exposure.

  5. Dichlorodiphenyltrichloroethane exposure induces the growth of hepatocellular carcinoma via Wnt/β-catenin pathway.

    Science.gov (United States)

    Jin, Xiao-Ting; Song, Li; Zhao, Jun-Yu; Li, Zhuo-Yu; Zhao, Mei-Rong; Liu, Wei-Ping

    2014-02-10

    Dichlorodiphenyltrichloroethane (DDT) is a persistent organic pollutant, involved in the progression of many cancers, including liver cancer. However, the underlying mechanism(s) of DDT, especially how low doses DDT cause liver cancer, is poorly understood. In this study, we evaluated the impact of p,p'-DDT on the growth of hepatocellular carcinoma using both in vitro and in vivo models. The present data indicated that the proliferation of HepG2 cells was strikingly promoted after exposed to p,p'-DDT for 4 days. In addition, reactive oxygen species (ROS) content was significantly elevated, accompanied with inhibitions of γ-glutamylcysteine synthetase (γ-GCS) and superoxide dismutase (SOD) activities. Interestingly, the levels of β-catenin and its downstream target genes (c-Myc and CyclinD1) were significantly up-regulated, and co-treatment of NAC, the ROS inhibitor, inhibited these over-expressed proteins. Moreover, the p,p'-DDT-stimulated proliferation of HepG2 cells could be reversed after NAC or β-catenin siRNA co-treatment. Likewise, p,p'-DDT treatment increased the growth of tumor in nude mice, stimulated oxidative stress and Wnt/β-catenin pathway. Our study indicates that low doses p,p'-DDT exposure promote the growth of hepatocellular carcinoma via Wnt/β-catenin pathway which is activated by oxidative stress. The finding suggests an association between low dose DDT exposure and liver cancer growth. Crown Copyright © 2013. Published by Elsevier Ireland Ltd. All rights reserved.

  6. Transcriptomic analysis in the developing zebrafish embryo after compound exposure: Individual gene expression and pathway regulation

    Energy Technology Data Exchange (ETDEWEB)

    Hermsen, Sanne A.B., E-mail: Sanne.Hermsen@rivm.nl [Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD, Maastricht (Netherlands); Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.178, 3508 TD, Utrecht (Netherlands); Pronk, Tessa E. [Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Department of Toxicogenomics, Maastricht University, P.O. Box 616, 6200 MD, Maastricht (Netherlands); Brandhof, Evert-Jan van den [Centre for Environmental Quality, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Ven, Leo T.M. van der [Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Piersma, Aldert H. [Centre for Health Protection, National Institute for Public Health and the Environment (RIVM), P.O. Box 1, 3720 BA Bilthoven (Netherlands); Institute for Risk Assessment Sciences (IRAS), Utrecht University, P.O. Box 80.178, 3508 TD, Utrecht (Netherlands)

    2013-10-01

    The zebrafish embryotoxicity test is a promising alternative assay for developmental toxicity. Classically, morphological assessment of the embryos is applied to evaluate the effects of compound exposure. However, by applying differential gene expression analysis the sensitivity and predictability of the test may be increased. For defining gene expression signatures of developmental toxicity, we explored the possibility of using gene expression signatures of compound exposures based on commonly expressed individual genes as well as based on regulated gene pathways. Four developmental toxic compounds were tested in concentration-response design, caffeine, carbamazepine, retinoic acid and valproic acid, and two non-embryotoxic compounds, D-mannitol and saccharin, were included. With transcriptomic analyses we were able to identify commonly expressed genes, which were mostly development related, after exposure to the embryotoxicants. We also identified gene pathways regulated by the embryotoxicants, suggestive of their modes of action. Furthermore, whereas pathways may be regulated by all compounds, individual gene expression within these pathways can differ for each compound. Overall, the present study suggests that the use of individual gene expression signatures as well as pathway regulation may be useful starting points for defining gene biomarkers for predicting embryotoxicity. - Highlights: • The zebrafish embryotoxicity test in combination with transcriptomics was used. • We explored two approaches of defining gene biomarkers for developmental toxicity. • Four compounds in concentration-response design were tested. • We identified commonly expressed individual genes as well as regulated gene pathways. • Both approaches seem suitable starting points for defining gene biomarkers.

  7. Modeling biological pathway dynamics with timed automata.

    Science.gov (United States)

    Schivo, Stefano; Scholma, Jetse; Wanders, Brend; Urquidi Camacho, Ricardo A; van der Vet, Paul E; Karperien, Marcel; Langerak, Rom; van de Pol, Jaco; Post, Janine N

    2014-05-01

    Living cells are constantly subjected to a plethora of environmental stimuli that require integration into an appropriate cellular response. This integration takes place through signal transduction events that form tightly interconnected networks. The understanding of these networks requires capturing their dynamics through computational support and models. ANIMO (analysis of Networks with Interactive Modeling) is a tool that enables the construction and exploration of executable models of biological networks, helping to derive hypotheses and to plan wet-lab experiments. The tool is based on the formalism of Timed Automata, which can be analyzed via the UPPAAL model checker. Thanks to Timed Automata, we can provide a formal semantics for the domain-specific language used to represent signaling networks. This enforces precision and uniformity in the definition of signaling pathways, contributing to the integration of isolated signaling events into complex network models. We propose an approach to discretization of reaction kinetics that allows us to efficiently use UPPAAL as the computational engine to explore the dynamic behavior of the network of interest. A user-friendly interface hides the use of Timed Automata from the user, while keeping the expressive power intact. Abstraction to single-parameter kinetics speeds up construction of models that remain faithful enough to provide meaningful insight. The resulting dynamic behavior of the network components is displayed graphically, allowing for an intuitive and interactive modeling experience.

  8. Ontology modeling for generation of clinical pathways

    Directory of Open Access Journals (Sweden)

    Jasmine Tehrani

    2012-12-01

    Full Text Available Purpose: Increasing costs of health care, fuelled by demand for high quality, cost-effective healthcare has drove hospitals to streamline their patient care delivery systems. One such systematic approach is the adaptation of Clinical Pathways (CP as a tool to increase the quality of healthcare delivery. However, most organizations still rely on are paper-based pathway guidelines or specifications, which have limitations in process management and as a result can influence patient safety outcomes. In this paper, we present a method for generating clinical pathways based on organizational semiotics by capturing knowledge from syntactic, semantic and pragmatic to social level. Design/methodology/approach: The proposed modeling approach to generation of CPs adopts organizational semiotics and enables the generation of semantically rich representation of CP knowledge. Semantic Analysis Method (SAM is applied to explicitly represent the semantics of the concepts, their relationships and patterns of behavior in terms of an ontology chart. Norm Analysis Method (NAM is adopted to identify and formally specify patterns of behavior and rules that govern the actions identified on the ontology chart. Information collected during semantic and norm analysis is integrated to guide the generation of CPs using best practice represented in BPMN thus enabling the automation of CP. Findings: This research confirms the necessity of taking into consideration social aspects in designing information systems and automating CP. The complexity of healthcare processes can be best tackled by analyzing stakeholders, which we treat as social agents, their goals and patterns of action within the agent network. Originality/value: The current modeling methods describe CPs from a structural aspect comprising activities, properties and interrelationships. However, these methods lack a mechanism to describe possible patterns of human behavior and the conditions under which the

  9. The Aggregate Exposure Pathway (AEP): A conceptual framework for advancing exposure science research and applications

    Science.gov (United States)

    Historically, risk assessment has relied upon toxicological data to obtain hazard-based reference levels, which are subsequently compared to exposure estimates to determine whether an unacceptable risk to public health may exist. Recent advances in analytical methods, biomarker ...

  10. CONSEXPO 3.0, consumer exposure and uptake models

    NARCIS (Netherlands)

    Veen MP van; LBM

    2001-01-01

    The report provides a modelling approach to consumer exposure to chemicals, based on mathematical contact, exposure and uptake models. For each route of exposure, a number of exposure and uptake models are included. A general framework joins the exposure and uptake models selected by the user. By

  11. Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver

    Science.gov (United States)

    Pulmonary Ozone Exposure Alters Essential Metabolic Pathways involved in Glucose Homeostasis in the Liver D.B. Johnson, 1 W.O. Ward, 2 V.L. Bass, 2 M.C.J. Schladweiler, 2A.D. Ledbetter, 2 D. Andrews, and U.P. Kodavanti 2 1 Curriculum in Toxicology, UNC School of Medicine, Cha...

  12. EPA's SHEDS-multimedia model: children's cumulative pyrethroid exposure estimates and evaluation against NHANES biomarker data

    Science.gov (United States)

    The U.S. EPA's SHEDS-Multimedia model was applied to enhance the understanding of children's exposures and doses to multiple pyrethroid pesticides, including major contributing chemicals and pathways. This paper presents combined dietary and residential exposure estimates and cum...

  13. [A model for training in laryngeal exposure].

    Science.gov (United States)

    Gotanda, Jun

    2005-07-01

    Laryngeal exposure, applying forward and upward force by laryngoscope after placement of the blade head at the vallecula, is most difficult for begginers to learn in tracheal intubation. It is not so easy to practice at home as the laryngoscope is shaped to lift the tongue upward only. Beginners must establish a proper image of moving the left hand for laryngeal exposure and must be trained in this technique prior to tracheal intubation of patients. Not only begginers but also veterans may struggle with intubating mannequins. The author made a simple model for training laryngeal exposure by Macintosh blade. It has two resembling parts of epiglottis with hyoepiglottic ligament and jaw. It is constructed so that the epiglottis-like part can be elevated only when force through the blade is applied in an correct direction upon it. In this model, beginner can move laryngoscope easily in many ways by his hand before achieving good laryngeal exposure.

  14. 78 FR 60870 - Exposure Modeling Public Meeting

    Science.gov (United States)

    2013-10-02

    ... abstract requests are announced through the ``empmlist'' forum on the LYRIS list server at https://lists...) using long-term ground water monitoring data. 11. Comparing ground water models--why are there..., Leaching, Pesticide exposure assessment, Pesticide monitoring, Sorption model, Spray drift, Surface water...

  15. Multi-Omics Reveals that Lead Exposure Disturbs Gut Microbiome Development, Key Metabolites, and Metabolic Pathways.

    Science.gov (United States)

    Gao, Bei; Chi, Liang; Mahbub, Ridwan; Bian, Xiaoming; Tu, Pengcheng; Ru, Hongyu; Lu, Kun

    2017-04-17

    Lead exposure remains a global public health issue, and the recent Flint water crisis has renewed public concern about lead toxicity. The toxicity of lead has been well established in a variety of systems and organs. The gut microbiome has been shown to be highly involved in many critical physiological processes, including food digestion, immune system development, and metabolic homeostasis. However, despite the key role of the gut microbiome in human health, the functional impact of lead exposure on the gut microbiome has not been studied. The aim of this study is to define gut microbiome toxicity induced by lead exposure in C57BL/6 mice using multiomics approaches, including 16S rRNA sequencing, whole genome metagenomics sequencing, and gas chromatography-mass spectrometry (GC-MS) metabolomics. 16S rRNA sequencing revealed that lead exposure altered the gut microbiome trajectory and phylogenetic diversity. Metagenomics sequencing and metabolomics profiling showed that numerous metabolic pathways, including vitamin E, bile acids, nitrogen metabolism, energy metabolism, oxidative stress, and the defense/detoxification mechanism, were significantly disturbed by lead exposure. These perturbed molecules and pathways may have important implications for lead toxicity in the host. Taken together, these results demonstrated that lead exposure not only altered the gut microbiome community structures/diversity but also greatly affected metabolic functions, leading to gut microbiome toxicity.

  16. Stochastic modeling of virus capsid assembly pathways

    Science.gov (United States)

    Schwartz, Russell

    2009-03-01

    Virus capsids have become a key model system for understanding self-assembly due to their high complexity, robust and efficient assembly processes, and experimental tractability. Our ability to directly examine and manipulate capsid assembly kinetics in detail nonetheless remains limited, creating a need for computer models that can infer experimentally inaccessible features of the assembly process and explore the effects of hypothetical manipulations on assembly trajectories. We have developed novel algorithms for stochastic simulation of capsid assembly [1,2] that allow us to model capsid assembly over broad parameter spaces [3]. We apply these methods to study the nature of assembly pathway control in virus capsids as well as their sensitivity to assembly conditions and possible experimental interventions. [4pt] [1] F. Jamalyaria, R. Rohlfs, and R. Schwartz. J Comp Phys 204, 100 (2005). [0pt] [2] N. Misra and R. Schwartz. J Chem Phys 129, in press (2008). [0pt] [3] B. Sweeney, T. Zhang, and R. Schwartz. Biophys J 94, 772 (2008).

  17. Interpreting metabolomic profiles using unbiased pathway models.

    Directory of Open Access Journals (Sweden)

    Rahul C Deo

    2010-02-01

    Full Text Available Human disease is heterogeneous, with similar disease phenotypes resulting from distinct combinations of genetic and environmental factors. Small-molecule profiling can address disease heterogeneity by evaluating the underlying biologic state of individuals through non-invasive interrogation of plasma metabolite levels. We analyzed metabolite profiles from an oral glucose tolerance test (OGTT in 50 individuals, 25 with normal (NGT and 25 with impaired glucose tolerance (IGT. Our focus was to elucidate underlying biologic processes. Although we initially found little overlap between changed metabolites and preconceived definitions of metabolic pathways, the use of unbiased network approaches identified significant concerted changes. Specifically, we derived a metabolic network with edges drawn between reactant and product nodes in individual reactions and between all substrates of individual enzymes and transporters. We searched for "active modules"--regions of the metabolic network enriched for changes in metabolite levels. Active modules identified relationships among changed metabolites and highlighted the importance of specific solute carriers in metabolite profiles. Furthermore, hierarchical clustering and principal component analysis demonstrated that changed metabolites in OGTT naturally grouped according to the activities of the System A and L amino acid transporters, the osmolyte carrier SLC6A12, and the mitochondrial aspartate-glutamate transporter SLC25A13. Comparison between NGT and IGT groups supported blunted glucose- and/or insulin-stimulated activities in the IGT group. Using unbiased pathway models, we offer evidence supporting the important role of solute carriers in the physiologic response to glucose challenge and conclude that carrier activities are reflected in individual metabolite profiles of perturbation experiments. Given the involvement of transporters in human disease, metabolite profiling may contribute to improved

  18. Gene networks and toxicity pathways induced by acute cadmium exposure in adult largemouth bass (Micropterus salmoides)

    Energy Technology Data Exchange (ETDEWEB)

    Mehinto, Alvine C., E-mail: alvinam@sccwrp.org [Southern California Coastal Water Research Project, Costa Mesa, CA 92626 (United States); Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States); Prucha, Melinda S. [Department of Human Genetics, Yerkes National Primate Research Center, Emory University, Atlanta, GA 30322 (United States); Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States); Colli-Dula, Reyna C.; Kroll, Kevin J.; Lavelle, Candice M.; Barber, David S. [Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States); Vulpe, Christopher D. [Department of Nutritional Sciences and Toxicology, University of California, Berkeley, CA 94720 (United States); Denslow, Nancy D. [Department of Physiological Sciences and Center for Environmental and Human Toxicology, University of Florida, Gainesville, FL 32611 (United States)

    2014-07-01

    Highlights: • Low-level acute cadmium exposure elicited tissue-specific gene expression changes. • Molecular initiating events included oxidative stress and disruption of DNA repair. • Metallothionein, a marker of metal exposure, was not significantly affected. • We report effects of cadmium on cholesterol metabolism and steroid synthesis. • Diabetic complications and impaired reproduction are potential adverse outcomes. - Abstract: Cadmium is a heavy metal that can accumulate to toxic levels in the environment leading to detrimental effects in animals and humans including kidney, liver and lung injuries. Using a transcriptomics approach, genes and cellular pathways affected by a low dose of cadmium were investigated. Adult largemouth bass were intraperitoneally injected with 20 μg/kg of cadmium chloride (mean exposure level – 2.6 μg of cadmium per fish) and microarray analyses were conducted in the liver and testis 48 h after injection. Transcriptomic profiles identified in response to cadmium exposure were tissue-specific with the most differential expression changes found in the liver tissues, which also contained much higher levels of cadmium than the testis. Acute exposure to a low dose of cadmium induced oxidative stress response and oxidative damage pathways in the liver. The mRNA levels of antioxidants such as catalase increased and numerous transcripts related to DNA damage and DNA repair were significantly altered. Hepatic mRNA levels of metallothionein, a molecular marker of metal exposure, did not increase significantly after 48 h exposure. Carbohydrate metabolic pathways were also disrupted with hepatic transcripts such as UDP-glucose, pyrophosphorylase 2, and sorbitol dehydrogenase highly induced. Both tissues exhibited a disruption of steroid signaling pathways. In the testis, estrogen receptor beta and transcripts linked to cholesterol metabolism were suppressed. On the contrary, genes involved in cholesterol metabolism were highly

  19. Noise Exposure Model MOD-5 : Volume 2

    Science.gov (United States)

    1971-06-01

    The report contains three sections. The first two sections are contained in Volume 1. It contains an airport analysis which describes the noise exposure model MOD-5 from the perspective of analysing an airport in order to develop the program input mo...

  20. Noise Exposure Model MOD-5 : Volume 1

    Science.gov (United States)

    1971-06-01

    The report contains three sections. The first two sections are contained in Volume 1. It contains an airport analysis which describes the noise exposure model MOD-5 from the perspective of analysing an airport in order to develop the program input mo...

  1. Health assessment of future PM2.5 exposures from indoor, outdoor, and secondhand tobacco smoke concentrations under alternative policy pathways in Ulaanbaatar, Mongolia.

    Science.gov (United States)

    Hill, L Drew; Edwards, Rufus; Turner, Jay R; Argo, Yuma D; Olkhanud, Purevdorj B; Odsuren, Munkhtuul; Guttikunda, Sarath; Ochir, Chimedsuren; Smith, Kirk R

    2017-01-01

    Winter air pollution in Ulaanbaatar, Mongolia is among the worst in the world. The health impacts of policy decisions affecting air pollution exposures in Ulaanbaatar were modeled and evaluated under business as usual and two more-strict alternative emissions pathways through 2024. Previous studies have relied on either outdoor or indoor concentrations to assesses the health risks of air pollution, but the burden is really a function of total exposure. This study combined projections of indoor and outdoor concentrations of PM2.5 with population time-activity estimates to develop trajectories of total age-specific PM2.5 exposure for the Ulaanbaatar population. Indoor PM2.5 contributions from secondhand tobacco smoke (SHS) were estimated in order to fill out total exposures, and changes in population and background disease were modeled. The health impacts were derived using integrated exposure-response curves from the Global Burden of Disease Study. Annual average population-weighted PM2.5 exposures at baseline (2014) were estimated at 59 μg/m3. These were dominated by exposures occurring indoors, influenced considerably by infiltrated outdoor pollution. Under current control policies, exposures increased slightly to 60 μg/m3 by 2024; under moderate emissions reductions and under a switch to clean technologies, exposures were reduced from baseline levels by 45% and 80%, respectively. The moderate improvement pathway decreased per capita annual disability-adjusted life year (DALY) and death burdens by approximately 40%. A switch to clean fuels decreased per capita annual DALY and death burdens by about 85% by 2024 with the relative SHS contribution increasing substantially. This study demonstrates a way to combine estimated changes in total exposure, background disease and population levels, and exposure-response functions to project the health impacts of alternative policy pathways. The resulting burden analysis highlights the need for aggressive action, including

  2. Health assessment of future PM2.5 exposures from indoor, outdoor, and secondhand tobacco smoke concentrations under alternative policy pathways in Ulaanbaatar, Mongolia.

    Directory of Open Access Journals (Sweden)

    L Drew Hill

    Full Text Available Winter air pollution in Ulaanbaatar, Mongolia is among the worst in the world. The health impacts of policy decisions affecting air pollution exposures in Ulaanbaatar were modeled and evaluated under business as usual and two more-strict alternative emissions pathways through 2024. Previous studies have relied on either outdoor or indoor concentrations to assesses the health risks of air pollution, but the burden is really a function of total exposure. This study combined projections of indoor and outdoor concentrations of PM2.5 with population time-activity estimates to develop trajectories of total age-specific PM2.5 exposure for the Ulaanbaatar population. Indoor PM2.5 contributions from secondhand tobacco smoke (SHS were estimated in order to fill out total exposures, and changes in population and background disease were modeled. The health impacts were derived using integrated exposure-response curves from the Global Burden of Disease Study.Annual average population-weighted PM2.5 exposures at baseline (2014 were estimated at 59 μg/m3. These were dominated by exposures occurring indoors, influenced considerably by infiltrated outdoor pollution. Under current control policies, exposures increased slightly to 60 μg/m3 by 2024; under moderate emissions reductions and under a switch to clean technologies, exposures were reduced from baseline levels by 45% and 80%, respectively. The moderate improvement pathway decreased per capita annual disability-adjusted life year (DALY and death burdens by approximately 40%. A switch to clean fuels decreased per capita annual DALY and death burdens by about 85% by 2024 with the relative SHS contribution increasing substantially.This study demonstrates a way to combine estimated changes in total exposure, background disease and population levels, and exposure-response functions to project the health impacts of alternative policy pathways. The resulting burden analysis highlights the need for aggressive

  3. Chronic Low Dose Chlorine Exposure Aggravates Allergic Inflammation and Airway Hyperresponsiveness and Activates Inflammasome Pathway

    Science.gov (United States)

    Kim, Sae-Hoon; Park, Da-Eun; Lee, Hyun-Seung; Kang, Hye-Ryun; Cho, Sang-Heon

    2014-01-01

    Background Epidemiologic clinical studies suggested that chronic exposure to chlorine products is associated with development of asthma and aggravation of asthmatic symptoms. However, its underlying mechanism was not clearly understood. Studies were undertaken to define the effects and mechanisms of chronic low-dose chlorine exposure in the pathogenesis of airway inflammation and airway hyperresponsiveness (AHR). Methods Six week-old female BALB/c mice were sensitized and challenged with OVA in the presence and absence of chronic low dose chlorine exposure of naturally vaporized gas of 5% sodium hypochlorite solution. Airway inflammation and AHR were evaluated by bronchoalveolar lavage (BAL) cell recovery and non-invasive phlethysmography, respectively. Real-time qPCR, Western blot assay, and ELISA were used to evaluate the mRNA and protein expressions of cytokines and other inflammatory mediators. Human A549 and murine epithelial (A549 and MLE12) and macrophage (AMJ2-C11) cells were used to define the responses to low dose chlorine exposure in vitro. Results Chronic low dose chlorine exposure significantly augmented airway inflammation and AHR in OVA-sensitized and challenged mice. The expression of Th2 cytokines IL-4 and IL-5 and proinflammatory cytokine IL-1β and IL-33 were significantly increased in OVA/Cl group compared with OVA group. The chlorine exposure also activates the major molecules associated with inflammasome pathway in the macrophages with increased expression of epithelial alarmins IL-33 and TSLP in vitro. Conclusion Chronic low dose exposure of chlorine aggravates allergic Th2 inflammation and AHR potentially through activation of inflammasome danger signaling pathways. PMID:25202911

  4. Repeated allergen exposure reduce early phase airway response and leukotriene release despite upregulation of 5-lipoxygenase pathways

    Directory of Open Access Journals (Sweden)

    Cui Zhi-Hua

    2012-03-01

    Full Text Available Abstract Background Allergen induced early phase airway response and airway plasma exudation are predominantly mediated by inflammatory mast cell mediators including histamine, cysteinyl leukotrienes (cysLTs and thromboxane A2 (TXA2. The aim of the present study was to evaluate whether repeated allergen exposure affects early phase airway response to allergen challenge. Methods A trimellitic anhydride (TMA sensitized guinea pig model was used to investigate the effects of low dose repeated allergen exposure on cholinergic airway responsiveness, early phase airway response and plasma exudation, as well as local airway production of mast cell derived cysteinyl leukotrienes and thromboxane B2 (TXB2 after allergen challenge. Results Repeated low dose allergen exposure increased cholinergic airway responsiveness. In contrast, early phase airway response and plasma exudation in response to a high-dose allergen challenge were strongly attenuated after repeated low dose allergen exposure. Inhibition of the airway response was unspecific to exposed allergen and independent of histamine receptor blocking. Furthermore, a significant reduction of cysteinyl leukotrienes and TXB2 was found in the airways of animals repeatedly exposed to a low dose allergen. However, in vitro stimulation of airway tissue from animals repeatedly exposed to a low dose allergen with arachidonic acid and calcium ionophore (A23187 induced production of cysteinyl leukotrienes and TXB2, suggesting enhanced activity of 5-lipoxygenase and cyclooxygenase pathways. Conclusions The inhibition of the early phase airway response, cysteinyl leukotriene and TXB2 production after repeated allergen exposure may result from unresponsive effector cells.

  5. Developmental Lead Exposure Alters Synaptogenesis through Inhibiting Canonical Wnt Pathway In Vivo and In Vitro

    Science.gov (United States)

    Hu, Fan; Xu, Li; Liu, Zhi-Hua; Ge, Meng-Meng; Ruan, Di-Yun; Wang, Hui-Li

    2014-01-01

    Lead (Pb) exposure has been implicated in the impairment of synaptic plasticity in the developing hippocampus, but the mechanism remains unclear. Here, we investigated whether developmental lead exposure affects the dendritic spine formation through Wnt signaling pathway in vivo and in vitro. Sprague–Dawley rats were exposed to lead throughout the lactation period and Golgi-Cox staining method was used to examine the spine density of pyramidal neurons in the hippocampal CA1 area of rats. We found that lead exposure significantly decreased the spine density in both 14 and 21 days-old pups, accompanied by a significant age-dependent decline of the Wnt7a expression and stability of its downstream protein (β-catenin). Furthermore, in cultured hippocampal neurons, lead (0.1 and 1 µM lead acetate) significantly decreased the spine density in a dose-dependent manner. Exogenous Wnt7a application attenuated the decrease of spine density and increased the stability of the downstream molecules in Wnt signaling pathway. Together, our results suggest that lead has a negative impact on spine outgrowth in the developing hippocampus through altering the canonical Wnt pathway. PMID:24999626

  6. Human inorganic mercury exposure, renal effects and possible pathways in Wanshan mercury mining area, China.

    Science.gov (United States)

    Li, Ping; Du, Buyun; Chan, Hing Man; Feng, Xinbin

    2015-07-01

    Rice can accumulate methylmercury (MeHg) and rice consumption is the main route of MeHg exposure for the local population in Guizhou, China. However, inorganic Hg (IHg) load in human body is not comprehensively studied in highly Hg polluted areas such as Hg mining areas. This study is designed to evaluate human IHg exposure, related renal effects and possible pathways in Wanshan Hg mining area, Guizhou, Southwest China. Residents lived within 3 km to the mine waste heaps showed high Urine Hg (UHg) concentrations and the geometrical means (Geomean) of UHg were 8.29, 5.13, and 10.3 μg/g Creatinine (Cr) at site A, D, and E, respectively. It demonstrated a gradient of UHg concentrations with the distance from the pollution sources. A significantly positive correlation between paired results for UHg concentrations and serum creatinine (SCr) was observed in this study, but not for UHg and blood urea nitrogen (BUN). There are significant increases of SCr in two quartiles with high UHg concentrations. The results indicated that human IHg exposure may cause impairment of renal function. By calculation of Probable Daily Intake from different routes, we found that dietary intake is the main pathway of IHg exposure for the local population, rather than inhalation of Hg vapor. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. Metabolic modeling of Rosmarinic acid biosynthetic pathway

    OpenAIRE

    Sundaram, Shanthy; Tripathi, Ashutosh; Gupta, Deepak K

    2010-01-01

    Rosmarinic acid (RA) is an ester of caffeic acid and 3, 4‐dihydroxyphenyllacticacid. It is commonly found in Coleus blumei, Salvia officinalis, Melissa officinalis and Rosmarinus officinalis. The biosynthesis of RA starts with precursor molecules L‐phenylalanine and L‐tyrosine. Simulation of RA biosynthetic pathway was done using Gepasi Software, includes the reaction kinetics of each step of the pathway and different integration methods such as Euler's method. Optimization of the significant...

  8. Integrated Exposure Modeling: A Model Using GIS and GLM

    OpenAIRE

    Holford, Theodore R.; Ebisu, Keita; McKay, Lisa A.; Gent, Janneane F.; Triche, Elizabeth W.; Bracken, Michael B; Leaderer, Brian P.

    2010-01-01

    Traffic exhaust is a source of air contaminants that have adverse health effects. Quantification of traffic as an exposure variable is complicated by aerosol dispersion related to variation in layout of roads, traffic density, meteorology, and topography. A statistical model is presented which uses Geographic Information Systems (GIS) technology to incorporate variables into a generalized linear model that estimates distribution of traffic-related pollution. Exposure from a source is expresse...

  9. The Health Impacts of Energy Policy Pathways in Ulaanbaatar, Mongolia: A Total Exposure Assessment

    Science.gov (United States)

    Hill, L. A.; Damdinsuren, Y.; Olkhanud, P. B.; Smith, K. R.; Turner, J. R.; Edwards, R.; Odsuren, M.; Ochir, C.

    2015-12-01

    Ulaanbaatar is home to nearly half of Mongolia's 2.8 million residents. The city's rapid growth, frigid winters, valley topography, and reliance on coal-fired stoves have led to some of the worst winter pollution levels in the world. To better understand this issue, we modeled integrated PM2.5exposures and related health impacts for various city-wide heating policies through 2024. This assessment is one of the first to employ a total exposure approach and results of the 2014 Comparative Risk Assessments of the Global Burden of Disease Project (CRA/GBD) in a policy-relevant energy study. Emissions related to heating, traffic, and power generation were considered under Business as Usual, Moderate Improvement, and Max Improvement scenarios. Calibrated outdoor models were combined with indoor models, local infiltration and time activity estimates, and demographic projections to estimate PM2.5exposures in 2014 and 2024. Indoor exposures were assigned by heating type, home type, and smoking status; outdoor exposures were assigned through geocoding. Population average annual exposures were calculated and applied to local disease rates and integrated exposure-response curves (2014 CRA/GBD) to arrive at annual projections of premature deaths and DALYs. We estimate 2014 annual average exposures at 68 μg/m3, dictated almost exclusively by indoor winter exposures. Under current trends, annual exposures increase 10% to 75 μg/m3 in 2024. This is in stark contrast to the moderate and max improvement scenarios, which lead to 2024 annual exposures that are 31%, and 68% lower, respectively. Under the Moderate scenario, 2024 per capita annual DALY and death burdens drop 26% and 22%, respectively, from 2014 levels. Under the Max scenario, 2024 per capita annual DALY and death burdens drop 71% and 66%, respectively, from 2014. SHS becomes a major contributor as emissions from other sectors decrease. Reductions are dominated by cardiovascular and lower respiratory diseases in children.

  10. Cadmium exposure pathways in a population living near a battery plant.

    Science.gov (United States)

    Hellström, Lennart; Persson, Bodil; Brudin, Lars; Grawé, Kierstin Petersson; Oborn, Ingrid; Järup, Lars

    2007-02-15

    The objectives of the present study were to assess the relative impact of different pathways of environmental cadmium (Cd) exposure and to evaluate the contribution from locally produced vegetables and root crops to the total dietary intake of Cd. Cadmium in urine was determined for 492 individuals living near a closed down battery factory in Sweden. For each individual we created an environmental exposure-index based on Cd emissions to ambient air and number of years living at various distances from the plant. This information as well as dietary data were collected via questionnaires. Samples of soil, carrots and/or potatoes were collected from 37 gardens and analysed for Cd concentration. Eating home grown vegetables/potatoes, environmental Cd-exposure-index, female gender, age above 30 years and smoking more than one pack of cigarettes daily for at least 10 years were found to be significantly associated with increased urine concentrations of Cd (UCd>1.0 nmol/mmol creatinine). We found a statistically significant relation between Cd in urine and environmental Cd-exposure-index in persons eating home grown vegetables/potatoes regularly. Cd concentrations in home grown carrots, potatoes and in garden soil were highest in the area closest to the factory. Daily consumption of potatoes and vegetables cultivated in the vicinity of the closed battery factory was estimated to increase Cd intake by 18-38%. The present study shows that consumption of locally grown vegetables and root crops was an important exposure pathway, in subjects living near a nickel-cadmium battery plant, whereas direct exposure via ambient air was less important.

  11. Novel personalized pathway-based metabolomics models reveal key metabolic pathways for breast cancer diagnosis

    DEFF Research Database (Denmark)

    Huang, Sijia; Chong, Nicole; Lewis, Nathan

    2016-01-01

    metabolomics data for disease diagnosis. Applying this method to blood-based breast cancer metabolomics data, we have discovered crucial metabolic pathway signatures for breast cancer diagnosis, especially early diagnosis. Further, this modeling approach may be generalized to other omics data types for disease.......993. Moreover, important metabolic pathways, such as taurine and hypotaurine metabolism and the alanine, aspartate, and glutamate pathway, are revealed as critical biological pathways for early diagnosis of breast cancer. Conclusions: We have successfully developed a new type of pathway-based model to study......Background: More accurate diagnostic methods are pressingly needed to diagnose breast cancer, the most common malignant cancer in women worldwide. Blood-based metabolomics is a promising diagnostic method for breast cancer. However, many metabolic biomarkers are difficult to replicate among studies...

  12. Modelling of skin exposure from distributed sources

    DEFF Research Database (Denmark)

    Fogh, C.L.; Andersson, Kasper Grann

    2000-01-01

    A simple model of indoor air pollution concentrations was used together with experimental results on deposition velocities to skin to calculate the skin dose from an outdoor plume of contaminants, The primary pathway was considered to be direct deposition to the skin from a homogeneously distribu...... distributed air source. The model has been used to show that skin deposition was a significant dose contributor for example when compared to inhalation dose. (C) 2000 British Occupational Hygiene Society, Published by Elsevier Science Ltd. All rights reserved....

  13. Modeling Exposure of Mammalian Predatorsto Anticoagulant Rodenticides

    DEFF Research Database (Denmark)

    Topping, Christopher John; Elmeros, Morten

    2016-01-01

    Anticoagulant rodenticides (AR) are a widespread and effective method of rodent control but there is concern about the impact these may have on non-target organisms, in particular secondary poisoning of rodent predators. Incidence and concentration of AR in free-living predators in Denmark is very...... as vectors of AR, and was used to evaluate likely impacts of restrictions imposed on AR use in Denmark banning the use of rodenticides for plant protection in woodlands and tree-crops. The model uses input based on frequencies and timings of baiting for rodent control for urban, rural and woodland locations...... and after the change in AR use. In most cases incidence of exposure to AR is predicted to be greater than 90%, although cessation of use in woodlots and Christmas tree plantations should reduce mean exposure concentrations. Model results suggest that the driver of high AR incidence in non-target small...

  14. Long-term human exposure to lead from different media and intake pathways

    DEFF Research Database (Denmark)

    Pizzol, Massimo; Thomsen, Marianne; Andersen, Mikael Skou

    2010-01-01

    , and predicting the resulting internal body exposure levels and effects that occur under long-term exposure conditions. In this paper, a modeling approach is used to meet these challenges with reference to Danish exposure conditions. Levels of lead content in various media have been coupled with data for lead......Lead (Pb) is well known as an environmental pollutant: it can accumulate in various media, so actual lead exposure reflects both historical and present contaminations. Two main challenges then emerge: obtaining updated information to gain an overall picture of the sources of exposure......–internalconcentration relationships for the direct linkage between lead in environmental media and resultingconcentrations of lead in blood are then presented....

  15. In Vitro Manganese Exposure Disrupts MAPK Signaling Pathways in Striatal and Hippocampal Slices from Immature Rats

    Directory of Open Access Journals (Sweden)

    Tanara Vieira Peres

    2013-01-01

    Full Text Available The molecular mechanisms mediating manganese (Mn-induced neurotoxicity, particularly in the immature central nervous system, have yet to be completely understood. In this study, we investigated whether mitogen-activated protein kinases (MAPKs and tyrosine hydroxylase (TH could represent potential targets of Mn in striatal and hippocampal slices obtained from immature rats (14 days old. The aim of this study was to evaluate if the MAPK pathways are modulated after subtoxic Mn exposure, which do not significantly affect cell viability. The concentrations of manganese chloride (MnCl2; 10–1,000 μM caused no change in cell viability in slices exposed for 3 or 6 hours. However, Mn exposure significantly increased extracellular signal-regulated kinase (ERK 1/2, as well as c-Jun N-terminal kinase (JNK 1/2/3 phosphorylation at both 3 and 6 hours incubations, in both brain structures. Furthermore, Mn exposure did not change the total content or phosphorylation of TH at the serine 40 site in striatal slices. Thus, Mn at concentrations that do not disrupt cell viability causes activation of MAPKs (ERK1/2 and JNK1/2/3 in immature hippocampal and striatal slices. These findings suggest that altered intracellular MAPKs signaling pathways may represent an early event concerning the effects of Mn in the immature brain.

  16. Operation of the computer model for microenvironment atomic oxygen exposure

    Science.gov (United States)

    Bourassa, R. J.; Gillis, J. R.; Gruenbaum, P. E.

    1995-01-01

    A computer model for microenvironment atomic oxygen exposure has been developed to extend atomic oxygen modeling capability to include shadowing and reflections. The model uses average exposure conditions established by the direct exposure model and extends the application of these conditions to treat surfaces of arbitrary shape and orientation.

  17. Developmental pathways from prenatal marijuana exposure to Cannabis Use Disorder in young adulthood.

    Science.gov (United States)

    Sonon, Kristen; Richardson, Gale A; Cornelius, Jack; Kim, Kevin H; Day, Nancy L

    Earlier studies reported an association between prenatal marijuana exposure (PME) and cognitive and behavioral problems in the offspring. A recent publication demonstrated the relation between PME and offspring marijuana use at age 22. There are no reports of the association between PME and Cannabis Use Disorder (CUD) at 22years, the age when use of marijuana and CUD peak. Subjects are from the Maternal Health Practices and Child Development Study, a longitudinal study of PME and other exposures during pregnancy. The cohort of mothers and their offspring has been followed since the fourth prenatal month through 22years of age. A path analysis was conducted on 590 mother-child pairs, representing 77% of the birth cohort, to examine potential pathways from PME to CUD in offspring at 22years of age. There is no direct effect of PME on CUD. There are, however, two indirect pathways from PME to CUD. In the first, the pathway from PME to CUD goes through offspring early age of marijuana onset. In the second, offspring depression at age 10 and early age of marijuana onset predict CUD. Although there is no direct effect of PME on CUD, there are significant indirect pathways from PME to CUD that affect the rate of CUD in the population. Thus, PME, offspring depression, and an early age of marijuana initiation, are significant points for intervention. As marijuana is legalized in more states, the rates of marijuana use will increase significantly, including during pregnancy, and the consequences of the association between PME and CUD will become even more significant from a public health perspective. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Mathematical modelling of the MAP kinase pathway using proteomic datasets.

    Science.gov (United States)

    Tian, Tianhai; Song, Jiangning

    2012-01-01

    The advances in proteomics technologies offer an unprecedented opportunity and valuable resources to understand how living organisms execute necessary functions at systems levels. However, little work has been done up to date to utilize the highly accurate spatio-temporal dynamic proteome data generated by phosphoprotemics for mathematical modeling of complex cell signaling pathways. This work proposed a novel computational framework to develop mathematical models based on proteomic datasets. Using the MAP kinase pathway as the test system, we developed a mathematical model including the cytosolic and nuclear subsystems; and applied the genetic algorithm to infer unknown model parameters. Robustness property of the mathematical model was used as a criterion to select the appropriate rate constants from the estimated candidates. Quantitative information regarding the absolute protein concentrations was used to refine the mathematical model. We have demonstrated that the incorporation of more experimental data could significantly enhance both the simulation accuracy and robustness property of the proposed model. In addition, we used the MAP kinase pathway inhibited by phosphatases with different concentrations to predict the signal output influenced by different cellular conditions. Our predictions are in good agreement with the experimental observations when the MAP kinase pathway was inhibited by phosphatase PP2A and MKP3. The successful application of the proposed modeling framework to the MAP kinase pathway suggests that our method is very promising for developing accurate mathematical models and yielding insights into the regulatory mechanisms of complex cell signaling pathways.

  19. Determinants of Dermal Exposure Relevant for Exposure Modelling in Regulatory Risk Assessment

    NARCIS (Netherlands)

    Marquart, J.; Brouwer, D.H.; Gijsbers, J.H.J.; Links, I.H.M.; Warren, N.; Hemmen, J.J. van

    2003-01-01

    Risk assessment of chemicals requires assessment of the exposure levels of workers. In the absence of adequate specific measured data, models are often used to estimate exposure levels. For dermal exposure only a few models exist, which are not validated externally. In the scope of a large European

  20. Alterations in the heme biosynthetic pathway as an index of exposure to toxins

    Energy Technology Data Exchange (ETDEWEB)

    Marks, G.S.; Zelt, D.T.; Cole, S.P.

    1982-07-01

    Under normal circumstances the heme biosynthetic pathway is carefully controlled and porphyrins are formed in only trace amounts. When control mechanisms are disturbed by xenobiotics, porphyrins may be formed and serve as a signal of the interaction between a xenobiotic and the heme biosynthetic pathway. For example, porphyrinuria was an early manifestation of a hexachlorobenzene-induced porphyria outbreak in Turkey. In humans exposed to polybrominated biphenyls and to 2,3,7,8-tetrachlorodibenzo-p-dioxin the urinary porphyrin pattern was significantly different from normal in a large number of exposed individuals. The question is raised whether measurement of urinary porphyrin profiles by improved methods will enable an estimate to be made of the extent of exposure to haloaromatic hydrocarbons in the human population. A wide variety of xenobiotics interact with the prosthetic heme of cytochrome P-450 forming novel N-alkylporphyrins. Identification of these N-alkylporphyrins in body fluids might provide a means of assessing exposure to a variety of xenobiotics in human populations.

  1. Impact of exposure time, particle size and uptake pathway on silver nanoparticle effects on circulating immune cells in mytilus galloprovincialis.

    Science.gov (United States)

    Bouallegui, Younes; Ben Younes, Ridha; Turki, Faten; Oueslati, Ridha

    2017-12-01

    Nanomaterials have increasingly emerged as potential pollutants to aquatic organisms. Nanomaterials are known to be taken up by hemocytes of marine invertebrates including Mytilus galloprovincialis. Indeed, assessments of hemocyte-related parameters are a valuable tool in the determination of potentials for nanoparticle (NP) toxicity. The present study assessed the effects from two size types of silver nanoparticles (AgNP: <50 nm and <100 nm) on the frequency of hemocytes subpopulations as immunomodulation biomarkers exposed in a mollusk host. Studies were performed using exposures prior to and after inhibition of potential NP uptake pathways (i.e. clathrin- and caveolae-mediated endocytosis) and over different durations of exposure (3, 6 and 12 h). Differential hemocyte counts (DHC) revealed significant variations in frequency of different immune cells in mussels exposed for 3 hr to either AgNP size. However, as exposure duration progressed cell levels were subsequently differentially altered depending on particle size (i.e. no significant effects after 3 h with larger AgNP). AgNP effects were also delayed/varied after blockade of either clathrin- or caveolae-mediated endocytosis. The results also noted significant negative correlations between changes in levels hyalinocytes and acidophils or in levels basophils and acidophils as a result of AgNP exposure. From these results, we concluded AgNP effects on mussels were size and duration of exposure dependent. This study highlighted how not only was NP size important, but that differing internalization mechanisms could be key factors impacting on the potential for NP in the environment to induce immunomodulation in a model/test sentinel host like M. galloprovincialis.

  2. Metabolic modeling of Rosmarinic acid biosynthetic pathway

    Science.gov (United States)

    Sundaram, Shanthy; Tripathi, Ashutosh; Gupta, Deepak K

    2010-01-01

    Rosmarinic acid (RA) is an ester of caffeic acid and 3, 4‐dihydroxyphenyllacticacid. It is commonly found in Coleus blumei, Salvia officinalis, Melissa officinalis and Rosmarinus officinalis. The biosynthesis of RA starts with precursor molecules L‐phenylalanine and L‐tyrosine. Simulation of RA biosynthetic pathway was done using Gepasi Software, includes the reaction kinetics of each step of the pathway and different integration methods such as Euler's method. Optimization of the significant parameters responsible for RA biosynthesis was carried out. As the goal of the work was to increase the productivity of i.e. to maximize the concentration of the RA, the final concentration of RA ([RA]t) was selected as an objective function and selected initial concentration of the Caffeoyl‐3’‐4’hydroxyphenyllactic acid (3’C4HPLA) as parameter constraint and varied its initial concentration as: 0≤ [3’C4HPLA]i ≤ 0.025. Several optimization methods such as Simulated annealing, Evolutionary algorithms and Genetic algorithms were used to optimize the objective function. After optimization the final concentration of RA was slightly higher (4.566132e‐002 mM) than before optimization (4.047119e‐ 002 mM). On the basis of results obtained, it is clear that 4‐hydroxyphenyllactic acid and 3’C4HPLA play major role in the high productivity of the RA. PMID:21364781

  3. Version control of pathway models using XML patches.

    Science.gov (United States)

    Saffrey, Peter; Orton, Richard

    2009-03-17

    Computational modelling has become an important tool in understanding biological systems such as signalling pathways. With an increase in size complexity of models comes a need for techniques to manage model versions and their relationship to one another. Model version control for pathway models shares some of the features of software version control but has a number of differences that warrant a specific solution. We present a model version control method, along with a prototype implementation, based on XML patches. We show its application to the EGF/RAS/RAF pathway. Our method allows quick and convenient storage of a wide range of model variations and enables a thorough explanation of these variations. Trying to produce these results without such methods results in slow and cumbersome development that is prone to frustration and human error.

  4. Stochastic modeling of near-field exposure to parabens in personal care products.

    Science.gov (United States)

    Csiszar, Susan A; Ernstoff, Alexi S; Fantke, Peter; Jolliet, Olivier

    2017-03-01

    Exposure assessment is a key step in determining risks to chemicals in consumer goods, including personal care products (PCPs). Exposure models can be used to estimate exposures to chemicals in the absence of biomonitoring data and as tools in chemical risk prioritization and screening. We apply a PCP exposure model based on the product intake fraction (PiF), which is defined as the fraction of chemical in a product that is taken in by the exposed population, to estimate chemical intake based on physicochemical properties and PCP usage characteristics. The PiF can be used to estimate route and pathway-specific exposures during both the use and disposal stages of a product. As a case study, we stochastically quantified population level exposures to parabens in PCPs, and compared estimates with biomarker values. We estimated exposure based on the usage of PCPs in the female US population, taking into account population variability, product usage characteristics, paraben occurrence in PCPs and the PiF. Intakes were converted to urine levels and compared with National Health and Nutrition Examination Survey (NHANES) biomonitoring data. Results suggest that for parabens, chemical exposure during product use is substantially larger than environmentally mediated exposure after product disposal. Modeled urine concentrations reflect well the NHANES variation of three orders of magnitude across parabens for the 50th, 75th, 90th, and 95th percentiles and were generally in good agreement with measurements, when taking uncertainty into account. This study presents an approach to estimate multi-pathway exposure to chemicals in PCPs and can be used as a tool within exposure-based screening of chemicals as well in higher tier exposure estimates.

  5. AirPEx: Air Pollution Exposure Model

    OpenAIRE

    Freijer JI; Bloemen HJTh; Loos S de; Marra M; Rombout PJA; Steentjes GM; Veen MP van; LBO

    1997-01-01

    Analysis of inhalatory exposure to air pollution is an important area of investigation when assessing the risks of air pollution for human health. Inhalatory exposure research focuses on the exposure of humans to air pollutants and the entry of these pollutants into the human respiratory tract. The principal grounds for studying the inhalatory exposure of humans to air pollutants are formed by the need for realistic exposure/dose estimates to evaluate the health effects of these pollutants. T...

  6. Integrated exposure modeling: a model using GIS and GLM.

    Science.gov (United States)

    Holford, Theodore R; Ebisu, Keita; McKay, Lisa A; Gent, Janneane F; Triche, Elizabeth W; Bracken, Michael B; Leaderer, Brian P

    2010-01-15

    Traffic exhaust is a source of air contaminants that have adverse health effects. Quantification of traffic as an exposure variable is complicated by aerosol dispersion related to variation in layout of roads, traffic density, meteorology, and topography. A statistical model is presented that uses Geographic Information Systems (GIS) technology to incorporate variables into a generalized linear model that estimates distribution of traffic-related pollution. Exposure from a source is expressed as an integral of a function proportional to average daily traffic and a nonparametric dispersion function, which takes the form of a step, polynomial, or spline model. The method may be applied using standard regression techniques for fitting generalized linear models. Modifiers of pollutant dispersion such as wind direction, meteorology, and landscape features can also be included. Two examples are given to illustrate the method. The first employs data from a study in which NO(2) (a known pollutant from automobile exhaust) was monitored outside of 138 Connecticut homes, providing a model for estimating NO(2) exposure. In the second example, estimated levels of nitrogen dioxide (NO(2)) from the model, as well as a separate spatial model, were used to analyze traffic-related health effects in a study of 761 infants.

  7. Exposure of Human Lung Cells to Tobacco Smoke Condensate Inhibits the Nucleotide Excision Repair Pathway.

    Directory of Open Access Journals (Sweden)

    Nathaniel Holcomb

    Full Text Available Exposure to tobacco smoke is the number one risk factor for lung cancer. Although the DNA damaging properties of tobacco smoke have been well documented, relatively few studies have examined its effect on DNA repair pathways. This is especially true for the nucleotide excision repair (NER pathway which recognizes and removes many structurally diverse DNA lesions, including those introduced by chemical carcinogens present in tobacco smoke. The aim of the present study was to investigate the effect of tobacco smoke on NER in human lung cells. We studied the effect of cigarette smoke condensate (CSC, a surrogate for tobacco smoke, on the NER pathway in two different human lung cell lines; IMR-90 lung fibroblasts and BEAS-2B bronchial epithelial cells. To measure NER, we employed a slot-blot assay to quantify the introduction and removal of UV light-induced 6-4 photoproducts and cyclobutane pyrimidine dimers. We find a dose-dependent inhibition of 6-4 photoproduct repair in both cell lines treated with CSC. Additionally, the impact of CSC on the abundance of various NER proteins and their respective RNAs was investigated. The abundance of XPC protein, which is required for functional NER, is significantly reduced by treatment with CSC while the abundance of XPA protein, also required for NER, is unaffected. Both XPC and XPA RNA levels are modestly reduced by CSC treatment. Finally, treatment of cells with MG-132 abrogates the reduction in the abundance of XPC protein produced by treatment with CSC, suggesting that CSC enhances proteasome-dependent turnover of the protein that is mediated by ubiquitination. Together, these findings indicate that tobacco smoke can inhibit the same DNA repair pathway that is also essential for the removal of some of the carcinogenic DNA damage introduced by smoke itself, increasing the DNA damage burden of cells exposed to tobacco smoke.

  8. Computational Modeling of Biological Systems From Molecules to Pathways

    CERN Document Server

    2012-01-01

    Computational modeling is emerging as a powerful new approach for studying and manipulating biological systems. Many diverse methods have been developed to model, visualize, and rationally alter these systems at various length scales, from atomic resolution to the level of cellular pathways. Processes taking place at larger time and length scales, such as molecular evolution, have also greatly benefited from new breeds of computational approaches. Computational Modeling of Biological Systems: From Molecules to Pathways provides an overview of established computational methods for the modeling of biologically and medically relevant systems. It is suitable for researchers and professionals working in the fields of biophysics, computational biology, systems biology, and molecular medicine.

  9. A kinetic model for the penicillin biosynthetic pathway in

    DEFF Research Database (Denmark)

    Nielsen, Jens; Jørgensen, Henrik

    1996-01-01

    A kinetic model for the first two steps in the penicillin biosynthetic pathway, i.e. the ACV synthetase (ACVS) and the isopenicillin N synthetase (IPNS) is proposed. The model is based on Michaelis-Menten type kinetics with non-competitive inhibition of the ACVS by ACV, and competitive inhibition...... of the IPNS by glutathione. The model predicted flux through the pathway corresponds well with the measured rate of penicillin biosynthesis. From the kinetic model the elasticity coefficients and the flux control coefficients are calculated throughout a fed-batch cultivation, and it is found...

  10. Developing a job-exposure matrix with exposure uncertainty from expert elicitation and data modeling.

    Science.gov (United States)

    Fischer, Heidi J; Vergara, Ximena P; Yost, Michael; Silva, Michael; Lombardi, David A; Kheifets, Leeka

    2017-01-01

    Job exposure matrices (JEMs) are tools used to classify exposures for job titles based on general job tasks in the absence of individual level data. However, exposure uncertainty due to variations in worker practices, job conditions, and the quality of data has never been quantified systematically in a JEM. We describe a methodology for creating a JEM which defines occupational exposures on a continuous scale and utilizes elicitation methods to quantify exposure uncertainty by assigning exposures probability distributions with parameters determined through expert involvement. Experts use their knowledge to develop mathematical models using related exposure surrogate data in the absence of available occupational level data and to adjust model output against other similar occupations. Formal expert elicitation methods provided a consistent, efficient process to incorporate expert judgment into a large, consensus-based JEM. A population-based electric shock JEM was created using these methods, allowing for transparent estimates of exposure.

  11. INDUSTRIAL ODORANTS - THE RELATIONSHIP BETWEEN MODELED EXPOSURE CONCENTRATIONS AND ANNOYANCE

    NARCIS (Netherlands)

    CAVALINI, PM

    1994-01-01

    In a series of epidemiologic studies, the relationship between objective exposure to odorant concentrations emitted by several industrial plants was investigated, as was the relationship between odor annoyance and subjective health complaints. Exposure was determined with a dispersion model of

  12. Modelling and Analysis of Biochemical Signalling Pathway Cross-talk

    Directory of Open Access Journals (Sweden)

    Robin Donaldson

    2010-02-01

    Full Text Available Signalling pathways are abstractions that help life scientists structure the coordination of cellular activity. Cross-talk between pathways accounts for many of the complex behaviours exhibited by signalling pathways and is often critical in producing the correct signal-response relationship. Formal models of signalling pathways and cross-talk in particular can aid understanding and drive experimentation. We define an approach to modelling based on the concept that a pathway is the (synchronising parallel composition of instances of generic modules (with internal and external labels. Pathways are then composed by (synchronising parallel composition and renaming; different types of cross-talk result from different combinations of synchronisation and renaming. We define a number of generic modules in PRISM and five types of cross-talk: signal flow, substrate availability, receptor function, gene expression and intracellular communication. We show that Continuous Stochastic Logic properties can both detect and distinguish the types of cross-talk. The approach is illustrated with small examples and an analysis of the cross-talk between the TGF-b/BMP, WNT and MAPK pathways.

  13. Relative Contributions of Agricultural Drift, Para-Occupational, and Residential Use Exposure Pathways to House Dust Pesticide Concentrations: Meta-Regression of Published Data.

    Science.gov (United States)

    Deziel, Nicole C; Freeman, Laura E Beane; Graubard, Barry I; Jones, Rena R; Hoppin, Jane A; Thomas, Kent; Hines, Cynthia J; Blair, Aaron; Sandler, Dale P; Chen, Honglei; Lubin, Jay H; Andreotti, Gabriella; Alavanja, Michael C R; Friesen, Melissa C

    2017-03-01

    Increased pesticide concentrations in house dust in agricultural areas have been attributed to several exposure pathways, including agricultural drift, para-occupational, and residential use. To guide future exposure assessment efforts, we quantified relative contributions of these pathways using meta-regression models of published data on dust pesticide concentrations. From studies in North American agricultural areas published from 1995 to 2015, we abstracted dust pesticide concentrations reported as summary statistics [e.g., geometric means (GM)]. We analyzed these data using mixed-effects meta-regression models that weighted each summary statistic by its inverse variance. Dependent variables were either the log-transformed GM (drift) or the log-transformed ratio of GMs from two groups (para-occupational, residential use). For the drift pathway, predicted GMs decreased sharply and nonlinearly, with GMs 64% lower in homes 250 m versus 23 m from fields (interquartile range of published data) based on 52 statistics from seven studies. For the para-occupational pathway, GMs were 2.3 times higher [95% confidence interval (CI): 1.5, 3.3; 15 statistics, five studies] in homes of farmers who applied pesticides more recently or frequently versus less recently or frequently. For the residential use pathway, GMs were 1.3 (95% CI: 1.1, 1.4) and 1.5 (95% CI: 1.2, 1.9) times higher in treated versus untreated homes, when the probability that a pesticide was used for the pest treatment was 1-19% and ≥ 20%, respectively (88 statistics, five studies). Our quantification of the relative contributions of pesticide exposure pathways in agricultural populations could improve exposure assessments in epidemiologic studies. The meta-regression models can be updated when additional data become available. Citation: Deziel NC, Beane Freeman LE, Graubard BI, Jones RR, Hoppin JA, Thomas K, Hines CJ, Blair A, Sandler DP, Chen H, Lubin JH, Andreotti G, Alavanja MC, Friesen MC. 2017

  14. AirPEx: Air Pollution Exposure Model

    NARCIS (Netherlands)

    Freijer JI; Bloemen HJTh; Loos S de; Marra M; Rombout PJA; Steentjes GM; Veen MP van; LBO

    1997-01-01

    Analysis of inhalatory exposure to air pollution is an important area of investigation when assessing the risks of air pollution for human health. Inhalatory exposure research focuses on the exposure of humans to air pollutants and the entry of these pollutants into the human respiratory tract. The

  15. Modelling biological pathway dynamics with Timed Automata

    NARCIS (Netherlands)

    Schivo, Stefano; Scholma, Jetse; Wanders, B.; Urquidi Camacho, R.A.; van der Vet, P.E.; Karperien, Hermanus Bernardus Johannes; Langerak, Romanus; van de Pol, Jan Cornelis; Post, Janine Nicole

    2012-01-01

    When analysing complex interaction networks occurring in biological cells, a biologist needs computational support in order to understand the effects of signalling molecules (e.g. growth factors, drugs). ANIMO (Analysis of Networks with Interactive MOdelling) is a tool that allows the user to create

  16. The landscape of existing models for high-throughput exposure assessment

    DEFF Research Database (Denmark)

    Jolliet, O.; Fantke, Peter; Huang, L.

    2017-01-01

    for skin permeation and volatilization as competing processes and that requires a limited number of readily available physiochemical properties would be suitable for LCA and HTS purposes. Thus, the multi-pathway exposure model for chemicals in cosmetics developed by Ernstoff et al.constitutes a suitable......Models are becoming increasingly available to model near-field fate and exposure, but not all are suited for high throughput. This presentation evaluates the available models for modeling exposure to chemicals in cosmetics, cleaning products, food contact and building materials. It assesses...... in indoor air (Little et al., 2012; Liu et al., 2013), but they do not well account for SVOC sorption into indoor surfaces and absorption into human skins (Huang et al., 2017). Thus a more comprehensive simplified solution is needed for SVOCs . For personal Care Products, a mass balance model that accounts...

  17. Air Pollution Exposure Modeling for Health Studies | Science ...

    Science.gov (United States)

    Dr. Michael Breen is leading the development of air pollution exposure models, integrated with novel personal sensor technologies, to improve exposure and risk assessments for individuals in health studies. He is co-investigator for multiple health studies assessing the exposure and effects of air pollutants. These health studies include participants with asthma, diabetes, and coronary artery disease living in various U.S. cities. He has developed, evaluated, and applied novel exposure modeling and time-activity tools, which includes the Exposure Model for Individuals (EMI), GPS-based Microenvironment Tracker (MicroTrac) and Exposure Tracker models. At this seminar, Dr. Breen will present the development and application of these models to predict individual-level personal exposures to particulate matter (PM) for two health studies in central North Carolina. These health studies examine the association between PM and adverse health outcomes for susceptible individuals. During Dr. Breen’s visit, he will also have the opportunity to establish additional collaborations with researchers at Harvard University that may benefit from the use of exposure models for cohort health studies. These research projects that link air pollution exposure with adverse health outcomes benefit EPA by developing model-predicted exposure-dose metrics for individuals in health studies to improve the understanding of exposure-response behavior of air pollutants, and to reduce participant

  18. Early postnatal exposure to isoflurane causes cognitive deficits and disrupts development of newborn hippocampal neurons via activation of the mTOR pathway.

    Science.gov (United States)

    Kang, Eunchai; Jiang, Danye; Ryu, Yun Kyoung; Lim, Sanghee; Kwak, Minhye; Gray, Christy D; Xu, Michael; Choi, Jun H; Junn, Sue; Kim, Jieun; Xu, Jing; Schaefer, Michele; Johns, Roger A; Song, Hongjun; Ming, Guo-Li; Mintz, C David

    2017-07-01

    Clinical and preclinical studies indicate that early postnatal exposure to anesthetics can lead to lasting deficits in learning and other cognitive processes. The mechanism underlying this phenomenon has not been clarified and there is no treatment currently available. Recent evidence suggests that anesthetics might cause persistent deficits in cognitive function by disrupting key events in brain development. The hippocampus, a brain region that is critical for learning and memory, contains a large number of neurons that develop in the early postnatal period, which are thus vulnerable to perturbation by anesthetic exposure. Using an in vivo mouse model we demonstrate abnormal development of dendrite arbors and dendritic spines in newly generated dentate gyrus granule cell neurons of the hippocampus after a clinically relevant isoflurane anesthesia exposure conducted at an early postnatal age. Furthermore, we find that isoflurane causes a sustained increase in activity in the mechanistic target of rapamycin pathway, and that inhibition of this pathway with rapamycin not only reverses the observed changes in neuronal development, but also substantially improves performance on behavioral tasks of spatial learning and memory that are impaired by isoflurane exposure. We conclude that isoflurane disrupts the development of hippocampal neurons generated in the early postnatal period by activating a well-defined neurodevelopmental disease pathway and that this phenotype can be reversed by pharmacologic inhibition.

  19. The “CROMa” Project: A Care Pathway for Clinical Management of Patients with Bisphosphonate Exposure

    Directory of Open Access Journals (Sweden)

    Mauro Capocci

    2014-01-01

    Full Text Available Aim. To describe 7 years of activity of “CROMa” (Coordination of Research on Osteonecrosis of the Jaws project of “Sapienza” University of Rome. Materials and Methods. A preventive and therapeutic care pathway was created for patients with bisphosphonates (BPs exposure. Demographic, social, behavioural, pharmacological, and clinical variables were registered in a dedicated database. Results. In the project, 502 patients, 403 females and 99 males, were observed. Bone pathologies were 79% osteometabolic diseases (OMD and 21% metastatic cancer (CA. Females were 90% in OMD group and 41% in CA. BP administration was 54% oral, 31% IV, and 11% IM; 89% of BPs were amino-BP and 11% non-amino-BP. Consistently with bone pathology (OMD/CA, alendronate appears to be prevalent for OMD (40% relative, while zoledronate was indicated in 92% of CA patients. Out of 502 cases collected, 28 BRONJ were detected: 17 of them were related to IV BP treatment. Preventive oral assessment was required for 50% of CA patients and by 4% of OMD patients. Conclusions. The proposed care pathway protocols for BP exposed patients appeared to be useful to meet treatment and preventive needs, in both oncological and osteometabolic diseases patients. Patients’ and physicians’ prevention awareness can be the starting point of a multilevel prevention system.

  20. Quantitative Modeling of the Alternative Pathway of the Complement System.

    Science.gov (United States)

    Zewde, Nehemiah; Gorham, Ronald D; Dorado, Angel; Morikis, Dimitrios

    2016-01-01

    The complement system is an integral part of innate immunity that detects and eliminates invading pathogens through a cascade of reactions. The destructive effects of the complement activation on host cells are inhibited through versatile regulators that are present in plasma and bound to membranes. Impairment in the capacity of these regulators to function in the proper manner results in autoimmune diseases. To better understand the delicate balance between complement activation and regulation, we have developed a comprehensive quantitative model of the alternative pathway. Our model incorporates a system of ordinary differential equations that describes the dynamics of the four steps of the alternative pathway under physiological conditions: (i) initiation (fluid phase), (ii) amplification (surfaces), (iii) termination (pathogen), and (iv) regulation (host cell and fluid phase). We have examined complement activation and regulation on different surfaces, using the cellular dimensions of a characteristic bacterium (E. coli) and host cell (human erythrocyte). In addition, we have incorporated neutrophil-secreted properdin into the model highlighting the cross talk of neutrophils with the alternative pathway in coordinating innate immunity. Our study yields a series of time-dependent response data for all alternative pathway proteins, fragments, and complexes. We demonstrate the robustness of alternative pathway on the surface of pathogens in which complement components were able to saturate the entire region in about 54 minutes, while occupying less than one percent on host cells at the same time period. Our model reveals that tight regulation of complement starts in fluid phase in which propagation of the alternative pathway was inhibited through the dismantlement of fluid phase convertases. Our model also depicts the intricate role that properdin released from neutrophils plays in initiating and propagating the alternative pathway during bacterial infection.

  1. ARSENIC: A Review on Exposure Pathways, Accumulation, Mobility and Transmission into the Human Food Chain.

    Science.gov (United States)

    Arslan, Beste; Djamgoz, Mustafa B A; Akün, Ertan

    This review deals with exposure pathways of arsenic (As), as well as its transfer and uptake processes from its source to the human body. It is proven fact that uptake of inorganic As for a long period can lead to chronic As poisoning and a variety of adverse health effects such as skin, lung and bladder cancer, in addition to cardiovascular diseases, diabetes and gastrointestinal symptoms. As exposure occurs primarily from consumption of potable water containing high amounts of inorganic As and also from consumption of crops cultivated in As contaminated agricultural fields-either naturally or anthropogenically through contaminated air or pesticides-or irrigated with As containing water. In this review, light is shed on the transfer mechanism of As through the food chain and the parameters that enhance mobility of As in the environment. Amounts of As accumulation in plants and the transfer mechanisms are also quite different. These differences in As accumulation, such as in leaves, stems, fruits and roots, are discussed in detail. Moreover, presence of As in some vegetables consumed is given by investigating recent research articles that deal with As concentrations, especially in edible parts. Some comparative data are also presented, concerning the level of concentration of As in rice during washing, cooking and processing stages.

  2. Prenatal ethanol exposure alters ethanol-induced Fos immunoreactivity and dopaminergic activity in the mesocorticolimbic pathway of the adolescent brain.

    Science.gov (United States)

    Fabio, M C; Vivas, L M; Pautassi, R M

    2015-08-20

    Prenatal ethanol exposure (PEE) promotes alcohol intake during adolescence, as shown in clinical and pre-clinical animal models. The mechanisms underlying this effect of prenatal ethanol exposure on postnatal ethanol intake remain, however, mostly unknown. Few studies assessed the effects of moderate doses of prenatal ethanol on spontaneous and ethanol-induced brain activity on adolescence. This study measured, in adolescent (female) Wistar rats prenatally exposed to ethanol (0.0 or 2.0g/kg/day, gestational days 17-20) or non-manipulated (NM group) throughout pregnancy, baseline and ethanol-induced cathecolaminergic activity (i.e., colocalization of c-Fos and tyrosine hydroxylase) in ventral tegmental area (VTA), and baseline and ethanol-induced Fos immunoreactivity (ir) in nucleus accumbens shell and core (AcbSh and AcbC, respectively) and prelimbic (PrL) and infralimbic (IL) prefrontal cortex. The rats were challenged with ethanol (dose: 0.0, 1.25, 2.5 or 3.25g/kg, i.p.) at postnatal day 37. Rats exposed to vehicle prenatally (VE group) exhibited reduced baseline dopaminergic tone in VTA; an effect that was inhibited by prenatal ethanol exposure (PEE group). Dopaminergic activity in VTA after the postnatal ethanol challenge was greater in PEE than in VE or NM animals. Ethanol-induced Fos-ir at AcbSh was found after 1.25g/kg and 2.5g/kg ethanol, in VE and PEE rats, respectively. PEE did not alter ethanol-induced Fos-ir at IL but reduced ethanol-induced Fos-ir at PrL. These results suggest that prenatal ethanol exposure heightens dopaminergic activity in the VTA and alters the response of the mesocorticolimbic pathway to postnatal ethanol exposure. These effects may underlie the enhanced vulnerability to develop alcohol-use disorders of adolescents with a history of in utero ethanol exposure. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  3. Global Exposure Modelling of Semivolatile Organic Compounds

    Science.gov (United States)

    Guglielmo, F.; Lammel, G.; Maier-Reimer, E.

    2008-12-01

    Organic compounds which are persistent and toxic as the agrochemicals γ-hexachlorocyclohexane (γ-HCH, lindane) and dichlorodiphenyltrichloroethane (DDT) pose a hazard for the ecosystems. These compounds are semivolatile, hence multicompartmental substances and subject to long-range transport (LRT) in atmosphere and ocean. Being lipophilic, they accumulate in exposed organism tissues and biomagnify along food chains. The multicompartmental global fate and LRT of DDT and lindane in the atmosphere and ocean have been studied using application data for 1980, on a decadal scale using a model based on the coupling of atmosphere and (for the first time for these compounds) ocean General Circulation Models (ECHAM5 and MPI-OM). The model system encompasses furthermore 2D terrestrial compartments (soil and vegetation) and sea ice, a fully dynamic atmospheric aerosol (HAM) module and an ocean biogeochemistry module (HAMOCC5). Large mass fractions of the compounds are found in soil. Lindane is also found in comparable amount in ocean. DDT has the longest residence time in almost all compartments. The sea ice compartment locally almost inhibits volatilization from the sea. The air/sea exchange is also affected , up to a reduction of 35 % for DDT by partitioning to the organic phases (suspended and dissolved particulate matter) in the global oceans. Partitioning enhances vertical transport in the sea. Ocean dynamics are found to be more significant for vertical transport than sinking associated with particulate matter. LRT in the global environment is determined by the fast atmospheric circulation. Net meridional transport taking place in the ocean is locally effective mostly via western boundary currents, upon applications at mid- latitudes. The pathways of the long-lived semivolatile organic compounds studied include a sequence of several cycles of volatilisation, transport in the atmosphere, deposition and transport in the ocean (multihopping substances). Multihopping is

  4. Low-Frequency Electromagnetic Field Exposure Enhances Extracellular Trap Formation by Human Neutrophils through the NADPH Pathway.

    Science.gov (United States)

    Golbach, Lieke A; Scheer, Marleen H; Cuppen, Jan J M; Savelkoul, Huub; Verburg-van Kemenade, B M Lidy

    2015-01-01

    Low-frequency (LF) electromagnetic fields (EMFs) are abundantly present in modern society, and the potential biological consequences of exposure to these fields are under intense debate. Immune cells are suggested as possible target cells, though a clear mechanism is lacking. Considering their crucial role in innate immune activation, we selected an ex vivo exposure set-up with human neutrophils to investigate a possible correlation between neutrophil extracellular trap (NET) formation and LF EMF exposure. Our study shows that formation of NETs is enhanced by LF EMF exposure. Enhanced NET formation leads to increased antimicrobial properties as well as damage to surrounding cells. We found that LF-EMF-induced NET formation is dependent on the NADPH oxidase pathway and production of reactive oxygen species. Additionally, LF EMF exposure does not influence autophagy and PAD4 activity. Our study provides a mechanism by which exposure to LF EMFs could influence the innate immune system. © 2015 S. Karger AG, Basel.

  5. Development of a pluripotent stem cell derived neuronal model to identify chemically induced pathway perturbations in relation to neurotoxicity: Effects of CREB pathway inhibition

    Energy Technology Data Exchange (ETDEWEB)

    Pistollato, Francesca; Louisse, Jochem; Scelfo, Bibiana; Mennecozzi, Milena [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy); Accordi, Benedetta; Basso, Giuseppe [Oncohematology Laboratory, Department of Woman and Child Health, University of Padova, Padova (Italy); Gaspar, John Antonydas [Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne, Cologne (Germany); Zagoura, Dimitra; Barilari, Manuela; Palosaari, Taina [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy); Sachinidis, Agapios [Center of Physiology and Pathophysiology, Institute of Neurophysiology, University of Cologne, Cologne (Germany); Bremer-Hoffmann, Susanne, E-mail: susanne.bremer@jrc.ec.europa.eu [Institute for Health and Consumer Protection (IHCP), JRC, Ispra (Italy)

    2014-10-15

    According to the advocated paradigm shift in toxicology, acquisition of knowledge on the mechanisms underlying the toxicity of chemicals, such as perturbations of biological pathways, is of primary interest. Pluripotent stem cells (PSCs), such as human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), offer a unique opportunity to derive physiologically relevant human cell types to measure molecular and cellular effects of such pathway modulations. Here we compared the neuronal differentiation propensity of hESCs and hiPSCs with the aim to develop novel hiPSC-based tools for measuring pathway perturbation in relation to molecular and cellular effects in vitro. Among other fundamental pathways, also, the cAMP responsive element binding protein (CREB) pathway was activated in our neuronal models and gave us the opportunity to study time-dependent effects elicited by chemical perturbations of the CREB pathway in relation to cellular effects. We show that the inhibition of the CREB pathway, using 2-naphthol-AS-E-phosphate (KG-501), induced an inhibition of neurite outgrowth and synaptogenesis, as well as a decrease of MAP2{sup +} neuronal cells. These data indicate that a CREB pathway inhibition can be related to molecular and cellular effects that may be relevant for neurotoxicity testing, and, thus, qualify the use of our hiPSC-derived neuronal model for studying chemical-induced neurotoxicity resulting from pathway perturbations. - Highlights: • HESCs derived neuronal cells serve as benchmark for iPSC based neuronal toxicity test development. • Comparisons between hESCs and hiPSCs demonstrated variability of the epigenetic state • CREB pathway modulation have been explored in relation to the neurotoxicant exposure KG-501 • hiPSC might be promising tools to translate theoretical AoPs into toxicological in vitro tests.

  6. Using chemical kinetics to model biochemical pathways.

    Science.gov (United States)

    Le Novère, Nicolas; Endler, Lukas

    2013-01-01

    Chemical kinetics is the study of the rate of reactions transforming some chemical entities into other chemical entities. Over the twentieth century it has become one of the cornerstones of biochemistry. When in the second half of the century basic knowledge of cellular processes became sufficient to understand quantitatively metabolic networks, chemical kinetics associated with systems theory led to the development of what would become an important branch of systems biology. In this chapter we introduce basic concepts of chemical and enzyme kinetics, and show how the temporal evolution of a reaction system can be described by ordinary differential equations. Finally we present a method to apply this type of approach to model any regulatory network.

  7. Validation of the dermal exposure model in ECETOC TRA.

    Science.gov (United States)

    Marquart, Hans; Franken, Remy; Goede, Henk; Fransman, Wouter; Schinkel, Jody

    2017-08-01

    The ECETOC TRA model (presently version 3.1) is often used to estimate worker inhalation and dermal exposure in regulatory risk assessment. The dermal model in ECETOC TRA has not yet been validated by comparison with independent measured exposure levels. This was the goal of the present study. Measured exposure levels and relevant contextual information were gathered via literature search, websites of relevant occupational health institutes and direct requests for data to industry. Exposure data were clustered in so-called exposure cases, which are sets of data from one data source that are expected to have the same values for input parameters in the ECETOC TRA dermal exposure model. For each exposure case, the 75th percentile of measured values was calculated, because the model intends to estimate these values. The input values for the parameters in ECETOC TRA were assigned by an expert elicitation and consensus building process, based on descriptions of relevant contextual information.From more than 35 data sources, 106 useful exposure cases were derived, that were used for direct comparison with the model estimates. The exposure cases covered a large part of the ECETOC TRA dermal exposure model. The model explained 37% of the variance in the 75th percentiles of measured values. In around 80% of the exposure cases, the model estimate was higher than the 75th percentile of measured values. In the remaining exposure cases, the model estimate may not be sufficiently conservative.The model was shown to have a clear bias towards (severe) overestimation of dermal exposure at low measured exposure values, while all cases of apparent underestimation by the ECETOC TRA dermal exposure model occurred at high measured exposure values. This can be partly explained by a built-in bias in the effect of concentration of substance in product used, duration of exposure and the use of protective gloves in the model. The effect of protective gloves was calculated to be on average a

  8. Stochastic modeling of near-field exposure to parabens in personal care products

    DEFF Research Database (Denmark)

    Csiszar, Susan A.; Ernstoff, Alexi; Fantke, Peter

    2017-01-01

    a PCP exposure model based on the product intake fraction (PiF), which is defined as the fraction of chemical in a product that is taken in by the exposed population, to estimate chemical intake based on physicochemical properties and PCP usage characteristics. The PiF can be used to estimate route...... and pathway-specific exposures during both the use and disposal stages of a product. As a case study, we stochastically quantified population level exposures to parabens in PCPs, and compared estimates with biomarker values. We estimated exposure based on the usage of PCPs in the female US population, taking...... into account population variability, product usage characteristics, paraben occurrence in PCPs and the PiF. Intakes were converted to urine levels and compared with National Health and Nutrition Examination Survey (NHANES) biomonitoring data. Results suggest that for parabens, chemical exposure during product...

  9. Exploration of potential biomarkers and related biological pathways for PCB exposure in maternal and cord serum: A pilot birth cohort study in Chiba, Japan.

    Science.gov (United States)

    Eguchi, Akifumi; Sakurai, Kenichi; Watanabe, Masahiro; Mori, Chisato

    2017-05-01

    Polychlorinated biphenyls (PCBs) have been associated with adverse human reproductive and fetal developmental measures or outcomes because of their endocrine-disrupting effects; however, the biological mechanisms of adverse effects of PCB exposure in humans are not currently well established. In this study, we aimed to identify the biological pathways and potential biomarkers of PCB exposure in maternal and umbilical cord serum using a hydrophilic interaction chromatography-tandem mass spectrometry (HILIC-MS/MS) metabolomics platform. The median concentration of total PCBs in maternal (n=93) and cord serum (n=93) were 350 and 70pgg(-1) wet wt, respectively. PCB levels in maternal and fetal serum from the Chiba Study of Mother and Children's Health (C-MACH) cohort are comparable to those of earlier cohort studies conducted in Japan, the USA, and European countries. We used the random forest model with the metabolome profile to predict exposure levels of PCB (first quartile [Q1] and fourth quartile [Q4]) for pregnant women and fetuses. In the prediction model for classification of Q1 versus Q4 (area-under-curve [AUC]: pregnant women=0.812 and fetuses=0.919), citraconic acid level in maternal serum and ethanolamine, p-hydroxybenzoate, and purine levels in cord serum had >0.70 AUC values. These candidate biomarkers and metabolite included in composited models were related to glutathione and amino acid metabolism in maternal serum and the amino acid metabolism and ubiquinone and other terpenoid-quinone biosynthesis in cord serum (FDR PCB exposure in pregnant women and fetuses. These results showed that metabolome analysis might be useful to explore potential biomarkers and related biological pathways for PCB exposure. Thus, more detailed studies are needed to verify sensitivity of the biomarkers and clarify the biochemical changes resulting from PCB exposure. Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

  10. Genes and pathways underlying susceptibility to impaired lung function in the context of environmental tobacco smoke exposure

    NARCIS (Netherlands)

    de Jong, K; Vonk, J M; Imboden, M; Lahousse, L; Hofman, A; Brusselle, G G; Probst-Hensch, N M; Postma, D S; Boezen, H M

    2017-01-01

    Background: Studies aiming to assess genetic susceptibility for impaired lung function levels upon exposure to environmental tobacco smoke (ETS) have thus far focused on candidate-genes selected based on a-priori knowledge of potentially relevant biological pathways, such as glutathione

  11. Children's Lead Exposure: A Multimedia Modeling Analysis to Guide Public Health Decision-Making.

    Science.gov (United States)

    Zartarian, Valerie; Xue, Jianping; Tornero-Velez, Rogelio; Brown, James

    2017-09-12

    Drinking water and other sources for lead are the subject of public health concerns around the Flint, Michigan, drinking water and East Chicago, Indiana, lead in soil crises. In 2015, the U.S. Environmental Protection Agency (EPA)'s National Drinking Water Advisory Council (NDWAC) recommended establishment of a "health-based, household action level" for lead in drinking water based on children's exposure. The primary objective was to develop a coupled exposure-dose modeling approach that can be used to determine what drinking water lead concentrations keep children's blood lead levels (BLLs) below specified values, considering exposures from water, soil, dust, food, and air. Related objectives were to evaluate the coupled model estimates using real-world blood lead data, to quantify relative contributions by the various media, and to identify key model inputs. A modeling approach using the EPA's Stochastic Human Exposure and Dose Simulation (SHEDS)-Multimedia and Integrated Exposure Uptake and Biokinetic (IEUBK) models was developed using available data. This analysis for the U.S. population of young children probabilistically simulated multimedia exposures and estimated relative contributions of media to BLLs across all population percentiles for several age groups. Modeled BLLs compared well with nationally representative BLLs (0-23% relative error). Analyses revealed relative importance of soil and dust ingestion exposure pathways and associated Pb intake rates; water ingestion was also a main pathway, especially for infants. This methodology advances scientific understanding of the relationship between lead concentrations in drinking water and BLLs in children. It can guide national health-based benchmarks for lead and related community public health decisions. https://doi.org/10.1289/EHP1605.

  12. Use of computational models to reconstruct and predict trichloroethylene exposure.

    Science.gov (United States)

    Maslia, M L; Aral, M M; Williams, R C; Williams-Fleetwood, S; Hayes, L C; Wilder, L C

    1996-01-01

    In this study, a type frequently encountered by ATSDR, groundwater and surface-water contamination have occurred near the Gratuity Road site in the town of Groton, Massachusetts. A petitioned public health assessment for the Gratuity Road site identified the primary contaminants as trichloro-ethylene (TCE), 1,1,1-trichloroethane (TCA), hexavalent chromium (Cr+6), chromium (Cr), and lead (Pb) (ATSDR 1992). The health assessment also indicated that off-site residential groundwater wells had been contaminated with TCE and TCA. Because direct measures of historical exposure to TCE are unavailable for the Gratuity Road site, computational models were used to reconstruct and predict exposure to TCE. These computational models included environmental transport and exposure models. For the environmental transport models, numerical methods were used to approximate the equations of groundwater flow and contaminant transport. Results of using environmental transport models provided us with the spatial and temporal database necessary to conduct an exposure analysis. This database indicated that groundwater concentrations of TCE typically exceeded EPA's MCL of 5 ppb for TCE. The study demonstrated that although a hazardous waste site can be remediated, nearby populations may experience significant exposure because of historical contamination, which will not be captured by remediation activities. The exposure analysis used simulated concentrations of TCE predicted by environmental transport models. These concentrations were used to compare exposure to TCE from inhalation in a one-compartment model shower with exposure from ingestion of domestic water contaminated by TCE. The exposure model indicated that exposure to TCE by the inhalation route during showering is nearly identical to exposure by ingestion of domestic water supplies contaminated with TCE. As a result, entry by inhalation route is as important as entry by ingestion route when conducting exposure analyses of

  13. Cryoablation of anteroseptal accessory pathways in children with limited fluoroscopy exposure.

    Science.gov (United States)

    Ergul, Yakup; Tola, Hasan Tahsin; Kiplapinar, Neslihan; Akdeniz, Celal; Saygi, Murat; Tuzcu, Volkan

    2013-04-01

    Due to its safety profile, cryoablation is used increasingly in pediatric patients, especially for septal arrhythmia substrates. Recent advances in electroanatomical-mapping technologies have resulted in a decrease or complete elimination of fluoroscopy exposure during catheter ablation procedures. The aim of this study was to assess the efficacy and safety of cryoablation of anteroseptal accessory pathways (APs) using electroanatomical-mapping system guidance with limited fluoroscopy exposure. A total of 24 patients underwent cryoablation of anteroseptal APs between July 2010 and April 2012. Cryomapping was performed with a 6 mm-tip catheter at -30 °C before the lesions were delivered. An 8 mm-tip catheter was used in one patient. The EnSite system (St. Jude Medical, St Paul, MN) was used in all procedures. The mean age was 11.9 ± 4.3 years. Acute success rate was 95.8 % (23 of 24). The mean procedure and cryoablation durations were 168 ± 58 min and 1,463 ± 525 s, respectively. Limited fluoroscopy was used only in 7 patients, and the mean fluoroscopy time was 1.7 ± 1.8 min (range 0.1-4 min) in these patients. Recurrence was noted in 2 patients (8.7 %) who underwent a second successful cryoablation procedure. The patient who underwent a failed attempt during the first procedure was successfully treated with a repeat procedure. The resultant long-term success rate was 100 % at a mean follow-up period of 14.2 ± 7.7 months. There were no complications except for transient atrioventricular block in one patient. Cryoablation of anteroseptal APs can be performed effectively and safely in children using a limited fluoroscopic approach with the help of electroanatomical-mapping systems.

  14. Effects of electromagnetic fields exposure on plasma hormonal and inflammatory pathway biomarkers in male workers of a power plant.

    Science.gov (United States)

    Wang, Zhaopin; Fei, Ying; Liu, Hui; Zheng, Shuangshuang; Ding, Zheyuan; Jin, Wen; Pan, Yifeng; Chen, Zexin; Wang, Lijuan; Chen, Guangdi; Xu, Zhengping; Zhu, Yongjian; Yu, Yunxian

    2016-01-01

    The potential health risks of electromagnetic fields (EMFs) have currently raised considerable public concerns. The aim of this study was to evaluate the effects of EMF exposure on levels of plasma hormonal and inflammatory pathway biomarkers in male workers of an electric power plant. Seventy-seven male workers with high occupational EMF exposure and 77 male controls with low exposure, matched by age, were selected from a cross-sectional study. Moreover, high EMF exposure group was with walkie-talkies usage and exposed to power frequency EMF at the work places for a longer duration than control group. A questionnaire was applied to obtain relevant information, including sociodemographic characteristics, lifestyle factors, and EMF exposures. Plasma levels of testosterone, estradiol, melatonin, NF-κB, heat-shock protein (HSP) 70, HSP27, and TET1 were determined by an enzyme-linked immunosorbent assay. EMF exposure group had statistically significantly lower levels of testosterone (β = -0.3 nmol/L, P = 0.015), testosterone/estradiol (T/E2) ratio (β = -15.6, P = 0.037), and NF-κB (β = -20.8 ng/L, P = 0.045) than control group. Moreover, joint effects between occupational EMF exposure and employment duration, mobile phone fees, years of mobile phone usage, and electric fees on levels of testosterone and T/E2 ratio were observed. Nevertheless, no statistically significant associations of EMF exposures with plasma estradiol, melatonin, HSP70, HSP27, and TET1 were found. The findings showed that chronic exposure to EMF could decrease male plasma testosterone and T/E2 ratio, and it might possibly affect reproductive functions in males. No significant associations of EMF exposure with inflammatory pathway biomarkers were found.

  15. Effects of electromagnetic fields exposure on plasma hormonal and inflammatory pathway biomarkers in male workers of a power plant

    Energy Technology Data Exchange (ETDEWEB)

    Wang, Zhaopin; Fei, Ying; Liu, Hui [Zhejiang Univ., Hangzhou (China). Dept. of Epidemiology and Health Statistics; Zhejiang Univ., Hangzhou (China). Chronic Disease Research Inst.; and others

    2016-01-15

    The potential health risks of electromagnetic fields (EMFs) have currently raised considerable public concerns. The aim of this study was to evaluate the effects of EMF exposure on levels of plasma hormonal and inflammatory pathway biomarkers in male workers of an electric power plant. Seventy-seven male workers with high occupational EMF exposure and 77 male controls with low exposure, matched by age, were selected from a cross-sectional study. Moreover, high EMF exposure group was with walkie-talkies usage and exposed to power frequency EMF at the work places for a longer duration than control group. A questionnaire was applied to obtain relevant information, including sociodemographic characteristics, lifestyle factors, and EMF exposures. Plasma levels of testosterone, estradiol, melatonin, NF-KB, heat-shock protein (HSP) 70, HSP27, and TET1 were determined by an enzyme-linked immunosorbent assay. EMF exposure group had statistically significantly lower levels of testosterone (β = -0.3 nmol/L, P = 0.015), testosterone/estradiol (T/E2) ratio (β = -15.6, P = 0.037), and NF-KB (β = -20.8 ng/L, P = 0.045) than control group. Moreover, joint effects between occupational EMF exposure and employment duration, mobile phone fees, years of mobile phone usage, and electric fees on levels of testosterone and T/E2 ratio were observed. Nevertheless, no statistically significant associations of EMF exposures with plasma estradiol, melatonin, HSP70, HSP27, and TET1 were found. The findings showed that chronic exposure to EMF could decrease male plasma testosterone and T/E2 ratio, and it might possibly affect reproductive functions in males. No significant associations of EMF exposure with inflammatory pathway biomarkers were found.

  16. SHEDS-HT: An Integrated Probabilistic Exposure Model for ...

    Science.gov (United States)

    United States Environmental Protection Agency (USEPA) researchers are developing a strategy for highthroughput (HT) exposure-based prioritization of chemicals under the ExpoCast program. These novel modeling approaches for evaluating chemicals based on their potential for biologically relevant human exposures will inform toxicity testing and prioritization for chemical risk assessment. Based on probabilistic methods and algorithms developed for The Stochastic Human Exposure and Dose Simulation Model for Multimedia, Multipathway Chemicals (SHEDS-MM), a new mechanistic modeling approach has been developed to accommodate high-throughput (HT) assessment of exposure potential. In this SHEDS-HT model, the residential and dietary modules of SHEDS-MM have been operationally modified to reduce the user burden, input data demands, and run times of the higher-tier model, while maintaining critical features and inputs that influence exposure. The model has been implemented in R; the modeling framework links chemicals to consumer product categories or food groups (and thus exposure scenarios) to predict HT exposures and intake doses. Initially, SHEDS-HT has been applied to 2507 organic chemicals associated with consumer products and agricultural pesticides. These evaluations employ data from recent USEPA efforts to characterize usage (prevalence, frequency, and magnitude), chemical composition, and exposure scenarios for a wide range of consumer products. In modeling indirec

  17. Development of an Ingestion Pathway Model for AXAIRQ

    Energy Technology Data Exchange (ETDEWEB)

    Simpkins, A.A.

    1999-01-13

    AXAIRQ is a dose mode code used for prospective accident assessment at the Savannah River Site and is primarily used to show regulatory compliance. For completeness of pathway analysis, an ingestion model, AXINGST, has been developed for use with, and incorporation in, AXAIRQ. Currently available ingestion models were referenced as a basis for AXINGST. AXINGST calculates a conservative ingestion dose following an atmospheric release of radionuclides and includes site specific variables where applicable.

  18. Exposure to atrazine affects the expression of key genes in metabolic pathways integral to energy homeostasis in Xenopus laevis tadpoles

    Energy Technology Data Exchange (ETDEWEB)

    Zaya, Renee M., E-mail: renee.zaya@wmich.edu [Great Lakes Environmental and Molecular Sciences Center, Department of Biological Sciences, 3425 Wood Hall, Western Michigan University, 1903 West Michigan Avenue, Kalamazoo, MI 49008 (United States); Amini, Zakariya, E-mail: zakariya.amini@wmich.edu [Great Lakes Environmental and Molecular Sciences Center, Department of Biological Sciences, 3425 Wood Hall, Western Michigan University, 1903 West Michigan Avenue, Kalamazoo, MI 49008 (United States); Whitaker, Ashley S., E-mail: ashley.s.whitaker@wmich.edu [Great Lakes Environmental and Molecular Sciences Center, Department of Biological Sciences, 3425 Wood Hall, Western Michigan University, 1903 West Michigan Avenue, Kalamazoo, MI 49008 (United States); Ide, Charles F., E-mail: charles.ide@wmich.edu [Great Lakes Environmental and Molecular Sciences Center, Department of Biological Sciences, 3425 Wood Hall, Western Michigan University, 1903 West Michigan Avenue, Kalamazoo, MI 49008 (United States)

    2011-08-15

    In our laboratory, Xenopus laevis tadpoles exposed throughout development to 200 or 400 {mu}g/L atrazine, concentrations reported to periodically occur in puddles, vernal ponds and runoff soon after application, were smaller and had smaller fat bodies (the tadpole's lipid storage organ) than controls. It was hypothesized that these changes were due to atrazine-related perturbations of energy homeostasis. To investigate this hypothesis, selected metabolic responses to exposure at the transcriptional and biochemical levels in atrazine-exposed tadpoles were measured. DNA microarray technology was used to determine which metabolic pathways were affected after developmental exposure to 400 {mu}g/L atrazine. From these data, genes representative of the affected pathways were selected for assay using quantitative real time polymerase chain reaction (qRT-PCR) to measure changes in expression during a 2-week exposure to 400 {mu}g/L. Finally, ATP levels were measured from tadpoles both early in and at termination of exposure to 200 and 400 {mu}g/L. Microarray analysis revealed significant differential gene expression in metabolic pathways involved with energy homeostasis. Pathways with increased transcription were associated with the conversion of lipids and proteins into energy. Pathways with decreased transcription were associated with carbohydrate metabolism, fat storage, and protein synthesis. Using qRT-PCR, changes in gene expression indicative of an early stress response to atrazine were noted. Exposed tadpoles had significant decreases in acyl-CoA dehydrogenase (AD) and glucocorticoid receptor protein (GR) mRNA after 24 h of exposure, and near-significant (p = 0.07) increases in peroxisome proliferator-activated receptor {beta} (PPAR-{beta}) mRNA by 72 h. Decreases in AD suggested decreases in fatty acid {beta}-oxidation while decreases in GR may have been a receptor desensitization response to a glucocorticoid surge. Involvement of PPAR-{beta}, an energy

  19. Comparative genomic analyses identify common molecular pathways modulated upon exposure to low doses of arsenic and cadmium

    Directory of Open Access Journals (Sweden)

    Fry Rebecca C

    2011-04-01

    Full Text Available Abstract Background Exposure to the toxic metals arsenic and cadmium is associated with detrimental health effects including cancers of various organs. While arsenic and cadmium are well known to cause adverse health effects at high doses, the molecular impact resulting from exposure to environmentally relevant doses of these metals remains largely unexplored. Results In this study, we examined the effects of in vitro exposure to either arsenic or cadmium in human TK6 lymphoblastoid cells using genomics and systems level pathway mapping approaches. A total of 167 genes with differential expression were identified following exposure to either metal with surprisingly no overlap between the two. Real-time PCR was used to confirm target gene expression changes. The gene sets were overlaid onto protein-protein interaction maps to identify metal-induced transcriptional networks. Interestingly, both metal-induced networks were significantly enriched for proteins involved in common biological processes such as tumorigenesis, inflammation, and cell signaling. These findings were further supported by gene set enrichment analysis. Conclusions This study is the first to compare the transcriptional responses induced by low dose exposure to cadmium and arsenic in human lymphoblastoid cells. These results highlight that even at low levels of exposure both metals can dramatically influence the expression of important cellular pathways.

  20. A statistical framework for the validation of a population exposure model based on personal exposure data

    Science.gov (United States)

    Rodriguez, Delphy; Valari, Myrto; Markakis, Konstantinos; Payan, Sébastien

    2016-04-01

    Currently, ambient pollutant concentrations at monitoring sites are routinely measured by local networks, such as AIRPARIF in Paris, France. Pollutant concentration fields are also simulated with regional-scale chemistry transport models such as CHIMERE (http://www.lmd.polytechnique.fr/chimere) under air-quality forecasting platforms (e.g. Prev'Air http://www.prevair.org) or research projects. These data may be combined with more or less sophisticated techniques to provide a fairly good representation of pollutant concentration spatial gradients over urban areas. Here we focus on human exposure to atmospheric contaminants. Based on census data on population dynamics and demographics, modeled outdoor concentrations and infiltration of outdoor air-pollution indoors we have developed a population exposure model for ozone and PM2.5. A critical challenge in the field of population exposure modeling is model validation since personal exposure data are expensive and therefore, rare. However, recent research has made low cost mobile sensors fairly common and therefore personal exposure data should become more and more accessible. In view of planned cohort field-campaigns where such data will be available over the Paris region, we propose in the present study a statistical framework that makes the comparison between modeled and measured exposures meaningful. Our ultimate goal is to evaluate the exposure model by comparing modeled exposures to monitor data. The scientific question we address here is how to downscale modeled data that are estimated on the county population scale at the individual scale which is appropriate to the available measurements. To assess this question we developed a Bayesian hierarchical framework that assimilates actual individual data into population statistics and updates the probability estimate.

  1. Extracellular vesicle-driven information mediates the long-term effects of particulate matter exposure on coagulation and inflammation pathways.

    Science.gov (United States)

    Pavanello, Sofia; Bonzini, Matteo; Angelici, Laura; Motta, Valeria; Pergoli, Laura; Hoxha, Mirjam; Cantone, Laura; Pesatori, Angela Cecilia; Apostoli, Pietro; Tripodi, Armando; Baccarelli, Andrea; Bollati, Valentina

    2016-09-30

    Continuous exposure to particulate air pollution (PM) is a serious worldwide threat to public health as it coherently links with increased morbidity and mortality of cardiorespiratory diseases (CRD), and of type 2 diabetes (T2D). Extracellular vesicles (EVs) are circular plasma membrane fragments released from human cells that transfer microRNAs between tissues. In the present work it was explored the hypothesis that EVs with their encapsulated microRNAs (EVmiRNAs) contents might mediate PM effects by triggering key pathways in CRD and T2D. Expression of EVmiRNAs analyzed by real-time PCR was correlated with oxidative stress, coagulation and inflammation markers, from healthy steel plant workers (n=55) with a well-characterized exposure to PM and PM-associated metals. All p-values were adjusted for multiple comparisons. In-silico Ingenuity Pathway Analysis (IPA) was performed to identify biological pathways regulated by PM-associated EVmiRNAs. Increased expression in 17 EVmiRNAs is associated with PM and metal exposure (pinflammation, coagulation and glucose homeostasis pathways. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

  2. Applying Aggregate Exposure Pathway and Adverse Outcome Pathway frameworks to link toxicity testing data to exposure-relevant and biologically-relevant responses

    Science.gov (United States)

    Hazard assessment for nanomaterials often involves applying in vitro dose-response data to estimate potential health risks that arise from exposure to products that contain nanomaterials. However, much uncertainty is inherent in relating bioactivities observed in an in vitro syst...

  3. Modelling Human Exposure to Chemicals in Food

    NARCIS (Netherlands)

    Slob W

    1993-01-01

    Exposure to foodborne chemicals is often estimated using the average consumption pattern in the human population. To protect the human population instead of the average individual, however, interindividual variability in consumption behaviour must be taken into account. This report shows how food

  4. Predictive exposure modelling for pesticide registration purposes

    NARCIS (Netherlands)

    Hemmen, J.J. van

    1993-01-01

    The health risk to the agricultural worker using pesticides is important for registration procedures since during mixing, loading and application he or she handles undiluted as well as diluted pesticide formulations. Furthermore, exposure may occur during daily activities in the crop (e.g.

  5. Media Exposure: How Models Simplify Sampling

    DEFF Research Database (Denmark)

    Mortensen, Peter Stendahl

    1998-01-01

    In media planning, the distribution of exposures to more ad spots in more media (print, TV, radio) is crucial to the evaluation of the campaign. If such information should be sampled, it would only be possible in expensive panel-studies (eg TV-meter panels). Alternatively, the distribution...

  6. Exposure Scenarios and Unit Dose Factors for the Hanford Immobilized Low Activity Tank Waste Performance Assessment

    Energy Technology Data Exchange (ETDEWEB)

    RITTMANN, P.D.

    1999-12-29

    Exposure scenarios are defined to identify potential pathways and combinations of pathways that could lead to radiation exposure from immobilized tank waste. Appropriate data and models are selected to permit calculation of dose factors for each exposure

  7. Animal Model Selection for Inhalational HCN Exposure

    Science.gov (United States)

    2016-08-01

    phosphate pathway by decreasing the rate of glycolysis, and inhibition of the tricarboxylic acid cycle with marked metabolic acidosis (Ballantyne... Canine 100 NA Pritchard, 2007; WHO, 2004 Swine 3404 1 McNamara, 1976 1466 3 607 10 688 90 NHP 96-2171 (87-196 ppm ) 30 Purser et al, 1984...pulmonary studies (Laboratory Animal Medicine, 2002, 1984; Biology and Diseases of the Ferret, 1998). Canine The dog is commonly used in safety

  8. Presence of insoluble Tau following rotenone exposure ameliorates basic pathways associated with neurodegeneration

    Directory of Open Access Journals (Sweden)

    Rodrigo S. Chaves

    2016-12-01

    Full Text Available Protein aggregation is an important feature of neurodegenerative disorders. In Alzheimer's disease (AD protein aggregates are composed of hyperphosphorylated Tau and amyloid beta peptide (Aβ. Despite the involvement and identification of the molecular composition of these aggregates, their role in AD pathophysiology is not fully understood. However, depositions of these insoluble aggregates are typically reported as pathogenic and toxic for cell homeostasis. New evidences suggest that the deposition of these aggregates is a protective mechanism that preserves cell from toxic insults associated with the early stages of neurodegenerative diseases. To better understand the biological role of the protein aggregation with regard its effects in cellular homeostasis, the present study investigated the role of insoluble Tau and Tau aggregates on crucial cellular parameters such as redox homeostasis, proteasome activity and autophagy in hippocampal cell cultures and hippocampus of aged Lewis rats using a rotenone-induced aggregation model. Neurons were exposed to rotenone in different concentrations and exposure times aiming to determine the interval required for Tau aggregation. Our experimental design allowed us to demonstrate that rotenone exposure induces Tau hyperphosphorylation and aggregation in a concentration and time-dependent manner. Oxidative stress triggered by rotenone exposure was observed with the absence of Tau aggregates and was reduced or absent when Tau aggregates were present. This reduction of oxidative stress along with the presence of insoluble Tau was independent of alterations in antioxidant enzymes activities or cell death. In addition, rotenone induced oxidative stress was mainly associated with decrease in proteasome activity and autophagy flux. Conversely, when insoluble Tau appeared, autophagy turns to be overactivated while proteasome activity remained low. Our studies significantly advance the understanding that Tau

  9. Prenatal ethanol exposure increases osteoarthritis susceptibility in female rat offspring by programming a low-functioning IGF-1 signaling pathway

    Science.gov (United States)

    Ni, Qubo; Tan, Yang; Zhang, Xianrong; Luo, Hanwen; Deng, Yu; Magdalou, Jacques; Chen, Liaobin; Wang, Hui

    2015-10-01

    Epidemiological evidence indicates that osteoarthritis (OA) and prenatal ethanol exposure (PEE) are both associated with low birth weight but possible causal interrelationships have not been investigated. To investigate the effects of PEE on the susceptibility to OA in adult rats that experienced intrauterine growth retardation (IUGR), and to explore potential intrauterine mechanisms, we established the rat model of IUGR by PEE and dexamethasone, and the female fetus and 24-week-old adult offspring subjected to strenuous running for 6 weeks were sacrificed. Knee joints were collected from fetuses and adult offspring for histochemistry, immunohistochemistry and qPCR assays. Histological analyses and the Mankin score revealed increased cartilage destruction and accelerated OA progression in adult offspring from the PEE group compared to the control group. Immunohistochemistry showed reduced expression of insulin-like growth factor-1 (IGF-1) signaling pathway components. Furthermore, fetuses in the PEE group experienced IUGR but exhibited a higher postnatal growth rate. The expression of many IGF-1 signaling components was downregulated, which coincided with reduced amounts of type II collagen in the epiphyseal cartilage of fetuses in the PEE group. These results suggest that PEE enhances the susceptibility to OA in female adult rat offspring by down-regulating IGF-1 signaling and retarding articular cartilage development.

  10. Modeling methylene chloride exposure-reduction options for home paint-stripper users.

    Science.gov (United States)

    Riley, D M; Small, M J; Fischhoff, B

    2000-01-01

    Home improvement is a popular activity, but one that can also involve exposure to hazardous substances. Paint stripping is of particular concern because of the high potential exposures to methylene chloride, a solvent that is a potential human carcinogen and neurotoxicant. This article presents a general methodology for evaluating the effectiveness of behavioral interventions for reducing these risks. It doubles as a model that assesses exposure patterns, incorporating user time-activity patterns and risk-mitigation strategies. The model draws upon recent innovations in indoor air-quality modeling to estimate exposure through inhalation and dermal pathways to paint-stripper users. It is designed to use data gathered from home paint-stripper users about room characteristics, amount of stripper used, time-activity patterns and exposure-reduction strategies (e.g., increased ventilation and modification in the timing of stripper application, scraping, and breaks). Results indicate that the effectiveness of behavioral interventions depends strongly on characteristics of the room (e.g., size, number and size of doors and windows, base air-exchange rates). The greatest simple reduction in exposure is achieved by using an exhaust fan in addition to opening windows and doors. These results can help identify the most important information for product labels and other risk-communication materials.

  11. Repeated Moderate Noise Exposure in the Rat--an Early Adulthood Noise Exposure Model.

    Science.gov (United States)

    Mannström, Paula; Kirkegaard, Mette; Ulfendahl, Mats

    2015-12-01

    In this study, we investigated the effects of varying intensity levels of repeated moderate noise exposures on hearing. The aim was to define an appropriate intensity level that could be repeated several times without giving rise to a permanent hearing loss, and thus establish a model for early adulthood moderate noise exposure in rats. Female Sprague-Dawley rats were exposed to broadband noise for 90 min, with a 50 % duty cycle at levels of 101, 104, 107, or 110 dB sound pressure level (SPL), and compared to a control group of non-exposed animals. Exposure was repeated every 6 weeks for a maximum of six repetitions or until a permanent hearing loss was observed. Hearing was assessed by the auditory brainstem response (ABR). Rats exposed to the higher intensities of 107 and 110 dB SPL showed permanent threshold shifts following the first exposure, while rats exposed to 101 and 104 dB SPL could be exposed at least six times without a sustained change in hearing thresholds. ABR amplitudes decreased over time for all groups, including the non-exposed control group, while the latencies were unaffected. A possible change in noise susceptibility following the repeated moderate noise exposures was tested by subjecting the animals to high-intensity noise exposure of 110 dB for 4 h. Rats previously exposed repeatedly to 104 dB SPL were slightly more resistant to high-intensity noise exposure than non-exposed rats or rats exposed to 101 dB SPL. Repeated moderate exposure to 104 dB SPL broadband noise is a viable model for early adulthood noise exposure in rats and may be useful for the study of noise exposure on age-related hearing loss.

  12. The Aggregate Exposure Pathway (AEP): A conceptual framework for advancing exposure science research and transforming risk assessment

    Science.gov (United States)

    Recent advances in analytical methods, biomarker discovery, cell-based assay development, computational tools, sensor/monitor, and omics technology have enabled new streams of exposure and toxicity data to be generated at higher volumes and speed. These new data offer the opport...

  13. Dose conversion factors for radiation doses at normal operation discharges. E. Exposure pathways and radioecological data; Dosomraekningsfaktorer foer normaldriftutslaepp. C. Exponeringsvaegar och radioekologiska data

    Energy Technology Data Exchange (ETDEWEB)

    Karlsson, Sara; Aquilonius, Karin

    2001-10-01

    A study has been performed in order to develop and extend existing models for dose estimations at emissions of radioactive substances from nuclear facilities in Sweden. This report presents a review of all exposure pathways in the project, in order to secure that no important contributions have been omitted. The radioecological data that should be used in calculating conversion factors for air and water emissions are also reviewed. Nuclid-specific conversion factors have been calculated for radiation doses from inhalation and intake for children in different age groups.

  14. Interactions between polymorphisms in the aryl hydrocarbon receptor signalling pathway and exposure to persistent organochlorine pollutants affect human semen quality

    DEFF Research Database (Denmark)

    Brokken, L J S; Lundberg, P J; Spanò, M

    2014-01-01

    Persistent organic pollutants (POPs) may affect male reproductive function. Many dioxin-like POPs exert their effects by activation of the aryl hydrocarbon receptor (AHR) signalling pathway. We analysed whether gene-environment interactions between polymorphisms in AHR (R554K) and AHR repressor (...... and the expression of the pro-apoptotic marker protein Fas. The data indicate that susceptibility to adverse effects of POP exposure on male reproductive function is dependent on polymorphisms in genes involved in AHR signalling....

  15. Modeling the effects of a Staphylococcal Enterotoxin B (SEB on the apoptosis pathway

    Directory of Open Access Journals (Sweden)

    Hammamieh Rasha

    2006-05-01

    Full Text Available Abstract Background The lack of detailed understanding of the mechanism of action of many biowarfare agents poses an immediate challenge to biodefense efforts. Many potential bioweapons have been shown to affect the cellular pathways controlling apoptosis 1234. For example, pathogen-produced exotoxins such as Staphylococcal Enterotoxin B (SEB and Anthrax Lethal Factor (LF have been shown to disrupt the Fas-mediated apoptotic pathway 24. To evaluate how these agents affect these pathways it is first necessary to understand the dynamics of a normally functioning apoptosis network. This can then serve as a baseline against which a pathogen perturbed system can be compared. Such comparisons can expose both the proteins most susceptible to alteration by the agent as well as the most critical reaction rates to better instill control on a biological network. Results We explore this through the modeling and simulation of the Fas-mediated apoptotic pathway under normal and SEB influenced conditions. We stimulated human Jurkat cells with an anti-Fas antibody in the presence and absence of SEB and determined the relative levels of seven proteins involved in the core pathway at five time points following exposure. These levels were used to impute relative rate constants and build a quantitative model consisting of a series of ordinary differential equations (ODEs that simulate the network under both normal and pathogen-influenced conditions. Experimental results show that cells exposed to SEB exhibit an increase in the rate of executioner caspase expression (and subsequently apoptosis of 1 hour 43 minutes (± 14 minutes, as compared to cells undergoing normal cell death. Conclusion Our model accurately reflects these results and reveals intervention points that can be altered to restore SEB-influenced system dynamics back to levels within the range of normal conditions.

  16. Literature review on induced exposure models, Task 2 HS-270

    Science.gov (United States)

    1982-02-01

    Sections 1, 2 and 3 of this report describe the development of : induced exposure models, together with d discussion of questions : of validity. These Sections focus on the most important and : relevant results from the literature, while Appendix A c...

  17. [Development and verification of Chinese dietary exposure evaluation model software].

    Science.gov (United States)

    Liu, Pei; Li, Jing-xin; Sun, Jin-fang; Xue, Jianping; Chen, Bing-wei; Zhang, Hong; Yu, Xiao-jin; Wang, Can-nan; Yuan, Bao-jun; Ma, Yong-jian; Tian, Zi-hua

    2010-03-01

    To develop the dietary exposure evaluation model software accredited of Chinese intellectual property rights and to verify the rationality and accuracy of the results from the probabilistic model in Chinese dietary exposure evaluation model software according to international standards. The software of SAS was used to build various evaluation model based on the data from Chinese dietary survey and the chemical compound in food surveillance and to design an operation interface. The results from probabilistic dietary exposure model for children 2 - 7 years old were compared with that from duplicate portion study of 2-7 years children dietary exposure in Jinhu, Jiangsu province in order to analyze the rationality of model. The results from probabilistic model of dietary exposure were compared with the results from @Risk software to verify the correction of the probabilistic model by using the same data of randomly selected 10 000 study subjects from national dietary survey. While, the mean drift was used as an internal index to illustrate the accuracy of the computation. Chinese dietary exposure evaluation software was developed successfully. On the rationality, the results from probabilistic model were lower than that from the point estimation (e.g., cucumber: the result of point estimation of acephate was 4.78 microg x kg(-1) x d(-1), while the results of probabilistic model which was 0.39 microg x kg(-1) x d(-1)). Meanwhile the results from probabilistic model were higher than the results of duplicate portion study (on the P95, the result of probabilistic model of Pb exposure in children was 11.08 microg x kg(-1) x d(-1), while the results of duplicate portion study was 5.75 microg x kg(-1) x d(-1)). On accuracy, the results from @Risk and the probabilistic model were highly consistent (on the P95, the result of probabilistic assessment of acephate diet exposure was 4.27 microg x kg(-1) x d(-1), while the results of duplicate portion study was 4.24 microg x kg(-1

  18. Measured and modeled personal and environmental NO2 exposure

    Directory of Open Access Journals (Sweden)

    Stroh Emilie

    2012-06-01

    Full Text Available Abstract Background Measured or modeled levels of outdoor air pollution are being used as proxies for individual exposure in a growing number of epidemiological studies. We studied the accuracy of such approaches, in comparison with measured individual levels, and also combined modeled levels for each subject’s workplace with the levels at their residence to investigate the influence of living and working in different places on individual exposure levels. Methods A GIS-based dispersion model and an emissions database were used to model concentrations of NO2 at the subject’s residence. Modeled levels were then compared with measured levels of NO2. Personal exposure was also modeled based on levels of NO2 at the subject’s residence in combination with levels of NO2 at their workplace during working hours. Results There was a good agreement between measured façade levels and modeled residential NO2 levels (rs = 0.8, p > 0.001; however, the agreement between measured and modeled outdoor levels and measured personal exposure was poor with overestimations at low levels and underestimation at high levels (rs = 0.5, p > 0.001 and rs = 0.4, p > 0.001 even when compensating for workplace location (rs = 0.4, p > 0.001. Conclusion Modeling residential levels of NO2 proved to be a useful method of estimating façade concentrations. However, the agreement between outdoor levels (both modeled and measured and personal exposure was, although significant, rather poor even when compensating for workplace location. These results indicate that personal exposure cannot be fully approximated by outdoor levels and that differences in personal activity patterns or household characteristics should be carefully considered when conducting exposure studies. This is an important finding that may help to correct substantial bias in epidemiological studies.

  19. Measured and modeled personal and environmental NO2 exposure.

    Science.gov (United States)

    Stroh, Emilie; Rittner, Ralf; Oudin, Anna; Ardö, Jonas; Jakobsson, Kristina; Björk, Jonas; Tinnerberg, Håkan

    2012-06-09

    Measured or modeled levels of outdoor air pollution are being used as proxies for individual exposure in a growing number of epidemiological studies. We studied the accuracy of such approaches, in comparison with measured individual levels, and also combined modeled levels for each subject's workplace with the levels at their residence to investigate the influence of living and working in different places on individual exposure levels. A GIS-based dispersion model and an emissions database were used to model concentrations of NO2 at the subject's residence. Modeled levels were then compared with measured levels of NO2. Personal exposure was also modeled based on levels of NO2 at the subject's residence in combination with levels of NO2 at their workplace during working hours. There was a good agreement between measured façade levels and modeled residential NO2 levels (rs = 0.8, p > 0.001); however, the agreement between measured and modeled outdoor levels and measured personal exposure was poor with overestimations at low levels and underestimation at high levels (rs = 0.5, p > 0.001 and rs = 0.4, p > 0.001) even when compensating for workplace location (rs = 0.4, p > 0.001). Modeling residential levels of NO2 proved to be a useful method of estimating façade concentrations. However, the agreement between outdoor levels (both modeled and measured) and personal exposure was, although significant, rather poor even when compensating for workplace location. These results indicate that personal exposure cannot be fully approximated by outdoor levels and that differences in personal activity patterns or household characteristics should be carefully considered when conducting exposure studies. This is an important finding that may help to correct substantial bias in epidemiological studies.

  20. Modeling Exposure to Persistent Chemicals in Hazard and Risk Assessment

    Energy Technology Data Exchange (ETDEWEB)

    Cowan-Ellsberry, Christina E.; McLachlan, Michael S.; Arnot, Jon A.; MacLeod, Matthew; McKone, Thomas E.; Wania, Frank

    2008-11-01

    Fate and exposure modeling has not thus far been explicitly used in the risk profile documents prepared to evaluate significant adverse effect of candidate chemicals for either the Stockholm Convention or the Convention on Long-Range Transboundary Air Pollution. However, we believe models have considerable potential to improve the risk profiles. Fate and exposure models are already used routinely in other similar regulatory applications to inform decisions, and they have been instrumental in building our current understanding of the fate of POP and PBT chemicals in the environment. The goal of this paper is to motivate the use of fate and exposure models in preparing risk profiles in the POP assessment procedure by providing strategies for incorporating and using models. The ways that fate and exposure models can be used to improve and inform the development of risk profiles include: (1) Benchmarking the ratio of exposure and emissions of candidate chemicals to the same ratio for known POPs, thereby opening the possibility of combining this ratio with the relative emissions and relative toxicity to arrive at a measure of relative risk. (2) Directly estimating the exposure of the environment, biota and humans to provide information to complement measurements, or where measurements are not available or are limited. (3) To identify the key processes and chemical and/or environmental parameters that determine the exposure; thereby allowing the effective prioritization of research or measurements to improve the risk profile. (4) Predicting future time trends including how quickly exposure levels in remote areas would respond to reductions in emissions. Currently there is no standardized consensus model for use in the risk profile context. Therefore, to choose the appropriate model the risk profile developer must evaluate how appropriate an existing model is for a specific setting and whether the assumptions and input data are relevant in the context of the application

  1. Exposure to 1950-MHz TD-SCDMA electromagnetic fields affects the apoptosis of astrocytes via caspase-3-dependent pathway.

    Directory of Open Access Journals (Sweden)

    Yu-xiao Liu

    Full Text Available The usage of mobile phone increases globally. However, there is still a paucity of data about the impact of electromagnetic fields (EMF on human health. This study investigated whether EMF radiation would alter the biology of glial cells and act as a tumor-promoting agent. We exposed rat astrocytes and C6 glioma cells to 1950-MHz TD-SCDMA for 12, 24 and 48 h respectively, and found that EMF exposure had differential effects on rat astroctyes and C6 glioma cells. A 48 h of exposure damaged the mitochondria and induced significant apoptosis of astrocytes. Moreover, caspase-3, a hallmark of apoptosis, was highlighted in astrocytes after 48 h of EMF exposure, accompanied by a significantly increased expression of bax and reduced level of bcl-2. The tumorigenicity assays demonstrated that astrocytes did not form tumors in both control and exposure groups. In contrast, the unexposed and exposed C6 glioma cells show no significant differences in both biological feature and tumor formation ability. Therefore, our results implied that exposure to the EMF of 1950-MHz TD-SCDMA may not promote the tumor formation, but continuous exposure damaged the mitochondria of astrocytes and induce apoptosis through a caspase-3-dependent pathway with the involvement of bax and bcl-2.

  2. Dysregulation of metabolic pathways in a mouse model of allergic asthma.

    Science.gov (United States)

    Quinn, K D; Schedel, M; Nkrumah-Elie, Y; Joetham, A; Armstrong, M; Cruickshank-Quinn, C; Reisdorph, R; Gelfand, E W; Reisdorph, N

    2017-09-01

    Asthma is a complex lung disease resulting from the interplay of genetic and environmental factors. To understand the molecular changes that occur during the development of allergic asthma without genetic and environmental confounders, an experimental model of allergic asthma in mice was used. Our goals were to (1) identify changes at the small molecule level due to allergen exposure, (2) determine perturbed pathways due to disease, and (3) determine whether small molecule changes correlate with lung function. In this experimental model of allergic asthma, matched bronchoalveolar lavage (BAL) fluid and plasma were collected from three groups of C57BL6 mice (control vs sensitized and/or challenged with ovalbumin, n=3-5/group) 6 hour, 24 hour, and 48 hour after the last challenge. Samples were analyzed using liquid chromatography-mass spectrometry-based metabolomics. Airway hyper-responsiveness (AHR) measurements and differential cell counts were performed. In total, 398 and 368 dysregulated metabolites in the BAL fluid and plasma of sensitized and challenged mice were identified, respectively. These belonged to four, interconnected pathways relevant to asthma pathogenesis: sphingolipid metabolism (P=6.6×10(-5) ), arginine and proline metabolism (P=1.12×10(-7) ), glycerophospholipid metabolism (P=1.3×10(-10) ), and the neurotrophin signaling pathway (P=7.0×10(-6) ). Furthermore, within the arginine and proline metabolism pathway, a positive correlation between urea-1-carboxylate and AHR was observed in plasma metabolites, while ornithine revealed a reciprocal effect. In addition, agmatine positively correlated with lung eosinophilia. These findings point to potential targets and pathways that may be central to asthma pathogenesis and can serve as novel therapeutic targets. © 2017 EAACI and John Wiley and Sons A/S. Published by John Wiley and Sons Ltd.

  3. A multi-pathway model for Photosynthetic reaction center

    CERN Document Server

    Qin, M; Yi, X X

    2015-01-01

    Charge separation in light-harvesting complexes occurs in a pair of tightly coupled chlorophylls at the heart of photosynthetic reaction centers of both plants and bacteria. Recently it has been shown that quantum coherence can, in principle, enhance the efficiency of a solar cell, working like a quantum heat engine (QHE). Here, we propose a biological quantum heat engine (BQHE) motivated by Photosystem {\\rm II} reaction center (PS{\\rm II} RC) to describe the charge separation. Our model mainly considers two charge-separation pathways more than that in the published literature. The two pathways can interfere via cross-couplings and work together to enhance the charge-separation yields. We explore how these cross-couplings increase the current and voltage of the charge separation and discuss the advantages of multiple pathways in terms of current and power. The robustness of the BQHE against the charge recombination in natural PS{\\rm II} RC and dephasing induced by environments is also explored, and extension ...

  4. Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

    Science.gov (United States)

    Voorhees, Jaymie R.; Rohlman, Diane S.; Lein, Pamela J.; Pieper, Andrew A.

    2017-01-01

    Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the occupational setting, also pose serious risks to people. For example, multiple epidemiological studies have identified associations between occupational OP exposure and neurodegenerative disease, psychiatric illness, and sensorimotor deficits. Rigorous scientific investigation of the basic science mechanisms underlying these epidemiological findings requires valid preclinical models in which tightly-regulated exposure paradigms can be correlated with neurotoxicity. Here, we review the experimental models of occupational OP exposure currently used in the field. We found that animal studies simulating occupational OP exposures do indeed show evidence of neurotoxicity, and that utilization of these models is helping illuminate the mechanisms underlying OP-induced neurological sequelae. Still, further work is necessary to evaluate exposure levels, protection methods, and treatment strategies, which taken together could serve to modify guidelines for improving workplace conditions globally. PMID:28149268

  5. The Aggregate Exposure Pathway (AEP) and Adverse Outcome Pathway (AOP) frameworks facilitate the integration of human health and ecological endpoints for Cumulative Risk Assessment (CRA)

    Science.gov (United States)

    Cumulative risk assessment (CRA) methods promote the use of a conceptual site model (CSM) to apportion exposures and integrate risk from multiple stressors. While CSMs may encompass multiple species, evaluating end points across taxa can be challenging due to data availability an...

  6. Model of the pathway of −1 frameshifting: Long pausing

    Directory of Open Access Journals (Sweden)

    Ping Xie

    2016-03-01

    Full Text Available It has been characterized that the programmed ribosomal −1 frameshifting often occurs at the slippery sequence on the presence of a downstream mRNA pseudoknot. In some prokaryotic cases such as the dnaX gene of Escherichia coli, an additional stimulatory signal—an upstream, internal Shine–Dalgarno (SD sequence—is also necessary to stimulate the efficient −1 frameshifting. However, the molecular and physical mechanism of the −1 frameshifting is poorly understood. Here, we propose a model of the pathway of the −1 translational frameshifting during ribosome translation of the dnaX −1 frameshift mRNA. With the model, the single-molecule fluorescence data (Chen et al. (2014 [29] on the dynamics of the shunt either to long pausing or to normal translation, the tRNA transit and sampling dynamics in the long-paused rotated state, the EF-G sampling dynamics, the mean rotated-state lifetimes, etc., are explained quantitatively. Moreover, the model is also consistent with the experimental data (Yan et al. (2015 [30] on translocation excursions and broad branching of frameshifting pathways. In addition, we present some predicted results, which can be easily tested by future optical trapping experiments.

  7. Problem gambling in adolescents: an examination of the pathways model.

    Science.gov (United States)

    Gupta, Rina; Nower, Lia; Derevensky, Jeffrey L; Blaszczynski, Alex; Faregh, Neda; Temcheff, Caroline

    2013-09-01

    This research tests the applicability of the Integrated Pathways Model for gambling to adolescent problem gamblers, utilizing a cross-sectional design and self-report questionnaires. Although the overall sample consisted of 1,133 adolescents (Quebec: n = 994, 87.7 %; Ontario: n = 139, 12.3 %: Male = 558, 49.5 %; Female = 569, 50.5 %), only problem gamblers were retained in testing the model (N = 109). Personality and clinical features were assessed using the Millon Adolescent Clinical Inventory, attention deficit hyperactivity (ADHD) using the Conners-Wells' Adolescent Self-Report Scale, and the DSM-IV-MR-J and Gambling Activities Questionnaire to determine gambling severity and reasons for gambling. Latent class analysis concluded 5 classes, yet still provided preliminary support for three distinct subgroups similar to those proposed by the Pathways Model, adding a depression only subtype, and a subtype of problem gamblers experiencing both internalizing and externalizing disorders. ADHD symptoms were found to be common to 4 of the 5 classes.

  8. Computational Graph Theoretical Model of the Zebrafish Sensorimotor Pathway

    Science.gov (United States)

    Peterson, Joshua M.; Stobb, Michael; Mazzag, Bori; Gahtan, Ethan

    2011-11-01

    Mapping the detailed connectivity patterns of neural circuits is a central goal of neuroscience and has been the focus of extensive current research [4, 3]. The best quantitative approach to analyze the acquired data is still unclear but graph theory has been used with success [3, 1]. We present a graph theoretical model with vertices and edges representing neurons and synaptic connections, respectively. Our system is the zebrafish posterior lateral line sensorimotor pathway. The goal of our analysis is to elucidate mechanisms of information processing in this neural pathway by comparing the mathematical properties of its graph to those of other, previously described graphs. We create a zebrafish model based on currently known anatomical data. The degree distributions and small-world measures of this model is compared to small-world, random and 3-compartment random graphs of the same size (with over 2500 nodes and 160,000 connections). We find that the zebrafish graph shows small-worldness similar to other neural networks and does not have a scale-free distribution of connections.

  9. 75 FR 22401 - Exposure Modeling Public Meeting

    Science.gov (United States)

    2010-04-28

    ... abstract requests are announced through the ``empmlist'' forum on the LYRIS list server at https://lists..., Modeling, Monitoring, Pesticides. Dated: April 10, 2010. Donald J. Brady, Director, Environmental Fate and...

  10. 76 FR 365 - Exposure Modeling Public Meeting

    Science.gov (United States)

    2011-01-04

    ... LYRIS list server at https://lists.epa.gov/read/all_forums/ . III. How can I request to participate in... Environmental protection, modeling, monitoring, pesticides. Dated: December 28, 2010. Arthur-Jean Williams...

  11. The behavioral ecology of secondhand smoke exposure: A pathway to complete tobacco control.

    Science.gov (United States)

    Hovell, Melbourne F; Hughes, Suzanne C

    2009-11-01

    This article outlines a theoretical framework for research concerning secondhand smoke exposure (SHSe) prevention as a means to curtail the tobacco industry. The Behavioral Ecological Model (BEM) assumes interlocking social contingencies of reinforcement (i.e., rewards or punishments) from the highest level of society (e.g., taxing cigarette sales) to physiological reactions to nicotine that influence smoking and SHSe. We review selected research concerning both policy and clinical efforts to restrict smoking and/or SHSe. Research to date has focused on smoking cessation with modest to weak effects. The BEM and empirical evidence suggest that cultural contingencies of reinforcement should be emphasized to protect people from SHSe, especially vulnerable children, pregnant women, the ill, the elderly, and low-income adults who have not "elected" to smoke. Doing so will protect vulnerable populations from industry-produced SHSe and may yield more and longer-lasting cessation. Interventions that reduce SHSe may serve as a Trojan horse to counter the tobacco industry. Future studies should: (a) guide policies to restrict SHSe; (b) develop powerful community and clinical interventions to reduce SHSe; (c) test the degree to which policies and other contexts enhance the effects of clinical interventions (e.g., media programs disclosing the disingenuous marketing by the industry); and (d) investigate the effects of all health care providers' ability to reduce SHSe and generate an antitobacco culture, by advising all clients to avoid starting to smoke, to protect their children from SHSe, and to quit smoking.

  12. Astronaut EVA Exposure Estimates from CAD Model Spacesuit Geometry

    OpenAIRE

    GIOVANNI DE, ANGELIS; Brooke M., ANDERSON; William, ATWELL; John E., NEALY; Garry D., QUALLS; John W., WILSON; Old Dominion University:NASA Langley Research Center:Istituto Superiore di Sanita'; Swales Aerospace Corporation; The Boeing Company; Old Dominion University; NASA Langley Research Center

    2004-01-01

    Ongoing assembly and maintenance activities at the International Space Station (ISS) require much more extravehicular activity (EVA) than did the earlier U.S. Space Shuttle missions. It is thus desirable to determine and analyze, and possibly foresee, as accurately as possible what radiation exposures crew members involved in EVAs will experience in order to minimize risks and to establish exposure limits that must not to be exceeded. A detailed CAD model of the U.S. Space Shuttle EVA Spacesu...

  13. Modeling population exposures to silver nanoparticles present in consumer products

    Science.gov (United States)

    Royce, Steven G.; Mukherjee, Dwaipayan; Cai, Ting; Xu, Shu S.; Alexander, Jocelyn A.; Mi, Zhongyuan; Calderon, Leonardo; Mainelis, Gediminas; Lee, KiBum; Lioy, Paul J.; Tetley, Teresa D.; Chung, Kian Fan; Zhang, Junfeng; Georgopoulos, Panos G.

    2014-11-01

    Exposures of the general population to manufactured nanoparticles (MNPs) are expected to keep rising due to increasing use of MNPs in common consumer products (PEN 2014). The present study focuses on characterizing ambient and indoor population exposures to silver MNPs (nAg). For situations where detailed, case-specific exposure-related data are not available, as in the present study, a novel tiered modeling system, Prioritization/Ranking of Toxic Exposures with GIS (geographic information system) Extension (PRoTEGE), has been developed: it employs a product life cycle analysis (LCA) approach coupled with basic human life stage analysis (LSA) to characterize potential exposures to chemicals of current and emerging concern. The PRoTEGE system has been implemented for ambient and indoor environments, utilizing available MNP production, usage, and properties databases, along with laboratory measurements of potential personal exposures from consumer spray products containing nAg. Modeling of environmental and microenvironmental levels of MNPs employs probabilistic material flow analysis combined with product LCA to account for releases during manufacturing, transport, usage, disposal, etc. Human exposure and dose characterization further employ screening microenvironmental modeling and intake fraction methods combined with LSA for potentially exposed populations, to assess differences associated with gender, age, and demographics. Population distributions of intakes, estimated using the PRoTEGE framework, are consistent with published individual-based intake estimates, demonstrating that PRoTEGE is capable of capturing realistic exposure scenarios for the US population. Distributions of intakes are also used to calculate biologically relevant population distributions of uptakes and target tissue doses through human airway dosimetry modeling that takes into account product MNP size distributions and age-relevant physiological parameters.

  14. Arctic pathways of Pacific Water: Arctic Ocean Model Intercomparison experiments

    Science.gov (United States)

    Karcher, Michael; Proshutinsky, Andrey; Gerdes, Rüdiger; de Cuevas, Beverly; Golubeva, Elena; Kauker, Frank; Nguyen, An T.; Platov, Gennady A.; Wadley, Martin; Watanabe, Eiji; Coward, Andrew C.; Nurser, A. J. George

    2016-01-01

    Abstract Pacific Water (PW) enters the Arctic Ocean through Bering Strait and brings in heat, fresh water, and nutrients from the northern Bering Sea. The circulation of PW in the central Arctic Ocean is only partially understood due to the lack of observations. In this paper, pathways of PW are investigated using simulations with six state‐of‐the art regional and global Ocean General Circulation Models (OGCMs). In the simulations, PW is tracked by a passive tracer, released in Bering Strait. Simulated PW spreads from the Bering Strait region in three major branches. One of them starts in the Barrow Canyon, bringing PW along the continental slope of Alaska into the Canadian Straits and then into Baffin Bay. The second begins in the vicinity of the Herald Canyon and transports PW along the continental slope of the East Siberian Sea into the Transpolar Drift, and then through Fram Strait and the Greenland Sea. The third branch begins near the Herald Shoal and the central Chukchi shelf and brings PW into the Beaufort Gyre. In the models, the wind, acting via Ekman pumping, drives the seasonal and interannual variability of PW in the Canadian Basin of the Arctic Ocean. The wind affects the simulated PW pathways by changing the vertical shear of the relative vorticity of the ocean flow in the Canada Basin. PMID:27818853

  15. The defense potential of glutathione-ascorbate dependent detoxification pathway to sulfur dioxide exposure in Tagetes erecta.

    Science.gov (United States)

    Wei, Aili; Fu, Baochun; Wang, Yunshan; Li, Rui; Zhang, Chao; Cao, Dongmei; Zhang, Xiaobing; Duan, Jiuju

    2015-01-01

    Sulfur dioxide (SO2) exposure is associated with increased risk of various damages to plants. However, little is known about the defense response in ornamental plants. In this study, an artificial fumigation protocol was carried out to study the defense potential of the glutathione (GSH)-ascorbate (AsA) dependent detoxification pathway to SO2 exposure in Tagetes erecta. The results show that when the plants were exposed to different doses of SO2 (0, 15, 30, 50 or 80 mg m(-3)) for different times (6, 12, 18, 24 or 33 h), SO2 induced oxidative stress was confirmed by the increased hydrogen peroxide (H2O2), malondialdehyde (MDA) and relative conductivity of membrane (RC) in a dose-dependent manner for different exposure times. However, the increased levels for H2O2, MDA and RC were not significant vis-a-vis the control when SO2 doses and exposure times were lower than 15 mg m(-3)/33 h, 30 mg m(-3)/24 h or 50 mg m(-3)/12 h (p>0.05). The results could be explained by the increases in the content of reduced form of glutathione (GSH), total glutathione (TGSH), ascorbate (AsA), ratio of GSH/GSSG (oxidized form of glutathione), activities of ascorbate peroxidase (APX), glutathione peroxidase (GPX), glutathione reductase (GR) and glutathione S-transferases (GST). On the other hand, exposure to higher doses of SO2 and longer exposure times, the values of the GSH-AsA dependent antioxidative indices decreased significantly (p<0.01), manifested by increased levels of H2O2. Furthermore, the levels of H2O2, MDA and RC varied little when SO2 doses and exposure times reached a 'critical' value (50 mg m(-3)/24 h). The defense ability of T. erecta to SO2 reached nearly extremity. To summarize, the response of T. erecta to elevated SO2 was related to higher H2O2 levels. GSH-AsA dependent detoxification pathway played an important role in against SO2-induced toxicity, although the defense response could not sufficiently alleviate oxidative damage when SO2 doses and exposure times

  16. The effect of noise exposure on insulin sensitivity in mice may be mediated by the JNK/IRS1 pathway.

    Science.gov (United States)

    Liu, Lijie; Fang, Cong; Yang, Jing; Zhang, Hongyu; Huang, Yi; Xuan, Chuanying; Wang, Yongfang; Li, Shengwei; Sha, Jun; Zha, Mingming; Guo, Min

    2018-02-12

    Epidemiological studies have suggested that noise exposure may increase the risk of type 2 diabetes mellitus (T2DM), and experimental studies have demonstrated that noise exposure can induce insulin resistance in rodents. The aim of the present study was to explore noise-induced processes underlying impaired insulin sensitivity in mice. Male ICR mice were randomly divided into four groups: a control group without noise exposure and three noise groups exposed to white noise at a 95-dB sound pressure level for 4 h/day for 1, 10, or 20 days (N1D, N10D, and N20D, respectively). Systemic insulin sensitivity was evaluated at 1 day, 1 week, and 1 month post-noise exposure (1DPN, 1WPN, and 1MPN) via insulin tolerance tests (ITTs). Several insulin-related processes, including the phosphorylation of Akt, IRS1, and JNK in the animals' skeletal muscles, were examined using standard immunoblots. Biomarkers of inflammation (circulating levels of TNF-α and IL-6) and oxidative stress (SOD and CAT activities and MDA levels in skeletal muscles) were measured via chemical analyses. The data obtained in this study showed the following: (1) The impairment of systemic insulin sensitivity was transient in the N1D group but prolonged in the N10D and N20D groups. (2) Noise exposure led to enhanced JNK phosphorylation and IRS1 serine phosphorylation as well as reduced Akt phosphorylation in skeletal muscles in response to exogenous insulin stimulation. (3) Plasma levels of TNF-α and IL-6, CAT activity, and MDA concentrations in skeletal muscles were elevated after 20 days of noise exposure. Impaired insulin sensitivity in noise-exposed mice might be mediated by an enhancement of the JNK/IRS1 pathway. Inflammation and oxidative stress might contribute to insulin resistance after chronic noise exposure.

  17. Separation of uncertainty and interindividual variability in human exposure modeling.

    NARCIS (Netherlands)

    Ragas, A.M.J.; Brouwer, F.P.E.; Buchner, F.L.; Hendriks, H.W.; Huijbregts, M.A.J.

    2009-01-01

    The NORMTOX model predicts the lifetime-averaged exposure to contaminants through multiple environmental media, that is, food, air, soil, drinking and surface water. The model was developed to test the coherence of Dutch environmental quality objectives (EQOs). A set of EQOs is called coherent if

  18. Stoffenmanager exposure model: company-specific exposure assessments using a Bayesian methodology.

    NARCIS (Netherlands)

    Ven, P. van de; Fransman, W.; Schinkel, J.; Rubingh, C.; Warren, N.; Tielemans, E.

    2010-01-01

    The web-based tool "Stoffenmanager" was initially developed to assist small- and medium-sized enterprises in the Netherlands to make qualitative risk assessments and to provide advice on control at the workplace. The tool uses a mechanistic model to arrive at a "Stoffenmanager score" for exposure.

  19. Modelling pathways to Rubisco degradation: a structural equation network modelling approach.

    Directory of Open Access Journals (Sweden)

    Catherine Tétard-Jones

    Full Text Available 'Omics analysis (transcriptomics, proteomics quantifies changes in gene/protein expression, providing a snapshot of changes in biochemical pathways over time. Although tools such as modelling that are needed to investigate the relationships between genes/proteins already exist, they are rarely utilised. We consider the potential for using Structural Equation Modelling to investigate protein-protein interactions in a proposed Rubisco protein degradation pathway using previously published data from 2D electrophoresis and mass spectrometry proteome analysis. These informed the development of a prior model that hypothesised a pathway of Rubisco Large Subunit and Small Subunit degradation, producing both primary and secondary degradation products. While some of the putative pathways were confirmed by the modelling approach, the model also demonstrated features that had not been originally hypothesised. We used Bayesian analysis based on Markov Chain Monte Carlo simulation to generate output statistics suggesting that the model had replicated the variation in the observed data due to protein-protein interactions. This study represents an early step in the development of approaches that seek to enable the full utilisation of information regarding the dynamics of biochemical pathways contained within proteomics data. As these approaches gain attention, they will guide the design and conduct of experiments that enable 'Omics modelling to become a common place practice within molecular biology.

  20. Chapter three: methodology of exposure modeling

    CSIR Research Space (South Africa)

    Moschandreas, DJ

    2002-12-01

    Full Text Available and Turner, 1996). Steady-state Gaussian plume dispersion models require hourly single-point meteorological data at the surface and an upper air station to estimate the mixing 928 D.J. Moschandreas et al. / Chemosphere 49 (2002) 923?946 height. More... require core parameters (Table 1). These include surface wind direction, wind speed, air temperature and cloud data. In addition, upper air data, typically measured twice per day, determines wind, temperature, and humidity changes with height (Schulze...

  1. Robustness of modelled ozone exposures and doses

    Energy Technology Data Exchange (ETDEWEB)

    Tuovinen, J.-P. [Finnish Meteorological Institute, P.O. Box 503, FI-00101 Helsinki (Finland)]. E-mail: juha-pekka.tuovinen@fmi.fi; Simpson, D. [Norwegian Meteorological Institute, P.O. Box 43, Blindern, N-0313 Oslo (Norway); Emberson, L. [Stockholm Environment Institute at York, University of York, York YO10 5DD (United Kingdom); Ashmore, M. [Stockholm Environment Institute at York, University of York, York YO10 5DD (United Kingdom); Gerosa, G. [Universita Cattolica del Sacro Cuore, Via Musei 41, I-25121 Brescia (Italy)

    2007-04-15

    This study evaluates the robustness of the AOTX and AF{sub st} Y indices for assessing the ozone-induced risk to vegetation. These indices represent the accumulated concentration and stomatal flux, respectively, above a threshold value. The robustness is expressed as the sensitivity to changes in inputs and the uncertainty due to input errors. The input data are taken from a regional-scale chemical transport model. Both indices show increasing sensitivity with increasing threshold values. The sensitivity depends on the threshold and the characteristics of the frequency distribution for concentrations and stomatal fluxes. AF{sub st} Y appears less sensitive than AOTX for the thresholds adopted for critical levels. The couplings between concentration gradients and deposition algorithms complicate the assessment of the total uncertainty. For AF{sub st} Y, the uncertainty due to the modelled stomatal conductance may sometimes increase, but sometimes decrease, the overall uncertainty significantly. In particular, the maximum stomatal conductance plays an important role in determining the uncertainty. - The AF{sub st} Y index is less sensitive to uncertainties than AOTX, but depends strongly on the stomatal conductance model.

  2. A generalized dose-response relationship for adenovirus infection and illness by exposure pathway

    NARCIS (Netherlands)

    Teunis, P.; Schijven, J.; Rutjes, S.

    2016-01-01

    Adenoviruses are found everywhere in the environment, and cause various health problems including symptoms of enteric illness, and respiratory illness. Despite their significance to public health, few studies have addressed the health risks associated with exposure to adenovirus. Human challenge

  3. First report of Legionella pneumophila in car cabin air filters. Are these a potential exposure pathway for professional drivers?

    Science.gov (United States)

    Alexandropoulou, Ioanna G; Konstantinidis, Theocharis G; Parasidis, Theodoros A; Nikolaidis, Christos; Panopoulou, Maria; Constantinidis, Theodoros C

    2013-12-01

    Recent findings have identified professional drivers as being at an increased risk of Legionnaires' disease. Our hypothesis was that used car cabin air filters represent a reservoir of Legionella bacteria, and thus a potential pathway for contamination. We analysed used cabin air filters from various types of car. The filters were analysed by culture and by molecular methods. Our findings indicated that almost a third of air filters were colonized with Legionella pneumophila. Here, we present the first finding of Legionella spp. in used car cabin air filters. Further investigations are needed in order to confirm this exposure pathway. The presence of Legionella bacteria in used cabin air filters may have been an unknown source of infection until now.

  4. Deterministic modelling and stochastic simulation of biochemical pathways using MATLAB.

    Science.gov (United States)

    Ullah, M; Schmidt, H; Cho, K H; Wolkenhauer, O

    2006-03-01

    The analysis of complex biochemical networks is conducted in two popular conceptual frameworks for modelling. The deterministic approach requires the solution of ordinary differential equations (ODEs, reaction rate equations) with concentrations as continuous state variables. The stochastic approach involves the simulation of differential-difference equations (chemical master equations, CMEs) with probabilities as variables. This is to generate counts of molecules for chemical species as realisations of random variables drawn from the probability distribution described by the CMEs. Although there are numerous tools available, many of them free, the modelling and simulation environment MATLAB is widely used in the physical and engineering sciences. We describe a collection of MATLAB functions to construct and solve ODEs for deterministic simulation and to implement realisations of CMEs for stochastic simulation using advanced MATLAB coding (Release 14). The program was successfully applied to pathway models from the literature for both cases. The results were compared to implementations using alternative tools for dynamic modelling and simulation of biochemical networks. The aim is to provide a concise set of MATLAB functions that encourage the experimentation with systems biology models. All the script files are available from www.sbi.uni-rostock.de/ publications_matlab-paper.html.

  5. Modelling exposure of mammalian predators to anticoagulant rodenticide

    Directory of Open Access Journals (Sweden)

    Christopher John Topping

    2016-12-01

    Full Text Available Anticoagulant rodenticides (AR are a widespread and effective method of rodent control but there is concern about the impact these may have on non-target organisms, in particular secondary poisoning of rodent predators. Incidence and concentration of AR in free-living predators in Denmark is very high. We postulate that this is caused by widespread exposure due to widespread use of AR in Denmark in and around buildings. To investigate this theory a spatio-temporal model of AR use and mammalian predator distribution was created. This model was supported by data from an experimental study of mice as vectors of AR, and was used to evaluate likely impacts of restrictions imposed on AR use in Denmark banning the use of rodenticides for plant protection in woodlands and tree-crops. The model uses input based on frequencies and timings of baiting for rodent control for urban, rural and woodland locations and creates an exposure map based on spatio-temporal modelling of movement of mice-vectored AR (based on Apodemus flavicollis. Simulated predator territories are super-imposed over this exposure map to create an exposure index. Predictions from the model concur with field studies of AR prevalence both before and after the change in AR use. In most cases incidence of exposure to AR is predicted to be greater than 90%, although cessation of use in woodlots and Christmas tree plantations should reduce mean exposure concentrations. Model results suggest that the driver of high AR incidence in non-target small mammal predators is likely to be the pattern of use and not the distance AR is vectored. Reducing baiting frequency by 75% had different effects depending on the landscape simulated, but having a maximum of 12% reduction in exposure incidence, and in one landscape a maximum reduction of <2%. We discuss sources of uncertainty in the model and directions for future development of predictive models for environmental impact assessment of rodenticides. The

  6. Designing a Care Pathway Model – A Case Study of the Outpatient Total Hip Arthroplasty Care Pathway

    Directory of Open Access Journals (Sweden)

    Robin I. Oosterholt

    2017-03-01

    Full Text Available Introduction: Although the clinical attributes of total hip arthroplasty (THA care pathways have been thoroughly researched, a detailed understanding of the equally important organisational attributes is still lacking. The aim of this article is to contribute with a model of the outpatient THA care pathway that depicts how the care team should be organised to enable patient discharge on the day of surgery. Theory: The outpatient THA care pathway enables patients to be discharged on the day of surgery, short- ening the length of stay and intensifying the provision and organisation of care. We utilise visual care modelling to construct a visual design of the organisation of the care pathway. Methods: An embedded case study was conducted of the outpatient THA care pathway at a teaching hospital in the Netherlands. The data were collected using a visual care modelling toolkit in 16 semi- structured interviews. Problems and inefficiencies in the care pathway were identified and addressed in the iterative design process. Results: The results are two visual models of the most critical phases of the outpatient THA care pathway: diagnosis & preparation (1 and mobilisation & discharge (4. The results show the care team composition, critical value exchanges, and sequence that enable patient discharge on the day of surgery. Conclusion: The design addressed existing problems and is an optimisation of the case hospital’s pathway. The network of actors consists of the patient (1, radiologist (1, anaesthetist (1, nurse specialist (1, pharmacist (1, orthopaedic surgeon (1,4, physiotherapist (1,4, nurse (4, doctor (4 and patient applica- tion (1,4. The critical value exchanges include patient preparation (mental and practical, patient education, aligned care team, efficient sequence of value exchanges, early patient mobilisation, flexible availability of the physiotherapist, functional discharge criteria, joint decision making and availability of the care team.

  7. Model of spacecraft atomic oxygen and solar exposure microenvironments

    Science.gov (United States)

    Bourassa, R. J.; Pippin, H. G.

    1993-01-01

    Computer models of environmental conditions in Earth orbit are needed for the following reasons: (1) derivation of material performance parameters from orbital test data, (2) evaluation of spacecraft hardware designs, (3) prediction of material service life, and (4) scheduling spacecraft maintenance. To meet these needs, Boeing has developed programs for modeling atomic oxygen (AO) and solar radiation exposures. The model allows determination of AO and solar ultraviolet (UV) radiation exposures for spacecraft surfaces (1) in arbitrary orientations with respect to the direction of spacecraft motion, (2) overall ranges of solar conditions, and (3) for any mission duration. The models have been successfully applied to prediction of experiment environments on the Long Duration Exposure Facility (LDEF) and for analysis of selected hardware designs for deployment on other spacecraft. The work on these models has been reported at previous LDEF conferences. Since publication of these reports, a revision has been made to the AO calculation for LDEF, and further work has been done on the microenvironments model for solar exposure.

  8. A GM-CSF/IL-33 pathway facilitates allergic airway responses to sub-threshold house dust mite exposure.

    Directory of Open Access Journals (Sweden)

    Alba Llop-Guevara

    Full Text Available Allergic asthma is a chronic immune-inflammatory disease of the airways. Despite aeroallergen exposure being universal, allergic asthma affects only a fraction of individuals. This is likely related, at least in part, to the extent of allergen exposure. Regarding house dust mite (HDM, we previously identified the threshold required to elicit allergic responses in BALB/c mice. Here, we investigated the impact of an initial immune perturbation on the response to sub-threshold HDM exposure. We show that transient GM-CSF expression in the lung facilitated robust eosinophilic inflammation, long-lasting antigen-specific Th2 responses, mucus production and airway hyperresponsiveness. This was associated with increased IL-33 levels and activated CD11b(+ DCs expressing OX40L. GM-CSF-driven allergic responses were significantly blunted in IL-33-deficient mice. IL-33 was localized on alveolar type II cells and in vitro stimulation of human epithelial cells with GM-CSF enhanced intracellular IL-33 independently of IL-1α. Likewise, GM-CSF administration in vivo resulted in increased levels of IL-33 but not IL-1α. These findings suggest that exposures to environmental agents associated with GM-CSF production, including airway infections and pollutants, may decrease the threshold of allergen responsiveness and, hence, increase the susceptibility to develop allergic asthma through a GM-CSF/IL-33/OX40L pathway.

  9. New Pathways between Group Theory and Model Theory

    CERN Document Server

    Fuchs, László; Goldsmith, Brendan; Strüngmann, Lutz

    2017-01-01

    This volume focuses on group theory and model theory with a particular emphasis on the interplay of the two areas. The survey papers provide an overview of the developments across group, module, and model theory while the research papers present the most recent study in those same areas. With introductory sections that make the topics easily accessible to students, the papers in this volume will appeal to beginning graduate students and experienced researchers alike. As a whole, this book offers a cross-section view of the areas in group, module, and model theory, covering topics such as DP-minimal groups, Abelian groups, countable 1-transitive trees, and module approximations. The papers in this book are the proceedings of the conference “New Pathways between Group Theory and Model Theory,” which took place February 1-4, 2016, in Mülheim an der Ruhr, Germany, in honor of the editors’ colleague Rüdiger Göbel. This publication is dedicated to Professor Göbel, who passed away in 2014. He was one of th...

  10. Model-Driven Paediatric Cardiomyopathy Pathways - A Clinical Impact Assessment.

    Science.gov (United States)

    Stroetmann, Karl A; Thiel, Rainer

    2017-01-01

    Intermediate results from an ongoing health technology assessment exercise of a simulation model of paediatric cardiomyopathy are reported. Comprehensive data on paediatric cardiomyopathy/heart failure, treatment options, incidence and prevalence, prognoses for different outcomes to be expected were collected. Based on this knowledge, a detailed clinical pathway model was developed and validated against the clinical workflow in a tertiary paediatric care hospital. It combines three disease stages and various treatment options with estimates of the probabilities of a child moving from one stage to another. To reflect the complexity of initial decision taking by clinicians, a three-stage Markov model was combined with a decision tree approach - a Markov decision process. A Markov Chain simulation tool was applied to compare estimates of transition probabilities and cost data of present standard of care treatment options for a cohort of children over ten years with expected improvements from using a clinical decision support tool based on the disease model under development. Early results indicate a slight increase of overall costs resulting from the extra cost of using such a tool in spite of some savings to be expected from improved care. However, the intangible benefits in life years saved of severely ill children and the improvement in QoL to be expected for moderately ill ones should more than compensate for this.

  11. Ising Model Reprogramming of a Repeat Protein's Equilibrium Unfolding Pathway.

    Science.gov (United States)

    Millership, C; Phillips, J J; Main, E R G

    2016-05-08

    Repeat proteins are formed from units of 20-40 aa that stack together into quasi one-dimensional non-globular structures. This modular repetitive construction means that, unlike globular proteins, a repeat protein's equilibrium folding and thus thermodynamic stability can be analysed using linear Ising models. Typically, homozipper Ising models have been used. These treat the repeat protein as a series of identical interacting subunits (the repeated motifs) that couple together to form the folded protein. However, they cannot describe subunits of differing stabilities. Here we show that a more sophisticated heteropolymer Ising model can be constructed and fitted to two new helix deletion series of consensus tetratricopeptide repeat proteins (CTPRs). This analysis, showing an asymmetric spread of stability between helices within CTPR ensembles, coupled with the Ising model's predictive qualities was then used to guide reprogramming of the unfolding pathway of a variant CTPR protein. The designed behaviour was engineered by introducing destabilising mutations that increased the thermodynamic asymmetry within a CTPR ensemble. The asymmetry caused the terminal α-helix to thermodynamically uncouple from the rest of the protein and preferentially unfold. This produced a specific, highly populated stable intermediate with a putative dimerisation interface. As such it is the first step in designing repeat proteins with function regulated by a conformational switch. Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.

  12. Spatial aspects of building and population exposure data and their implications for global earthquake exposure modeling

    Science.gov (United States)

    Dell’Acqua, F.; Gamba, P.; Jaiswal, K.

    2012-01-01

    This paper discusses spatial aspects of the global exposure dataset and mapping needs for earthquake risk assessment. We discuss this in the context of development of a Global Exposure Database for the Global Earthquake Model (GED4GEM), which requires compilation of a multi-scale inventory of assets at risk, for example, buildings, populations, and economic exposure. After defining the relevant spatial and geographic scales of interest, different procedures are proposed to disaggregate coarse-resolution data, to map them, and if necessary to infer missing data by using proxies. We discuss the advantages and limitations of these methodologies and detail the potentials of utilizing remote-sensing data. The latter is used especially to homogenize an existing coarser dataset and, where possible, replace it with detailed information extracted from remote sensing using the built-up indicators for different environments. Present research shows that the spatial aspects of earthquake risk computation are tightly connected with the availability of datasets of the resolution necessary for producing sufficiently detailed exposure. The global exposure database designed by the GED4GEM project is able to manage datasets and queries of multiple spatial scales.

  13. TOXICITY PATHWAY ANALYSIS IN AGING BROWN NORWAY RAT BRAIN FOLLOWING ACUTE TOLUENE EXPOSURE

    Science.gov (United States)

    The influence of aging on susceptibility to environmental stressors is poorly understood. To investigate the contribution of different life stages on response to toxicants, we examined the effects of acute exposure by oral gavage of the volatile organic solvent toluene (0.00, 0.3...

  14. Sex Differences in Adolescent Depression: Stress Exposure and Reactivity Models

    Science.gov (United States)

    Hankin, Benjamin L.; Mermelstein, Robin; Roesch, Linda

    2007-01-01

    Stress exposure and reactivity models were examined as explanations for why girls exhibit greater levels of depressive symptoms than boys. In a multiwave, longitudinal design, adolescents' depressive symptoms, alcohol usage, and occurrence of stressors were assessed at baseline, 6, and 12 months later (N=538; 54.5% female; ages 13-18, average…

  15. Task-based dermal exposure models for regulatory risk assessment

    NARCIS (Netherlands)

    Warren, N.D.; Marquart, H.; Christopher, Y.; Laitinen, J.; Hemmen, J.J. van

    2006-01-01

    The regulatory risk assessment of chemicals requires the estimation of occupational dermal exposure. Until recently, the models used were either based on limited data or were specific to a particular class of chemical or application. The EU project RISKOFDERM has gathered a considerable number of

  16. Population-based nutrikinetic modelling of phytochemical exposure

    NARCIS (Netherlands)

    Velzen, van E.J.J.; Westerhuis, J.A.; Grün, C.H.; Duynhoven, van J.P.M.; Jacobs, D.M.; Eilers, P.H.C.; Mulder, T.P.; Foltz, M.; Garczarek, U.; Kemperman, R.; Vaughan, E.E.; Smilde, A.K.

    2014-01-01

    The beneficial health effects of fruits and vegetables have been attributed to their polyphenol content. These compounds undergo many bioconversions in the body. Modeling polyphenol exposure of humans upon intake is a prerequisite for understanding the modulating effect of the food matrix and the

  17. A Model of Medical Countermeasures for Vesicant Exposure

    Science.gov (United States)

    2015-10-01

    their final version in a graphical user interface. This implementation of the model will include feedback and adjustments made after review of the...erythema in hairless guinea pigs after cutaneous sulfur mustard vapor exposure by pretreatment with niacinamide, promethazine and indomethacin. J Appl

  18. Maternal Disononyl Phthalate Exposure Activates Allergic Airway Inflammation via Stimulating the Phosphoinositide 3-kinase/Akt Pathway in Rat Pups.

    Science.gov (United States)

    Chen, Li; Chen, Jiao; Xie, Chang Ming; Zhao, Yan; Wang, Xiu; Zhang, Yun Hui

    2015-03-01

    To evaluate the effect of diisononyl phthalate (DINP) exposure during gestation and lacta- tion on allergic response in pups and to explore the role of phosphoinositide 3-kinase/Akt pathway on it. Female Wistar rats were treated with DINP at different dosages (0, 5, 50, and 500 mg/kg of body weight per day). The pups were sensitized and challenged by ovalbumin (OVA). The airway response was assessed; the airway histological studies were performed by hematoxylin and eosin (HE) staining; and the relative cytokines in phosphoinositide 3-kinase (PI3K)/Akt pathway were measured by enzyme-linked immunosorbent assay (ELISA) and western blot analysis. There was no significant difference in DINP's effect on airway hyperresponsiveness (AHR) between male pups and female pups. In the 50 mg/(kg·d) DINP-treated group, airway response to OVA significantly increased and pups showed dramatically enhanced pulmonary resistance (RI) compared with those from controls (P<0.05). Enhanced Akt phosphorylation and NF-κB translocation, and Th2 cytokines expression were observed in pups of 50 mg/(kg·d) DINP-treated group. However, in the 5 and 500 mg/(kg·d) DINP-treated pups, no significant effects were observed. There was an adjuvant effect of DINP on allergic airway inflammation in pups. Maternal DINP exposure could promote OVA-induced allergic airway response in pups in part by upregulation of PI3K/Akt pathway. Copyright © 2015 The Editorial Board of Biomedical and Environmental Sciences. Published by China CDC. All rights reserved.

  19. Modular and Stochastic Approaches to Molecular Pathway Models of ATM, TGF beta, and WNT Signaling

    Science.gov (United States)

    Cucinotta, Francis A.; O'Neill, Peter; Ponomarev, Artem; Carra, Claudio; Whalen, Mary; Pluth, Janice M.

    2009-01-01

    Deterministic pathway models that describe the biochemical interactions of a group of related proteins, their complexes, activation through kinase, etc. are often the basis for many systems biology models. Low dose radiation effects present a unique set of challenges to these models including the importance of stochastic effects due to the nature of radiation tracks and small number of molecules activated, and the search for infrequent events that contribute to cancer risks. We have been studying models of the ATM, TGF -Smad and WNT signaling pathways with the goal of applying pathway models to the investigation of low dose radiation cancer risks. Modeling challenges include introduction of stochastic models of radiation tracks, their relationships to more than one substrate species that perturb pathways, and the identification of a representative set of enzymes that act on the dominant substrates. Because several pathways are activated concurrently by radiation the development of modular pathway approach is of interest.

  20. Developmental exposure to estrogen alters differentiation and epigenetic programming in a human fetal prostate xenograft model.

    Directory of Open Access Journals (Sweden)

    Camelia M Saffarini

    Full Text Available Prostate cancer is the most frequent non-cutaneous malignancy in men. There is strong evidence in rodents that neonatal estrogen exposure plays a role in the development of this disease. However, there is little information regarding the effects of estrogen in human fetal prostate tissue. This study explored early life estrogen exposure, with and without a secondary estrogen and testosterone treatment in a human fetal prostate xenograft model. Histopathological lesions, proliferation, and serum hormone levels were evaluated at 7, 30, 90, and 200-day time-points after xenografting. The expression of 40 key genes involved in prostatic glandular and stromal growth, cell-cycle progression, apoptosis, hormone receptors and tumor suppressors was evaluated using a custom PCR array. Epigenome-wide analysis of DNA methylation was performed on whole tissue, and laser capture-microdissection (LCM isolated epithelial and stromal compartments of 200-day prostate xenografts. Combined initial plus secondary estrogenic exposures had the most severe tissue changes as revealed by the presence of hyperplastic glands at day 200. Gene expression changes corresponded with the cellular events in the KEGG prostate cancer pathway, indicating that initial plus secondary exposure to estrogen altered the PI3K-Akt signaling pathway, ultimately resulting in apoptosis inhibition and an increase in cell cycle progression. DNA methylation revealed that differentially methylated CpG sites significantly predominate in the stromal compartment as a result of estrogen-treatment, thereby providing new targets for future investigation. By using human fetal prostate tissue and eliminating the need for species extrapolation, this study provides novel insights into the gene expression and epigenetic effects related to prostate carcinogenesis following early life estrogen exposure.

  1. Terrestrial and marine perspectives on modeling organic matter degradation pathways.

    Science.gov (United States)

    Burd, Adrian B; Frey, Serita; Cabre, Anna; Ito, Takamitsu; Levine, Naomi M; Lønborg, Christian; Long, Matthew; Mauritz, Marguerite; Thomas, R Quinn; Stephens, Brandon M; Vanwalleghem, Tom; Zeng, Ning

    2016-01-01

    Organic matter (OM) plays a major role in both terrestrial and oceanic biogeochemical cycles. The amount of carbon stored in these systems is far greater than that of carbon dioxide (CO2 ) in the atmosphere, and annual fluxes of CO2 from these pools to the atmosphere exceed those from fossil fuel combustion. Understanding the processes that determine the fate of detrital material is important for predicting the effects that climate change will have on feedbacks to the global carbon cycle. However, Earth System Models (ESMs) typically utilize very simple formulations of processes affecting the mineralization and storage of detrital OM. Recent changes in our view of the nature of this material and the factors controlling its transformation have yet to find their way into models. In this review, we highlight the current understanding of the role and cycling of detrital OM in terrestrial and marine systems and examine how this pool of material is represented in ESMs. We include a discussion of the different mineralization pathways available as organic matter moves from soils, through inland waters to coastal systems and ultimately into open ocean environments. We argue that there is strong commonality between aspects of OM transformation in both terrestrial and marine systems and that our respective scientific communities would benefit from closer collaboration. © 2015 John Wiley & Sons Ltd.

  2. A Pilot Study on Integrating Videography and Environmental Microbial Sampling to Model Fecal Bacterial Exposures in Peri-Urban Tanzania

    Science.gov (United States)

    Julian, Timothy R.; Pickering, Amy J.

    2015-01-01

    Diarrheal diseases are a leading cause of under-five mortality and morbidity in sub-Saharan Africa. Quantitative exposure modeling provides opportunities to investigate the relative importance of fecal-oral transmission routes (e.g. hands, water, food) responsible for diarrheal disease. Modeling, however, requires accurate descriptions of individuals’ interactions with the environment (i.e., activity data). Such activity data are largely lacking for people in low-income settings. In the present study, we collected activity data and microbiological sampling data to develop a quantitative microbial exposure model for two female caretakers in peri-urban Tanzania. Activity data were combined with microbiological data of contacted surfaces and fomites (e.g. broom handle, soil, clothing) to develop example exposure profiles describing second-by-second estimates of fecal indicator bacteria (E. coli and enterococci) concentrations on the caretaker’s hands. The study demonstrates the application and utility of video activity data to quantify exposure factors for people in low-income countries and apply these factors to understand fecal contamination exposure pathways. This study provides both a methodological approach for the design and implementation of larger studies, and preliminary data suggesting contacts with dirt and sand may be important mechanisms of hand contamination. Increasing the scale of activity data collection and modeling to investigate individual-level exposure profiles within target populations for specific exposure scenarios would provide opportunities to identify the relative importance of fecal-oral disease transmission routes. PMID:26295964

  3. A Pilot Study on Integrating Videography and Environmental Microbial Sampling to Model Fecal Bacterial Exposures in Peri-Urban Tanzania.

    Directory of Open Access Journals (Sweden)

    Timothy R Julian

    Full Text Available Diarrheal diseases are a leading cause of under-five mortality and morbidity in sub-Saharan Africa. Quantitative exposure modeling provides opportunities to investigate the relative importance of fecal-oral transmission routes (e.g. hands, water, food responsible for diarrheal disease. Modeling, however, requires accurate descriptions of individuals' interactions with the environment (i.e., activity data. Such activity data are largely lacking for people in low-income settings. In the present study, we collected activity data and microbiological sampling data to develop a quantitative microbial exposure model for two female caretakers in peri-urban Tanzania. Activity data were combined with microbiological data of contacted surfaces and fomites (e.g. broom handle, soil, clothing to develop example exposure profiles describing second-by-second estimates of fecal indicator bacteria (E. coli and enterococci concentrations on the caretaker's hands. The study demonstrates the application and utility of video activity data to quantify exposure factors for people in low-income countries and apply these factors to understand fecal contamination exposure pathways. This study provides both a methodological approach for the design and implementation of larger studies, and preliminary data suggesting contacts with dirt and sand may be important mechanisms of hand contamination. Increasing the scale of activity data collection and modeling to investigate individual-level exposure profiles within target populations for specific exposure scenarios would provide opportunities to identify the relative importance of fecal-oral disease transmission routes.

  4. MODELING ENERGY EXPENDITURE AND OXYGEN CONSUMPTION IN HUMAN EXPOSURE MODELS: ACCOUNTING FOR FATIGUE AND EPOC

    Science.gov (United States)

    Human exposure and dose models often require a quantification of oxygen consumption for a simulated individual. Oxygen consumption is dependent on the modeled Individual's physical activity level as described in an activity diary. Activity level is quantified via standardized val...

  5. Electroanatomic mapping guided cryoablation of Mahaim pathways in children with limited fluoroscopy exposure.

    Science.gov (United States)

    Ozturk, Erkut; Ergul, Yakup; Tanidir, I Cansaran; Akdeniz, Celal; Tola, H Tahsin; Tuzcu, Volkan

    2015-03-01

    The presence of Mahaim accessory pathways (MAP) with anterograde decremental conduction is a disorder that leads to antidromic atrioventricular reentrant tachycardia. There are rare reports of cryoablation use in MAP. This study aims at sharing our experience with using cryoablation to treat MAP in children. Electrophysiology study and catheter ablation were performed in 14 patients diagnosed with Mahaim tachycardia between January 2010 and December 2013. Cryoablation was used in nine of the cases. A three-dimensional navigation system with surface electrode patches (EnSite System, St. Jude Medical Inc., St. Paul, MN, USA) was used for all procedures. The patients (two girls and seven boys) had a median age of 11.5 years (8-18 years) and a median weight of 67 kg (31-80 kg). Mahaim conduction was localized in the right posterolateral (n = 4), right lateral region (n = 2), right posteroseptal (n = 1), right anterolateral (n = 1), and right anterior (n = 1). A pathway potential was noted in six of nine cases at the tricuspid annulus. Catheter choices and acute success rates were as follows: cryoablation in four (three of four successful), radiofrequency catheter ablation (RFA) and cryoablation in five (successful in four of five). No fluoroscopy was used in six of nine patients. The mean procedure duration was 249 ± 90 minutes. No major complications were observed. The final long-term success rate for cryoablation was seven of nine (78%). Cryoablation can be used as a reliable and effective alternative to RFA in the treatment of Mahaim accessory conduction pathways in children. Prospective comparative studies are necessary in order to further evaluate the long-term efficacy of this method. ©2014 Wiley Periodicals, Inc.

  6. Modelling the bioaccumulation of persistent organic pollutants in agricultural food chains for regulatory exposure assessment.

    Science.gov (United States)

    Takaki, Koki; Wade, Andrew J; Collins, Chris D

    2017-02-01

    New models for estimating bioaccumulation of persistent organic pollutants in the agricultural food chain were developed using recent improvements to plant uptake and cattle transfer models. One model named AgriSim was based on K OW regressions of bioaccumulation in plants and cattle, while the other was a steady-state mechanistic model, AgriCom. The two developed models and European Union System for the Evaluation of Substances (EUSES), as a benchmark, were applied to four reported food chain (soil/air-grass-cow-milk) scenarios to evaluate the performance of each model simulation against the observed data. The four scenarios considered were as follows: (1) polluted soil and air, (2) polluted soil, (3) highly polluted soil surface and polluted subsurface and (4) polluted soil and air at different mountain elevations. AgriCom reproduced observed milk bioaccumulation well for all four scenarios, as did AgriSim for scenarios 1 and 2, but EUSES only did this for scenario 1. The main causes of the deviation for EUSES and AgriSim were the lack of the soil-air-plant pathway and the ambient air-plant pathway, respectively. Based on the results, it is recommended that soil-air-plant and ambient air-plant pathway should be calculated separately and the K OW regression of transfer factor to milk used in EUSES be avoided. AgriCom satisfied the recommendations that led to the low residual errors between the simulated and the observed bioaccumulation in agricultural food chain for the four scenarios considered. It is therefore recommended that this model should be incorporated into regulatory exposure assessment tools. The model uncertainty of the three models should be noted since the simulated concentration in milk from 5th to 95th percentile of the uncertainty analysis often varied over two orders of magnitude. Using a measured value of soil organic carbon content was effective to reduce this uncertainty by one order of magnitude.

  7. Modeling the exposure of children and adults via diet to chemicals in the environment with crop-specific models

    Energy Technology Data Exchange (ETDEWEB)

    Legind, Charlotte N. [Department of Environmental Engineering, Technical University of Denmark, Miljoevej 113, 2800 Kongens Lyngby (Denmark); Department of Agriculture and Ecology, Faculty of Life Sciences, University of Copenhagen, Hojbakkegard Alle 13, 2630 Taastrup (Denmark); Department of Environmental Chemistry and Microbiology, National Environmental Research Institute, University of Aarhus, Frederiksborgvej 399, 4000 Roskilde (Denmark)], E-mail: cnl@env.dtu.dk; Trapp, Stefan [Department of Environmental Engineering, Technical University of Denmark, Miljoevej 113, 2800 Kongens Lyngby (Denmark)

    2009-03-15

    Exposure to chemicals via diet is a major uptake pathway for many compounds but is often estimated in a rather generic way. We use a new model framework (NMF) with crop-specific models to predict the dietary intake by 4-5-year-old children and 14-75-year-old women of three environmental compounds from their background concentrations in soil and air. Calculated daily intakes of benzo(a)pyrene and 2,3,7,8-TCDD are in good agreement with measured results from diet studies. The major source of both compounds in human diet is deposition from air. Inhalation of air and ingestion of soil play a minor role. Children take up more than twice the amount than adults per kg bodyweight, due to higher consumption per kg bodyweight. Contrary, the methods for indirect human exposure suggested in the Technical Guidance Document (TGD) for chemical risk assessment in the EU lead to overprediction, due to unrealistic consumption data and a false root model. - This paper addresses exposure of children and adults to environmental chemicals via the terrestrial food chain using crop-specific plant uptake models.

  8. Using transportation demand models to assess regional noise exposure

    Science.gov (United States)

    Kaliski, Kenneth

    2005-09-01

    In the United States, most metropolitan areas run some type of transportation demand model to estimate regional travel patterns, and, to some extent, air pollution. The more advanced of these models accurately represent the geographic contours of the roadways (in contrast to the older straight-line node and link models). This allows an almost seamless integration of these new transportation demand models into noise prediction models. Combined with the locations of individual homes from a separate E911 database, we can readily make estimates of the noise exposure of populations over large areas. In this paper, the regional traffic noise exposure of residences of Chittenden County, VT is estimated and mapped. It was found that 30% of the residences are exposed to noise levels exceeding the WHO sleep disturbance level of 45 dB LAeq(8) and 20% of residences are exposed to levels exceeding the WHO ``serious annoyance'' level of 55 dB LAeq(16). Maps show noise contours as well as individual homes color coded based on relative day and night noise exposure levels. Measured sound level data are given for particular locations to validate the predictions.

  9. Pathways of change explaining the effect of smoke-free legislation on smoking cessation in the Netherlands: an application of the international tobacco control conceptual model

    NARCIS (Netherlands)

    Nagelhout, G.E.; de Vries, H.; Fong, G.T.; Candel, M.J.J.M.; Thrasher, J.F.; van den Putte, B.; Thompson, M.E.; Cummings, K.M.; Willemsen, M.C.

    2012-01-01

    Introduction: This study aims to test the pathways of change from individual exposure to smoke-free legislation on smoking cessation, as hypothesized in the International Tobacco Control (ITC) Conceptual Model. Methods: A nationally representative sample of Dutch smokers aged 15 years and older was

  10. Activation of Neutrophils via IP3 Pathway Following Exposure to Demodex-Associated Bacterial Proteins.

    Science.gov (United States)

    McMahon, Fred; Banville, Nessa; Bergin, David A; Smedman, Christian; Paulie, Staffan; Reeves, Emer; Kavanagh, Kevin

    2016-02-01

    Rosacea is a chronic inflammatory condition that predominantly affects the skin of the face. Sera from rosacea patients display elevated reactivity to proteins from a bacterium (Bacillus oleronius) originally isolated from a Demodex mite from a rosacea patient suggesting a possible role for bacteria in the induction and persistence of this condition. This work investigated the ability of B. oleronius proteins to activate neutrophils and demonstrated activation via the IP3 pathway. Activated neutrophils displayed increased levels of IP1 production, F-actin formation, chemotaxis, and production of the pro-inflammatory cytokines IL-1β and IL-6 following stimulation by pure and crude B. oleronius protein preparations (2 μg/ml), respectively. In addition, neutrophils exposed to pure and crude B. oleronius proteins (2 μg/ml) demonstrated increased release of internally stored calcium (Ca(2+)), a hallmark of the IP3 pathway of neutrophil activation. Neutrophils play a significant role in the inflammation associated with rosacea, and this work demonstrates how B. oleronius proteins can induce neutrophil recruitment and activation.

  11. Inhalation Exposure Input Parameters for the Biosphere Model

    Energy Technology Data Exchange (ETDEWEB)

    M. Wasiolek

    2006-06-05

    This analysis is one of the technical reports that support the Environmental Radiation Model for Yucca Mountain, Nevada (ERMYN), referred to in this report as the biosphere model. ''Biosphere Model Report'' (BSC 2004 [DIRS 169460]) describes in detail the conceptual model as well as the mathematical model and its input parameters. This report documents development of input parameters for the biosphere model that are related to atmospheric mass loading and supports the use of the model to develop biosphere dose conversion factors (BDCFs). The biosphere model is one of a series of process models supporting the total system performance assessment (TSPA) for a Yucca Mountain repository. ''Inhalation Exposure Input Parameters for the Biosphere Model'' is one of five reports that develop input parameters for the biosphere model. A graphical representation of the documentation hierarchy for the biosphere model is presented in Figure 1-1 (based on BSC 2006 [DIRS 176938]). This figure shows the interrelationships among the products (i.e., analysis and model reports) developed for biosphere modeling and how this analysis report contributes to biosphere modeling. This analysis report defines and justifies values of atmospheric mass loading for the biosphere model. Mass loading is the total mass concentration of resuspended particles (e.g., dust, ash) in a volume of air. Mass loading values are used in the air submodel of the biosphere model to calculate concentrations of radionuclides in air inhaled by a receptor and concentrations in air surrounding crops. Concentrations in air to which the receptor is exposed are then used in the inhalation submodel to calculate the dose contribution to the receptor from inhalation of contaminated airborne particles. Concentrations in air surrounding plants are used in the plant submodel to calculate the concentrations of radionuclides in foodstuffs contributed from uptake by foliar interception. This

  12. An in situ assessment of selenium bioaccumulation from water-, sediment-, and dietary-exposure pathways using caged Chironomus dilutus larvae.

    Science.gov (United States)

    Franz, Eric D; Wiramanaden, Cheryl I E; Gallego-Gallegos, Mercedes; Tse, Justin J; Phibbs, James; Janz, David M; Pickering, Ingrid J; Liber, Karsten

    2013-12-01

    An in situ caging study was conducted downstream of a metal mine in northern Canada to determine the significance of surface water versus sediment exposure on selenium (Se) bioaccumulation in the benthic invertebrate Chironomus dilutus. Laboratory-reared C. dilutus larvae were exposed to either site-specific whole-sediment and surface water or surface water only for 10 d at sites with differing sediment and Se characteristics. Results showed elevated whole-body Se concentrations in C. dilutus larvae when exposed to sediment and water, compared with larvae exposed to Se in the surface water only at concentrations ranging from <1 µg Se/L to 12 µg Se/L. In response to these findings, a second in situ experiment was conducted to investigate the importance of dietary Se (biofilm and detritus) versus whole-sediment-exposure pathways. Larvae exposed to sediment detritus had the highest Se concentrations after 10 d of exposure (15.6 ± 1.9 µg/g dry wt) compared with larvae exposed to whole-sediment (12.9 ± 1.7 µg/g dry wt) or biofilm (9.9 ± 1.6 µg/g dry wt). Detritus and biofilm appear to be enriched sources of organic Se, which are more bioaccumulative than inorganic Se. Midge larvae from the reference treatment contained elevated concentrations of diselenides (i.e., selenocystine), while larvae from the biofilm treatment had the highest concentrations of selenomethionine-like compounds, which may be a biomarker of elevated Se exposures derived from anthropogenic sources. Whenever possible, Se concentrations in the organic fraction of sediment should be measured separately from whole-sediment Se and used for more accurate ecological risk assessments of potential Se impacts on aquatic ecosystems. © 2013 SETAC.

  13. Bayesian network model for identification of pathways by integrating protein interaction with genetic interaction data.

    Science.gov (United States)

    Fu, Changhe; Deng, Su; Jin, Guangxu; Wang, Xinxin; Yu, Zu-Guo

    2017-09-21

    Molecular interaction data at proteomic and genetic levels provide physical and functional insights into a molecular biosystem and are helpful for the construction of pathway structures complementarily. Despite advances in inferring biological pathways using genetic interaction data, there still exists weakness in developed models, such as, activity pathway networks (APN), when integrating the data from proteomic and genetic levels. It is necessary to develop new methods to infer pathway structure by both of interaction data. We utilized probabilistic graphical model to develop a new method that integrates genetic interaction and protein interaction data and infers exquisitely detailed pathway structure. We modeled the pathway network as Bayesian network and applied this model to infer pathways for the coherent subsets of the global genetic interaction profiles, and the available data set of endoplasmic reticulum genes. The protein interaction data were derived from the BioGRID database. Our method can accurately reconstruct known cellular pathway structures, including SWR complex, ER-Associated Degradation (ERAD) pathway, N-Glycan biosynthesis pathway, Elongator complex, Retromer complex, and Urmylation pathway. By comparing N-Glycan biosynthesis pathway and Urmylation pathway identified from our approach with that from APN, we found that our method is able to overcome its weakness (certain edges are inexplicable). According to underlying protein interaction network, we defined a simple scoring function that only adopts genetic interaction information to avoid the balance difficulty in the APN. Using the effective stochastic simulation algorithm, the performance of our proposed method is significantly high. We developed a new method based on Bayesian network to infer detailed pathway structures from interaction data at proteomic and genetic levels. The results indicate that the developed method performs better in predicting signaling pathways than previously

  14. An ontology-based hierarchical semantic modeling approach to clinical pathway workflows.

    Science.gov (United States)

    Ye, Yan; Jiang, Zhibin; Diao, Xiaodi; Yang, Dong; Du, Gang

    2009-08-01

    This paper proposes an ontology-based approach of modeling clinical pathway workflows at the semantic level for facilitating computerized clinical pathway implementation and efficient delivery of high-quality healthcare services. A clinical pathway ontology (CPO) is formally defined in OWL web ontology language (OWL) to provide common semantic foundation for meaningful representation and exchange of pathway-related knowledge. A CPO-based semantic modeling method is then presented to describe clinical pathways as interconnected hierarchical models including the top-level outcome flow and intervention workflow level along a care timeline. Furthermore, relevant temporal knowledge can be fully represented by combing temporal entities in CPO and temporal rules based on semantic web rule language (SWRL). An illustrative example about a clinical pathway for cesarean section shows the applicability of the proposed methodology in enabling structured semantic descriptions of any real clinical pathway.

  15. Modeling Flight Attendants’ Exposures to Pesticide in Disinsected Aircraft Cabins

    Science.gov (United States)

    Zhang, Yong; Isukapalli, Sastry; Georgopoulos, Panos; Weisel, Clifford

    2014-01-01

    Aircraft cabin disinsection is required by some countries to kill insects that may pose risks to public health and native ecological systems. A probabilistic model has been developed by considering the microenvironmental dynamics of the pesticide in conjunction with the activity patterns of flight attendants, to assess their exposures and risks to pesticide in disinsected aircraft cabins under three scenarios of pesticide application. Main processes considered in the model are microenvironmental transport and deposition, volatilization, and transfer of pesticide when passengers and flight attendants come in contact with the cabin surfaces. The simulated pesticide airborne mass concentration and surface mass loadings captured measured ranges reported in the literature. The medians (means±standard devitions) of daily total exposures intakes were 0.24 (3.8±10.0), 1.4 (4.2±5.7) and 0.15 (2.1±3.2) μg/(day kg BW) for scenarios of Residual Application, Preflight and Top-of-Descent spraying, respectively. Exposure estimates were sensitive to parameters corresponding to pesticide deposition, body surface area and weight, surface-to-body transfer efficiencies, and efficiency of adherence to skin. Preflight spray posed 2.0 and 3.1 times higher pesticide exposure risk levels for flight attendants in disinsected aircraft cabins than Top-of-Descent spray and Residual Application, respectively. PMID:24251734

  16. Systems biology modeling of omics data: effect of cyclosporine a on the Nrf2 pathway in human renal cells.

    Science.gov (United States)

    Hamon, Jérémy; Jennings, Paul; Bois, Frederic Y

    2014-06-25

    Incorporation of omic data streams for building improved systems biology models has great potential for improving their predictions of biological outcomes. We have recently shown that cyclosporine A (CsA) strongly activates the nuclear factor (erythroid-derived 2)-like 2 pathway (Nrf2) in renal proximal tubular epithelial cells (RPTECs) exposed in vitro. We present here a quantitative calibration of a differential equation model of the Nrf2 pathway with a subset of the omics data we collected. In vitro pharmacokinetic data on CsA exchange between cells, culture medium and vial walls, and data on the time course of omics markers in response to CsA exposure were reasonably well fitted with a coupled PK-systems biology model. Posterior statistical distributions of the model parameter values were obtained by Markov chain Monte Carlo sampling in a Bayesian framework. A complex cyclic pattern of ROS production and control emerged at 5 μM CsA repeated exposure. Plateau responses were found at 15 μM exposures. Shortly above those exposure levels, the model predicts a disproportionate increase in cellular ROS quantity which is consistent with an in vitro EC50 of about 40 μM for CsA in RPTECs. The model proposed can be used to analyze and predict cellular response to oxidative stress, provided sufficient data to set its parameters to cell-specific values. Omics data can be used to that effect in a Bayesian statistical framework which retains prior information about the likely parameter values.

  17. Regression modeling of consumption or exposure variables classified by type.

    Science.gov (United States)

    Dorfman, A; Kimball, A W; Friedman, L A

    1985-12-01

    Consumption or exposure variables, as potential risk factors, are commonly measured and related to health effects. The measurements may be continuous or discrete, may be grouped into categories and may, in addition, be classified by type. Data analyses utilizing regression methods for the assessment of these risk factors present many problems of modeling and interpretation. Various models are proposed and evaluated, and recommendations are made. Use of the models is illustrated with Cox regression analyses of coronary heart disease mortality after 24 years of follow-up of subjects in the Framingham Study, with the focus being on alcohol consumption among these subjects.

  18. Human lead metabolism: Chronic exposure, bone lead and physiological models

    Science.gov (United States)

    Fleming, David Eric Berkeley

    Exposure to lead is associated with a variety of detrimental health effects. After ingestion or inhalation, lead may be taken up from the bloodstream and retained by bone tissue. X-ray fluorescence was used to make in vivo measurements of bone lead concentration at the tibia and calcaneus for 367 active and 14 retired lead smelter workers. Blood lead levels following a labour disruption were used in conjunction with bone lead readings to examine the endogenous release of lead from bone. Relations between bone lead and a cumulative blood lead index differed depending on time of hiring. This suggests that the transfer of lead from blood to bone has changed over time, possibly as a result of varying exposure conditions. A common polymorphism in the δ-aminolevulinate dehydratase (ALAD) enzyme may influence the distribution of lead in humans. Blood lead levels were higher for smelter workers expressing the more rare ALAD2 allele. Bone lead concentrations, however, were not significantly different. This implies that a smaller proportion of lead in blood is distributed to tissue for individuals expressing the ALAD2 allele. The O'Flaherty physiological model of lead metabolism was modified slightly and tested with input from the personal exposure histories of smelter workers. The model results were consistent with observation in tern of endogenous exposure to lead and accumulation of lead in cortical bone. Modelling the calcaneus as a trabecular bone site did not reproduce observed trends. variations in lead metabolism between different trabecular sites may therefore be significant. The model does not incorporate a genetic component, and its output did not reflect observed differences in this respect. This result provides further support for the influence of the ALAD polymorphism on lead metabolism. Experimental trials with a digital spectrometer revealed superior energy resolution and count throughput relative to the conventional X-ray fluorescence system. The associated

  19. [Exposure pathways to pesticides in schoolchildren in the Province of Talca, Chile].

    Science.gov (United States)

    Muñoz-Quezada, María Teresa; Lucero, Boris; Iglesias, Verónica; Muñoz, María Pía

    2014-01-01

    To describe pesticide concentrations in distinct environmental matrices at two time points (low and high seasons in local agricultural production) and to estimate the association between the presence of pesticide residues in matrices and the use of pesticides in the home with the sociodemographic variables of schoolchildren in the Province of Talca, Chile. A cross-sectional study was conducted in 190 schoolchildren. Families were surveyed about their children's vegetable consumption in school and at home, the use of pesticides in the home, and other sociodemographic variables. Additionally, we measured pesticide residues in vegetables and water consumed by the schoolchildren and in the soil of 14 schools. At both time points, the vegetable matrix had the highest pesticide concentration, both in urban and rural schoolchildren. The most common pesticide residues in vegetables were chlorpyrifos, diphenylamine, pyrimethanil, and thiabendazole. In the home, pyrethroid and organophosphate pesticides were mainly used in summer. Dangerous pesticide residues such as azinphos methyl and dimethoate were found in vegetables consumed by the children in schools and households, and organochlorines were found in the soil in some schools. Pesticide exposure should be limited and the health effects related to pesticide exposure should be assessed in the school population. Copyright © 2013 SESPAS. Published by Elsevier Espana. All rights reserved.

  20. GSM-like radiofrequency exposure induces apoptosis via caspase-dependent pathway in infant rabbits.

    Science.gov (United States)

    Meral, O; Ozgur, E; Kismali, G; Guler, G; Alpay, M; Sel, T; Seyhan, N

    2016-01-01

    There have been several Radio Frequency (RF) field researches on various populations and groups of different ages in recent years. However, the most important group for research has been declared as the pregnant women and their babies. The aim of the study was to analyse the effect on apoptotic factors of RF fields on newborn rabbit liver tissues. Cytochrome c and AIF (Apoptosis Inducing Factor) levels were measured by western blot and caspase 1, 3 and 9 activities were measured by colorimetric method. Cytochrome c and AIF levels were not altered, but all caspase activities were increased in female infant rabbits that exposed to 1800 MHz GSM-like RF signals when they reached 1 month of age and caspase 1 and caspase 3 levels were decreased in male infant rabbits that exposed to 1800 MHz GSM-like RF signals between 15th and 22nd days of the gestational period. Results showed that 1800 MHz GSM-like RF exposure might lead to apoptosis in infant rabbit's liver tissues. According to the results, we suggest that postnatal RF exposure causes caspase dependent apoptosis in female infant rabbits liver tissues (Tab. 1, Fig. 2, Ref. 27).

  1. Alternative Roles of STAT3 and MAPK Signaling Pathways in the MMPs Activation and Progression of Lung Injury Induced by Cigarette Smoke Exposure in ACE2 Knockout Mice.

    Science.gov (United States)

    Hung, Yi-Han; Hsieh, Wen-Yeh; Hsieh, Jih-Sheng; Liu, Fon-Chang; Tsai, Chin-Hung; Lu, Li-Che; Huang, Chen-Yi; Wu, Chien-Liang; Lin, Chih-Sheng

    2016-01-01

    Inflammation-mediated abnormalities in the renin-angiotensin system (RAS) and expression of matrix metalloproteinases (MMPs) are implicated in the pathogenesis of lung injury. Angiotensin converting enzyme II (ACE2), an angiotensin converting enzyme (ACE) homologue that displays antagonist effects on ACE/angiotensin II (Ang II) axis, could also play a protective role against lung diseases. However, the relationship between ACE2 and MMPs activation in lung injury is still largely unclear. The purpose of this study is to investigate whether MMPs activity could be affected by ACE2 and which ACE2 derived signaling pathways could be also involved via using a mouse model with lung injury induced by cigarette smoke (CS) exposure for 1 to 3 weeks. Wild-type (WT; C57BL/6) and ACE2 KO mice (ACE2(-/-)) were utilized to study CS-induced lung injury. Increases in the resting respiratory rate (RRR), pulmonary immunokines, leukocyte infiltration and bronchial hyperplasia were observed in the CS-exposed mice. Compared to WT mice, more serious physiopathological changes were found in ACE2(-/-) mice in the first week of CS exposure. CS exposure increased pulmonary ACE and ACE2 activities in WT mice, and significantly increased ACE in ACE2(-/-) mice. Furthermore, the activity of pulmonary MMPs was decreased in CS-exposed WT mice, whereas this activity was increased in ACE2(-/-) mice. CS exposure increased the pulmonary p-p38, p-JNK and p-ERK1/2 level in all mice. In ACE2(-/-) mice, a significant increase p-STAT3 signaling was detected; however, no effect was observed on the p-STAT3 level in WT mice. Our results support the hypothesis that ACE2 deficiency influences MMPs activation and STAT3 phosphorylation signaling to promote more pulmonary inflammation in the development of lung injury.

  2. Calculation of the radiation doses occurring in the human body for inadvertent ingestion of soil and other soil exposure pathways

    Science.gov (United States)

    Oner, F.; Okumuolu, N.

    2003-11-01

    We estimate the radiation doses in the human body, in the Gudalore region in India, following the inadvertent ingestion of soil and exposure to other soil pathways by measuring Th-232, U-238, and K-40. We estimate the equivalent dose in eleven different organs and the absorbed dose calculations for the whole body. The annual effective doses are calculated, the lowest is in Kariyasolai at 7.8 x 10(-3) mSv whereas the highest is in Ponnur at 8.9 x 10(-2) mSv. In all regions, the lowest equivalent doses through inadvertent soil ingestion are calculated in the kidney and thyroid whereas the highest doses are in the red marrow and on the bone surface.

  3. Assessing the risk of an excess fluoride intake among Swedish children in households with private wells--expanding static single-source methods to a probabilistic multi-exposure-pathway approach.

    Science.gov (United States)

    Augustsson, Anna; Berger, Tobias

    2014-07-01

    It is often assumed that water consumption is the major route of exposure for fluoride and analysis of water fluoride content is the most common approach for ensuring that the daily intake is not too high. In the present study, the risk of excess intake was characterized for children in households with private wells in Kalmar County, Sweden, where the natural geology shows local enrichments in fluorine. By comparing water concentrations with the WHO drinking water guideline (1.5 mg/L), it was found that 24% of the ca. 4800 sampled wells had a concentration above this limit, hence providing a figure for the number of children in the households concerned assessed to be at risk using this straightforward approach. The risk of an excess intake could, alternatively, also be characterized based on a tolerable daily intake (in this case the US EPA RfD of 0.06 mg/kg-day). The exposure to be evaluated was calculated using a probabilistic approach, where the variability in all exposure factors was considered, again for the same study population. The proportion of children assessed to be at risk after exposure from drinking water now increased to 48%, and when the probabilistic model was adjusted to also include other possible exposure pathways; beverages and food, ingestion of toothpaste, oral soil intake and dust inhalation, the number increased to 77%. Firstly, these results show how the risk characterization is affected by the basis of comparison. In this example, both of the reference values used are widely acknowledged. Secondly, it illustrates how much of the total exposure may be overlooked when only focusing on one exposure pathway, and thirdly, it shows the importance of considering the variability in all relevant pathways. Copyright © 2014 Elsevier Ltd. All rights reserved.

  4. Opioid pathways activation mediates the activity of nicorandil in experimental models of nociceptive and inflammatory pain.

    Science.gov (United States)

    Dutra, Marcela M G B; Nascimento Júnior, Elias B; Godin, Adriana M; Brito, Ana Mercy S; Melo, Ivo S F; Augusto, Paulo S A; Rodrigues, Felipe F; Araújo, Débora P; de Fátima, Ângelo; Coelho, Márcio M; Machado, Renes R

    2015-12-05

    We have previously demonstrated that nicorandil inhibits the second phase of the nociceptive response induced by formaldehyde. In the present study, we evaluated the effects induced by nicorandil in other models of nociceptive and inflammatory pain in mice and also whether opioid pathways activation mediates its activity. As we have previously demonstrated, per os (p.o.) administration of nicorandil (50, 100 or 150mg/kg; -1h) inhibited the second phase of the nociceptive response induced by intraplantar (i.pl.) injection of formaldehyde. Nicorandil (50, 100 or 150mg/kg; p.o., -1h) also exhibited activity in models of inflammatory pain induced by i.pl. injection of carrageenan (300μg) and nociceptive pain induced by exposure to noxious heat (50°C). Intraperitoneal (i.p.) administration of the opioid antagonist naltrexone (1, 5 or 10mg/kg, -30min) attenuated or abolished the antinociceptive activity of nicorandil (100mg/kg, p.o.) in the three experimental pain models. In conclusion, we demonstrate that nicorandil exhibits activity in different models of nociceptive and inflammatory pain. The demonstration that the antinociceptive effect induced by nicorandil is markedly attenuated by an opioid antagonist provides solid information about an important mechanism mediating the activity of this antianginal drug. Altogether, our data suggest that the clinical pain relief induced by nicorandil in heart ischemic conditions may result from both vasodilation and intrinsic analgesic activity. Copyright © 2015. Published by Elsevier B.V.

  5. Modelling and performance analysis of clinical pathways using the stochastic process algebra PEPA.

    Science.gov (United States)

    Yang, Xian; Han, Rui; Guo, Yike; Bradley, Jeremy; Cox, Benita; Dickinson, Robert; Kitney, Richard

    2012-01-01

    Hospitals nowadays have to serve numerous patients with limited medical staff and equipment while maintaining healthcare quality. Clinical pathway informatics is regarded as an efficient way to solve a series of hospital challenges. To date, conventional research lacks a mathematical model to describe clinical pathways. Existing vague descriptions cannot fully capture the complexities accurately in clinical pathways and hinders the effective management and further optimization of clinical pathways. Given this motivation, this paper presents a clinical pathway management platform, the Imperial Clinical Pathway Analyzer (ICPA). By extending the stochastic model performance evaluation process algebra (PEPA), ICPA introduces a clinical-pathway-specific model: clinical pathway PEPA (CPP). ICPA can simulate stochastic behaviours of a clinical pathway by extracting information from public clinical databases and other related documents using CPP. Thus, the performance of this clinical pathway, including its throughput, resource utilisation and passage time can be quantitatively analysed. A typical clinical pathway on stroke extracted from a UK hospital is used to illustrate the effectiveness of ICPA. Three application scenarios are tested using ICPA: 1) redundant resources are identified and removed, thus the number of patients being served is maintained with less cost; 2) the patient passage time is estimated, providing the likelihood that patients can leave hospital within a specific period; 3) the maximum number of input patients are found, helping hospitals to decide whether they can serve more patients with the existing resource allocation. ICPA is an effective platform for clinical pathway management: 1) ICPA can describe a variety of components (state, activity, resource and constraints) in a clinical pathway, thus facilitating the proper understanding of complexities involved in it; 2) ICPA supports the performance analysis of clinical pathway, thereby assisting

  6. Effect of exposure time, particle size and uptake pathways in immune cell lysosomal cytotoxicity of mussels exposed to silver nanoparticles.

    Science.gov (United States)

    Bouallegui, Younes; Ben Younes, Ridha; Turki, Faten; Mezni, Amine; Oueslati, Ridha

    2018-04-01

    Cytotoxicity evaluation of hemocytes (lysosomal membrane stability [LMS] assay) from Mytilus galloprovincialis Lamarck, exposed to a sublethal dose (100 μg/L) of two size of silver nanoparticles (AgNPs: <50 nm and <100 nm) - prior to and after inhibition of potential uptake pathways (i.e., clathrin- and caveolae-mediated endocytosis) within different times of exposure (3, 6, 12 h) - showed that there was a significant cytotoxic effect on immune cells of mussels exposed for different times to either AgNP size (p < 0.01); the greater effect was with the smaller size. However, hemocytes seemed more sensitive to the larger AgNP after clathrin-mediated endocytosis was blocked (p < 0.01); this was not so with inhibition of caveolae-mediated endocytosis. Dimethyl-sulfoxide (DMSO) did not impart a carrier-mediated effect despite an enhanced cytotoxicity when DMSO was present with AgNP. From these results, it is concluded that the immunotoxicity of AgNP in mussels was size-dependent as well as length of exposure-dependent. It was also clear that nanoparticles (NP) internalization mechanisms were a major factor underlying any toxicity.

  7. Virus-like particles activate type I interferon pathways to facilitate post-exposure protection against Ebola virus infection.

    Directory of Open Access Journals (Sweden)

    Natarajan Ayithan

    Full Text Available Ebola virus (EBOV causes a severe hemorrhagic disease with high fatality. Virus-like particles (VLPs are a promising vaccine candidate against EBOV. We recently showed that VLPs protect mice from lethal EBOV infection when given before or after viral infection. To elucidate pathways through which VLPs confer post-exposure protection, we investigated the role of type I interferon (IFN signaling. We found that VLPs lead to accelerated induction of IFN stimulated genes (ISGs in liver and spleen of wild type mice, but not in Ifnar-/- mice. Accordingly, EBOV infected Ifnar-/- mice, unlike wild type mice succumbed to death even after VLP treatment. The ISGs induced in wild type mice included anti-viral proteins and negative feedback factors known to restrict viral replication and excessive inflammatory responses. Importantly, proinflammatory cytokine/chemokine expression was much higher in WT mice without VLPs than mice treated with VLPs. In EBOV infected Ifnar-/- mice, however, uninhibited viral replication and elevated proinflammatory factor expression ensued, irrespective of VLP treatment, supporting the view that type I IFN signaling helps to limit viral replication and attenuate inflammatory responses. Further analyses showed that VLP protection requires the transcription factor, IRF8 known to amplify type I IFN signaling in dendritic cells and macrophages, the probable sites of initial EBOV infection. Together, this study indicates that VLPs afford post-exposure protection by promoting expeditious initiation of type I IFN signaling in the host.

  8. Virus-Like Particles Activate Type I Interferon Pathways to Facilitate Post-Exposure Protection against Ebola Virus Infection

    Science.gov (United States)

    Ayithan, Natarajan; Bradfute, Steven B.; Anthony, Scott M.; Stuthman, Kelly S.; Bavari, Sina; Bray, Mike; Ozato, Keiko

    2015-01-01

    Ebola virus (EBOV) causes a severe hemorrhagic disease with high fatality. Virus-like particles (VLPs) are a promising vaccine candidate against EBOV. We recently showed that VLPs protect mice from lethal EBOV infection when given before or after viral infection. To elucidate pathways through which VLPs confer post-exposure protection, we investigated the role of type I interferon (IFN) signaling. We found that VLPs lead to accelerated induction of IFN stimulated genes (ISGs) in liver and spleen of wild type mice, but not in Ifnar-/- mice. Accordingly, EBOV infected Ifnar-/- mice, unlike wild type mice succumbed to death even after VLP treatment. The ISGs induced in wild type mice included anti-viral proteins and negative feedback factors known to restrict viral replication and excessive inflammatory responses. Importantly, proinflammatory cytokine/chemokine expression was much higher in WT mice without VLPs than mice treated with VLPs. In EBOV infected Ifnar-/- mice, however, uninhibited viral replication and elevated proinflammatory factor expression ensued, irrespective of VLP treatment, supporting the view that type I IFN signaling helps to limit viral replication and attenuate inflammatory responses. Further analyses showed that VLP protection requires the transcription factor, IRF8 known to amplify type I IFN signaling in dendritic cells and macrophages, the probable sites of initial EBOV infection. Together, this study indicates that VLPs afford post-exposure protection by promoting expeditious initiation of type I IFN signaling in the host. PMID:25719445

  9. Dental fluorosis linked to degassing of Ambrym volcano, Vanuatu: a novel exposure pathway.

    Science.gov (United States)

    Allibone, Rachel; Cronin, Shane J; Charley, Douglas T; Neall, Vince E; Stewart, Robert B; Oppenheimer, Clive

    2012-04-01

    Ambrym in Vanuatu is a persistently degassing island volcano whose inhabitants harvest rainwater for their potable water needs. The findings from this study indicate that dental fluorosis is prevalent in the population due to fluoride contamination of rainwater by the volcanic plume. A dental survey was undertaken of 835 children aged 6-18 years using the Dean's Index of Fluorosis. Prevalence of dental fluorosis was found to be 96% in the target area of West Ambrym, 71% in North Ambrym, and 61% in Southeast Ambrym. This spatial distribution appears to reflect the prevailing winds and rainfall patterns on the island. Severe cases were predominantly in West Ambrym, the most arid part of the island, and the most commonly affected by the volcanic plume. Over 50 km downwind, on a portion of Malakula Island, the dental fluorosis prevalence was 85%, with 36% prevalence on Tongoa Island, an area rarely affected by volcanic emissions. Drinking water samples from West Ambrym contained fluoride levels from 0.7 to 9.5 ppm F (average 4.2 ppm F, n = 158) with 99% exceeding the recommended concentration of 1.0 ppm F. The pathway of fluoride-enriched rainwater impacting upon human health as identified in this study has not previously been recognised in the aetiology of fluorosis. This is an important consideration for populations in the vicinity of degassing volcanoes, particularly where rainwater comprises the primary potable water supply for humans or animals.

  10. Candida albicans β-Glucan Exposure Is Controlled by the Fungal CEK1-Mediated Mitogen-Activated Protein Kinase Pathway That Modulates Immune Responses Triggered through Dectin-1 ▿ †

    Science.gov (United States)

    Galán-Díez, Marta; Arana, David M.; Serrano-Gómez, Diego; Kremer, Leonor; Casasnovas, José M.; Ortega, Mara; Cuesta-Domínguez, Álvaro; Corbí, Angel L.; Pla, Jesús; Fernández-Ruiz, Elena

    2010-01-01

    Innate immunity to Candida albicans depends upon the recognition of molecular patterns on the fungal cell wall. However, the masking of major components such as β-glucan seems to be a mechanism that fungi have evolved to avoid immune cell recognition through the dectin-1 receptor. Although the role of C. albicans mitogen-activated protein kinase (MAPK) pathways as virulence determinants has been established previously with animal models, the mechanism involved in this behavior is largely unknown. In this study we demonstrate that a disruption of the C. albicans extracellular signal-regulated kinase (ERK)-like 1 (CEK1)-mediated MAPK pathway causes enhanced cell wall β-glucan exposure, triggering immune responses more efficiently than the wild type, as measured by dectin-1-mediated specific binding and human dendritic cell (hDC)- and macrophage-mediated phagocytosis, killing, and activation of intracellular signaling pathways. At the molecular level, the disruption of CEK1 resulted in altered spleen tyrosine kinase (Syk), Raf-1, and ERK1/2 activations together with IκB degradation on hDCs and increased dectin-1-dependent activator protein 1 (AP-1) activation on transfected cells. In addition, concurring with these altered pathways, we detected increased reactive oxygen species production and cytokine secretion. In conclusion, the CEK1-mediated MAPK pathway is involved in β-glucan exposure in a fungal pathogen, hence influencing dectin-1-dependent immune cell recognition, thus establishing this fungal intracellular signaling route as a promising novel therapeutic target. PMID:20100861

  11. Fluoride and arsenic exposure affects spatial memory and activates the ERK/CREB signaling pathway in offspring rats.

    Science.gov (United States)

    Zhu, Yu-Peng; Xi, Shu-Hua; Li, Ming-Yan; Ding, Ting-Ting; Liu, Nan; Cao, Fu-Yuan; Zeng, Yang; Liu, Xiao-Jing; Tong, Jun-Wang; Jiang, Shou-Fang

    2017-03-01

    Fluoride and arsenic are inorganic contaminants that occur in the natural environment. Chronic fluoride and/or arsenic exposure can induce developmental neurotoxicity and negatively influence intelligence in children, although the underlying molecular mechanisms are poorly understood. This study explored the effects of fluoride and arsenic exposure in drinking water on spatial learning, memory and key protein expression in the ERK/CREB signaling pathway in hippocampal and cerebral cortex tissue in rat offspring. Pregnant rats were divided into four groups. Control rats drank tap water, while rats in the three exposure groups drank water with sodium fluoride (100mg/L), sodium arsenite (75mg/L), and a sodium fluoride (100mg/L) and sodium arsenite (75mg/L) combination during gestation and lactation. After weaning, rat pups drank the same solution as their mothers. Spatial learning and memory ability of pups at postnatal day 21 (PND21) and postnatal day 42 (PND42) were measured using a Morris water maze. ERK, phospho-ERK (p-ERK), CREB and phospho-CREB (p-CREB) protein expression in the hippocampus and cerebral cortex was detected using Western blot. Compared with the control pups, escape latencies increased in PND42 pups exposed to arsenic and co-exposed to fluoride and arsenic, and the short-term and long-term spatial memory ability declined in pups exposed to fluoride and arsenic, both alone and in combination. Compared with controls, ERK and p-ERK levels decreased in the hippocampus and cerebral cortex in pups exposed to combined fluoride and arsenic. CREB protein expression in the cerebral cortex decreased in pups exposed to fluoride, arsenic, and the fluoride and arsenic combination. p-CREB protein expression in both the hippocampus and cerebral cortex was decreased in pups exposed to fluoride and arsenic in combination compared to the control group. There were negative correlation between the proteins expression and escape latency periods in pups. These data

  12. A Smarter Pathway for Delivering Cue Exposure Therapy? The Design and Development of a Smartphone App Targeting Alcohol Use Disorder.

    Science.gov (United States)

    Mellentin, Angelina Isabella; Stenager, Elsebeth; Nielsen, Bent; Nielsen, Anette Søgaard; Yu, Fei

    2017-01-30

    Although the number of alcohol-related treatments in app stores is proliferating, none of them are based on a psychological framework and supported by empirical evidence. Cue exposure treatment (CET) with urge-specific coping skills (USCS) is often used in Danish treatment settings. It is an evidence-based psychological approach that focuses on promoting "confrontation with alcohol cues" as a means of reducing urges and the likelihood of relapse. The objective of this study was to describe the design and development of a CET-based smartphone app; an innovative delivery pathway for treating alcohol use disorder (AUD). The treatment is based on Monty and coworkers' manual for CET with USCS (2002). It was created by a multidisciplinary team of psychiatrists, psychologists, programmers, and graphic designers as well as patients with AUD. A database was developed for the purpose of registering and monitoring training activities. A final version of the CET app and database was developed after several user tests. The final version of the CET app includes an introduction, 4 sessions featuring USCS, 8 alcohol exposure videos promoting the use of one of the USCS, and a results component providing an overview of training activities and potential progress. Real-time urges are measured before, during, and after exposure to alcohol cues and are registered in the app together with other training activity variables. Data packages are continuously sent in encrypted form to an external database and will be merged with other data (in an internal database) in the future. The CET smartphone app is currently being tested at a large-scale, randomized controlled trial with the aim of clarifying whether it can be classified as an evidence-based treatment solution. The app has the potential to augment the reach of psychological treatment for AUD.

  13. Cholinergic anti-inflammatory pathway in the non-obese diabetic mouse model

    NARCIS (Netherlands)

    Koopman, F. A.; Vosters, J. L.; Roescher, N.; Broekstra, N.; Tak, P. P.; Vervoordeldonk, M. J.

    2015-01-01

    Activation of the cholinergic anti-inflammatory pathway (CAP) has been shown to reduce inflammation in animal models, while abrogation of the pathway increases inflammation. We investigated whether modulation of CAP influences inflammation in the non-obese diabetic (NOD) mouse model for Sjögren's

  14. The dual pathway model of overeating. Replication and extension with actual food consumption

    NARCIS (Netherlands)

    Ouwens, Machteld A; van Strien, T; Leeuwe, J.F.J.; van der Staak, C P F

    van Strien et al. [van Strien, T., Engels, R. C. M. E., van Leeuwe, J., Snoek, H. M. (2005). The Stice model of overeating: tests in clinical and non-clinical samples. Appetite, 45, 205-213] extended the negative affect pathway of Stice's dual pathway model of overeating Stice [Stice, E. (1994).

  15. Disruption of apoptosis pathways involved in zebrafish gonad differentiation by 17α-ethinylestradiol and fadrozole exposures

    Energy Technology Data Exchange (ETDEWEB)

    Luzio, Ana, E-mail: aluzio@utad.pt [Centre for the Research and Technology of Agro-Environmental and Biological Sciences, CITAB, Departamento de Biologia e Ambiente (DeBA), University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Life Sciences and Environment School, University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Matos, Manuela [University of Lisbon, Faculty of Sciences, BioISI– Biosystems & Integrative Sciences Institute, Campo Grande, 1749-016 Lisbon (Portugal); Department of Genetics and Biotechnology, Life Sciences and Environment School (ECVA), University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Santos, Dércia [Life Sciences and Environment School, University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Fontaínhas-Fernandes, António A.; Monteiro, Sandra M. [Centre for the Research and Technology of Agro-Environmental and Biological Sciences, CITAB, Departamento de Biologia e Ambiente (DeBA), University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); Life Sciences and Environment School, University of Trás-os-Montes and Alto Douro, UTAD, Quinta de Prados, Vila Real, 5000-801 (Portugal); and others

    2016-08-15

    Highlights: • Apoptosis in females is avoided by anti-apoptotic pathways and in males is essential to the “juvenile ovary” failure. • BIRC5 is central to the regulation of zebrafish spermatogenesis. • EE2 did not change sex ratios, but Fadrozole induced masculinization with a significant increase in male proportion. • The few females identified after exposure to Fadrozole may have avoided sex reversal by increasing anti-apoptotic proteins. • EE2 increased the pro-apoptotic genes/proteins in males, promoting gonad differentiation. - Abstract: Zebrafish (Danio rerio) sex determination seems to involve genetic factors (GSD) but also environmental factors (ESD), such as endocrine disrupting chemicals (EDCs) that are known to mimic endogenous hormones and disrupt gonad differentiation. Apoptosis has also been proposed to play a crucial role in zebrafish gonad differentiation. Nevertheless, the interactions between EDCs and apoptosis have received little attention. Thus, this study aimed to assess if and which apoptotic pathways are involved in zebrafish gonad differentiation and how EDCs may interfere with this process. With these purposes, zebrafish were exposed to 17α-ethinylestradiol (EE{sub 2}, 4 ng/L) and fadrozole (Fad, 50 μg/L) from 2 h to 35 days post-fertilization (dpf). Afterwards, a gene expression analysis by qRT-PCR and a stereological analysis, based on systematic sampling and protein immunohistochemistry, were performed. The death receptors (FAS; TRADD), anti-apoptotic (BCL-2; MDM2), pro-apoptotic (CASP-2 and −6) and cell proliferation (BIRC5/survivin; JUN) genes and proteins were evaluated. In general, apoptosis was inhibited in females through the involvement of anti-apoptotic pathways, while in males apoptosis seemed to be crucial to the failure of the “juvenile ovary” development and the induction of testes transformation. The JUN protein was shown to be necessary in juvenile ovaries, while the BIRC5 protein seemed to be involved

  16. MEPAS exposure model updates to meet current EPA guidance

    Energy Technology Data Exchange (ETDEWEB)

    Strenge, D.L.; Droppo, J.G. Jr.

    1993-12-01

    The Multimedia Environmental Pollutant Assessment System (MEPAS) is a software package developed for the US Department of Energy (DOE) as a management tool to screen the many potential hazardous waste problems at DOE facilities across the country. The program considers both radioactive and chemical pollutants in estimating potential human health risks based on site-specific waste, environmental transport, and exposure characteristics. To support various DOE programs, recent modifications have been made to MEPAS to increase its applicability in analyzing the problems of mixed hazardous waste. Such analyses are needed to evaluate remediation options for mixed hazardous waste sites. This paper presents an overview of the MEPAS program and summarizes the current models used to translate environmental concentration values into projected intake by humans and, finally, into estimates of health risk. The recent modifications are described consistent with current EPA guidance for exposure and human health impact assessment.

  17. Predictive Models and Tools for Screening Chemicals under TSCA: Consumer Exposure Models 1.5

    Science.gov (United States)

    CEM contains a combination of models and default parameters which are used to estimate inhalation, dermal, and oral exposures to consumer products and articles for a wide variety of product and article use categories.

  18. Visinets: a web-based pathway modeling and dynamic visualization tool

    National Research Council Canada - National Science Library

    Spychala, Jozef; Spychala, Pawel; Gomez, Shawn; Weinreb, Gabriel E

    2015-01-01

    In this report we describe a novel graphically oriented method for pathway modeling and a software package that allows for both modeling and visualization of biological networks in a user-friendly format...

  19. Visinets: A Web-Based Pathway Modeling and Dynamic Visualization Tool: e0123773

    National Research Council Canada - National Science Library

    Jozef Spychala; Pawel Spychala; Shawn Gomez; Gabriel E Weinreb

    2015-01-01

      In this report we describe a novel graphically oriented method for pathway modeling and a software package that allows for both modeling and visualization of biological networks in a user-friendly format...

  20. Inhalation Exposure Input Parameters for the Biosphere Model

    Energy Technology Data Exchange (ETDEWEB)

    K. Rautenstrauch

    2004-09-10

    This analysis is one of 10 reports that support the Environmental Radiation Model for Yucca Mountain, Nevada (ERMYN) biosphere model. The ''Biosphere Model Report'' (BSC 2004 [DIRS 169460]) describes in detail the conceptual model as well as the mathematical model and its input parameters. This report documents development of input parameters for the biosphere model that are related to atmospheric mass loading and supports the use of the model to develop biosphere dose conversion factors (BDCFs). The biosphere model is one of a series of process models supporting the total system performance assessment (TSPA) for a Yucca Mountain repository. Inhalation Exposure Input Parameters for the Biosphere Model is one of five reports that develop input parameters for the biosphere model. A graphical representation of the documentation hierarchy for the ERMYN is presented in Figure 1-1. This figure shows the interrelationships among the products (i.e., analysis and model reports) developed for biosphere modeling, and the plan for development of the biosphere abstraction products for TSPA, as identified in the Technical Work Plan for Biosphere Modeling and Expert Support (BSC 2004 [DIRS 169573]). This analysis report defines and justifies values of mass loading for the biosphere model. Mass loading is the total mass concentration of resuspended particles (e.g., dust, ash) in a volume of air. Mass loading values are used in the air submodel of ERMYN to calculate concentrations of radionuclides in air inhaled by a receptor and concentrations in air surrounding crops. Concentrations in air to which the receptor is exposed are then used in the inhalation submodel to calculate the dose contribution to the receptor from inhalation of contaminated airborne particles. Concentrations in air surrounding plants are used in the plant submodel to calculate the concentrations of radionuclides in foodstuffs contributed from uptake by foliar interception.

  1. Geographical modeling of exposure risk to cyanobacteria for epidemiological purposes.

    Science.gov (United States)

    Serrano, Tania; Dupas, Rémi; Upegui, Erika; Buscail, Camille; Grimaldi, Catherine; Viel, Jean François

    2015-08-01

    The cyanobacteria-derived neurotoxin β-methylamino-L-alanine (BMAA) represents a plausible environmental trigger for amyotrophic lateral sclerosis (ALS), a debilitating and fatal neuromuscular disease. With the eutrophication of water bodies, cyanobacterial blooms and their toxins are becoming increasingly prevalent in France, especially in the Brittany region. Cyanobacteria are monitored at only a few recreational sites, preventing an estimation of exposure of the human population. By contrast, phosphorus, a limiting nutrient for cyanobacterial growth and thus considered a good proxy for cyanobacteria exposure, is monitored in many but not all surface water bodies. Our goal was to develop a geographic exposure indicator that could be used in epidemiological research. We considered the total phosphorus (TP) concentration (mg/L) of samples collected between October 2007 and September 2012 at 179 monitoring stations distributed throughout the Brittany region. Using readily available spatial data, we computed environmental descriptors at the watershed level with a Geographic Information System. Then, these descriptors were introduced into a backward stepwise linear regression model to predict the median TP concentration in unmonitored surface water bodies. TP concentrations in surface water follow an increasing gradient from West to East and inland to coast. The empirical concentration model included five predictor variables with a fair coefficient of determination (R(2) = 0.51). The specific total runoff and the watershed slope correlated negatively with the TP concentrations (p = 0.01 and pcyanobacteria exposure that can be used along with other risk factors in further ALS epidemiologic case-control studies. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. Modeling emission rates and exposures from outdoor cooking

    Science.gov (United States)

    Edwards, Rufus; Princevac, Marko; Weltman, Robert; Ghasemian, Masoud; Arora, Narendra K.; Bond, Tami

    2017-09-01

    Approximately 3 billion individuals rely on solid fuels for cooking globally. For a large portion of these - an estimated 533 million - cooking is outdoors, where emissions from cookstoves pose a health risk to both cooks and other household and village members. Models that estimate emissions rates from stoves in indoor environments that would meet WHO air quality guidelines (AQG), explicitly don't account for outdoor cooking. The objectives of this paper are to link health based exposure guidelines with emissions from outdoor cookstoves, using a Monte Carlo simulation of cooking times from Haryana India coupled with inverse Gaussian dispersion models. Mean emission rates for outdoor cooking that would result in incremental increases in personal exposure equivalent to the WHO AQG during a 24-h period were 126 ± 13 mg/min for cooking while squatting and 99 ± 10 mg/min while standing. Emission rates modeled for outdoor cooking are substantially higher than emission rates for indoor cooking to meet AQG, because the models estimate impact of emissions on personal exposure concentrations rather than microenvironment concentrations, and because the smoke disperses more readily outdoors compared to indoor environments. As a result, many more stoves including the best performing solid-fuel biomass stoves would meet AQG when cooking outdoors, but may also result in substantial localized neighborhood pollution depending on housing density. Inclusion of the neighborhood impact of pollution should be addressed more formally both in guidelines on emissions rates from stoves that would be protective of health, and also in wider health impact evaluation efforts and burden of disease estimates. Emissions guidelines should better represent the different contexts in which stoves are being used, especially because in these contexts the best performing solid fuel stoves have the potential to provide significant benefits.

  3. A chronic longitudinal characterization of neurobehavioral and neuropathological cognitive impairment in a mouse model of Gulf War agent exposure

    Directory of Open Access Journals (Sweden)

    Zuchra eZakirova

    2016-01-01

    Full Text Available Gulf War Illness (GWI is a chronic multisymptom illness with a central nervous system component that includes memory impairment as well as neurological and musculoskeletal deficits. Previous studies have shown that in the First Persian Gulf War conflict (1990-1991 exposure to Gulf War (GW agents, such as pyridostigmine bromide (PB and permethrin (PER, were key contributors to the etiology of GWI.For this study, we used our previously established mouse model of GW agent exposure (10 days PB+PER and undertook an extensive lifelong neurobehavioral characterization of the mice from 11 days to 22.5 months post exposure in order to address the persistence and chronicity of effects suffered by the current GWI patient population, 24 years post-exposure. Mice were evaluated using a battery of neurobehavioral testing paradigms, including Open Field Test, Elevated Plus Maze, Three Chamber Testing, Radial Arm Water Maze and Barnes Maze Test. We also carried out neuropathological analyses at 22.5 months post exposure to GW agents after the final behavioral testing. Our results demonstrate that PB+PER exposed mice exhibit neurobehavioral deficits beginning at the 13 months post exposure time point and continuing trends through the 22.5 month post exposure time point. Furthermore, neuropathological changes, including an increase in GFAP staining in the cerebral cortices of exposed mice, were noted 22.5 months post exposure. Thus, the persistent neuroinflammation evident in our model presents a platform with which to identify novel biological pathways, correlating with emergent outcomes that may be amenable to therapeutic targeting. Furthermore, in this work we confirmed our previous findings that GW agent exposure causes neuropathological changes, and have presented novel data which demonstrate increased disinhibition, and lack of social preference in PB+PER exposed mice at 13 months after exposure. We also extended upon our previous work to cover the lifespan

  4. Mathematical modelling and analysis of the brassinosteroid and gibberellin signalling pathways and their interactions.

    Science.gov (United States)

    Allen, Henry R; Ptashnyk, Mariya

    2017-11-07

    The plant hormones brassinosteroid (BR) and gibberellin (GA) have important roles in a wide range of processes involved in plant growth and development. In this paper we derive and analyse new mathematical models for the BR signalling pathway and for the crosstalk between the BR and GA signalling pathways. To analyse the effects of spatial heterogeneity of the signalling processes, along with spatially-homogeneous ODE models we derive coupled PDE-ODE systems modelling the temporal and spatial dynamics of molecules involved in the signalling pathways. The values of the parameters in the model for the BR signalling pathway are determined using experimental data on the gene expression of BR biosynthetic enzymes. The stability of steady state solutions of our mathematical model, shown for a wide range of parameters, can be related to the BR homeostasis which is essential for proper function of plant cells. Solutions of the mathematical model for the BR signalling pathway can exhibit oscillatory behaviour only for relatively large values of parameters associated with transcription factor brassinazole-resistant1's (BZR) phosphorylation state, suggesting that this process may be important in governing the stability of signalling processes. Comparison between ODE and PDE-ODE models demonstrates distinct spatial distribution in the level of BR in the cell cytoplasm, however the spatial heterogeneity has significant effect on the dynamics of the averaged solutions only in the case when we have oscillations in solutions for at least one of the models, i.e. for possibly biologically not relevant parameter values. Our results for the crosstalk model suggest that the interaction between transcription factors BZR and DELLA exerts more influence on the dynamics of the signalling pathways than BZR-mediated biosynthesis of GA, suggesting that the interaction between transcription factors may constitute the principal mechanism of the crosstalk between the BR and GA signalling

  5. A multi-platform metabolomics approach demonstrates changes in energy metabolism and the transsulfuration pathway in Chironomus tepperi following exposure to zinc

    Energy Technology Data Exchange (ETDEWEB)

    Long, Sara M., E-mail: hoskins@unimelb.edu.au [Centre for Aquatic Pollution, Identification and Management (CAPIM), School of BioSciences, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, 3052 (Australia); Tull, Dedreia L., E-mail: dedreia@unimelb.edu.au [Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road, Parkville, 3052 (Australia); Jeppe, Katherine J., E-mail: k.jeppe@unimelb.edu.au [Centre for Aquatic Pollution, Identification and Management (CAPIM), School of BioSciences, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, 3052 (Australia); Centre for Aquatic Pollution, Identification and Management (CAPIM), School of BioSciences, The University of Melbourne, 3010 (Australia); De Souza, David P., E-mail: desouzad@unimelb.edu.au [Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road, Parkville, 3052 (Australia); Dayalan, Saravanan, E-mail: sdayalan@unimelb.edu.au [Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road, Parkville, 3052 (Australia); Pettigrove, Vincent J., E-mail: vpet@unimelb.edu.au [Centre for Aquatic Pollution, Identification and Management (CAPIM), School of BioSciences, The University of Melbourne, 3010 (Australia); McConville, Malcolm J., E-mail: malcolmm@unimelb.edu.au [Metabolomics Australia, Bio21 Molecular Science and Biotechnology Institute, 30 Flemington Road, Parkville, 3052 (Australia); Hoffmann, Ary A., E-mail: ary@unimelb.edu.au [Centre for Aquatic Pollution, Identification and Management (CAPIM), School of BioSciences, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, 3052 (Australia); School of BioSciences, Bio21 Molecular Science and Biotechnology Institute, The University of Melbourne, 30 Flemington Road, Parkville, 3052 (Australia)

    2015-05-15

    Highlights: • An integrated metabolomics approach was applied to examine zinc exposure in midges. • Changes in carbohydrate and energy metabolism were observed using GC–MS. • Transsulfuration pathway is affected by zinc exposure. • Heavy metals other than zinc affect the transsulfuration pathways differently. - Abstract: Measuring biological responses in resident biota is a commonly used approach to monitoring polluted habitats. The challenge is to choose sensitive and, ideally, stressor-specific endpoints that reflect the responses of the ecosystem. Metabolomics is a potentially useful approach for identifying sensitive and consistent responses since it provides a holistic view to understanding the effects of exposure to chemicals upon the physiological functioning of organisms. In this study, we exposed the aquatic non-biting midge, Chironomus tepperi, to two concentrations of zinc chloride and measured global changes in polar metabolite levels using an untargeted gas chromatography–mass spectrometry (GC–MS) analysis and a targeted liquid chromatography–mass spectrometry (LC–MS) analysis of amine-containing metabolites. These data were correlated with changes in the expression of a number of target genes. Zinc exposure resulted in a reduction in levels of intermediates in carbohydrate metabolism (i.e., glucose 6-phosphate, fructose 6-phosphate and disaccharides) and an increase in a number of TCA cycle intermediates. Zinc exposure also resulted in decreases in concentrations of the amine containing metabolites, lanthionine, methionine and cystathionine, and an increase in metallothionein gene expression. Methionine and cystathionine are intermediates in the transsulfuration pathway which is involved in the conversion of methionine to cysteine. These responses provide an understanding of the pathways affected by zinc toxicity, and how these effects are different to other heavy metals such as cadmium and copper. The use of complementary

  6. A workflow to investigate exposure and pharmacokinetic influences on high-throughput in vitro chemical screening based on adverse outcome pathways, OpenTox USA 2015 Poster

    Science.gov (United States)

    Adverse outcome pathways (AOP) link known population outcomes to a molecular initiating event (MIE) that can be quantified using high-throughput in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires consideration of exposure and absorption,...

  7. Dose and Time Dependencies in Stress Pathway Responses during Chemical Exposure: Novel Insights from Gene Regulatory Networks

    Directory of Open Access Journals (Sweden)

    Terezinha M. Souza

    2017-10-01

    Full Text Available Perturbation of biological networks is often observed during exposure to xenobiotics, and the identification of disturbed processes, their dynamic traits, and dose–response relationships are some of the current challenges for elucidating the mechanisms determining adverse outcomes. In this scenario, reverse engineering of gene regulatory networks (GRNs from expression data may provide a system-level snapshot embedded within accurate molecular events. Here, we investigate the composition of GRNs inferred from groups of chemicals with two distinct outcomes, namely carcinogenicity [azathioprine (AZA and cyclophosphamide (CYC] and drug-induced liver injury (DILI; diclofenac, nitrofurantoin, and propylthiouracil, and a non-carcinogenic/non-DILI group (aspirin, diazepam, and omeprazole. For this, we analyzed publicly available exposed in vitro human data, taking into account dose and time dependencies. Dose–Time Network Identification (DTNI was applied to gene sets from exposed primary human hepatocytes using four stress pathways, namely endoplasmic reticulum (ER, NF-κB, NRF2, and TP53. Inferred GRNs suggested case specificity, varying in interactions, starting nodes, and target genes across groups. DILI and carcinogenic compounds were shown to directly affect all pathway-based GRNs, while non-DILI/non-carcinogenic chemicals only affected NF-κB. NF-κB-based GRNs clearly illustrated group-specific disturbances, with the cancer-related casein kinase CSNK2A1 being a target gene only in the carcinogenic group, and opposite regulation of NF-κB subunits being observed in DILI and non-DILI/non-carcinogenic groups. Target genes in NRF2-based GRNs shared by DILI and carcinogenic compounds suggested markers of hepatotoxicity. Finally, we indicate several of these group-specific interactions as potentially novel. In summary, our reversed-engineered GRNs are capable of revealing dose dependent, chemical-specific mechanisms of action in stress

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

    Energy Technology Data Exchange (ETDEWEB)

    McKone, T.E.

    1993-10-01

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

  9. Transient and persistent metabolomic changes in plasma following chronic cigarette smoke exposure in a mouse model.

    Directory of Open Access Journals (Sweden)

    Charmion I Cruickshank-Quinn

    Full Text Available Cigarette smoke exposure is linked to the development of a variety of chronic lung and systemic diseases in susceptible individuals. Metabolomics approaches may aid in defining disease phenotypes, may help predict responses to treatment, and could identify biomarkers of risk for developing disease. Using a mouse model of chronic cigarette smoke exposure sufficient to cause mild emphysema, we investigated whether cigarette smoke induces distinct metabolic profiles and determined their persistence following smoking cessation. Metabolites were extracted from plasma and fractionated based on chemical class using liquid-liquid and solid-phase extraction prior to performing liquid chromatography mass spectrometry-based metabolomics. Metabolites were evaluated for statistically significant differences among group means (p-value≤0.05 and fold change ≥1.5. Cigarette smoke exposure was associated with significant differences in amino acid, purine, lipid, fatty acid, and steroid metabolite levels compared to air exposed animals. Whereas 60% of the metabolite changes were reversible, 40% of metabolites remained persistently altered even following 2 months of smoking cessation, including nicotine metabolites. Validation of metabolite species and translation of these findings to human plasma metabolite signatures induced by cigarette smoking may lead to the discovery of biomarkers or pathogenic pathways of smoking-induced disease.

  10. Transient and Persistent Metabolomic Changes in Plasma following Chronic Cigarette Smoke Exposure in a Mouse Model

    Science.gov (United States)

    Cruickshank-Quinn, Charmion I.; Mahaffey, Spencer; Justice, Matthew J.; Hughes, Grant; Armstrong, Michael; Bowler, Russell P.; Reisdorph, Richard; Petrache, Irina; Reisdorph, Nichole

    2014-01-01

    Cigarette smoke exposure is linked to the development of a variety of chronic lung and systemic diseases in susceptible individuals. Metabolomics approaches may aid in defining disease phenotypes, may help predict responses to treatment, and could identify biomarkers of risk for developing disease. Using a mouse model of chronic cigarette smoke exposure sufficient to cause mild emphysema, we investigated whether cigarette smoke induces distinct metabolic profiles and determined their persistence following smoking cessation. Metabolites were extracted from plasma and fractionated based on chemical class using liquid-liquid and solid-phase extraction prior to performing liquid chromatography mass spectrometry-based metabolomics. Metabolites were evaluated for statistically significant differences among group means (p-value≤0.05) and fold change ≥1.5). Cigarette smoke exposure was associated with significant differences in amino acid, purine, lipid, fatty acid, and steroid metabolite levels compared to air exposed animals. Whereas 60% of the metabolite changes were reversible, 40% of metabolites remained persistently altered even following 2 months of smoking cessation, including nicotine metabolites. Validation of metabolite species and translation of these findings to human plasma metabolite signatures induced by cigarette smoking may lead to the discovery of biomarkers or pathogenic pathways of smoking-induced disease. PMID:25007263

  11. Environmental Pathway Models-Ground-Water Modeling in Support of Remedial Decision Making at Sites Contaminated with Radioactive Material

    Science.gov (United States)

    The Joint Interagency Environmental Pathway Modeling Working Group wrote this report to promote appropriate and consistent use of mathematical environmental models in the remediation and restoration of sites contaminated by radioactive substances.

  12. Subchronic Exposure to Arsenic Represses the TH/TRβ1-CaMK IV Signaling Pathway in Mouse Cerebellum

    Directory of Open Access Journals (Sweden)

    Huai Guan

    2016-01-01

    Full Text Available We previously reported that arsenic (As impaired learning and memory by down-regulating calmodulin-dependent protein kinase IV (CaMK IV in mouse cerebellum. It has been documented that the thyroid hormone receptor (TR/retinoid X receptor (RXR heterodimer and thyroid hormone (TH may be involved in the regulation of CaMK IV. To investigate whether As affects the TR/RXR heterodimer and TH, we determined As concentration in serum and cerebellum, 3,5,3’-triiodothyronine (T3 and thyroxin (T4 levels in serum, and expression of CaMK IV, TR and RXR in cerebellum of mice exposed to As. Cognition function was examined by the step-down passive avoidance task and Morris water maze (MWM tests. Morphology of the cerebellum was observed by Hematoxylin-Eosin staining under light microscope. Our results showed that the concentrations of As in the serum and cerebellum of mice both increased with increasing As-exposure level. A significant positive correlation was found between the two processes. Adeficit in learning and memory was found in the exposed mice. Abnormal morphologic changes of Purkinje cells were observed in cerebellum of the exposed mice. Moreover, the cerebellar expressions of CaMK IV protein and the TRβ gene, and TRβ1 protein were significantly lower in As-exposed mice than those in controls. Subchronic exposure to As appears to increase its level in serum and cerebella of mice, impairing learning and memory and down-regulating expression of TRβ1 as well as down-stream CaMK IV. It is also suggested that the increased As may be responsible for down-regulation of TRβ1 and CaMK IV in cerebellum and that the down-regulated TRβ1 may be involved in As-induced impairment of learning and memory via inhibiting CaMK IV and its down-stream pathway.

  13. Subchronic Exposure to Arsenic Represses the TH/TRβ1-CaMK IV Signaling Pathway in Mouse Cerebellum.

    Science.gov (United States)

    Guan, Huai; Li, Shuangyue; Guo, Yanjie; Liu, Xiaofeng; Yang, Yi; Guo, Jinqiu; Li, Sheng; Zhang, Cong; Shang, Lixin; Piao, Fengyuan

    2016-01-26

    We previously reported that arsenic (As) impaired learning and memory by down-regulating calmodulin-dependent protein kinase IV (CaMK IV) in mouse cerebellum. It has been documented that the thyroid hormone receptor (TR)/retinoid X receptor (RXR) heterodimer and thyroid hormone (TH) may be involved in the regulation of CaMK IV. To investigate whether As affects the TR/RXR heterodimer and TH, we determined As concentration in serum and cerebellum, 3,5,3'-triiodothyronine (T3) and thyroxin (T4) levels in serum, and expression of CaMK IV, TR and RXR in cerebellum of mice exposed to As. Cognition function was examined by the step-down passive avoidance task and Morris water maze (MWM) tests. Morphology of the cerebellum was observed by Hematoxylin-Eosin staining under light microscope. Our results showed that the concentrations of As in the serum and cerebellum of mice both increased with increasing As-exposure level. A significant positive correlation was found between the two processes. Adeficit in learning and memory was found in the exposed mice. Abnormal morphologic changes of Purkinje cells were observed in cerebellum of the exposed mice. Moreover, the cerebellar expressions of CaMK IV protein and the TRβ gene, and TRβ1 protein were significantly lower in As-exposed mice than those in controls. Subchronic exposure to As appears to increase its level in serum and cerebella of mice, impairing learning and memory and down-regulating expression of TRβ1 as well as down-stream CaMK IV. It is also suggested that the increased As may be responsible for down-regulation of TRβ1 and CaMK IV in cerebellum and that the down-regulated TRβ1 may be involved in As-induced impairment of learning and memory via inhibiting CaMK IV and its down-stream pathway.

  14. High Throughput Exposure Modeling of Semi-Volatile Chemicals in Articles of Commerce (ACS)

    Science.gov (United States)

    Risk due to chemical exposure is a function of both chemical hazard and exposure. Near-field exposures to chemicals in consumer products are identified as the main drivers of exposure and yet are not well quantified or understood. The ExpoCast project is developing a model that e...

  15. MERS-CoV at the Animal-Human interface: inputs on exposure pathways from an Expert-Opinion elicitation

    Directory of Open Access Journals (Sweden)

    Anna Funk

    2016-10-01

    Full Text Available Nearly four years after the first report of the emergence of Middle-East respiratory syndrome Coronavirus (MERS-CoV and nearly 1800 human cases later, the ecology of MERS-CoV, its epidemiology, and risk factors of MERS-CoV transmission between camels are poorly understood. Knowledge about the pathways and mechanisms of transmission from animals to humans is limited; as of yet, transmission risks have not been quantified. Moreover the divergent sanitary situations and exposures to animals among populations in the Arabian Peninsula, where human primary cases appear to dominate, vs. other regions in the Middle East and Africa, with no reported human clinical cases and where the virus has been detected only in dromedaries, represents huge scientific and health challenges. Here, we have used expert opinion elicitation in order to obtain ideas on relative importance of MERS-CoV risk factors and estimates of transmission risks from various types of contact between humans and dromedaries. Fourteen (14 experts with diverse and extensive experience in MERS-CoV relevant fields were enrolled and completed an online questionnaire that examined pathways based on several scenarios e.g. camels-camels, camels-human, bats/other species to camels/humans and the role of diverse biological substances (milk, urine etc. and potential fomites.Experts believed that dromedary camels play the largest role in MERS-CoV infection of other dromedaries; however, they also indicated a significant influence of the season (i.e. calving or weaning periods on transmission risk. All experts thought that MERS-CoV infected dromedaries and asymptomatic humans play the most important role in infection of humans, with bats and other species presenting a possible, but yet undefined, risk. Direct and indirect contact of humans with dromedary camels were identified as the most risky types of contact, when compared to consumption of various camel products, with estimated 'most

  16. Astronaut EVA exposure estimates from CAD model spacesuit geometry.

    Science.gov (United States)

    De Angelis, Giovanni; Anderson, Brooke M; Atwell, William; Nealy, John E; Qualls, Garry D; Wilson, John W

    2004-03-01

    Ongoing assembly and maintenance activities at the International Space Station (ISS) require much more extravehicular activity (EVA) than did the earlier U.S. Space Shuttle missions. It is thus desirable to determine and analyze, and possibly foresee, as accurately as possible what radiation exposures crew members involved in EVAs will experience in order to minimize risks and to establish exposure limits that must not to be exceeded. A detailed CAD model of the U.S. Space Shuttle EVA Spacesuit, developed at NASA Langley Research Center (LaRC), is used to represent the directional shielding of an astronaut; it has detailed helmet and backpack structures, hard upper torso, and multilayer space suit fabric material. The NASA Computerized Anatomical Male and Female (CAM and CAF) models are used in conjunction with the space suit CAD model for dose evaluation within the human body. The particle environments are taken from the orbit-averaged NASA AP8 and AE8 models at solar cycle maxima and minima. The transport of energetic particles through space suit materials and body tissue is calculated by using the NASA LaRC HZETRN code for hadrons and a recently developed deterministic transport code, ELTRN, for electrons. The doses within the CAM and CAF models are determined from energy deposition at given target points along 968 directional rays convergent on the points and are evaluated for several points on the skin and within the body. Dosimetric quantities include contributions from primary protons, light ions, and electrons, as well as from secondary brehmsstrahlung and target fragments. Directional dose patterns are displayed as rays and on spherical surfaces by the use of a color relative intensity representation.

  17. Indicators of residential traffic exposure: Modelled NOX, traffic proximity, and self-reported exposure in RHINE III

    Science.gov (United States)

    Carlsen, Hanne Krage; Bäck, Erik; Eneroth, Kristina; Gislason, Thorarinn; Holm, Mathias; Janson, Christer; Jensen, Steen Solvang; Johannessen, Ane; Kaasik, Marko; Modig, Lars; Segersson, David; Sigsgaard, Torben; Forsberg, Bertil; Olsson, David; Orru, Hans

    2017-10-01

    Few studies have investigated associations between self-reported and modelled exposure to traffic pollution. The objective of this study was to examine correlations between self-reported traffic exposure and modelled (a) NOX and (b) traffic proximity in seven different northern European cities; Aarhus (Denmark), Bergen (Norway), Gothenburg, Umeå, and Uppsala (Sweden), Reykjavik (Iceland), and Tartu (Estonia). We analysed data from the RHINE III (Respiratory Health in Northern Europe, http://www.rhine.nu)

  18. Mathematical modelling of the diurnal regulation of the MEP pathway in Arabidopsis

    National Research Council Canada - National Science Library

    Pokhilko, Alexandra; Bou‐Torrent, Jordi; Pulido, Pablo; Rodríguez‐Concepción, Manuel; Ebenhöh, Oliver

    2015-01-01

    ... quinones and hormones are synthesised in chloroplasts via the 2‐ C ‐methyl‐ d ‐erythritol 4‐phosphate ( MEP ) pathway. Here we develop a mathematical model of diurnal regulation of the MEP pathway in Arabidopsis thaliana...

  19. Cigarette smoke exposure reveals a novel role for the MEK/ERK1/2 MAPK pathway in regulation of CFTR.

    Science.gov (United States)

    Xu, Xiaohua; Balsiger, Robert; Tyrrell, Jean; Boyaka, Prosper N; Tarran, Robert; Cormet-Boyaka, Estelle

    2015-06-01

    Cystic fibrosis transmembrane conductance regulator plays a key role in maintenance of lung fluid homeostasis. Cigarette smoke decreases CFTR expression in the lung but neither the mechanisms leading to CFTR loss, nor potential ways to prevent its loss have been identified to date. The molecular mechanisms leading to down-regulation of CFTR by cigarette smoke were determined using pharmacologic inhibitors and silencing ribonucleic acids (RNAs). Using human bronchial epithelial cells, here we show that cigarette smoke induces degradation of CFTR that is attenuated by lysosomal inhibitors, but not proteasome inhibitors. Cigarette smoke can activate multiple signaling pathways in airway epithelial cells, including the MEK/Erk1/2 MAPK (MEK: mitogen-activated protein kinase/ERK kinase Erk1/2: extracellular signal-regulated kinase 1/2 MAPK: Mitogen-activated protein kinase) pathway regulating cell survival. Interestingly, pharmacological inhibition of the MEK/Erk1/2 MAPK pathway prevented the loss of plasma membrane CFTR upon cigarette smoke exposure. Similarly, decreased expression of Erk1/2 using silencing RNAs prevented the suppression of CFTR protein by cigarette smoke. Conversely, specific inhibitors of the c-Jun N-terminal kinase (JNK) or p38 MAPK pathways had no effect on CFTR decrease after cigarette smoke exposure. In addition, inhibition of the MEK/Erk1/2 MAPK pathway prevented the reduction of the airway surface liquid observed upon cigarette smoke exposure of primary human airway epithelial cells. Finally, addition of the antioxidant N-acetylcysteine inhibited activation of Erk1/2 by cigarette smoke and precluded the cigarette smoke-induced decrease of CFTR. These results show that the MEK/Erk1/2 MAPK pathway regulates plasma membrane CFTR in human airway cells. The MEK/Erk1/2 MAPK pathway should be considered as a target for strategies to maintain/restore CFTR expression in the lung of smokers. Copyright © 2015 Elsevier B.V. All rights reserved.

  20. A global perspective on the use, sales, exposure pathways, occurrence, fate and effects of veterinary antibiotics (VAs) in the environment

    Science.gov (United States)

    Sarmah, Ajit K.; Meyer, Michael T.; Boxall, Alistair B.A.

    2006-01-01

    Veterinary antibiotics (VAs) are widely used in many countries worldwide to treat disease and protect the health of animals. They are also incorporated into animal feed to improve growth rate and feed efficiency. As antibiotics are poorly adsorbed in the gut of the animals, the majority is excreted unchanged in faeces and urine. Given that land application of animal waste as a supplement to fertilizer is often a common practice in many countries, there is a growing international concern about the potential impact of antibiotic residues on the environment. Frequent use of antibiotics has also raised concerns about increased antibiotic resistance of microorganisms. We have attempted in this paper to summarize the latest information available in the literature on the use, sales, exposure pathways, environmental occurrence, fate and effects of veterinary antibiotics in animal agriculture. The review has focused on four important groups of antibiotics (tylosin, tetracycline, sulfonamides and, to a lesser extent, bacitracin) giving a background on their chemical nature, fate processes, occurrence, and effects on plants, soil organisms and bacterial community. Recognising the importance and the growing debate, the issue of antibiotic resistance due to the frequent use of antibiotics in food-producing animals is also briefly covered. The final section highlights some unresolved questions and presents a way forward on issues requiring urgent attention.

  1. Lipoxygenase pathway mediates increases of airway resistance and lung inflation induced by exposure to nanotitanium dioxide in rats.

    Science.gov (United States)

    Lee, Jyu-Feng; Tung, Shu-Ping; Wang, David; Yeh, Diana Yuwung; Fong, Yao; Young, Yu-Chung; Leu, Fur-Jiang

    2014-01-01

    Nanotitanium dioxide particle (nTiO2) inhalation has been reported to induce lung parenchymal injury. After inhalation of nTiO2, we monitored changes in 5-lipoxygenase, endothelial nitric oxide synthase (eNOS), and inducible nitric oxide synthase (iNOS) mRNA in rat lung tissue. Lung function parameters include specific airway resistance (SRaw), peak expiratory flow rate (PEF), functional residual capacity (FRC), and lung compliance (Cchord); blood white blood cell count (WBC), nitric oxide (NO), hydrogen peroxide, and lactic dehydrogenase (LDH); and lung lavage leukotriene C4, interleukin 6 (IL6), tumor necrotic factor α (TNFα), hydroxyl radicals, and NO. Leukotriene receptor antagonist MK571 and 5-lipoxygenase inhibitor MK886 were used for pharmacologic intervention. Compared to control, nTiO2 exposure induced near 5-fold increase in 5-lipoxygenase mRNA expression in lung tissue. iNOS mRNA increased while eNOS mRNA decreased. Lavage leukotriene C4; IL6; TNFα; NO; hydroxyl radicals; and blood WBC, NO, hydrogen peroxide, and LDH levels rose. Obstructive ventilatory insufficiency was observed. MK571 and MK886 both attenuated the systemic inflammation and lung function changes. We conclude that inhaled nTiO2 induces systemic inflammation, cytokine release, and oxidative and nitrosative stress in the lung. The lipoxygenase pathway products, mediated by oxygen radicals and WBC, play a critical role in the obstructive ventilatory insufficiency induced by nTiO2.

  2. Childhood Maltreatment Exposure and Disruptions in Emotion Regulation: A Transdiagnostic Pathway to Adolescent Internalizing and Externalizing Psychopathology

    Science.gov (United States)

    Jenness, Jessica L.; Stoep, Ann Vander; McCauley, Elizabeth; McLaughlin, Katie A.

    2016-01-01

    Child maltreatment is a robust risk factor for internalizing and externalizing psychopathology in children and adolescents. We examined the role of disruptions in emotion regulation processes as a developmental mechanism linking child maltreatment to the onset of multiple forms of psychopathology in adolescents. Specifically, we examined whether child maltreatment was associated with emotional reactivity and maladaptive cognitive and behavioral responses to distress, including rumination and impulsive behaviors, in two separate samples. We additionally investigated whether each of these components of emotion regulation were associated with internalizing and externalizing psychopathology and mediated the association between child maltreatment and psychopathology. Study 1 included a sample of 167 adolescents recruited based on exposure to physical, sexual, or emotional abuse. Study 2 included a sample of 439 adolescents in a community-based cohort study followed prospectively for 5 years. In both samples, child maltreatment was associated with higher levels of internalizing psychopathology, elevated emotional reactivity, and greater habitual engagement in rumination and impulsive responses to distress. In Study 2, emotional reactivity and maladaptive responses to distress mediated the association between child maltreatment and both internalizing and externalizing psychopathology. These findings provide converging evidence for the role of emotion regulation deficits as a transdiagnostic developmental pathway linking child maltreatment with multiple forms of psychopathology. PMID:27695145

  3. Modeling Exposures to the Oxidative Potential of PM10

    Science.gov (United States)

    2012-01-01

    Differences in the toxicity of ambient particulate matter (PM) due to varying particle composition across locations may contribute to variability in results from air pollution epidemiologic studies. Though most studies have used PM mass concentration as the exposure metric, an alternative which accounts for particle toxicity due to varying particle composition may better elucidate whether PM from specific sources is responsible for observed health effects. The oxidative potential (OP) of PM PM10) was measured as the rate of depletion of the antioxidant reduced glutathione (GSH) in a model of human respiratory tract lining fluid. Using a database of GSH OP measures collected in greater London, U.K. from 2002 to 2006, we developed and validated a predictive spatiotemporal model of the weekly GSH OP of PM10 that included geographic predictors. Predicted levels of OP were then used in combination with those of weekly PM10 mass to estimate exposure to PM10 weighted by its OP. Using cross-validation (CV), brake and tire wear emissions of PM10 from traffic within 50 m and tailpipe emissions of nitrogen oxides from heavy-goods vehicles within 100 m were important predictors of GSH OP levels. Predictive accuracy of the models was high for PM10 (CV R2=0.83) but only moderate for GSH OP (CV R2 = 0.44) when comparing weekly levels; however, the GSH OP model predicted spatial trends well (spatial CV R2 = 0.73). Results suggest that PM10 emitted from traffic sources, specifically brake and tire wear, has a higher OP than that from other sources, and that this effect is very local, occurring within 50–100 m of roadways. PMID:22731499

  4. Inhalation Exposure Input Parameters for the Biosphere Model

    Energy Technology Data Exchange (ETDEWEB)

    M. A. Wasiolek

    2003-09-24

    This analysis is one of the nine reports that support the Environmental Radiation Model for Yucca Mountain Nevada (ERMYN) biosphere model. The ''Biosphere Model Report'' (BSC 2003a) describes in detail the conceptual model as well as the mathematical model and its input parameters. This report documents a set of input parameters for the biosphere model, and supports the use of the model to develop biosphere dose conversion factors (BDCFs). The biosphere model is one of a series of process models supporting the Total System Performance Assessment (TSPA) for a Yucca Mountain repository. This report, ''Inhalation Exposure Input Parameters for the Biosphere Model'', is one of the five reports that develop input parameters for the biosphere model. A graphical representation of the documentation hierarchy for the ERMYN is presented in Figure 1-1. This figure shows the interrelationships among the products (i.e., analysis and model reports) developed for biosphere modeling, and the plan for development of the biosphere abstraction products for TSPA, as identified in the ''Technical Work Plan: for Biosphere Modeling and Expert Support'' (BSC 2003b). It should be noted that some documents identified in Figure 1-1 may be under development at the time this report is issued and therefore not available at that time. This figure is included to provide an understanding of how this analysis report contributes to biosphere modeling in support of the license application, and is not intended to imply that access to the listed documents is required to understand the contents of this analysis report. This analysis report defines and justifies values of mass loading, which is the total mass concentration of resuspended particles (e.g., dust, ash) in a volume of air. Measurements of mass loading are used in the air submodel of ERMYN to calculate concentrations of radionuclides in air surrounding crops and concentrations in air

  5. Assessment of Fecal Exposure Pathways in Low-Income Urban Neighborhoods in Accra, Ghana: Rationale, Design, Methods, and Key Findings of the SaniPath Study.

    Science.gov (United States)

    Robb, Katharine; Null, Clair; Teunis, Peter; Yakubu, Habib; Armah, George; Moe, Christine L

    2017-10-01

    Rapid urbanization has contributed to an urban sanitation crisis in low-income countries. Residents in low-income, urban neighborhoods often have poor sanitation infrastructure and services and may experience frequent exposure to fecal contamination through a range of pathways. There are little data to prioritize strategies to decrease exposure to fecal contamination in these complex and highly contaminated environments, and public health priorities are rarely considered when planning urban sanitation investments. The SaniPath Study addresses this need by characterizing pathways of exposure to fecal contamination. Over a 16 month period, an in-depth, interdisciplinary exposure assessment was conducted in both public and private domains of four neighborhoods in Accra, Ghana. Microbiological analyses of environmental samples and behavioral data collection techniques were used to quantify fecal contamination in the environment and characterize the behaviors of adults and children associated with exposure to fecal contamination. Environmental samples (n = 1,855) were collected and analyzed for fecal indicators and enteric pathogens. A household survey with 800 respondents and over 500 hours of structured observation of young children were conducted. Approximately 25% of environmental samples were collected in conjunction with structured observations (n = 441 samples). The results of the study highlight widespread and often high levels of fecal contamination in both public and private domains and the food supply. The dominant fecal exposure pathway for young children in the household was through consumption of uncooked produce. The SaniPath Study provides critical information on exposure to fecal contamination in low-income, urban environments and ultimately can inform investments and policies to reduce these public health risks.

  6. Use of an aggregate exposure model to estimate consumer exposure to fragrance ingredients in personal care and cosmetic products.

    Science.gov (United States)

    Safford, B; Api, A M; Barratt, C; Comiskey, D; Daly, E J; Ellis, G; McNamara, C; O'Mahony, C; Robison, S; Smith, B; Thomas, R; Tozer, S

    2015-08-01

    Ensuring the toxicological safety of fragrance ingredients used in personal care and cosmetic products is essential in product development and design, as well as in the regulatory compliance of the products. This requires an accurate estimation of consumer exposure which, in turn, requires an understanding of consumer habits and use of products. Where ingredients are used in multiple product types, it is important to take account of aggregate exposure in consumers using these products. This publication investigates the use of a newly developed probabilistic model, the Creme RIFM model, to estimate aggregate exposure to fragrance ingredients using the example of 2-phenylethanol (PEA). The output shown demonstrates the utility of the model in determining systemic and dermal exposure to fragrances from individual products, and aggregate exposure. The model provides valuable information not only for risk assessment, but also for risk management. It should be noted that data on the concentrations of PEA in products used in this article were obtained from limited sources and not the standard, industry wide surveys typically employed by the fragrance industry and are thus presented here to illustrate the output and utility of the newly developed model. They should not be considered an accurate representation of actual exposure to PEA. Copyright © 2015 Elsevier Inc. All rights reserved.

  7. 78 FR 13338 - Exposure Modeling Public Meeting; Notice of Public Meeting

    Science.gov (United States)

    2013-02-27

    ... dates and abstract requests are announced through the ``empmlist'' forum on the LYRIS list server at... (DWI PCA) Guidance. Other topics related to environmental exposure modeling and monitoring of..., pesticide exposure assessment, exposure modeling, pesticide monitoring, groundwater, PRZM-GW, SAM, PFAM, DWI...

  8. NLRP3 gene knockout blocks NF-κB and MAPK signaling pathway in CUMS-induced depression mouse model.

    Science.gov (United States)

    Su, Wen-Jun; Zhang, Yi; Chen, Ying; Gong, Hong; Lian, Yong-Jie; Peng, Wei; Liu, Yun-Zi; Wang, Yun-Xia; You, Zi-Li; Feng, Shi-Jie; Zong, Ying; Lu, Guo-Cai; Jiang, Chun-Lei

    2017-03-30

    Abundant researches indicate that neuroinflammation has important roles in the pathophysiology of depression. Our previous study found that the NLRP3 inflammasome mediated stress-induced depression-like behavior in mice via regulating neuroinflammation. However, it still remains unclear that how the NLRP3 inflammasome influences related inflammatory signaling pathway to contribute to neuroinflammation in depression. We used wild-type mice and NLRP3 gene knockout mice to explore the role of NLRP3 inflammasome and related inflammatory signaling pathways in chronic unpredictable mild stress (CUMS) induced depression mouse model. Both wild-type and NLRP3 knockout stress group mice gained less weight than control group mice after 4 weeks CUMS exposure. The wild-type mice subjected to 4 weeks CUMS displayed depression-like behaviors, including decreased sucrose preference and increased immobility time in the tail suspension test. The NLRP3 knockout stress group mice didn't demonstrate depression-like behaviors. The levels of interleukin-1β protein in serum and hippocampi of CUMS exposed wild-type mice were significantly higher, while the NLRP3 knockout stress group mice didn't show an elevation of interleukin-1β levels. Similarly to early researches, we found that CUMS led to promoted NLRP3 expression in hippocampi. In addition, the hippocampi in CUMS exposed wild-type mice had higher p-JNK and p-p38 protein expression, which indicated activation of the mitogen-activated protein kinases (MAPK) pathway. The knockout of NLRP3 gene inhibited CUMS-induced activation of the MAPK pathway. The nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) protein complex was activated in the hippocampi of wild-type mice after CUMS exposure, while knockout of NLRP3 gene hindered its activation. These data further proved that the NLRP3 inflammasome mediated CUMS-induced depression-like behavior. The NLRP3 inflammasome regulated CUMS-induced MAPK pathway and NF

  9. Quantifying children's aggregate (dietary and residential) exposure and dose to permethrin: application and evaluation of EPA's probabilistic SHEDS-Multimedia model

    Science.gov (United States)

    Zartarian, Valerie; Xue, Jianping; Glen, Graham; Smith, Luther; Tulve, Nicolle; Tornero-Velez, Rogelio

    2012-01-01

    Reliable, evaluated human exposure and dose models are important for understanding the health risks from chemicals. A case study focusing on permethrin was conducted because of this insecticide's widespread use and potential health effects. SHEDS-Multimedia was applied to estimate US population permethrin exposures for 3- to 5-year-old children from residential, dietary, and combined exposure routes, using available dietary consumption data, food residue data, residential concentrations, and exposure factors. Sensitivity and uncertainty analyses were conducted to identify key factors, pathways, and research needs. Model evaluation was conducted using duplicate diet data and biomonitoring data from multiple field studies, and comparison to other models. Key exposure variables were consumption of spinach, lettuce, and cabbage; surface-to-skin transfer efficiency; hand mouthing frequency; fraction of hand mouthed; saliva removal efficiency; fraction of house treated; and usage frequency. For children in households using residential permethrin, the non-dietary exposure route was most important, and when all households were included, dietary exposure dominated. SHEDS-Multimedia model estimates compared well to real-world measurements data; this exposure assessment tool can enhance human health risk assessments and inform children's health research. The case study provides insights into children's aggregate exposures to permethrin and lays the foundation for a future cumulative pyrethroid pesticides risk assessment. PMID:22434114

  10. Quantifying children's aggregate (dietary and residential) exposure and dose to permethrin: application and evaluation of EPA's probabilistic SHEDS-Multimedia model.

    Science.gov (United States)

    Zartarian, Valerie; Xue, Jianping; Glen, Graham; Smith, Luther; Tulve, Nicolle; Tornero-Velez, Rogelio

    2012-01-01

    Reliable, evaluated human exposure and dose models are important for understanding the health risks from chemicals. A case study focusing on permethrin was conducted because of this insecticide's widespread use and potential health effects. SHEDS-Multimedia was applied to estimate US population permethrin exposures for 3- to 5-year-old children from residential, dietary, and combined exposure routes, using available dietary consumption data, food residue data, residential concentrations, and exposure factors. Sensitivity and uncertainty analyses were conducted to identify key factors, pathways, and research needs. Model evaluation was conducted using duplicate diet data and biomonitoring data from multiple field studies, and comparison to other models. Key exposure variables were consumption of spinach, lettuce, and cabbage; surface-to-skin transfer efficiency; hand mouthing frequency; fraction of hand mouthed; saliva removal efficiency; fraction of house treated; and usage frequency. For children in households using residential permethrin, the non-dietary exposure route was most important, and when all households were included, dietary exposure dominated. SHEDS-Multimedia model estimates compared well to real-world measurements data; this exposure assessment tool can enhance human health risk assessments and inform children's health research. The case study provides insights into children's aggregate exposures to permethrin and lays the foundation for a future cumulative pyrethroid pesticides risk assessment.

  11. Recommended Henry’s Law Constants for Non-Groundwater Pathways Models in GoldSim

    Energy Technology Data Exchange (ETDEWEB)

    Dyer, J. [Savannah River Site (SRS), Aiken, SC (United States). Savannah River National Lab. (SRNL)

    2017-06-20

    This memorandum documents the source and numerical value of Henry’s law constants for volatile radionuclides of interest used in the non-groundwater (air and radon) pathways models for the 2018 E-Area Performance Assessment.

  12. Exposure to Deepwater Horizon oil and Corexit 9500 at low concentrations induces transcriptional changes and alters immune transcriptional pathways in sheepshead minnows.

    Science.gov (United States)

    Jones, Elizabeth R; Martyniuk, Christopher J; Morris, Jeffrey M; Krasnec, Michelle O; Griffitt, Robert J

    2017-09-01

    The 2010 Deepwater Horizon (DWH) oil spill caused the release of 4.9 million barrels of crude oil into the Gulf of Mexico, followed by the application of 2.9 million L of the dispersant, Corexit™ to mitigate the spread of oil. The spill resulted in substantial shoreline oiling, potentially exposing coastal organisms to polyaromatic hydrocarbon (PAH) and dispersant contaminants. To investigate molecular effects in fish following exposure to environmentally relevant concentrations of DWH oil and dispersants, we exposed adult sheepshead minnows (Cyprinodon variegatus) to two concentrations of high-energy water-accommodated fraction (HEWAF), chemically enhanced water-accommodated fraction (CEWAF) or Corexit 9500™ for 7 and 14days. Resulting changes in hepatic gene expression were measured using 8×15K microarrays. Analytical chemistry confirmed PAH concentrations in HEWAF and CEWAF treatments were low (ranging from 0.26 to 5.98μg/L), and likely representative of post-spill environmental concentrations. We observed significant changes to gene expression in all treatments (relative to controls), with Corexit and CEWAF having a greater effect on expression patterns in the liver than HEWAF treatments. Sub-network enrichment analysis of biological pathways revealed that the greatest number of altered pathways in high dose HEWAF and CEWAF treatments occurred following a 7-day exposure. Pathways related to immunity comprised the majority of pathways affected in each treatment, followed by pathways related to blood and circulation processes. Our results indicate that oil composition, concentration, and exposure duration all affect molecular responses in exposed fish, and suggest that low-concentration exposures may result in sub-lethal adverse effects. Copyright © 2017 Elsevier Inc. All rights reserved.

  13. Mechanotransduction map: simulation model, molecular pathway, gene set.

    Science.gov (United States)

    Dent, Jennifer E; Devescovi, Valentina; Li, Han; Di Lena, Pietro; Lu, Youtao; Liu, Yuanhua; Nardini, Christine

    2015-04-01

    Mechanotransduction--the ability to output a biochemical signal from a mechanical input--is related to the initiation and progression of a broad spectrum of molecular events. Yet, the characterization of mechanotransduction lacks some of the most basic tools as, for instance, it can hardly be recognized by enrichment analysis tools, nor could we find any pathway representation. This greatly limits computational testing and hypothesis generation on mechanotransduction biological relevance and involvement in disease or physiological mechanisms. We here present a molecular map of mechanotransduction, built in CellDesigner to warrant that maximum information is embedded in a compact network format. To validate the map's necessity we tested its redundancy in comparison with existing pathways, and to estimate its sufficiency, we quantified its ability to reproduce biological events with dynamic simulations, using Signaling Petri Networks. SMBL language map is available in the Supplementary Data: core_map.xml, basic_map.xml. Supplementary data are available at Bioinformatics online. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

  14. Comparative transcriptomics reveals genes involved in metabolic and immune pathways in the digestive gland of scallop Chlamys farreri following cadmium exposure

    Science.gov (United States)

    Zhang, Hui; Zhai, Yuxiu; Yao, Lin; Jiang, Yanhua; Li, Fengling

    2017-05-01

    Chlamys farreri is an economically important mollusk that can accumulate excessive amounts of cadmium (Cd). Studying the molecular mechanism of Cd accumulation in bivalves is difficult because of the lack of genome background. Transcriptomic analysis based on high-throughput RNA sequencing has been shown to be an efficient and powerful method for the discovery of relevant genes in non-model and genome reference-free organisms. Here, we constructed two cDNA libraries (control and Cd exposure groups) from the digestive gland of C. farreri and compared the transcriptomic data between them. A total of 227 673 transcripts were assembled into 105 071 unigenes, most of which shared high similarity with sequences in the NCBI non-redundant protein database. For functional classification, 24 493 unigenes were assigned to Gene Ontology terms. Additionally, EuKaryotic Ortholog Groups and Kyoto Encyclopedia of Genes and Genomes analyses assigned 12 028 unigenes to 26 categories and 7 849 unigenes to five pathways, respectively. Comparative transcriptomics analysis identified 3 800 unigenes that were differentially expressed in the Cd-treated group compared with the control group. Among them, genes associated with heavy metal accumulation were screened, including metallothionein, divalent metal transporter, and metal tolerance protein. The functional genes and predicted pathways identified in our study will contribute to a better understanding of the metabolic and immune system in the digestive gland of C. farreri. In addition, the transcriptomic data will provide a comprehensive resource that may contribute to the understanding of molecular mechanisms that respond to marine pollutants in bivalves.

  15. Early Brain Response to Low-Dose Radiation Exposure Involves Molecular Networks and Pathways Associated with Cognitive Functions, Advanced Aging and Alzheimer's Disease

    Energy Technology Data Exchange (ETDEWEB)

    Lowe, Xiu R; Bhattacharya, Sanchita; Marchetti, Francesco; Wyrobek, Andrew J.

    2008-06-06

    Understanding the cognitive and behavioral consequences of brain exposures to low-dose ionizing radiation has broad relevance for health risks from medical radiation diagnostic procedures, radiotherapy, environmental nuclear contamination, as well as earth orbit and space missions. Analyses of transcriptome profiles of murine brain tissue after whole-body radiation showed that low-dose exposures (10 cGy) induced genes not affected by high dose (2 Gy), and low-dose genes were associated with unique pathways and functions. The low-dose response had two major components: pathways that are consistently seen across tissues, and pathways that were brain tissue specific. Low-dose genes clustered into a saturated network (p < 10{sup -53}) containing mostly down-regulated genes involving ion channels, long-term potentiation and depression, vascular damage, etc. We identified 9 neural signaling pathways that showed a high degree of concordance in their transcriptional response in mouse brain tissue after low-dose radiation, in the aging human brain (unirradiated), and in brain tissue from patients with Alzheimer's disease. Mice exposed to high-dose radiation did not show these effects and associations. Our findings indicate that the molecular response of the mouse brain within a few hours after low-dose irradiation involves the down-regulation of neural pathways associated with cognitive dysfunctions that are also down regulated in normal human aging and Alzheimer's disease.

  16. Constraint-based modeling and kinetic analysis of the Smad dependent TGF-beta signaling pathway.

    Directory of Open Access Journals (Sweden)

    Zhike Zi

    Full Text Available BACKGROUND: Investigation of dynamics and regulation of the TGF-beta signaling pathway is central to the understanding of complex cellular processes such as growth, apoptosis, and differentiation. In this study, we aim at using systems biology approach to provide dynamic analysis on this pathway. METHODOLOGY/PRINCIPAL FINDINGS: We proposed a constraint-based modeling method to build a comprehensive mathematical model for the Smad dependent TGF-beta signaling pathway by fitting the experimental data and incorporating the qualitative constraints from the experimental analysis. The performance of the model generated by constraint-based modeling method is significantly improved compared to the model obtained by only fitting the quantitative data. The model agrees well with the experimental analysis of TGF-beta pathway, such as the time course of nuclear phosphorylated Smad, the subcellular location of Smad and signal response of Smad phosphorylation to different doses of TGF-beta. CONCLUSIONS/SIGNIFICANCE: The simulation results indicate that the signal response to TGF-beta is regulated by the balance between clathrin dependent endocytosis and non-clathrin mediated endocytosis. This model is useful to be built upon as new precise experimental data are emerging. The constraint-based modeling method can also be applied to quantitative modeling of other signaling pathways.

  17. Predictive Modeling of Terrestrial Radiation Exposure from Geologic Materials

    Energy Technology Data Exchange (ETDEWEB)

    Malchow, Russell L. [National Security Technologies, LLC; Haber, Daniel University of Nevada, Las Vegas; Burnley, Pamela [University of Nevada, Las Vegas; Marsac, Kara [University of Nevada, Las Vegas; Hausrath, Elisabeth [University of Nevada, Las Vegas; Adcock, Christopher [University of Nevada, Las Vegas

    2015-01-01

    Aerial gamma ray surveys are important for those working in nuclear security and industry for determining locations of both anthropogenic radiological sources and natural occurrences of radionuclides. During an aerial gamma ray survey, a low flying aircraft, such as a helicopter, flies in a linear pattern across the survey area while measuring the gamma emissions with a sodium iodide (NaI) detector. Currently, if a gamma ray survey is being flown in an area, the only way to correct for geologic sources of gamma rays is to have flown the area previously. This is prohibitively expensive and would require complete national coverage. This project’s goal is to model the geologic contribution to radiological backgrounds using published geochemical data, GIS software, remote sensing, calculations, and modeling software. K, U and Th are the three major gamma emitters in geologic material. U and Th are assumed to be in secular equilibrium with their daughter isotopes. If K, U, and Th abundance values are known for a given geologic unit the expected gamma ray exposure rate can be calculated using the Grasty equation or by modeling software. Monte Carlo N-Particle Transport software (MCNP), developed by Los Alamos National Laboratory, is modeling software designed to simulate particles and their interactions with matter. Using this software, models have been created that represent various lithologies. These simulations randomly generate gamma ray photons at energy levels expected from natural radiologic sources. The photons take a random path through the simulated geologic media and deposit their energy at the end of their track. A series of nested spheres have been created and filled with simulated atmosphere to record energy deposition. Energies deposited are binned in the same manner as the NaI detectors used during an aerial survey. These models are used in place of the simplistic Grasty equation as they take into account absorption properties of the lithology which the

  18. Altered Expression of Genes in Signaling Pathways Regulating Proliferation of Hematopoietic Stem and Progenitor Cells in Mice with Subchronic Benzene Exposure.

    Science.gov (United States)

    Sun, Rongli; Zhang, Juan; Xiong, Mengzhen; Wei, Haiyan; Tan, Kehong; Yin, Lihong; Pu, Yuepu

    2015-08-07

    Leukemias and hematopoietic disorders induced by benzene may arise from the toxicity of benzene to hematopoietic stem or progenitor cells (HS/PCs). Since there is a latency period between initial benzene exposure and the development of leukemia, subsequent impact of benzene on HS/PCs are crucial for a deeper understanding of the carcinogenicity and hematotoxicity in post-exposure stage. This study aims to explore the effects of benzene on HS/PCs and gene-expression in Wnt, Notch and Hh signaling pathways in post-exposure stage. The C3H/He mice were injected subcutaneously with benzene (0, 150, 300 mg/kg/day) for three months and were monitored for another 10 months post-exposure. The body weights were monitored, the relative organ weights, blood parameters and bone marrow smears were examined. Frequency of lineage(-) sca-1(+) c-kit(+) (LSK) cells, capability of colony forming and expression of genes in Wnt, Notch and Hedghog (Hh) signaling pathways were also analyzed. The colony formation of the progenitor cells for BFU-E, CFU-GEMM and CFU-GM was significantly decreased with increasing benzene exposure relative to controls, while no significant difference was observed in colonies for CFU-G and CFU-M. The mRNA level of cyclin D1 was increased and Notch 1 and p53 were decreased in LSK cells in mice exposed to benzene but with no statistical significance. These results suggest that subsequent toxic effects of benzene on LSK cells and gene expression in Wnt, Notch and Hh signaling pathways persist in post-exposure stage and may play roles in benzene-induced hematotoxicity.

  19. Reaction pathways in atomistic models of thin film growth

    Science.gov (United States)

    Lloyd, Adam L.; Zhou, Ying; Yu, Miao; Scott, Chris; Smith, Roger; Kenny, Steven D.

    2017-10-01

    The atomistic processes that form the basis of thin film growth often involve complex multi-atom movements of atoms or groups of atoms on or close to the surface of a substrate. These transitions and their pathways are often difficult to predict in advance. By using an adaptive kinetic Monte Carlo (AKMC) approach, many complex mechanisms can be identified so that the growth processes can be understood and ultimately controlled. Here the AKMC technique is briefly described along with some special adaptions that can speed up the simulations when, for example, the transition barriers are small. Examples are given of such complex processes that occur in different material systems especially for the growth of metals and metallic oxides.

  20. Adolescent Conflict as a Developmental Process in the Prospective Pathway from Exposure to Interparental Violence to Dating Violence

    Science.gov (United States)

    Narayan, Angela J.; Englund, Michelle M.; Carlson, Elizabeth A.; Egeland, Byron

    2013-01-01

    Within a developmental psychopathology framework, the current study examined adolescent conflict (age 16) with families, best friends, and dating partners as mediators in the prospective pathway from exposure to interparental violence (EIPV) in early childhood (0–64 months) to dating violence perpetration and victimization in early adulthood (age 23). Adolescent conflict was predicted to partially mediate EIPV and dating violence with significant direct paths from EIPV to dating violence, given the extant literature on the salience of early childhood EIPV for later maladjustment. Participants (N = 182; 99 males, 83 females; 67% Caucasian, 11% African-American, 18% other, 4% unreported) were drawn from a larger prospective study of high-risk mothers (aged 12–34 years) that followed their children from birth through adulthood. EIPV and adolescent conflict were rated from interviews with mothers and participants, and dating violence (physical perpetration and victimization) was assessed with the Conflict Tactics Scale. Path analyses showed that EIPV in early childhood (a) directly predicted dating violence perpetration in early adulthood and (b) predicted conflict with best friends, which in turn predicted dating violence perpetration. Although mediation of best friend conflict was not evident, indirect effects of EIPV to dating violence were found through externalizing behaviors in adolescence and life stress in early adulthood. Findings highlight that conflict with best friends is affected by EIPV and predicts dating violence, suggesting that it may be a promising target for relationship-based interventions for youth with EIPV histories. Furthermore, deleterious early experiences and contemporaneous risk factors are salient predictors of dating violence. PMID:23979004

  1. The multimedia models for the evaluation of exposure bond to the atmospheric emissions of classified installations; Les modeles multimedia pour l'evaluation des expositions liees aux emissions atmospheriques des installations classees

    Energy Technology Data Exchange (ETDEWEB)

    Bonnard, R

    2001-12-15

    Risk assessment and environmental impacts studies are realized to preserve the public health. Today one of the most used approach is the use of an atmospheric dispersion model to assess the risks. The data are then injected in a calculation software of exposure bond to polluted soils, to evaluate the risks of non direct exposure. This report details and evaluates the models corresponding to the need: the methodology for assessing Health Risks associated with multiple pathways of exposure to combustor, human health risk assessment proto col for hazardous waste combustion facilities, EUSES, CALTOX, MEPAS, MEND-TOX, RESRAD, MMSOILS, FRAMES-HWIR, PC-GEMS and TRIM. (A.L.B.)

  2. The multi-modal responses of a physical head model subjected to various blast exposure conditions

    Science.gov (United States)

    Ouellet, S.; Phillippens, M.

    2017-11-01

    The local and global biomechanical response of the body to a blast wave is the first step of a sequence that leads to the development of stresses and strains which can exceed the tolerance of brain tissue. These stresses and strains may then lead to neuro-physical changes in the brain and contribute to initiate a cascade of events leading to injury. The specific biomechanical pathways by which the blast energy is transmitted through the head structure are, however, not clearly understood. Multiple transmission mechanisms have been proposed to explain the generation of brain stresses following the impingement of a blast wave on the head. With the use of a physical head model, the work presented here aims at demonstrating that the proposed transmission mechanisms are not mutually exclusive. They are part of a continuum of head responses where, depending on the exposure conditions, a given mechanism may or may not dominate. This article presents the joint analysis of previous blast test results generated with the brain injury protection evaluation device (BIPED) headform under four significantly different exposure conditions. The focus of the analysis is to demonstrate how the nature of the recorded response is highly dependent on the exposure characteristics and consequently, on the method used to reproduce blast exposure in a laboratory environment. The timing and magnitude of the variations in intra-cranial pressures (ICP) were analysed relative to the external pressure field in order to better understand the wave dynamics occurring within the brain structure of the headform. ICP waveforms were also analysed in terms of their energy spectral density to better identify the energy partitioning between the different modes of response. It is shown that the BIPED response is multi-modal and that the energy partitioning between its different modes of response is greatly influenced by exposure characteristics such as external peak overpressure, impulse, blast wave

  3. RAMS Model for Terrestrial Pathways Version 3. 0 (for microcomputers). Model-Simulation

    Energy Technology Data Exchange (ETDEWEB)

    Niebla, E.

    1989-01-01

    The RAMS Model for Terrestrial Pathways is a computer program for calculation of numeric criteria for land application and distribution and marketing of sludges under the sewage-sludge regulations at 40 CFR Part 503. The risk-assessment models covered assume that municipal sludge with specified characteristics is spread across a defined area of ground at a known rate once each year for a given number of years. Risks associated with direct land application of sludge applied after distribution and marketing are both calculated. The computer program calculates the maximum annual loading of contaminants that can be land applied and still meet the risk criteria specified as input. Software Description: The program is written in the Turbo/Basic programming language for implementation on IBM PC/AT or compatible machines using DOS 3.0 or higher operating system. Minimum core storage is 512K.

  4. Non Linear Programming (NLP) formulation for quantitative modeling of protein signal transduction pathways.

    Science.gov (United States)

    Mitsos, Alexander; Melas, Ioannis N; Morris, Melody K; Saez-Rodriguez, Julio; Lauffenburger, Douglas A; Alexopoulos, Leonidas G

    2012-01-01

    Modeling of signal transduction pathways plays a major role in understanding cells' function and predicting cellular response. Mathematical formalisms based on a logic formalism are relatively simple but can describe how signals propagate from one protein to the next and have led to the construction of models that simulate the cells response to environmental or other perturbations. Constrained fuzzy logic was recently introduced to train models to cell specific data to result in quantitative pathway models of the specific cellular behavior. There are two major issues in this pathway optimization: i) excessive CPU time requirements and ii) loosely constrained optimization problem due to lack of data with respect to large signaling pathways. Herein, we address both issues: the former by reformulating the pathway optimization as a regular nonlinear optimization problem; and the latter by enhanced algorithms to pre/post-process the signaling network to remove parts that cannot be identified given the experimental conditions. As a case study, we tackle the construction of cell type specific pathways in normal and transformed hepatocytes using medium and large-scale functional phosphoproteomic datasets. The proposed Non Linear Programming (NLP) formulation allows for fast optimization of signaling topologies by combining the versatile nature of logic modeling with state of the art optimization algorithms.

  5. Non Linear Programming (NLP formulation for quantitative modeling of protein signal transduction pathways.

    Directory of Open Access Journals (Sweden)

    Alexander Mitsos

    Full Text Available Modeling of signal transduction pathways plays a major role in understanding cells' function and predicting cellular response. Mathematical formalisms based on a logic formalism are relatively simple but can describe how signals propagate from one protein to the next and have led to the construction of models that simulate the cells response to environmental or other perturbations. Constrained fuzzy logic was recently introduced to train models to cell specific data to result in quantitative pathway models of the specific cellular behavior. There are two major issues in this pathway optimization: i excessive CPU time requirements and ii loosely constrained optimization problem due to lack of data with respect to large signaling pathways. Herein, we address both issues: the former by reformulating the pathway optimization as a regular nonlinear optimization problem; and the latter by enhanced algorithms to pre/post-process the signaling network to remove parts that cannot be identified given the experimental conditions. As a case study, we tackle the construction of cell type specific pathways in normal and transformed hepatocytes using medium and large-scale functional phosphoproteomic datasets. The proposed Non Linear Programming (NLP formulation allows for fast optimization of signaling topologies by combining the versatile nature of logic modeling with state of the art optimization algorithms.

  6. Assessment on personal exposure to particulate compounds using an empirical exposure model in an elderly community in Tianjin, China.

    Science.gov (United States)

    Xu, Jia; Zhang, Nan; Han, Bin; You, Yan; Zhou, Jian; Zhang, Jiefeng; Niu, Can; Liu, Yating; He, Fei; Ding, Xiao; Bai, Zhipeng

    2016-12-01

    Using central site measurement data to predict personal exposure to particulate matter (PM) is challenging, because people spend most of their time indoors and ambient contribution to personal exposure is subject to infiltration conditions affected by many factors. Efforts in assessing and predicting exposure on the basis of associated indoor/outdoor and central site monitoring were limited in China. This study collected daily personal exposure, residential indoor/outdoor and community central site PM filter samples in an elderly community during the non-heating and heating periods in 2009 in Tianjin, China. Based on the chemical analysis results of particulate species, mass concentrations of the particulate compounds were estimated and used to reconstruct the PM mass for mass balance analysis. The infiltration factors (Finf) of particulate compounds were estimated using both robust regression and mixed effect regression methods, and further estimated the exposure factor (Fpex) according to participants' time-activity patterns. Then an empirical exposure model was developed to predict personal exposure to PM and particulate compounds as the sum of ambient and non-ambient contributions. Results showed that PM mass observed during the heating period could be well represented through chemical mass reconstruction, because unidentified mass was minimal. Excluding the high observations (>300μg/m(3)), this empirical exposure model performed well for PM and elemental carbon (EC) that had few indoor sources. These results support the use of Fpex as an indicator for ambient contribution predictions, and the use of empirical non-ambient contribution to assess exposure to particulate compounds. Copyright © 2016 Elsevier B.V. All rights reserved.

  7. A new stochastic and state space model of human colon cancer incorporating multiple pathways.

    Science.gov (United States)

    Tan, Wai Y; Yan, Xiao W

    2010-04-20

    Studies by molecular biologists and geneticists have shown that tumors of human colon cancer are developed from colon stem cells through two mechanisms: The chromosomal instability and the micro-satellite instability. The purpose of this paper is therefore to develop a new stochastic and state space model for carcinogenesis of human colon cancer incorporating these biological mechanisms. Based on recent biological studies, in this paper we have developed a state space model for human colon cancer. In this state space model, the stochastic system is represented by a stochastic model, involving 2 different pathways-the chromosomal instability pathway and the micro-satellite instability pathway; the observation, cancer incidence data, is represented by a statistical model. Based on this model we have developed a generalized Bayesian approach to estimate the parameters through the posterior modes of the parameters via Gibbs sampling procedures. We have applied this model to fit and analyze the SEER data of human colon cancers from NCI/NIH. Our results indicate that the model not only provides a logical avenue to incorporate biological information but also fits the data much better than other models including the 4-stage single pathway model. This model not only would provide more insights into human colon cancer but also would provide useful guidance for its prevention and control and for prediction of future cancer cases.

  8. Towards a Pathway Inventory of the Human Brain for Modeling Disease Mechanisms Underlying Neurodegeneration.

    Science.gov (United States)

    Iyappan, Anandhi; Gündel, Michaela; Shahid, Mohammad; Wang, Jiali; Li, Hui; Mevissen, Heinz-Theodor; Müller, Bernd; Fluck, Juliane; Jirsa, Viktor; Domide, Lia; Younesi, Erfan; Hofmann-Apitius, Martin

    2016-04-12

    Molecular signaling pathways have been long used to demonstrate interactions among upstream causal molecules and downstream biological effects. They show the signal flow between cell compartments, the majority of which are represented as cartoons. These are often drawn manually by scanning through the literature, which is time-consuming, static, and non-interoperable. Moreover, these pathways are often devoid of context (condition and tissue) and biased toward certain disease conditions. Mining the scientific literature creates new possibilities to retrieve pathway information at higher contextual resolution and specificity. To address this challenge, we have created a pathway terminology system by combining signaling pathways and biological events to ensure a broad coverage of the entire pathway knowledge domain. This terminology was applied to mining biomedical papers and patents about neurodegenerative diseases with focus on Alzheimer's disease. We demonstrate the power of our approach by mapping literature-derived signaling pathways onto their corresponding anatomical regions in the human brain under healthy and Alzheimer's disease states. We demonstrate how this knowledge resource can be used to identify a putative mechanism explaining the mode-of-action of the approved drug Rasagiline, and show how this resource can be used for fingerprinting patents to support the discovery of pathway knowledge for Alzheimer's disease. Finally, we propose that based on next-generation cause-and-effect pathway models, a dedicated inventory of computer-processable pathway models specific to neurodegenerative diseases can be established, which hopefully accelerates context-specific enrichment analysis of experimental data with higher resolution and richer annotations.

  9. Modelling compartmentalization towards elucidation and engineering of spatial organization in biochemical pathways.

    Science.gov (United States)

    Menon, Govind; Okeke, Chinedu; Krishnan, J

    2017-09-21

    Compartmentalization is a fundamental ingredient, central to the functioning of biological systems at multiple levels. At the cellular level, compartmentalization is a key aspect of the functioning of biochemical pathways and an important element used in evolution. It is also being exploited in multiple contexts in synthetic biology. Accurate understanding of the role of compartments and designing compartmentalized systems needs reliable modelling/systems frameworks. We examine a series of building blocks of signalling and metabolic pathways with compartmental organization. We systematically analyze when compartmental ODE models can be used in these contexts, by comparing these models with detailed reaction-transport models, and establishing a correspondence between the two. We build on this to examine additional complexities associated with these pathways, and also examine sample problems in the engineering of these pathways. Our results indicate under which conditions compartmental models can and cannot be used, why this is the case, and what augmentations are needed to make them reliable and predictive. We also uncover other hidden consequences of employing compartmental models in these contexts. Or results contribute a number of insights relevant to the modelling, elucidation, and engineering of biochemical pathways with compartmentalization, at the core of systems and synthetic biology.

  10. Mathematical modelling of the diurnal regulation of the MEP pathway in Arabidopsis.

    Science.gov (United States)

    Pokhilko, Alexandra; Bou-Torrent, Jordi; Pulido, Pablo; Rodríguez-Concepción, Manuel; Ebenhöh, Oliver

    2015-05-01

    Isoprenoid molecules are essential elements of plant metabolism. Many important plant isoprenoids, such as chlorophylls, carotenoids, tocopherols, prenylated quinones and hormones are synthesised in chloroplasts via the 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway. Here we develop a mathematical model of diurnal regulation of the MEP pathway in Arabidopsis thaliana. We used both experimental and theoretical approaches to integrate mechanisms potentially involved in the diurnal control of the pathway. Our data show that flux through the MEP pathway is accelerated in light due to the photosynthesis-dependent supply of metabolic substrates of the pathway and the transcriptional regulation of key biosynthetic genes by the circadian clock. We also demonstrate that feedback regulation of both the activity and the abundance of the first enzyme of the MEP pathway (1-deoxy-D-xylulose 5-phosphate synthase, DXS) by pathway products stabilizes the flux against changes in substrate supply and adjusts the flux according to product demand under normal growth conditions. These data illustrate the central relevance of photosynthesis, the circadian clock and feedback control of DXS for the diurnal regulation of the MEP pathway. © 2015 The Authors. New Phytologist © 2015 New Phytologist Trust.

  11. Boolean Modeling of Cellular and Molecular Pathways Involved in Influenza Infection

    Directory of Open Access Journals (Sweden)

    Christopher S. Anderson

    2016-01-01

    Full Text Available Systems virology integrates host-directed approaches with molecular profiling to understand viral pathogenesis. Self-contained statistical approaches that combine expression profiles of genes with the available databases defining the genes involved in the pathways (gene-sets have allowed characterization of predictive gene-signatures associated with outcome of the influenza virus (IV infection. However, such enrichment techniques do not take into account interactions among pathways that are responsible for the IV infection pathogenesis. We investigate dendritic cell response to seasonal H1N1 influenza A/New Caledonia/20/1999 (NC infection and infer the Boolean logic rules underlying the interaction network of ligand induced signaling pathways and transcription factors. The model reveals several novel regulatory modes and provides insights into mechanism of cross talk between NFκB and IRF mediated signaling. Additionally, the logic rule underlying the regulation of IL2 pathway that was predicted by the Boolean model was experimentally validated. Thus, the model developed in this paper integrates pathway analysis tools with the dynamic modeling approaches to reveal the regulation between signaling pathways and transcription factors using genome-wide transcriptional profiles measured upon influenza infection.

  12. Application of biotests for the characterization of exposure pathways for endocrine disrupters from plastics; Anwendung von Biotests zur Charakterisierung der Expositionspfade fuer Umwelthormone aus Kunststoffen

    Energy Technology Data Exchange (ETDEWEB)

    Wagner, Martin; Oehlmann, Joerg [Frankfurt Univ., Frankfurt am Main (Germany). Abteilung Aquatische Oekotoxikologie

    2011-12-15

    The present project aims to characterise the exposure pathways for endocrine disruptors from plastic materials. A bioassay-based approach was employed to investigate and characterise the endocrine activity. Migration studies with food packaging and plastic preforms document the leaching of estrogen-like compounds from several types of plastic in the Yeast Estrogen Screen and the E-Screen. Additionally, anti-estrogenic activity was predominant in many samples. The detection of complex migration profiles provides evidence for the leaching of several, diverse-acting endocrine disruptors. Moreover, extracts of plastic food packaging exhibited agonistic activity on the estrogen receptor, retinoid X receptor, and vitamin D receptor. A theoretical exposure assessment for marine molluscs implies that endocrine disruptors from plastic might induce relevant effect in the environment. Within the exemplary investigation of bottled mineral water, 60% of the products were characterised as significantly estrogenic using the YES and E-Screen. These in vitro data point to the plastic packaging being one source of estrogenic contamination. An in vivo study employing the estrogen-sensitive model organism Potamopyrgus antipodarum supports this hypothesis. By using several analytical techniques (GC-MS, LC-MS/MS) we identified several well-known endocrine disruptors in bottled water and the plastic material, e.g. numerous phthalates and phenols. Moreover, potent antagonists of the estrogen and androgen receptor were extracted from bottled water. In a non-target analysis (Orbitrap-MS) a compound with the exact mass of 363.1992 [M+H{sup +}] correlated highly significantly with the biological activity. On the basis of the methods optimised and applied within the project we elaborated a set of aspects that are crucial for the applicability of bioassays to characterise the endocrine activity of complex samples. Employing a bioassay-based approach we provide evidence for the presence and

  13. Incorporating biological pathways via a Markov random field model in genome-wide association studies.

    Directory of Open Access Journals (Sweden)

    Min Chen

    2011-04-01

    Full Text Available Genome-wide association studies (GWAS examine a large number of markers across the genome to identify associations between genetic variants and disease. Most published studies examine only single markers, which may be less informative than considering multiple markers and multiple genes jointly because genes may interact with each other to affect disease risk. Much knowledge has been accumulated in the literature on biological pathways and interactions. It is conceivable that appropriate incorporation of such prior knowledge may improve the likelihood of making genuine discoveries. Although a number of methods have been developed recently to prioritize genes using prior biological knowledge, such as pathways, most methods treat genes in a specific pathway as an exchangeable set without considering the topological structure of a pathway. However, how genes are related with each other in a pathway may be very informative to identify association signals. To make use of the connectivity information among genes in a pathway in GWAS analysis, we propose a Markov Random Field (MRF model to incorporate pathway topology for association analysis. We show that the conditional distribution of our MRF model takes on a simple logistic regression form, and we propose an iterated conditional modes algorithm as well as a decision theoretic approach for statistical inference of each gene's association with disease. Simulation studies show that our proposed framework is more effective to identify genes associated with disease than a single gene-based method. We also illustrate the usefulness of our approach through its applications to a real data example.

  14. Flash Vacuum Pyrolysis of Lignin Model Compounds: Reaction Pathways of Aromatic Methoxy Groups

    Energy Technology Data Exchange (ETDEWEB)

    Britt, P.F.; Buchanan, A.C., III; Martineau, D.R.

    1999-03-21

    Currently, there is interest in utilizing lignin, a major constituent of biomass, as a renewable source of chemicals and fuels. High yields of liquid products can be obtained from the flash or fast pyrolysis of biomass, but the reaction pathways that lead to product formation are not understood. To provide insight into the primary reaction pathways under process relevant conditions, we are investigating the flash vacuum pyrolysis (FVP) of lignin model compounds at 500 C. This presentation will focus on the FVP of {beta}-ether linkages containing aromatic methoxy groups and the reaction pathways of methoxy-substituted phenoxy radicals.

  15. Calmodulin Mediates DNA Repair Pathways Involving H2AX in Response to Low-Dose Radiation Exposure of RAW 264.7 Macrophages

    Energy Technology Data Exchange (ETDEWEB)

    Smallwood, Heather S.; Lopez Ferrer, Daniel; Eberlein, P. Elis; Watson, David J.; Squier, Thomas C.

    2009-02-05

    Understanding the molecular mechanisms that modulate macrophage radioresistance is necessary for the development of effective radiation therapies, as tumor-associated macrophages promote both angiogenesis and matrix remodeling that, in turn, enhance metastasis. In this respect, we have identified a dose-dependent increase in the abundance of the calcium regulatory protein calmodulin (CaM) in RAW 264.7 macrophages upon irradiation. CaM overexpression results in increased macrophage survival following radiation exposure, acting to diminish the sensitivity to low-dose exposures. Increases in CaM abundance also result in an increase in the number of phosphorylated histone H2AX protein complexes associated with DNA repair following macrophage irradiation, with no change in the extent of double-stranded DNA damage. In comparison, when NFκB-dependent pathways are inhibited, through the expression of a dominant-negative IκB construct, there is no significant increase in phosphorylated H2AX upon irradiation. These results indicate that the molecular basis for the up-regulation of histone H2AX mediated DNA-repair pathways is not the result of nonspecific NFκB-dependent pathways or a specific threshold of DNA damage. Rather, increases in CaM abundance act to minimize the low-dose hypersensitivity to radiation to enhance macrophage radioresistance through processes that include the upregulation of DNA repair pathways involving histone protein H2AX phosphorylation.

  16. Modeling terrestrial nitrogen pathways from manure and artificial fertilizer using the CESM

    Science.gov (United States)

    Riddick, S. N.; Hess, P. G.; Mahowald, N. M.; Ward, D. S.

    2013-12-01

    Nitrogen applied to the surface of the land for agricultural purposes represents a significant source of reactive nitrogen (Nr) that can either volatilize as ammonia (NH3), run-off during rain events or form plant useable nitrogen in the soil. To investigate temporal and spatial heterogeneity of nitrogen pathways on a global scale, we developed a semi-empirical parameterization to estimate volatilization, run-off and formation soil Nr from sources of animal manure and artificial fertilizer within an Earth System Model. The results estimate the global distribution of nitrogen pathways from Nr applied to the land surface on an annual basis. Using our climate dependent approach, we estimate global nitrogen pathways from manure at 21.7, 29.0 and 56.4 Tg N per year for NH3 emission, soil Nr and Nr dissolved during rain events, respectively. The model also predicted nitrogen pathways from fertilizer from NH3 emission, soil Nr and Nr dissolved during rain events at 8.4, 26.5 and 51.1 Tg N per year, respectively. The model was also run from 1850 to 2000 using a transient simulation which predicted that, even though absolute values of all nitrogen pathways are increasing, partitioning of nitrogen pathways is dependent on the amount of nitrogen applied to the surface. Being able to predict these pathways is environmentally important when trying to understand the current impact of fertilizer as well as how nitrogen pathways may change as fertilizer use increases in future coupled with a changing climate. Schematic of the model addition to CLM4.5 described in this paper. This study adds nitrogen to the surface as fertilizer, urine or manure and calculates the resulting ammonia (NH3) emission, dissolved nitrogen run-off and above ground nitrate (NO3-) formed.

  17. Improved statistical model checking methods for pathway analysis.

    Science.gov (United States)

    Koh, Chuan Hock; Palaniappan, Sucheendra K; Thiagarajan, P S; Wong, Limsoon

    2012-01-01

    Statistical model checking techniques have been shown to be effective for approximate model checking on large stochastic systems, where explicit representation of the state space is impractical. Importantly, these techniques ensure the validity of results with statistical guarantees on errors. There is an increasing interest in these classes of algorithms in computational systems biology since analysis using traditional model checking techniques does not scale well. In this context, we present two improvements to existing statistical model checking algorithms. Firstly, we construct an algorithm which removes the need of the user to define the indifference region, a critical parameter in previous sequential hypothesis testing algorithms. Secondly, we extend the algorithm to account for the case when there may be a limit on the computational resources that can be spent on verifying a property; i.e, if the original algorithm is not able to make a decision even after consuming the available amount of resources, we resort to a p-value based approach to make a decision. We demonstrate the improvements achieved by our algorithms in comparison to current algorithms first with a straightforward yet representative example, followed by a real biological model on cell fate of gustatory neurons with microRNAs.

  18. Propagation modelling based on airborne particle release data from nanostructured materials for exposure estimation and prediction

    Science.gov (United States)

    Göhler, Daniel; Gritzki, Ralf; Stintz, Michael; Rösler, Markus; Felsmann, Clemens

    2017-06-01

    The gap between release and exposure is limiting the current risk assessment of nanostructured materials. Both, release and exposure were connected to each other by transport and transformation processes and require therefore the description/specification of complex exposure scenarios. Within this study, propagation modelling based on experimentally determined airborne particle release data was used for exposure estimation and prediction in a defined model room. Therefore, 9 different exposure scenarios based on 3 release scenarios and 3 ventilation scenarios were analysed. Results for near field considerations have shown that the level of inhalation exposure is fundamentally defined by the present exposure scenario, that personal heat can cause particle availability in the breathing zone and that highest exposure levels arise immediate during material processing.

  19. Overview of EPA CSS Intramural Research on Life Cycle and Human Exposure Modeling

    Science.gov (United States)

    Improved human exposure modeling in life cycle assessmentsModeling and assessment for chemicals/products with less extensive dataMore rapid and higher throughput assessmentsLife Cycle-Human Exposure Modeling (LC-HEM) tool usable by Offices/Regions and by external stakeholders

  20. Bivariate Left-Censored Bayesian Model for Predicting Exposure: Preliminary Analysis of Worker Exposure during the Deepwater Horizon Oil Spill.

    Science.gov (United States)

    Groth, Caroline; Banerjee, Sudipto; Ramachandran, Gurumurthy; Stenzel, Mark R; Sandler, Dale P; Blair, Aaron; Engel, Lawrence S; Kwok, Richard K; Stewart, Patricia A

    2017-01-01

    In April 2010, the Deepwater Horizon oil rig caught fire and exploded, releasing almost 5 million barrels of oil into the Gulf of Mexico over the ensuing 3 months. Thousands of oil spill workers participated in the spill response and clean-up efforts. The GuLF STUDY being conducted by the National Institute of Environmental Health Sciences is an epidemiological study to investigate potential adverse health effects among these oil spill clean-up workers. Many volatile chemicals were released from the oil into the air, including total hydrocarbons (THC), which is a composite of the volatile components of oil including benzene, toluene, ethylbenzene, xylene, and hexane (BTEXH). Our goal is to estimate exposure levels to these toxic chemicals for groups of oil spill workers in the study (hereafter called exposure groups, EGs) with likely comparable exposure distributions. A large number of air measurements were collected, but many EGs are characterized by datasets with a large percentage of censored measurements (below the analytic methods' limits of detection) and/or a limited number of measurements. We use THC for which there was less censoring to develop predictive linear models for specific BTEXH air exposures with higher degrees of censoring. We present a novel Bayesian hierarchical linear model that allows us to predict, for different EGs simultaneously, exposure levels of a second chemical while accounting for censoring in both THC and the chemical of interest. We illustrate the methodology by estimating exposure levels for several EGs on the Development Driller III, a rig vessel charged with drilling one of the relief wells. The model provided credible estimates in this example for geometric means, arithmetic means, variances, correlations, and regression coefficients for each group. This approach should be considered when estimating exposures in situations when multiple chemicals are correlated and have varying degrees of censoring. © The Author 2017

  1. Inferring predominant pathways in cellular models of breast cancer using limited sample proteomic profiling

    Directory of Open Access Journals (Sweden)

    Klinke David J

    2010-06-01

    Full Text Available Abstract Background Molecularly targeted drugs inhibit aberrant signaling within oncogenic pathways. Identifying the predominant pathways at work within a tumor is a key step towards tailoring therapies to the patient. Clinical samples pose significant challenges for proteomic profiling, an attractive approach for identifying predominant pathways. The objective of this study was to determine if information obtained from a limited sample (i.e., a single gel replicate can provide insight into the predominant pathways in two well-characterized breast cancer models. Methods A comparative proteomic analysis of total cell lysates was obtained from two cellular models of breast cancer, BT474 (HER2+/ER+ and SKBR3 (HER2+/ER-, using two-dimensional electrophoresis and MALDI-TOF mass spectrometry. Protein interaction networks and canonical pathways were extracted from the Ingenuity Pathway Knowledgebase (IPK based on association with the observed pattern of differentially expressed proteins. Results Of the 304 spots that were picked, 167 protein spots were identified. A threshold of 1.5-fold was used to select 62 proteins used in the analysis. IPK analysis suggested that metabolic pathways were highly associated with protein expression in SKBR3 cells while cell motility pathways were highly associated with BT474 cells. Inferred protein networks were confirmed by observing an up-regulation of IGF-1R and profilin in BT474 and up-regulation of Ras and enolase in SKBR3 using western blot. Conclusion When interpreted in the context of prior information, our results suggest that the overall patterns of differential protein expression obtained from limited samples can still aid in clinical decision making by providing an estimate of the predominant pathways that underpin cellular phenotype.

  2. Static analysis of a Model of the LDL degradation pathway

    DEFF Research Database (Denmark)

    Pilegaard, Henrik; Nielson, Flemming; Nielson, Hanne Riis

    2005-01-01

    BioAmbients is a derivative of mobile ambients that has shown promise of describing interesting features of the behaviour of biological systems. As for other ambient calculi static program analysis can be used to compute safe approximations of the behavior of modelled systems. We use these tools ...

  3. Transcriptional Modulation of the ERK1/2 MAPK and NF-kB pathways in Human Urothelial cells after trivalent arsenical exposure: Implications for urinary bladder cancer

    Science.gov (United States)

    Chronic exposure to drinking water contaminated with inorganic arsenic (iAs) is associated with an increased risk ofurinary bladder (DB) cancers in humans. Rodent models administered particular arsenicals have indicated urothelial necrosis followed by regenerative proliferation i...

  4. Modelling the interplay between childhood and adult adversity in pathways to psychosis: initial evidence from the AESOP study.

    Science.gov (United States)

    Morgan, C; Reininghaus, U; Fearon, P; Hutchinson, G; Morgan, K; Dazzan, P; Boydell, J; Kirkbride, J B; Doody, G A; Jones, P B; Murray, R M; Craig, T

    2014-01-01

    There is evidence that a range of socio-environmental exposures is associated with an increased risk of psychosis. However, despite the fact that such factors probably combine in complex ways to increase risk, the majority of studies have tended to consider each exposure separately. In light of this, we sought to extend previous analyses of data from the AESOP (Aetiology and Ethnicity in Schizophrenia and Other Psychoses) study on childhood and adult markers of disadvantage to examine how they combine to increase risk of psychosis, testing both mediation (path) models and synergistic effects. All patients with a first episode of psychosis who made contact with psychiatric services in defined catchment areas in London and Nottingham, UK (n = 390) and a series of community controls (n = 391) were included in the AESOP study. Data relating to clinical and social variables, including parental separation and loss, education and adult disadvantage, were collected from cases and controls. There was evidence that the effect of separation from, but not death of, a parent in childhood on risk of psychosis was partially mediated through subsequent poor educational attainment (no qualifications), adult social disadvantage and, to a lesser degree, low self-esteem. In addition, there was strong evidence that separation from, but not death of, a parent combined synergistically with subsequent disadvantage to increase risk. These effects held for all ethnic groups in the sample. Exposure to childhood and adult disadvantage may combine in complex ways to push some individuals along a predominantly sociodevelopmental pathway to psychosis.

  5. Computational modelling of cancerous mutations in the EGFR/ERK signalling pathway

    Directory of Open Access Journals (Sweden)

    Gormand Amelie

    2009-10-01

    Full Text Available Abstract Background The Epidermal Growth Factor Receptor (EGFR activated Extracellular-signal Regulated Kinase (ERK pathway is a critical cell signalling pathway that relays the signal for a cell to proliferate from the plasma membrane to the nucleus. Deregulation of the EGFR/ERK pathway due to alterations affecting the expression or function of a number of pathway components has long been associated with numerous forms of cancer. Under normal conditions, Epidermal Growth Factor (EGF stimulates a rapid but transient activation of ERK as the signal is rapidly shutdown. Whereas, under cancerous mutation conditions the ERK signal cannot be shutdown and is sustained resulting in the constitutive activation of ERK and continual cell proliferation. In this study, we have used computational modelling techniques to investigate what effects various cancerous alterations have on the signalling flow through the ERK pathway. Results We have generated a new model of the EGFR activated ERK pathway, which was verified by our own experimental data. We then altered our model to represent various cancerous situations such as Ras, B-Raf and EGFR mutations, as well as EGFR overexpression. Analysis of the models showed that different cancerous situations resulted in different signalling patterns through the ERK pathway, especially when compared to the normal EGF signal pattern. Our model predicts that cancerous EGFR mutation and overexpression signals almost exclusively via the Rap1 pathway, predicting that this pathway is the best target for drugs. Furthermore, our model also highlights the importance of receptor degradation in normal and cancerous EGFR signalling, and suggests that receptor degradation is a key difference between the signalling from the EGF and Nerve Growth Factor (NGF receptors. Conclusion Our results suggest that different routes to ERK activation are being utilised in different cancerous situations which therefore has interesting implications

  6. IntPath--an integrated pathway gene relationship database for model organisms and important pathogens.

    Science.gov (United States)

    Zhou, Hufeng; Jin, Jingjing; Zhang, Haojun; Yi, Bo; Wozniak, Michal; Wong, Limsoon

    2012-01-01

    Pathway data are important for understanding the relationship between genes, proteins and many other molecules in living organisms. Pathway gene relationships are crucial information for guidance, prediction, reference and assessment in biochemistry, computational biology, and medicine. Many well-established databases--e.g., KEGG, WikiPathways, and BioCyc--are dedicated to collecting pathway data for public access. However, the effectiveness of these databases is hindered by issues such as incompatible data formats, inconsistent molecular representations, inconsistent molecular relationship representations, inconsistent referrals to pathway names, and incomprehensive data from different databases. In this paper, we overcome these issues through extraction, normalization and integration of pathway data from several major public databases (KEGG, WikiPathways, BioCyc, etc). We build a database that not only hosts our integrated pathway gene relationship data for public access but also maintains the necessary updates in the long run. This public repository is named IntPath (Integrated Pathway gene relationship database for model organisms and important pathogens). Four organisms--S. cerevisiae, M. tuberculosis H37Rv, H. Sapiens and M. musculus--are included in this version (V2.0) of IntPath. IntPath uses the "full unification" approach to ensure no deletion and no introduced noise in this process. Therefore, IntPath contains much richer pathway-gene and pathway-gene pair relationships and much larger number of non-redundant genes and gene pairs than any of the single-source databases. The gene relationships of each gene (measured by average node degree) per pathway are significantly richer. The gene relationships in each pathway (measured by average number of gene pairs per pathway) are also considerably richer in the integrated pathways. Moderate manual curation are involved to get rid of errors and noises from source data (e.g., the gene ID errors in WikiPathways and

  7. Determination of Highly Sensitive Biological Cell Model Systems to Screen BPA-Related Health Hazards Using Pathway Studio.

    Science.gov (United States)

    Ryu, Do-Yeal; Rahman, Md Saidur; Pang, Myung-Geol

    2017-09-06

    Bisphenol-A (BPA) is a ubiquitous endocrine-disrupting chemical. Recently, many issues have arisen surrounding the disease pathogenesis of BPA. Therefore, several studies have been conducted to investigate the proteomic biomarkers of BPA that are associated with disease processes. However, studies on identifying highly sensitive biological cell model systems in determining BPA health risk are lacking. Here, we determined suitable cell model systems and potential biomarkers for predicting BPA-mediated disease using the bioinformatics tool Pathway Studio. We compiled known BPA-mediated diseases in humans, which were categorized into five major types. Subsequently, we investigated the differentially expressed proteins following BPA exposure in several cell types, and analyzed the efficacy of altered proteins to investigate their associations with BPA-mediated diseases. Our results demonstrated that colon cancer cells (SW480), mammary gland, and Sertoli cells were highly sensitive biological model systems, because of the efficacy of predicting the majority of BPA-mediated diseases. We selected glucose-6-phosphate dehydrogenase (G6PD), cytochrome b-c1 complex subunit 1 (UQCRC1), and voltage-dependent anion-selective channel protein 2 (VDAC2) as highly sensitive biomarkers to predict BPA-mediated diseases. Furthermore, we summarized proteomic studies in spermatozoa following BPA exposure, which have recently been considered as another suitable cell type for predicting BPA-mediated diseases.

  8. Air Pollution Exposure Modeling for Epidemiology Studies and Public Health

    Science.gov (United States)

    Air pollution epidemiology studies of ambient fine particulate matter (PM2.5) often use outdoor concentrations as exposure surrogates. These surrogates can induce exposure error since they do not account for (1) time spent indoors with ambient PM2.5 levels attenuated from outdoor...

  9. Economic modelling of diagnostic and treatment pathways in National Institute for Health and Care Excellence clinical guidelines: the Modelling Algorithm Pathways in Guidelines (MAPGuide) project.

    Science.gov (United States)

    Lord, J; Willis, S; Eatock, J; Tappenden, P; Trapero-Bertran, M; Miners, A; Crossan, C; Westby, M; Anagnostou, A; Taylor, S; Mavranezouli, I; Wonderling, D; Alderson, P; Ruiz, F

    2013-12-01

    National Institute for Health and Care Excellence (NICE) clinical guidelines (CGs) make recommendations across large, complex care pathways for broad groups of patients. They rely on cost-effectiveness evidence from the literature and from new analyses for selected high-priority topics. An alternative approach would be to build a model of the full care pathway and to use this as a platform to evaluate the cost-effectiveness of multiple topics across the guideline recommendations. In this project we aimed to test the feasibility of building full guideline models for NICE guidelines and to assess if, and how, such models can be used as a basis for cost-effectiveness analysis (CEA). A 'best evidence' approach was used to inform the model parameters. Data were drawn from the guideline documentation, advice from clinical experts and rapid literature reviews on selected topics. Where possible we relied on good-quality, recent UK systematic reviews and meta-analyses. Two published NICE guidelines were used as case studies: prostate cancer and atrial fibrillation (AF). Discrete event simulation (DES) was used to model the recommended care pathways and to estimate consequent costs and outcomes. For each guideline, researchers not involved in model development collated a shortlist of topics suggested for updating. The modelling teams then attempted to evaluate options related to these topics. Cost-effectiveness results were compared with opinions about the importance of the topics elicited in a survey of stakeholders. The modelling teams developed simulations of the guideline pathways and disease processes. Development took longer and required more analytical time than anticipated. Estimates of cost-effectiveness were produced for six of the nine prostate cancer topics considered, and for five of eight AF topics. The other topics were not evaluated owing to lack of data or time constraints. The modelled results suggested 'economic priorities' for an update that differed from

  10. PAH exposure through soil ingestion: Combining digestion models and bioassays

    Energy Technology Data Exchange (ETDEWEB)

    Wiele, T.R. van de; Verstraete, W. [Ghent University (BE).Laboratory Microbial Ecology and Technology (LabMET); Siciliano, S.D. [University of Saskatchewan (Canada). Department of Soil Science

    2003-07-01

    Exposure to environmental contaminants through soil ingestion is an important issue in current health risk assessment. Polycyclic aromatic hydrocarbons (PAH) or their metabolites pose risks to humans due to their toxic, mutagenic, carcinogenic or even (anti)estrogenic properties. PAH mobilization from a soil matrix (49.1{+-}1.5 mg PAH/kg DW) was assessed using a Simulator of the Human Intestinal Microbial Ecosystem (SHIME). PAH GC-MS analysis was performed on the pellet and supernatant of SHIME digests and gave 101, 92, 89 and 97% recovery for water, stomach, duodenal and colon digests, respectively. PAH release was highest for the water extract (0.51%) and the stomach digestion (0.44%). Lower mobilized fractions in the duodenum (0.13%) and colon (0.30%) digests could be attributed to PAH complexation with bile salts, dissolved organic matter or colon microbiota. The digestion model provides us with relevant information to what extent soil bound PAHs are mobilized in the gastrointestinal tract and thus reach the gut wall, prior to absorption. (orig.)

  11. Innovation and entrepreneurship as pathways for new teaching / learning models

    Directory of Open Access Journals (Sweden)

    Helen Kelle dos Santos Costa

    2017-10-01

    Full Text Available Introduction: Modern times demand from society a new attitude, new attitudes, a new way of thinking and seeing the world. It is thus necessary that Education, the foundation for building a society, once again reinvents, innovates and adapts the demands that the process of human development requires. Objective: To emphasize the importance of Innovation and Entrepreneurship as tools for the development of new models of teaching / learning so that there is an education that meets the new social demands. Methodology: The article was structured from a Bibliographic research on theories and models of teaching / learning through an analytical reading, able to identify the characteristics for the effective realization of entrepreneurship in education in an innovative way. Results: The models of education are in constant process of evolution, the adoption of good practices and new resources that can help in teachinglearning as motivating agent of entrepreneurship in education through innovation is a reality to be reviewed by society as a whole. Conclusions: This study is expected to be an important tool for behavioral and / or economic change, with the aim of making the results successful for all parties involved in the attempt to corroborate with the entrepreneurship ecosystem through continuous and increasing multiplication of knowledge.

  12. NEMix: single-cell nested effects models for probabilistic pathway stimulation.

    Directory of Open Access Journals (Sweden)

    Juliane Siebourg-Polster

    2015-04-01

    Full Text Available Nested effects models have been used successfully for learning subcellular networks from high-dimensional perturbation effects that result from RNA interference (RNAi experiments. Here, we further develop the basic nested effects model using high-content single-cell imaging data from RNAi screens of cultured cells infected with human rhinovirus. RNAi screens with single-cell readouts are becoming increasingly common, and they often reveal high cell-to-cell variation. As a consequence of this cellular heterogeneity, knock-downs result in variable effects among cells and lead to weak average phenotypes on the cell population level. To address this confounding factor in network inference, we explicitly model the stimulation status of a signaling pathway in individual cells. We extend the framework of nested effects models to probabilistic combinatorial knock-downs and propose NEMix, a nested effects mixture model that accounts for unobserved pathway activation. We analyzed the identifiability of NEMix and developed a parameter inference scheme based on the Expectation Maximization algorithm. In an extensive simulation study, we show that NEMix improves learning of pathway structures over classical NEMs significantly in the presence of hidden pathway stimulation. We applied our model to single-cell imaging data from RNAi screens monitoring human rhinovirus infection, where limited infection efficiency of the assay results in uncertain pathway stimulation. Using a subset of genes with known interactions, we show that the inferred NEMix network has high accuracy and outperforms the classical nested effects model without hidden pathway activity. NEMix is implemented as part of the R/Bioconductor package 'nem' and available at www.cbg.ethz.ch/software/NEMix.

  13. An integrated model for assessing heavy metal exposure risk to migratory birds in wetland ecosystem: A case study in Dongting Lake Wetland, China.

    Science.gov (United States)

    Liu, Jiayu; Liang, Jie; Yuan, Xingzhong; Zeng, Guangming; Yuan, Yujie; Wu, Haipeng; Huang, Xiaolong; Liu, Junfeng; Hua, Shanshan; Li, Fei; Li, Xiaodong

    2015-09-01

    Heavy metal contamination is present in wetland ecosystem worldwide, and quantitative risk assessment model is significant. In this study, an exposure model was integrated for assessing heavy metal exposure risk to migratory birds in Dongting Lake Wetland (DTW). The concentrations of Cr, Cu, Pb, Cd, Hg and As in water, plant, soil and fish were investigated from 9 migratory bird habitats. The results showed that exposure doses from drinking water pathways were very low. There was a sensitive area that Cd and As exposure doses exceeded the most conservative tolerable daily intake, which is located at the estuary of Xiang River. In general, Dunlin had a greater risk than Eurasian Spoonbill. Hg, Pb and Cr were likely to have adverse effect on carnivorous migrants in DTW, while Cu and Cd were considered to be relatively safe. Almost all heavy metals were at no risk for Lesser White-fronted Goose in DTW. Copyright © 2015 Elsevier Ltd. All rights reserved.

  14. In utero exposure to a maternal high-fat diet alters the epigenetic histone code in a murine model.

    Science.gov (United States)

    Suter, Melissa A; Ma, Jun; Vuguin, Patricia M; Hartil, Kirsten; Fiallo, Ariana; Harris, R Alan; Charron, Maureen J; Aagaard, Kjersti M

    2014-05-01

    Data from animal models show that in utero exposure to a maternal high-fat diet (HFD) renders susceptibility of these offspring to the adult onset of metabolic syndrome. We and others have previously shown that epigenetic modifications to histones may serve as a molecular memory of the in utero exposure, rendering the risk of adult disease. Because mice heterozygous for the Glut4 gene (insulin sensitive glucose transporter) born to wild-type (WT) mothers demonstrate exacterbated metabolic syndrome when exposed to an HFD in utero, we sought to analyze the genome-wide epigenetic changes that occur in the fetal liver in susceptible offspring. WT and Glut4(+/-) (G4(+/-)) offspring of WT mothers that were exposed either to a control or an HFD in utero were studied. Immunoblotting was used to measure hepatic histone modifications of fetal and 5-week animals. Chromatin immunoprecipitation (ChIP) followed by hybridization to chip arrays (ChIP-on-chip) was used to detect genome-wide changes of histone modifications with HFD exposure. We found that levels of hepatic H3K14ac and H3K9me3 significantly increased with HFD exposure in WT and G4(+/-) fetal and 5-week offspring. Pathway analysis of our ChIP-on-chip data revealed differential H3K14ac and H3K9me3 enrichment along pathways that regulate lipid metabolism, specifically in the promoter regions of Pparg, Ppara, Rxra, and Rora. We conclude that HFD exposure in utero is associated with functional alterations to fetal hepatic histone modifications in both WT and G4(+/-) offspring, some of which persist up to 5 weeks of age. Copyright © 2014 Mosby, Inc. All rights reserved.

  15. Anaerobic model for high-solids or high-temperature digestion - additional pathway of acetate oxidation.

    Science.gov (United States)

    Wett, B; Takács, I; Batstone, D; Wilson, C; Murthy, S

    2014-01-01

    Current anaerobic digestion models cannot properly simulate processes that are operated under high solids concentrations or high temperatures. A modification to existing models has been implemented by adding important missing degradation pathways, to accommodate these systems without artificially recalibrating the model parameters. Specifically, we implemented the alternate acetate oxidizing mechanism that is more tolerant to ammonia than the standard aceticlastic pathway. Inhibition values were estimated and an empirical function has been used to apply ammonia inhibition. The model also relates metabolic activity to un-ionised species such as undissociated acetic acid as substrate (although not obligatory for all organisms) and unionised ammonia as inhibitor. The model relies on an equilibrium chemistry module (e.g. including the phosphate buffer), resulting in more accurate pH predictions, which is crucial for proper modeling of CO2 and NH3 stripping. Calibration results from three case-studies modeling thermal hydrolysis and subsequent digestion of sludge are presented.

  16. Evaluating indoor exposure modeling alternatives for LCA: A case study in the vehicle repair industry

    Energy Technology Data Exchange (ETDEWEB)

    Demou, Evangelia; Hellweg, Stefanie; Wilson, Michael P.; Hammond, S. Katharine; McKone, Thomas E.

    2009-05-01

    We evaluated three exposure models with data obtained from measurements among workers who use"aerosol" solvent products in the vehicle repair industry and with field experiments using these products to simulate the same exposure conditions. The three exposure models were the: 1) homogeneously-mixed-one-box model, 2) multi-zone model, and 3) eddy-diffusion model. Temporally differentiated real-time breathing zone volatile organic compound (VOC) concentration measurements, integrated far-field area samples, and simulated experiments were used in estimating parameters, such as emission rates, diffusivity, and near-field dimensions. We assessed differences in model input requirements and their efficacy for predictive modeling. The One-box model was not able to resemble the temporal profile of exposure concentrations, but it performed well concerning time-weighted exposure over extended time periods. However, this model required an adjustment for spatial concentration gradients. Multi-zone models and diffusion-models may solve this problem. However, we found that the reliable use of both these models requires extensive field data to appropriately define pivotal parameters such as diffusivity or near-field dimensions. We conclude that it is difficult to apply these models for predicting VOC exposures in the workplace. However, for comparative exposure scenarios in life-cycle assessment they may be useful.

  17. Identification of Potential Drug Targets in Cancer Signaling Pathways using Stochastic Logical Models.

    Science.gov (United States)

    Zhu, Peican; Aliabadi, Hamidreza Montazeri; Uludağ, Hasan; Han, Jie

    2016-03-18

    The investigation of vulnerable components in a signaling pathway can contribute to development of drug therapy addressing aberrations in that pathway. Here, an original signaling pathway is derived from the published literature on breast cancer models. New stochastic logical models are then developed to analyze the vulnerability of the components in multiple signalling sub-pathways involved in this signaling cascade. The computational results are consistent with the experimental results, where the selected proteins were silenced using specific siRNAs and the viability of the cells were analyzed 72 hours after silencing. The genes elF4E and NFkB are found to have nearly no effect on the relative cell viability and the genes JAK2, Stat3, S6K, JUN, FOS, Myc, and Mcl1 are effective candidates to influence the relative cell growth. The vulnerabilities of some targets such as Myc and S6K are found to vary significantly depending on the weights of the sub-pathways; this will be indicative of the chosen target to require customization for therapy. When these targets are utilized, the response of breast cancers from different patients will be highly variable because of the known heterogeneities in signaling pathways among the patients. The targets whose vulnerabilities are invariably high might be more universally acceptable targets.

  18. VISIBIOweb: visualization and layout services for BioPAX pathway models

    Science.gov (United States)

    Dilek, Alptug; Belviranli, Mehmet E.; Dogrusoz, Ugur

    2010-01-01

    With recent advancements in techniques for cellular data acquisition, information on cellular processes has been increasing at a dramatic rate. Visualization is critical to analyzing and interpreting complex information; representing cellular processes or pathways is no exception. VISIBIOweb is a free, open-source, web-based pathway visualization and layout service for pathway models in BioPAX format. With VISIBIOweb, one can obtain well-laid-out views of pathway models using the standard notation of the Systems Biology Graphical Notation (SBGN), and can embed such views within one's web pages as desired. Pathway views may be navigated using zoom and scroll tools; pathway object properties, including any external database references available in the data, may be inspected interactively. The automatic layout component of VISIBIOweb may also be accessed programmatically from other tools using Hypertext Transfer Protocol (HTTP). The web site is free and open to all users and there is no login requirement. It is available at: http://visibioweb.patika.org. PMID:20460470

  19. Modeling of miRNA and drug action in the EGFR signaling pathway.

    Directory of Open Access Journals (Sweden)

    Jian Li

    Full Text Available MicroRNAs have gained significant interest due to their widespread occurrence and diverse functions as regulatory molecules, which are essential for cell division, growth, development and apoptosis in eukaryotes. The epidermal growth factor receptor (EGFR signaling pathway is one of the best investigated cellular signaling pathways regulating important cellular processes and its deregulation is associated with severe diseases, such as cancer. In this study, we introduce a systems biological model of the EGFR signaling pathway integrating validated miRNA-target information according to diverse studies, in order to demonstrate essential roles of miRNA within this pathway. The model consists of 1241 reactions and contains 241 miRNAs. We analyze the impact of 100 specific miRNA inhibitors (anit-miRNAs on this pathway and propose that the embedded miRNA-network can help to identify new drug targets of the EGFR signaling pathway and thereby support the development of new therapeutic strategies against cancer.

  20. A pedagogical walkthrough of computational modeling and simulation of Wnt signaling pathway using static causal models in MATLAB

    OpenAIRE

    Sinha, Shriprakash

    2016-01-01

    Simulation study in systems biology involving computational experiments dealing with Wnt signaling pathways abound in literature but often lack a pedagogical perspective that might ease the understanding of beginner students and researchers in transition, who intend to work on the modeling of the pathway. This paucity might happen due to restrictive business policies which enforce an unwanted embargo on the sharing of important scientific knowledge. A tutorial introduction to computational mo...

  1. Extinction pathways and outbreak vulnerability in a stochastic Ebola model.

    Science.gov (United States)

    Nieddu, Garrett T; Billings, Lora; Kaufman, James H; Forgoston, Eric; Bianco, Simone

    2017-02-01

    A zoonotic disease is a disease that can be passed from animals to humans. Zoonotic viruses may adapt to a human host eventually becoming endemic in humans, but before doing so punctuated outbreaks of the zoonotic virus may be observed. The Ebola virus disease (EVD) is an example of such a disease. The animal population in which the disease agent is able to reproduce in sufficient number to be able to transmit to a susceptible human host is called a reservoir. There is little work devoted to understanding stochastic population dynamics in the presence of a reservoir, specifically the phenomena of disease extinction and reintroduction. Here, we build a stochastic EVD model and explicitly consider the impacts of an animal reservoir on the disease persistence. Our modelling approach enables the analysis of invasion and fade-out dynamics, including the efficacy of possible intervention strategies. We investigate outbreak vulnerability and the probability of local extinction and quantify the effective basic reproduction number. We also consider the effects of dynamic population size. Our results provide an improved understanding of outbreak and extinction dynamics in zoonotic diseases, such as EVD. © 2017 The Author(s).

  2. Python framework for kinetic modeling of electronically excited reaction pathways

    Science.gov (United States)

    Verboncoeur, John; Parsey, Guy; Guclu, Yaman; Christlieb, Andrew

    2012-10-01

    The use of plasma energy to enhance and control the chemical reactions during combustion, a technology referred to as ``plasma assisted combustion'' (PAC), can result in a variety of beneficial effects: e.g. stable lean operation, pollution reduction, and wider range of p-T operating conditions. While experimental evidence abounds, theoretical understanding of PAC is at best incomplete, and numerical tools still lack in reliable predictive capabilities. In the context of a joint experimental-numerical effort at Michigan State University, we present here an open-source modular Python framework dedicated to the dynamic optimization of non-equilibrium PAC systems. Multiple sources of experimental reaction data, e.g. reaction rates, cross-sections and oscillator strengths, are used in order to quantify the effect of data uncertainty and limiting assumptions. A collisional-radiative model (CRM) is implemented to organize reactions by importance and as a potential means of measuring a non-Maxwellian electron energy distribution function (EEDF), when coupled to optical emission spectroscopy data. Finally, we explore scaling laws in PAC parameter space using a kinetic global model (KGM) accelerated with CRM optimized reaction sequences and sparse stiff integrators.

  3. His electrogram alternans (Zhang's phenomenon) and a new model of dual pathway atrioventricular node conduction.

    Science.gov (United States)

    Zhang, Youhua

    2016-01-01

    In contrast to the current textbook model and the current clinical index of dual pathway atrioventricular (AV) nodal conduction, here we summarize the discovery and validation of Zhang's phenomenon (originally His electrogram alternans) as a new index of dual pathway conduction. We also describe the new findings of transverse-versus-longitudinal electrical propagation within the AV node as the electrophysiological basis underlining this new index. Thus, a new index and a new model of dual pathway AV conduction are being developed. We have reviewed current literature and provided evidence supporting a new index and a new model of dual pathway AV conduction. Recent data revealed that during fast pathway conduction, electrical excitation in the AV node propagates in a superior to inferior direction across AV conduction axis and fiber orientation to reach first the superior His bundle fibers. However, this transverse conduction can fail easily within the superior nodal domain at fast rates. The failing of transverse propagation permits electrical excitation formed at the posterior/inferior nodal region to propagate longitudinally along fiber orientation in a posterior to anterior direction through the inferior nodal domain to reach the inferior His bundle (slow pathway conduction). This transverse-versus-longitudinal electrical propagation within the AV node results in a functional dissociation in the distal node and formation of dual inputs into the His bundle, providing the electrophysiological basis for the formation of Zhang's phenomenon (His electrogram alternans). Based on strong experimental data, a new index and a new model of dual pathway AV nodal conduction are emerging, although they are still awaiting clinical validation.

  4. A Geographic Approach to Modelling Human Exposure to Traffic Air Pollution using GIS

    DEFF Research Database (Denmark)

    Jensen, S. S.

    , to automatically generate street configuration data based on digital maps, the BBR and GIS; to predict the temporal variation in traffic and related parameters; and to provide hourly background levels for the OSPM model. The potentials for application of the exposure model have been discussed within air pollution......A new exposure model has been developed that is based on a physical, single media (air) and single source (traffic) microenvironmental approach that estimates traffic related exposures geographically with the postal address as exposure indicator. The microenvironments: residence, workplace...... at the address all the time, and an exposure estimate is also defined that takes into account the time the person spends at the address assuming standardised time-profiles depending on age groups. The exposure model takes advantage of a standard Geographic Information System (GIS) (ArcView and Avenue...

  5. A Longitudinal Empirical Investigation of the Pathways Model of Problem Gambling.

    Science.gov (United States)

    Allami, Youssef; Vitaro, Frank; Brendgen, Mara; Carbonneau, René; Lacourse, Éric; Tremblay, Richard E

    2017-12-01

    The pathways model of problem gambling suggests the existence of three developmental pathways to problem gambling, each differentiated by a set of predisposing biopsychosocial characteristics: behaviorally conditioned (BC), emotionally vulnerable (EV), and biologically vulnerable (BV) gamblers. This study examined the empirical validity of the Pathways Model among adolescents followed up to early adulthood. A prospective-longitudinal design was used, thus overcoming limitations of past studies that used concurrent or retrospective designs. Two samples were used: (1) a population sample of French-speaking adolescents (N = 1033) living in low socio-economic status (SES) neighborhoods from the Greater Region of Montreal (Quebec, Canada), and (2) a population sample of adolescents (N = 3017), representative of French-speaking students in Quebec. Only participants with at-risk or problem gambling by mid-adolescence or early adulthood were included in the main analysis (n = 180). Latent Profile Analyses were conducted to identify the optimal number of profiles, in accordance with participants' scores on a set of variables prescribed by the Pathways Model and measured during early adolescence: depression, anxiety, impulsivity, hyperactivity, antisocial/aggressive behavior, and drug problems. A four-profile model fit the data best. Three profiles differed from each other in ways consistent with the Pathways Model (i.e., BC, EV, and BV gamblers). A fourth profile emerged, resembling a combination of EV and BV gamblers. Four profiles of at-risk and problem gamblers were identified. Three of these profiles closely resemble those suggested by the Pathways Model.

  6. Effect of Mitochondrial Oxidative Stress and Age on the Signaling Pathway of Ultrafine Particulate Matter Exposure in Murine Aorta

    Science.gov (United States)

    Epidemiological studies have linked ultrafine particulate matter (PM) exposure and adverse cardiovascular events. PM-induced oxidative stress is believed to be a key mechanism contributing to the adverse short-term vascular effects of air pollution exposure. Advanced age is one ...

  7. Refinement of the tripartite influence model for men: dual body image pathways to body change behaviors.

    Science.gov (United States)

    Tylka, Tracy L

    2011-06-01

    Although muscularity and body fat concerns are central to conceptualizing men's body image, they have not been examined together within existing structural models. This study refined the tripartite influence model (Thompson, Heinberg, Altabe, & Tantleff-Dunn, 1999) by including dual body image pathways (muscularity and body fat dissatisfaction) to engagement in muscular enhancement and disordered eating behaviors, respectively, and added dating partners as a source of social influence. Latent variable structural equation modeling analyses supported this quadripartite model in 473 undergraduate men. Nonsignificant paths were trimmed and two unanticipated paths were added. Muscularity dissatisfaction and body fat dissatisfaction represented dual body image pathways to men's engagement in muscularity enhancement behaviors and disordered eating behaviors, respectively. Pressures to be mesomorphic from friends, family, media, and dating partners made unique contributions to the model. Internalization of the mesomorphic ideal, muscularity dissatisfaction, and body fat dissatisfaction played key meditational roles within the model. Copyright © 2011 Elsevier Ltd. All rights reserved.

  8. Modeling Diverse Pathways to Age Progressive Volcanism in Subduction Zones.

    Science.gov (United States)

    Kincaid, C. R.; Szwaja, S.; Sylvia, R. T.; Druken, K. A.

    2015-12-01

    One of the best, and most challenging clues to unraveling mantle circulation patterns in subduction zones comes in the form of age progressive volcanic and geochemical trends. Hard fought geological data from many subduction zones, like Tonga-Lau, the Cascades and Costa-Rica/Nicaragua, reveal striking temporal patterns used in defining mantle flow directions and rates. We summarize results from laboratory subduction models showing a range in circulation and thermal-chemical transport processes. These interaction styles are capable of producing such trends, often reflecting apparent instead of actual mantle velocities. Lab experiments use a glucose working fluid to represent Earth's upper mantle and kinematically driven plates to produce a range in slab sinking and related wedge transport patterns. Kinematic forcing assumes most of the super-adiabatic temperature gradient available to drive major downwellings is in the tabular slabs. Moreover, sinking styles for fully dynamic subduction depend on many complicating factors that are only poorly understood and which can vary widely even for repeated parameter combinations. Kinematic models have the benefit of precise, repeatable control of slab motions and wedge flow responses. Results generated with these techniques show the evolution of near-surface thermal-chemical-rheological heterogeneities leads to age progressive surface expressions in a variety of ways. One set of experiments shows that rollback and back-arc extension combine to produce distinct modes of linear, age progressive melt delivery to the surface through a) erosion of the rheological boundary layer beneath the overriding plate, and deformation and redistribution of both b) mantle residuum produced from decompression melting and c) formerly active, buoyant plumes. Additional experiments consider buoyant diapirs rising in a wedge under the influence of rollback, back-arc spreading and slab-gaps. Strongly deflected diapirs, experiencing variable rise

  9. A Workflow to Investigate Exposure and Pharmacokinetic Influences on High-Throughput in Vitro Chemical Screening Based on Adverse Outcome Pathways.

    Science.gov (United States)

    Phillips, Martin B; Leonard, Jeremy A; Grulke, Christopher M; Chang, Daniel T; Edwards, Stephen W; Brooks, Raina; Goldsmith, Michael-Rock; El-Masri, Hisham; Tan, Yu-Mei

    2016-01-01

    Adverse outcome pathways (AOPs) link adverse effects in individuals or populations to a molecular initiating event (MIE) that can be quantified using in vitro methods. Practical application of AOPs in chemical-specific risk assessment requires incorporation of knowledge on exposure, along with absorption, distribution, metabolism, and excretion (ADME) properties of chemicals. We developed a conceptual workflow to examine exposure and ADME properties in relation to an MIE. The utility of this workflow was evaluated using a previously established AOP, acetylcholinesterase (AChE) inhibition. Thirty chemicals found to inhibit human AChE in the ToxCast™ assay were examined with respect to their exposure, absorption potential, and ability to cross the blood-brain barrier (BBB). Structures of active chemicals were compared against structures of 1,029 inactive chemicals to detect possible parent compounds that might have active metabolites. Application of the workflow screened 10 "low-priority" chemicals of 30 active chemicals. Fifty-two of the 1,029 inactive chemicals exhibited a similarity threshold of ≥ 75% with their nearest active neighbors. Of these 52 compounds, 30 were excluded due to poor absorption or distribution. The remaining 22 compounds may inhibit AChE in vivo either directly or as a result of metabolic activation. The incorporation of exposure and ADME properties into the conceptual workflow eliminated 10 "low-priority" chemicals that may otherwise have undergone additional, resource-consuming analyses. Our workflow also increased confidence in interpretation of in vitro results by identifying possible "false negatives." Phillips MB, Leonard JA, Grulke CM, Chang DT, Edwards SW, Brooks R, Goldsmith MR, El-Masri H, Tan YM. 2016. A workflow to investigate exposure and pharmacokinetic influences on high-throughput in vitro chemical screening based on adverse outcome pathways. Environ Health Perspect 124:53-60; http://dx.doi.org/10.1289/ehp.1409450.

  10. Neurotoxicity in Preclinical Models of Occupational Exposure to Organophosphorus Compounds

    OpenAIRE

    Voorhees, Jaymie R.; Rohlman, Diane S.; Lein, Pamela J.; Pieper, Andrew A.

    2017-01-01

    © 2017 Voorhees, Rohlman, Lein and Pieper. Organophosphorus (OPs) compounds are widely used as insecticides, plasticizers, and fuel additives. These compounds potently inhibit acetylcholinesterase (AChE), the enzyme that inactivates acetylcholine at neuronal synapses, and acute exposure to high OP levels can cause cholinergic crisis in humans and animals. Evidence further suggests that repeated exposure to lower OP levels insufficient to cause cholinergic crisis, frequently encountered in the...

  11. Modeling time-varying exposure using inverse probability of treatment weights

    NARCIS (Netherlands)

    Grafféo, Nathalie; Latouche, Aurélien; Geskus, Ronald B.; Chevret, Sylvie

    2017-01-01

    For estimating the causal effect of treatment exposure on the occurrence of adverse events, inverse probability weights (IPW) can be used in marginal structural models to correct for time-dependent confounding. The R package ipw allows IPW estimation by modeling the relationship between the exposure

  12. Groundwater Pathway Model for the Los Alamos National Laboratory Technical Area 21, Material Disposal Area T

    Energy Technology Data Exchange (ETDEWEB)

    Stauffer, Philip H. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Levitt, Daniel G. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Miller, Terry Ann [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Jordan, Amy [Neptune Inc, Los Alamos, NM (United States); Chu, Shaoping [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Dash, Zora [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-02-09

    This report consists of four major sections, including this introductory section. Section 2 provides an overview of previous investigations related to the development of the current sitescale model. The methods and data used to develop the 3-D groundwater model and the techniques used to distill that model into a form suitable for use in the GoldSim models are discussed in Section 3. Section 4 presents the results of the model development effort and discusses some of the uncertainties involved. Three attachments that provide details about the components and data used in this groundwater pathway model are also included with this report.

  13. Cross-interference of two model peroxisome proliferators in peroxisomal and estrogenic pathways in brown trout hepatocytes

    Energy Technology Data Exchange (ETDEWEB)

    Madureira, Tânia Vieira, E-mail: tvmadureira@icbas.up.pt [Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U. Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos (Portugal); Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U. Porto), Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto (Portugal); Pinheiro, Ivone; Malhão, Fernanda; Lopes, Célia [Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U. Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos (Portugal); Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto (U. Porto), Laboratory of Histology and Embryology, Department of Microscopy, Rua Jorge Viterbo Ferreira 228, P 4050-313 Porto (Portugal); Urbatzka, Ralph [Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U. Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos (Portugal); Castro, L. Filipe C. [Interdisciplinary Centre of Marine and Environmental Research (CIIMAR/CIMAR), University of Porto (U. Porto), Terminal de Cruzeiros do Porto de Leixões, Av. General Norton de Matos s/n, 4450-208 Matosinhos (Portugal); Faculty of Sciences (FCUP), University of Porto (U. Porto), Department of Biology, Rua do Campo Alegre, P 4169-007 Porto (Portugal); and others

    2017-06-15

    Highlights: • Brown trout hepatocytes seem to be a low responder to model peroxisome proliferators. • Most peroxisomal targets were not affected by Wy-14,643 and clofibrate exposures. • Some estrogenic-related genes were up-regulated after 150 μM of Wy-14,643. • Wy-14,643 increase VtgA and ERα mRNA levels, while ICI 182,780 revert the effect. • Cross-interference in peroxisomal and estrogenic pathways should be more explored. - Abstract: Peroxisome proliferators cause species-specific effects, which seem to be primarily transduced by peroxisome proliferator-activated receptor alpha (PPARα). Interestingly, PPARα has a close interrelationship with estrogenic signaling, and this latter has already been promptly activated in brown trout primary hepatocytes. Thus, and further exploring this model, we assess here the reactivity of two PPARα agonists in direct peroxisomal routes and, in parallel the cross-interferences in estrogen receptor (ER) mediated paths. To achieve these goals, three independent in vitro studies were performed using single exposures to clofibrate – CLF (50, 500 and 1000 μM), Wy-14,643 – Wy (50 and 150 μM), GW6471 – GW (1 and 10 μM), and mixtures, including PPARα agonist or antagonist plus an ER agonist or antagonist. Endpoints included gene expression analysis of peroxisome/lipidic related genes (encoding apolipoprotein AI – ApoAI, fatty acid binding protein 1 – Fabp1, catalase – Cat, 17 beta-hydroxysteroid dehydrogenase 4 – 17β-HSD4, peroxin 11 alpha – Pex11α, PPARαBb, PPARαBa and urate oxidase – Uox) and those encoding estrogenic targets (ERα, ERβ-1 and vitellogenin A – VtgA). A quantitative morphological approach by using a pre-validated catalase immunofluorescence technique allowed checking possible changes in peroxisomes. Our results show a low responsiveness of trout hepatocytes to model PPARα agonists in direct target receptor pathways. Additionally, we unveiled interferences in estrogenic

  14. Pathway Model of the Kinetics of the TGFbeta Antagonist Smad7 and Cross-Talk with the ATM and WNT Pathways

    Science.gov (United States)

    Carra, Claudio; Wang, Minli; Huff, Janice L.; Hada, Megumi; ONeill, Peter; Cucinotta, Francis A.

    2010-01-01

    Signal transduction controls cellular and tissue responses to radiation. Transforming growth factor beta (TGFbeta) is an important regulator of cell growth and differentiation and tissue homeostasis, and is often dis-regulated in tumor formation. Mathematical models of signal transduction pathways can be used to elucidate how signal transduction varies with radiation quality, and dose and dose-rate. Furthermore, modeling of tissue specific responses can be considered through mechanistic based modeling. We developed a mathematical model of the negative feedback regulation by Smad7 in TGFbeta-Smad signaling and are exploring possible connections to the WNT/beta -catenin, and ATM/ATF2 signaling pathways. A pathway model of TGFbeta-Smad signaling that includes Smad7 kinetics based on data in the scientific literature is described. Kinetic terms included are TGFbeta/Smad transcriptional regulation of Smad7 through the Smad3-Smad4 complex, Smad7-Smurf1 translocation from nucleus to cytoplasm, and Smad7 negative feedback regulation of the TGFO receptor through direct binding to the TGFO receptor complex. The negative feedback controls operating in this pathway suggests non-linear responses in signal transduction, which are described mathematically. We then explored possibilities for cross-talk mediated by Smad7 between DNA damage responses mediated by ATM, and with the WNT pathway and consider the design of experiments to test model driven hypothesis. Numerical comparisons of the mathematical model to experiments and representative predictions are described.

  15. Technical report of EFSA prepared by the Assessment Methodology Unit on Quantitative pathway analysis of the exposure of the wheat production area with Tilletia indica M. teliospores one year after importation of US wheat for grain into the EU and desert durum wheat into Italy. Appendix B, to the Scientific Opinion on a quantitative pathway analysis of the likelihood of Tilletia indica M. introduction into EU with importation of US wheat of EFSA Panel on Plant Health (PLH)

    DEFF Research Database (Denmark)

    Baker, R.; Candresse, T.; Dormannsné Simon, E.

    2010-01-01

    The EFSA Plant Health Unit asked the Assessment Methodology Unit to recalculate and update the Quantitative Pathway Analysis of the exposure of the EU wheat production area with Tilletia indica M. teliospores provided by USDA APHIS. Simulations were computed, for importations of US wheat into EU....... This technical report contains a full description of the calculations and results. The description and discussion of the scenario and model can be found in the Scientific Opinion on a quantitative pathway analysis of the likelihood of Tilletia indica M. introduction into EU with importation of US wheat of EFSA...

  16. A compartmental model of the cAMP/PKA/MAPK pathway in Bio-PEPA

    Directory of Open Access Journals (Sweden)

    Federica Ciocchetta

    2009-11-01

    Full Text Available The vast majority of biochemical systems involve the exchange of information between different compartments, either in the form of transportation or via the intervention of membrane proteins which are able to transmit stimuli between bordering compartments. The correct quantitative handling of compartments is, therefore, extremely important when modelling real biochemical systems. The Bio-PEPA process algebra is equipped with the capability of explicitly defining quantitative information such as compartment volumes and membrane surface areas. Furthermore, the recent development of the Bio-PEPA Eclipse Plug-in allows us to perform a correct stochastic simulation of multi-compartmental models. Here we present a Bio-PEPA compartmental model of the cAMP/PKA/MAPK pathway. We analyse the system using the Bio-PEPA Eclipse Plug-in and we show the correctness of our model by comparison with an existing ODE model. Furthermore, we perform computational experiments in order to investigate certain properties of the pathway. Specifically, we focus on the system response to the inhibition and strengthening of feedback loops and to the variation in the activity of key pathway reactions and we observe how these modifications affect the behaviour of the pathway. These experiments are useful to understand the control and regulatory mechanisms of the system.

  17. Modeling the Cumulative Effects of Social Exposures on Health: Moving beyond Disease-Specific Models

    Directory of Open Access Journals (Sweden)

    Heather L. White

    2013-03-01

    Full Text Available The traditional explanatory models used in epidemiology are “disease specific”, identifying risk factors for specific health conditions. Yet social exposures lead to a generalized, cumulative health impact which may not be specific to one illness. Disease-specific models may therefore misestimate social factors’ effects on health. Using data from the Canadian Community Health Survey and Canada 2001 Census we construct and compare “disease-specific” and “generalized health impact” (GHI models to gauge the negative health effects of one social exposure: socioeconomic position (SEP. We use logistic and multinomial multilevel modeling with neighbourhood-level material deprivation, individual-level education and household income to compare and contrast the two approaches. In disease-specific models, the social determinants under study were each associated with the health conditions of interest. However, larger effect sizes were apparent when outcomes were modeled as compound health problems (0, 1, 2, or 3+ conditions using the GHI approach. To more accurately estimate social exposures’ impacts on population health, researchers should consider a GHI framework.

  18. Systems biology by the rules: hybrid intelligent systems for pathway modeling and discovery.

    Science.gov (United States)

    Bosl, William J

    2007-02-15

    Expert knowledge in journal articles is an important source of data for reconstructing biological pathways and creating new hypotheses. An important need for medical research is to integrate this data with high throughput sources to build useful models that span several scales. Researchers traditionally use mental models of pathways to integrate information and development new hypotheses. Unfortunately, the amount of information is often overwhelming and these are inadequate for predicting the dynamic response of complex pathways. Hierarchical computational models that allow exploration of semi-quantitative dynamics are useful systems biology tools for theoreticians, experimentalists and clinicians and may provide a means for cross-communication. A novel approach for biological pathway modeling based on hybrid intelligent systems or soft computing technologies is presented here. Intelligent hybrid systems, which refers to several related computing methods such as fuzzy logic, neural nets, genetic algorithms, and statistical analysis, has become ubiquitous in engineering applications for complex control system modeling and design. Biological pathways may be considered to be complex control systems, which medicine tries to manipulate to achieve desired results. Thus, hybrid intelligent systems may provide a useful tool for modeling biological system dynamics and computational exploration of new drug targets. A new modeling approach based on these methods is presented in the context of hedgehog regulation of the cell cycle in granule cells. Code and input files can be found at the Bionet website: www.chip.ord/~wbosl/Software/Bionet. This paper presents the algorithmic methods needed for modeling complicated biochemical dynamics using rule-based models to represent expert knowledge in the context of cell cycle regulation and tumor growth. A notable feature of this modeling approach is that it allows biologists to build complex models from their knowledge base without

  19. Systems biology by the rules: hybrid intelligent systems for pathway modeling and discovery

    Directory of Open Access Journals (Sweden)

    Bosl William J

    2007-02-01

    Full Text Available Abstract Background Expert knowledge in journal articles is an important source of data for reconstructing biological pathways and creating new hypotheses. An important need for medical research is to integrate this data with high throughput sources to build useful models that span several scales. Researchers traditionally use mental models of pathways to integrate information and development new hypotheses. Unfortunately, the amount of information is often overwhelming and these are inadequate for predicting the dynamic response of complex pathways. Hierarchical computational models that allow exploration of semi-quantitative dynamics are useful systems biology tools for theoreticians, experimentalists and clinicians and may provide a means for cross-communication. Results A novel approach for biological pathway modeling based on hybrid intelligent systems or soft computing technologies is presented here. Intelligent hybrid systems, which refers to several related computing methods such as fuzzy logic, neural nets, genetic algorithms, and statistical analysis, has become ubiquitous in engineering applications for complex control system modeling and design. Biological pathways may be considered to be complex control systems, which medicine tries to manipulate to achieve desired results. Thus, hybrid intelligent systems may provide a useful tool for modeling biological system dynamics and computational exploration of new drug targets. A new modeling approach based on these methods is presented in the context of hedgehog regulation of the cell cycle in granule cells. Code and input files can be found at the Bionet website: www.chip.ord/~wbosl/Software/Bionet. Conclusion This paper presents the algorithmic methods needed for modeling complicated biochemical dynamics using rule-based models to represent expert knowledge in the context of cell cycle regulation and tumor growth. A notable feature of this modeling approach is that it allows biologists

  20. Phthalate exposure through different pathways and allergic sensitization in preschool children with asthma, allergic rhinoconjunctivitis and atopic dermatitis

    DEFF Research Database (Denmark)

    Bekö, Gabriel; Callesen, Michael; Weschler, Charles J.

    2015-01-01

    Studies in rodents indicate that phthalates can function as adjuvants, increasing the potency of allergens. Meanwhile, epidemiological studies have produced inconsistent findings regarding relationships between phthalate exposures and allergic disease in humans. The present study examined phthalate...... exposure and allergic sensitization in a large group of 3-5 year old children: 300 random controls and 200 cases with asthma, rhinoconjunctivitis or atopic dermatitis as reported in questionnaires. The children were clinically examined to confirm their health status. Blood samples were analyzed for Ig......) and sensitization and allergic disease. No direct associations were found between phthalate exposures and asthma, rhinoconjunctivitis or atopic dermatitis. However, among children with these diseases, there were significant associations between non-dietary exposures to DnBP, BBzP and DEHP in the indoor environment...

  1. Simulation of a Petri net-based model of the terpenoid biosynthesis pathway.

    Science.gov (United States)

    Hawari, Aliah Hazmah; Mohamed-Hussein, Zeti-Azura

    2010-02-09

    The development and simulation of dynamic models of terpenoid biosynthesis has yielded a systems perspective that provides new insights into how the structure of this biochemical pathway affects compound synthesis. These insights may eventually help identify reactions that could be experimentally manipulated to amplify terpenoid production. In this study, a dynamic model of the terpenoid biosynthesis pathway was constructed based on the Hybrid Functional Petri Net (HFPN) technique. This technique is a fusion of three other extended Petri net techniques, namely Hybrid Petri Net (HPN), Dynamic Petri Net (HDN) and Functional Petri Net (FPN). The biological data needed to construct the terpenoid metabolic model were gathered from the literature and from biological databases. These data were used as building blocks to create an HFPNe model and to generate parameters that govern the global behaviour of the model. The dynamic model was simulated and validated against known experimental data obtained from extensive literature searches. The model successfully simulated metabolite concentration changes over time (pt) and the observations correlated with known data. Interactions between the intermediates that affect the production of terpenes could be observed through the introduction of inhibitors that established feedback loops within and crosstalk between the pathways. Although this metabolic model is only preliminary, it will provide a platform for analysing various high-throughput data, and it should lead to a more holistic understanding of terpenoid biosynthesis.

  2. Epicutaneous exposure to nickel induces nickel allergy in mice via a MyD88-dependent and interleukin-1-dependent pathway

    DEFF Research Database (Denmark)

    Vennegaard, Marie T; Dyring-Andersen, Beatrice; Skov, Lone

    2014-01-01

    of nickel in the epidermis, and induces nickel allergy in mice. The allergic response to nickel following epicutaneous exposure is MyD88-dependent and interleukin (IL)-1 receptor-dependent, but independent of toll-like receptor (TLR)-4. CONCLUSION: This new model for nickel allergy that reflects...... epicutaneous exposure to nickel in humans shows that nickel allergy is dependent on MyD88 and IL-1 receptor signalling, but independent of TLR4....

  3. [Care pathways of cancer patients: Modeling and risks analysis induced by oral anticancer drugs].

    Science.gov (United States)

    Renet, Sophie; Maritaz, Christophe; Lotz, Jean-Pierre; Burnel, Sylvie; Paubel, Pascal

    2016-04-01

    The care pathway of cancer patients is complex and therefore difficult to define. The oral anticancers (AKPO) have shown their benefits to patients and health professionals, however, the risks induced on the care pathway remain unknown. The objective of the study is to define, quantify the risks from AKPO and their effects on the care pathway (breakdown [Ds], rupture [Rt]). From the proposed care pathway model, FMEA method is used to analyze risks. For the 3 identified processes (1 monotherapy, 2 bitherapies: 2 AKPO or 1 AKPO/1 AKIV), analysis revealed an average of 91 risks, 173 Ds, 147 Rt, increased for 1 AKPO/1 AKIV therapy. The administration and delivery are the most risky steps. The lack of training and information of patients and healthcare professionals generates 80% of Ds and Rt. This model confirms the complexity, variability of the care pathway. The development of actions to improve town-hospital coordination and exchange of information is required to optimize and secure the route, confirming the objectives of "Plan Cancer 3". Copyright © 2015 Société Française du Cancer. Published by Elsevier Masson SAS. All rights reserved.

  4. Acting in solidarity : Testing an extended dual pathway model of collective action by bystander group members

    NARCIS (Netherlands)

    Saab, Rim; Tausch, Nicole; Spears, Russell; Cheung, Wing-Yee

    We examined predictors of collective action among bystander group members in solidarity with a disadvantaged group by extending the dual pathway model of collective action, which proposes one efficacy-based and one emotion-based path to collective action (Van Zomeren, Spears, Fischer, & Leach,

  5. Protesters as "passionate economists" : A dynamic dual pathway model of approach coping with collective disadvantage

    NARCIS (Netherlands)

    van Zomeren, Martijn; Leach, Colin Wayne; Spears, Russell

    To explain the psychology behind individuals' motivation to participate in collective action against collective disadvantage (e.g., protest marches), the authors introduce a dynamic dual pathway model of approach coping that integrates many common explanations of collective action (i.e., group

  6. The dual pathway to creativity model: creative ideation as a function of flexibility and persistence

    NARCIS (Netherlands)

    Nijstad, B.A.; de Dreu, C.K.W.; Rietzschel, E.F.; Baas, M.

    2010-01-01

    The dual pathway to creativity model argues that creativity—the generation of original and appropriate ideas—is a function of cognitive flexibility and cognitive persistence, and that dispositional or situational variables may influence creativity either through their effects on flexibility, on

  7. The dual pathway to creativity model : Creative ideation as a function of flexibility and persistence

    NARCIS (Netherlands)

    Nijstad, B.A.; De Dreu, C.K.W.; Rietzschel, E.F.; Baas, M.

    2010-01-01

    The dual pathway to creativity model argues that creativity-the generation of original and appropriate ideas-is a function of cognitive flexibility and cognitive persistence, and that dispositional or situational variables may influence creativity either through their effects on flexibility, on

  8. Identifying parasitic current pathways in CIGS solar cells by modelling dark JV response

    NARCIS (Netherlands)

    Williams, B.L.; Smit, S.; Kniknie, B.J.; Bakkers, N.J.; Kessels, W.M.M.; Schropp, R.E.I.; Creatore, M.

    2014-01-01

    The presence of undetermined shunt pathways in CIGS solar cells can be severely limiting to the reproducibility of individual cell efficiency, both at lab-scale, and particularly in a roll-to-roll process. Here, a general model that describes the dark J-V characteristics of CIGS devices, accounting

  9. Experimental evidence for a dual pathway model analysis of coping with the climate crisis

    NARCIS (Netherlands)

    van Zomeren, Martijn; Spears, Russell; Leach, Colinn Wayne

    2010-01-01

    Two experiments examined the psychological power of fear and group efficacy beliefs to increase environmental action intentions against the climate crisis Extending a dual pathway model of coping with collective disadvantage results showed evidence for emotion-focused approach coping Environmental

  10. Temperament Pathways to Childhood Disruptive Behavior and Adolescent Substance Abuse: Testing a Cascade Model

    Science.gov (United States)

    Martel, Michelle M.; Pierce, Laura; Nigg, Joel T.; Jester, Jennifer M.; Adams, Kenneth; Puttler, Leon I.; Buu, Anne; Fitzgerald, Hiram; Zucker, Robert A.

    2009-01-01

    Temperament traits may increase risk for developmental psychopathology like Attention-Deficit/Hyperactivity Disorder (ADHD) and disruptive behaviors during childhood, as well as predisposing to substance abuse during adolescence. In the current study, a cascade model of trait pathways to adolescent substance abuse was examined. Component…

  11. Long-term recovery from hippocampal-related behavioral and biochemical abnormalities induced by noise exposure during brain development. Evaluation of auditory pathway integrity.

    Science.gov (United States)

    Uran, S L; Gómez-Casati, M E; Guelman, L R

    2014-10-01

    Sound is an important part of man's contact with the environment and has served as critical means for survival throughout his evolution. As a result of exposure to noise, physiological functions such as those involving structures of the auditory and non-auditory systems might be damaged. We have previously reported that noise-exposed developing rats elicited hippocampal-related histological, biochemical and behavioral changes. However, no data about the time lapse of these changes were reported. Moreover, measurements of auditory pathway function were not performed in exposed animals. Therefore, with the present work, we aim to test the onset and the persistence of the different extra-auditory abnormalities observed in noise-exposed rats and to evaluate auditory pathway integrity. Male Wistar rats of 15 days were exposed to moderate noise levels (95-97 dB SPL, 2 h a day) during one day (acute noise exposure, ANE) or during 15 days (sub-acute noise exposure, SANE). Hippocampal biochemical determinations as well as short (ST) and long term (LT) behavioral assessments were performed. In addition, histological and functional evaluations of the auditory pathway were carried out in exposed animals. Our results show that hippocampal-related behavioral and biochemical changes (impairments in habituation, recognition and associative memories as well as distortion of anxiety-related behavior, decreases in reactive oxygen species (ROS) levels and increases in antioxidant enzymes activities) induced by noise exposure were almost completely restored by PND 90. In addition, auditory evaluation shows that increased cochlear thresholds observed in exposed rats were re-established at PND 90, although with a remarkable supra-threshold amplitude reduction. These data suggest that noise-induced hippocampal and auditory-related alterations are mostly transient and that the effects of noise on the hippocampus might be, at least in part, mediated by the damage on the auditory pathway

  12. Molecular pathways associated with the nutritional programming of plant-based diet acceptance in rainbow trout following an early feeding exposure.

    Science.gov (United States)

    Balasubramanian, Mukundh N; Panserat, Stephane; Dupont-Nivet, Mathilde; Quillet, Edwige; Montfort, Jerome; Le Cam, Aurelie; Medale, Francoise; Kaushik, Sadasivam J; Geurden, Inge

    2016-06-13

    The achievement of sustainable feeding practices in aquaculture by reducing the reliance on wild-captured fish, via replacement of fish-based feed with plant-based feed, is impeded by the poor growth response seen in fish fed high levels of plant ingredients. Our recent strategy to nutritionally program rainbow trout by early short-term exposure to a plant-based (V) diet versus a control fish-based (M) diet at the first-feeding fry stage when the trout fry start to consume exogenous feed, resulted in remarkable improvements in feed intake, growth and feed utilization when the same fish were challenged with the diet V (V-challenge) at the juvenile stage, several months following initial exposure. We employed microarray expression analysis at the first-feeding and juvenile stages to deduce the mechanisms associated with the nutritional programming of plant-based feed acceptance in trout. Transcriptomic analysis was performed on rainbow trout whole fry after 3 weeks exposure to either diet V or diet M at the first feeding stage (3-week), and in the whole brain and liver of juvenile trout after a 25 day V-challenge, using a rainbow trout custom oligonucleotide microarray. Overall, 1787 (3-week + Brain) and 924 (3-week + Liver) mRNA probes were affected by the early-feeding exposure. Gene ontology and pathway analysis of the corresponding genes revealed that nutritional programming affects pathways of sensory perception, synaptic transmission, cognitive processes and neuroendocrine peptides in the brain; whereas in the liver, pathways mediating intermediary metabolism, xenobiotic metabolism, proteolysis, and cytoskeletal regulation of cell cycle are affected. These results suggest that the nutritionally programmed enhanced acceptance of a plant-based feed in rainbow trout is driven by probable acquisition of flavour and feed preferences, and reduced sensitivity to changes in hepatic metabolic and stress pathways. This study outlines the molecular mechanisms

  13. Modeling Of In-Vehicle Human Exposure to Ambient Fine Particulate Matter

    Science.gov (United States)

    Liu, Xiaozhen; Frey, H. Christopher

    2012-01-01

    A method for estimating in-vehicle PM2.5 exposure as part of a scenario-based population simulation model is developed and assessed. In existing models, such as the Stochastic Exposure and Dose Simulation model for Particulate Matter (SHEDS-PM), in-vehicle exposure is estimated using linear regression based on area-wide ambient PM2.5 concentration. An alternative modeling approach is explored based on estimation of near-road PM2.5 concentration and an in-vehicle mass balance. Near-road PM2.5 concentration is estimated using a dispersion model and fixed site monitor (FSM) data. In-vehicle concentration is estimated based on air exchange rate and filter efficiency. In-vehicle concentration varies with road type, traffic flow, windspeed, stability class, and ventilation. Average in-vehicle exposure is estimated to contribute 10 to 20 percent of average daily exposure. The contribution of in-vehicle exposure to total daily exposure can be higher for some individuals. Recommendations are made for updating exposure models and implementation of the alternative approach. PMID:23101000

  14. Air Pollution and Lung Function in Dutch Children : A Comparison of Exposure Estimates and Associations Based on Land Use Regression and Dispersion Exposure Modeling Approaches

    NARCIS (Netherlands)

    Wang, Meng; Gehring, Ulrike; Hoek, Gerard; Keuken, Menno; Jonkers, Sander; Beelen, Rob; Eeftens, Marloes; Postma, Dirkje S.; Brunekreef, Bert

    BACKGROUND: There is limited knowledge about the extent to which estimates of air pollution effects on health are affected by the choice for a specific exposure model. OBJECTIVES: We aimed to evaluate the correlation between long-term air pollution exposure estimates using two commonly used exposure

  15. Air Pollution and Lung Function in Dutch Children: A Comparison of Exposure Estimates and Associations Based on Land Use Regression and Dispersion Exposure Modeling Approaches

    NARCIS (Netherlands)

    Wang, Meng; Gehring, Ulrike; Hoek, Gerard; Keuken, Menno; Jonkers, Sander; Beelen, Rob; Eeftens, Marloes; Postma, Dirkje S; Brunekreef, Bert

    BACKGROUND: There is limited knowledge about the extent to which estimates of air pollution effects on health are affected by the choice for a specific exposure model. OBJECTIVES: We aimed to evaluate the correlation between long-term air pollution exposure estimates using two commonly used exposure

  16. Simulation of Population-Based Commuter Exposure to NO2 Using Different Air Pollution Models

    Directory of Open Access Journals (Sweden)

    Martina S. Ragettli

    2014-05-01

    Full Text Available We simulated commuter routes and long-term exposure to traffic-related air pollution during commute in a representative population sample in Basel (Switzerland, and evaluated three air pollution models with different spatial resolution for estimating commute exposures to nitrogen dioxide (NO2 as a marker of long-term exposure to traffic-related air pollution. Our approach includes spatially and temporally resolved data on actual commuter routes, travel modes and three air pollution models. Annual mean NO2 commuter exposures were similar between models. However, we found more within-city and within-subject variability in annual mean (±SD NO2 commuter exposure with a high resolution dispersion model (40 ± 7 µg m−3, range: 21–61 than with a dispersion model with a lower resolution (39 ± 5 µg m−3; range: 24–51, and a land use regression model (41 ± 5 µg m−3; range: 24–54. Highest median cumulative exposures were calculated along motorized transport and bicycle routes, and the lowest for walking. For estimating commuter exposure within a city and being interested also in small-scale variability between roads, a model with a high resolution is recommended. For larger scale epidemiological health assessment studies, models with a coarser spatial resolution are likely sufficient, especially when study areas include suburban and rural areas.

  17. Characterization of {sup 241}Am and {sup 134}Cs bioaccumulation in the king scallop Pecten maximus: investigation via three exposure pathways

    Energy Technology Data Exchange (ETDEWEB)

    Metian, Marc, E-mail: metian@hawaii.edu [International Atomic Energy Agency, Marine Environment Laboratories, 4, Quai Antoine Ier, MC-98000, Principality of Monaco (Monaco); Littoral Environnement et Societes (LIENSs), UMR 6250, CNRS-Universite de La Rochelle, 2 rue Olympe de Gouges, F-17042 La Rochelle Cedex 01 (France); Warnau, Michel; Teyssie, Jean-Louis [International Atomic Energy Agency, Marine Environment Laboratories, 4, Quai Antoine Ier, MC-98000, Principality of Monaco (Monaco); Bustamante, Paco, E-mail: paco.bustamante@univ-lr.fr [Littoral Environnement et Societes (LIENSs), UMR 6250, CNRS-Universite de La Rochelle, 2 rue Olympe de Gouges, F-17042 La Rochelle Cedex 01 (France)

    2011-06-15

    In order to understand the bioaccumulation of {sup 241}Am and {sup 134}Cs in scallops living in sediments, the uptake and depuration kinetics of these two elements were investigated in the king scallop Pecten maximus exposed via seawater, food, or sediment under laboratory conditions. Generally, {sup 241}Am accumulation was higher and its retention was stronger than {sup 134}Cs. This was especially obvious when considering whole animals exposed through seawater with whole-body concentration factors (CF{sub 7d}) of 62 vs. 1, absorption efficiencies (A{sub 0l}) of 78 vs. 45 for seawater and biological half-lives (T{sub b1/2l}) of 892 d vs. 22 d for {sup 241}Am and {sup 134}Cs, respectively. In contrast, following a single feeding with radiolabelled phytoplankton, the assimilation efficiency (AE) and T{sub b1/2l} of {sup 134}Cs were higher than those of {sup 241}Am (AE: 28% vs. 20%; T{sub b1/2l}: 14 d vs. 9 d). Among scallop tissues, the shells always contained the higher proportion of the total body burden of {sup 241}Am whatever the exposure pathway. In contrast, the whole soft parts presented the major fraction of whole-body burden of {sup 134}Cs, which was generally associated with muscular tissues. Our results showed that the two radionuclides have contrasting behaviors in scallops, in relation to their physico-chemical properties. - Highlights: > We determined Am and Cs uptake and depuration kinetics following seawater, food and sediment exposures. > We determined radionuclide tissue distribution after exposure and after depuration periods. > Am was mainly associated to the shell whatever the exposure pathway was. > Transfer processes occurred between soft and hard tissues for Am.

  18. Position-specific isotope modeling of organic micropollutants transformation through different reaction pathways

    DEFF Research Database (Denmark)

    Jin, Biao; Rolle, Massimo

    2016-01-01

    to simultaneously evaluate concentration as well as bulk and position-specific multi-element isotope evolution during the transformation of organic micropollutants. The model explicitly simulates position-specific isotopologues for those atoms that experience isotope effects and, thereby, provides a mechanistic......The degradation of organic micropollutants occurs via different reaction pathways. Compound specific isotope analysis is a valuable tool to identify such degradation pathways in different environmental systems. We propose a mechanism-based modeling approach that provides a quantitative framework...... description of isotope fractionation occurring at different molecular positions. To demonstrate specific features of the modeling approach, we simulated the degradation of three selected organic micropollutants: dichlorobenzamide (BAM), isoproturon (IPU) and diclofenac (DCF). The model accurately reproduces...

  19. Effects of acute and chronic exposure to both 900 MHz and 2100 MHz electromagnetic radiation on glutamate receptor signaling pathway.

    Science.gov (United States)

    Gökçek-Saraç, Çiğdem; Er, Hakan; Kencebay Manas, Ceren; Kantar Gok, Deniz; Özen, Şükrü; Derin, Narin

    2017-09-01

    To demonstrate the molecular effects of acute and chronic exposure to both 900 and 2100 MHz radiofrequency electromagnetic radiation (RF-EMR) on the hippocampal level/activity of some of the enzymes - including PKA, CaMKIIα, CREB, and p44/42 MAPK - from N-methyl-D-aspartate receptor (NMDAR)-related signaling pathways. Rats were divided into the following groups: sham rats, and rats exposed to 900 and 2100 MHz RF-EMR for 2 h/day for acute (1 week) or chronic (10 weeks), respectively. Western blotting and activity measurement assays were used to assess the level/activity of the selected enzymes. The obtained results revealed that the hippocampal level/activity of selected enzymes was significantly higher in the chronic groups as compared to the acute groups at both 900 and 2100 MHz RF-EMR exposure. In addition, hippocampal level/activity of selected enzymes was significantly higher at 2100 MHz RF-EMR than 900 MHz RF-EMR in both acute and chronic groups. The present study provides experimental evidence that both exposure duration (1 week versus 10 weeks) and different carrier frequencies (900 vs. 2100 MHz) had different effects on the protein expression of hippocampus in Wistar rats, which might encourage further research on protection against RF-EMR exposure.

  20. Quantitative modeling of responses to chronic ionizing radiation exposure using targeted and non-targeted effects.

    Directory of Open Access Journals (Sweden)

    Igor Shuryak

    Full Text Available The biological effects of chronic ionizing radiation exposure can be difficult to study, but important to understand in order to protect the health of occupationally-exposed persons and victims of radiological accidents or malicious events. They include targeted effects (TE caused by ionizations within/close to nuclear DNA, and non-targeted effects (NTE caused by damage to other cell structures and/or activation of stress-signaling pathways in distant cells. Data on radiation damage in animal populations exposed over multiple generations to wide ranges of dose rates after the Chernobyl nuclear-power-plant accident are very useful for enhancing our understanding of these processes. We used a mechanistically-motivated mathematical model which includes TE and NTE to analyze a large published data set on chromosomal aberrations in pond snail (Lymnaea stagnalis embryos collected over 16 years from water bodies contaminated by Chernobyl fallout, and from control locations. The fraction of embryo cells with aberrations increased dramatically (>10-fold and non-linearly over a dose rate range of 0.03-420 μGy/h (0.00026-3.7 Gy/year. NTE were very important for describing the non-linearity of this radiation response: the TE-only model (without NTE performed dramatically worse than the TE+NTE model. NTE were predicted to reach ½ of maximal intensity at 2.5 μGy/h (0.022 Gy/year and to contribute >90% to the radiation response slope at dose rates <11 μGy/h (0.1 Gy/year. Internally-incorporated 90Sr was possibly more effective per unit dose than other radionuclides. The radiation response shape for chromosomal aberrations in snail embryos was consistent with data for a different endpoint: the fraction of young amoebocytes in adult snail haemolymph. Therefore, radiation may affect different snail life stages by similar mechanisms. The importance of NTE in our model-based analysis suggests that the search for modulators of NTE-related signaling pathways

  1. Determining the validity of exposure models for environmental epidemiology : predicting electromagnetic fields from mobile phone base stations

    NARCIS (Netherlands)

    Beekhuizen, Johan

    2014-01-01

    One of the key challenges in environmental epidemiology is the exposure assessment of large populations. Spatial exposure models have been developed that predict exposure to the pollutant of interest for large study sizes. However, the validity of these exposure models is often unknown. In this

  2. Modeling tribal exposures to methyl mercury from fish consumption

    Science.gov (United States)

    Exposure assessment and risk management considerations for tribal fish consumption are different than for the general U.S. population because of higher fish intake from subsistence fishing and/or from unique cultural practices. This research summarizes analyses of available data ...

  3. Elderly Exposure to Air Pollutants : Measuring, assessing and modelling

    NARCIS (Netherlands)

    Almeida-Silva, M.A.

    2016-01-01

    This Thesis focuses on the estimation of the human exposure to air pollutants, and gives special attention to one of the most susceptible groups in the general population - elders. To fulfil the goal the work was conducted following the risk assessment paradigm and, consequently, was divided into 5

  4. Bayesian Hierarchical Modeling of Cardiac Response to Particulate Matter Exposure

    Science.gov (United States)

    Studies have linked increased levels of particulate air pollution to decreased autonomic control, as measured by heart rate variability (HRV), particularly in populations such as the elderly. In this study, we use data obtained from the 1998 USEPA epidemiology-exposure longitudin...

  5. Pathway model, superstatistics, Tsallis statistics, and a generalized measure of entropy

    Science.gov (United States)

    Mathai, A. M.; Haubold, H. J.

    2007-02-01

    The pathway model of Mathai [A pathway to matrix-variate gamma and normal densities, Linear Algebra Appl. 396 (2005) 317 328] is shown to be inferable from the maximization of a certain generalized entropy measure. This entropy is a variant of the generalized entropy of order α, considered in Mathai and Rathie [Basic Concepts in Information Theory and Statistics: Axiomatic Foundations and Applications, Wiley Halsted, New York and Wiley Eastern, New Delhi, 1975], and it is also associated with Shannon, Boltzmann Gibbs, Rényi, Tsallis, and Havrda Charvát entropies. The generalized entropy measure introduced here is also shown to have interesting statistical properties and it can be given probabilistic interpretations in terms of inaccuracy measure, expected value, and information content in a scheme. Particular cases of the pathway model are shown to be Tsallis statistics [C. Tsallis, Possible generalization of Boltzmann-Gibbs statistics, J. Stat. Phys. 52 (1988) 479 487] and superstatistics introduced by Beck and Cohen [Superstatistics, Physica A 322 (2003) 267 275]. The pathway model's connection to fractional calculus is illustrated by considering a fractional reaction equation.

  6. Pathogenesis pathways of idiopathic pulmonary fibrosis in bleomycin-induced lung injury model in mice.

    Science.gov (United States)

    Shi, Keyun; Jiang, Jianzhong; Ma, Tieliang; Xie, Jing; Duan, Lirong; Chen, Ruhua; Song, Ping; Yu, Zhixin; Liu, Chao; Zhu, Qin; Zheng, Jinxu

    2014-01-01

    Our objective was to investigate the pathogenesis pathways of idiopathic pulmonary fibrosis (IPF). Bleomycin (BLM) induced animal models of experimental lung fibrosis were used. CHIP assay was executed to find the link between Smad3 and IL-31, and the expressions of TGF-β1, Smad3, IL-31 and STAT1 were detected to find whether they were similar with each other. We found that in the early injury or inflammation of the animal model, BLM promoted the development of inflammation, leading to severe pulmonary fibrosis. Then the expression of TGF-β1 and Smad3 increased. Activated Smad3 bound to the IL-31 promoter region, followed by the activation of JAK-STAT pathways. The inhibitor of TGF-β1 receptor decreased the IL-31 expression and knocking-down of IL-31 also decreased the STAT1 expression. We conclude that there is a pathway of pathogenesis in BLM-induced mouse model that involves the TGF-β, IL-31 and JAKs/STATs pathway. Copyright © 2013 Elsevier B.V. All rights reserved.

  7. DFT-based Green's function pathways model for prediction of bridge-mediated electronic coupling.

    Science.gov (United States)

    Berstis, Laura; Baldridge, Kim K

    2015-12-14

    A density functional theory-based Green's function pathway model is developed enabling further advancements towards the long-standing challenge of accurate yet inexpensive prediction of electron transfer rate. Electronic coupling predictions are demonstrated to within 0.1 eV of experiment for organic and biological systems of moderately large size, with modest computational expense. Benchmarking and comparisons are made across density functional type, basis set extent, and orbital localization scheme. The resulting framework is shown to be flexible and to offer quantitative prediction of both electronic coupling and tunneling pathways in covalently bound non-adiabatic donor-bridge-acceptor (D-B-A) systems. A new localized molecular orbital Green's function pathway method (LMO-GFM) adaptation enables intuitive understanding of electron tunneling in terms of through-bond and through-space interactions.

  8. Modelling plant invasion pathways in protected areas under climate change: implication for invasion management

    Directory of Open Access Journals (Sweden)

    C.-J. Wang

    2017-12-01

    Full Text Available Global climate change may enable invasive plant species (IPS to invade protected areas (PAs, but plant invasion on a global scale has not yet been explicitly addressed. Here, we mapped the potential invasion pathways for IPS in PAs across the globe and explored potential factors determining the pathways of plant invasion under climate change. We used species distribution modelling to estimate the suitable habitats of 386 IPS and applied a corridor analysis to compute the potential pathways of IPS in PAs under climate change. Subsequently, we analysed the potential factors affecting the pathways in PAs. According to our results, the main potential pathways of IPS in PAs are in Europe, eastern Australia, New Zealand, southern Africa, and eastern regions of South America and are strongly influenced by changes in temperature and precipitation. Protected areas can play an important role in preventing and controlling the spread of IPS under climate change. This is due to the fact that measures are taken to monitor climate change in detail, to provide effective management near or inside PAs, and to control the introduction of IPS with a high capacity for natural dispersal. A review of conservation policies in PAs is urgently needed.

  9. Modeling the altered expression levels of genes on signaling pathways in tumors as causal bayesian networks.

    Science.gov (United States)

    Neapolitan, Richard; Xue, Diyang; Jiang, Xia

    2014-01-01

    This paper concerns a study indicating that the expression levels of genes in signaling pathways can be modeled using a causal Bayesian network (BN) that is altered in tumorous tissue. These results open up promising areas of future research that can help identify driver genes and therapeutic targets. So, it is most appropriate for the cancer informatics community. Our central hypothesis is that the expression levels of genes that code for proteins on a signal transduction network (STP) are causally related and that this causal structure is altered when the STP is involved in cancer. To test this hypothesis, we analyzed 5 STPs associated with breast cancer, 7 STPs associated with other cancers, and 10 randomly chosen pathways, using a breast cancer gene expression level dataset containing 529 cases and 61 controls. We identified all the genes related to each of the 22 pathways and developed separate gene expression datasets for each pathway. We obtained significant results indicating that the causal structure of the expression levels of genes coding for proteins on STPs, which are believed to be implicated in both breast cancer and in all cancers, is more altered in the cases relative to the controls than the causal structure of the randomly chosen pathways.

  10. Methylerythritol phosphate pathway to isoprenoids: kinetic modeling and in silico enzyme inhibitions in Plasmodium falciparum.

    Science.gov (United States)

    Singh, Vivek Kumar; Ghosh, Indira

    2013-09-02

    The methylerythritol phosphate (MEP) pathway of Plasmodium falciparum (P. falciparum) has become an attractive target for anti-malarial drug discovery. This study describes a kinetic model of this pathway, its use in validating 1-deoxy-d-xylulose 5-phosphate reductoisomerase (DXR) as drug target from the systemic perspective, and additional target identification, using metabolic control analysis and in silico inhibition studies. In addition to DXR, 1-deoxy-d-xylulose 5-phosphate synthase (DXS) can be targeted because it is the first enzyme of the pathway and has the highest flux control coefficient followed by that of DXR. In silico inhibition of both enzymes caused large decrement in the pathway flux. An added advantage of targeting DXS is its influence on vitamin B1 and B6 biosynthesis. Two more potential targets, 2-C-methyl-d-erythritol 2,4-cyclodiphosphate synthase and 1-hydroxy-2-methyl-2-(E)-butenyl 4-diphosphate synthase, were also identified. Their inhibition caused large accumulation of their substrates causing instability of the system. This study demonstrates that both types of enzyme targets, one acting via flux reduction and the other by metabolite accumulation, exist in P. falciparum MEP pathway. These groups of targets can be exploited for independent anti-malarial drugs. Copyright © 2013 Federation of European Biochemical Societies. Published by Elsevier B.V. All rights reserved.

  11. A high protein diet during pregnancy affects hepatic gene expression of energy sensing pathways along ontogenesis in a porcine model.

    Directory of Open Access Journals (Sweden)

    Michael Oster

    Full Text Available In rodent models and in humans the impact of gestational diets on the offspring's phenotype was shown experimentally and epidemiologically. The underlying programming of fetal development was shown to be associated with an increased risk of degenerative diseases in adulthood, including the metabolic syndrome. There are clues that diet-dependent modifications of the metabolism during fetal life can persist until adulthood. This leads to the hypothesis that the offspring's transcriptomes show short-term and long-term changes depending on the maternal diet. To this end pregnant German landrace gilts were fed either a high protein diet (HP, 30% CP or an adequate protein diet (AP, 12% CP throughout pregnancy. Hepatic transcriptome profiles of the offspring were analyzed at prenatal (94 dpc and postnatal stages (1, 28, 188 dpn. Depending on the gestational dietary exposure, mRNA expression levels of genes related to energy metabolism, N-metabolism, growth factor signaling pathways, lipid metabolism, nucleic acid metabolism and stress/immune response were affected either in a short-term or in a long-term manner. Gene expression profiles at fetal stage 94 dpc were almost unchanged between the diets. The gestational HP diet affected the hepatic expression profiles at prenatal and postnatal stages. The effects encompassed a modulation of the genome in terms of an altered responsiveness of energy and nutrient sensing pathways. Differential expression of genes related to energy production and nutrient utilization contribute to the maintenance of development and growth performance within physiological norms, however the modulation of these pathways may be accompanied by a predisposition for metabolic disturbances up to adult stages.

  12. A high protein diet during pregnancy affects hepatic gene expression of energy sensing pathways along ontogenesis in a porcine model.

    Science.gov (United States)

    Oster, Michael; Murani, Eduard; Metges, Cornelia C; Ponsuksili, Siriluck; Wimmers, Klaus

    2011-01-01

    In rodent models and in humans the impact of gestational diets on the offspring's phenotype was shown experimentally and epidemiologically. The underlying programming of fetal development was shown to be associated with an increased risk of degenerative diseases in adulthood, including the metabolic syndrome. There are clues that diet-dependent modifications of the metabolism during fetal life can persist until adulthood. This leads to the hypothesis that the offspring's transcriptomes show short-term and long-term changes depending on the maternal diet. To this end pregnant German landrace gilts were fed either a high protein diet (HP, 30% CP) or an adequate protein diet (AP, 12% CP) throughout pregnancy. Hepatic transcriptome profiles of the offspring were analyzed at prenatal (94 dpc) and postnatal stages (1, 28, 188 dpn). Depending on the gestational dietary exposure, mRNA expression levels of genes related to energy metabolism, N-metabolism, growth factor signaling pathways, lipid metabolism, nucleic acid metabolism and stress/immune response were affected either in a short-term or in a long-term manner. Gene expression profiles at fetal stage 94 dpc were almost unchanged between the diets. The gestational HP diet affected the hepatic expression profiles at prenatal and postnatal stages. The effects encompassed a modulation of the genome in terms of an altered responsiveness of energy and nutrient sensing pathways. Differential expression of genes related to energy production and nutrient utilization contribute to the maintenance of development and growth performance within physiological norms, however the modulation of these pathways may be accompanied by a predisposition for metabolic disturbances up to adult stages.

  13. Comparing population recovery after insecticide exposure for four aquatic invertebrate species using models of different complexity.

    Science.gov (United States)

    Baveco, J M Hans; Norman, Steve; Roessink, Ivo; Galic, Nika; Van den Brink, Paul J

    2014-07-01

    Population models, in particular individual-based models (IBMs), are becoming increasingly important in chemical risk assessment. They can be used to assess recovery of spatially structured populations after chemical exposure that varies in time and space. The authors used an IBM coupled to a toxicokinetic-toxicodynamic model, the threshold damage model (TDM), to assess recovery times for 4 aquatic organisms, after insecticide application, in a nonseasonal environment and in 3 spatial settings (pond, stream, and ditch). The species had different life histories (e.g., voltinism, reproductive capacity, mobility). Exposure was derived from a pesticide fate model, following standard European Union scenarios. The results of the IBM-TDM were compared with results from simpler models: one in which exposure was linked to effects by means of concentration-effect relationships (IBM-CE) and one in which the IBM was replaced by a nonspatial, logistic growth model (logistic). For the first, exposure was based on peak concentrations only; for the second, exposure was spatially averaged as well. By using comparisons between models of different complexity and species with different life histories, the authors obtained an understanding of the role spatial processes play in recovery and the conditions under which the full time-varying exposure needs to be considered. The logistic model, which is amenable to an analytic approach, provided additional insights into the sensitivity of recovery times to density dependence and spatial dimensions. © 2014 SETAC.

  14. A geographic approach to modelling human exposure to traffic air pollution using GIS

    Energy Technology Data Exchange (ETDEWEB)

    Solvang Jensen, S.

    1998-10-01

    A new exposure model has been developed that is based on a physical, single media (air) and single source (traffic) micro environmental approach that estimates traffic related exposures geographically with the postal address as exposure indicator. The micro environments: residence, workplace and street (road user exposure) may be considered. The model estimates outdoor levels for selected ambient air pollutants (benzene, CO, NO{sub 2} and O{sub 3}). The influence of outdoor air pollution on indoor levels can be estimated using average (I/O-ratios. The model has a very high spatial resolution (the address), a high temporal resolution (one hour) and may be used to predict past, present and future exposures. The model may be used for impact assessment of control measures provided that the changes to the model inputs are obtained. The exposure model takes advantage of a standard Geographic Information System (GIS) (ArcView and Avenue) for generation of inputs, for visualisation of input and output, and uses available digital maps, national administrative registers and a local traffic database, and the Danish Operational Street Pollution Model (OSPM). The exposure model presents a new approach to exposure determination by integration of digital maps, administrative registers, a street pollution model and GIS. New methods have been developed to generate the required input parameters for the OSPM model: to geocode buildings using cadastral maps and address points, to automatically generate street configuration data based on digital maps, the BBR and GIS; to predict the temporal variation in traffic and related parameters; and to provide hourly background levels for the OSPM model. (EG) 109 refs.

  15. A geographic approach to modelling human exposure to traffic air pollution using GIS. Separate appendix report

    Energy Technology Data Exchange (ETDEWEB)

    Solvang Jensen, S.

    1998-10-01

    A new exposure model has been developed that is based on a physical, single media (air) and single source (traffic) micro environmental approach that estimates traffic related exposures geographically with the postal address as exposure indicator. The micro environments: residence, workplace and street (road user exposure) may be considered. The model estimates outdoor levels for selected ambient air pollutants (benzene, CO, NO{sub 2} and O{sub 3}). The influence of outdoor air pollution on indoor levels can be estimated using average (I/O-ratios. The model has a very high spatial resolution (the address), a high temporal resolution (one hour) and may be used to predict past, present and future exposures. The model may be used for impact assessment of control measures provided that the changes to the model inputs are obtained. The exposure model takes advantage of a standard Geographic Information System (GIS) (ArcView and Avenue) for generation of inputs, for visualisation of input and output, and uses available digital maps, national administrative registers and a local traffic database, and the Danish Operational Street Pollution Model (OSPM). The exposure model presents a new approach to exposure determination by integration of digital maps, administrative registers, a street pollution model and GIS. New methods have been developed to generate the required input parameters for the OSPM model: to geocode buildings using cadastral maps and address points, to automatically generate street configuration data based on digital maps, the BBR and GIS; to predict the temporal variation in traffic and related parameters; and to provide hourly background levels for the OSPM model. (EG)

  16. A Drosophila model for fetal alcohol syndrome disorders: role for the insulin pathway.

    Science.gov (United States)

    McClure, Kimberly D; French, Rachael L; Heberlein, Ulrike

    2011-05-01

    Prenatal exposure to ethanol in humans results in a wide range of developmental abnormalities, including growth deficiency, developmental delay, reduced brain size, permanent neurobehavioral abnormalities and fetal death. Here we describe the use of Drosophila melanogaster as a model for exploring the effects of ethanol exposure on development and behavior. We show that developmental ethanol exposure causes reduced viability, developmental delay and reduced adult body size. We find that flies reared on ethanol-containing food have smaller brains and imaginal discs, which is due to reduced cell division rather than increased apoptosis. Additionally, we show that, as in mammals, flies reared on ethanol have altered responses to ethanol vapor exposure as adults, including increased locomotor activation, resistance to the sedating effects of the drug and reduced tolerance development upon repeated ethanol exposure. We have found that the developmental and behavioral defects are largely due to the effects of ethanol on insulin signaling; specifically, a reduction in Drosophila insulin-like peptide (Dilp) and insulin receptor expression. Transgenic expression of Dilp proteins in the larval brain suppressed both the developmental and behavioral abnormalities displayed by ethanol-reared adult flies. Our results thus establish Drosophila as a useful model system to uncover the complex etiology of fetal alcohol syndrome.

  17. GEM System: automatic prototyping of cell-wide metabolic pathway models from genomes

    Directory of Open Access Journals (Sweden)

    Nakayama Yoichi

    2006-03-01

    Full Text Available Abstract Background Successful realization of a "systems biology" approach to analyzing cells is a grand challenge for our understanding of life. However, current modeling approaches to cell simulation are labor-intensive, manual affairs, and therefore constitute a major bottleneck in the evolution of computational cell biology. Results We developed the Genome-based Modeling (GEM System for the purpose of automatically prototyping simulation models of cell-wide metabolic pathways from genome sequences and other public biological information. Models generated by the GEM System include an entire Escherichia coli metabolism model comprising 968 reactions of 1195 metabolites, achieving 100% coverage when compared with the KEGG database, 92.38% with the EcoCyc database, and 95.06% with iJR904 genome-scale model. Conclusion The GEM System prototypes qualitative models to reduce the labor-intensive tasks required for systems biology research. Models of over 90 bacterial genomes are available at our web site.

  18. Studying permethrin exposure in flight attendants using a physiologically based pharmacokinetic model.

    Science.gov (United States)

    Wei, Binnian; Isukapalli, Sastry S; Weisel, Clifford P

    2013-07-01

    Assessment of potential health risks to flight attendants from exposure to pyrethroid insecticides, used for aircraft disinsection, is limited because of (a) lack of information on exposures to these insecticides, and (b) lack of tools for linking these exposures to biomarker data. We developed and evaluated a physiologically based pharmacokinetic (PBPK) model to assess the exposure of flight attendants to the pyrethroid insecticide permethrin attributable to aircraft disinsection. The permethrin PBPK model was developed by adapting previous models for pyrethroids, and was parameterized using currently available metabolic parameters for permethrin. The human permethrin model was first evaluated with data from published human studies. Then, it was used to estimate urinary metabolite concentrations of permethrin in flight attendants who worked in aircrafts, which underwent residual and pre-flight spray treatments. The human model was also applied to analyze the toxicokinetics following permethrin exposures attributable to other aircraft disinsection scenarios. Predicted levels of urinary 3-phenoxybenzoic acid (3-PBA), a metabolite of permethrin, following residual disinsection treatment were comparable to the measurements made for flight attendants. Simulations showed that the median contributions of the dermal, oral and inhalation routes to permethrin exposure in flight attendants were 83.5%, 16.1% and 0.4% under residual treatment scenario, respectively, and were 5.3%, 5.0% and 89.7% under pre-flight spray scenario, respectively. The PBPK model provides the capability to simulate the toxicokinetic profiles of permethrin, and can be used in the studies on human exposure to permethrin.

  19. Modeling exposure to air pollution and cardiovascular mortality: the ESCAPE study

    NARCIS (Netherlands)

    Wang, M.

    2013-01-01

    Exposure assessment is one of the key issues for health effect estimates in environmental epidemiology. Recent interest has increased in exposure modeling incorporating Geographic Information System (GIS) data to capture small-scale spatial variability in air pollution concentrations. Land use

  20. An Exploratory Study: Assessment of Modeled Dioxin Exposure in Ceramic Art Studios (Final Report, 2008)

    Science.gov (United States)

    EPA announced the availability of the final report, An Exploratory Study: Assessment of Modeled Dioxin Exposure in Ceramic Art Studios. This report investigates the potential dioxin exposure to artists/hobbyists who use ball clay to make pottery and related products. Derm...

  1. Low-frequency electromagnetic field exposure enhances extracellular trap formation by human neutrophils through the NADPH pathway

    NARCIS (Netherlands)

    Golbach, L.A.; Scheer, M.H.; Cuppen, J.J.M.; Savelkoul, H.F.J.; Verburg-van Kemenade, B.M.L.

    2015-01-01

    Low-frequency (LF) electromagnetic fields (EMFs) are abundantly present in modern society, and the potential biological consequences of exposure to these fields are under intense debate. Immune cells are suggested as possible target cells, though a clear mechanism is lacking. Considering their

  2. Chronic Nicotine Exposure Induces a Long-Lasting and Pathway-Specific Facilitation of LTP in the Amygdala

    Science.gov (United States)

    Huang, Yan-You; Kandel, Eric R.; Levine, Amir

    2008-01-01

    Nicotine, in the form of tobacco, is the most commonly used drug of abuse. In addition to its rewarding properties, nicotine also affects many cognitive and emotional processes that involve several brain regions, including hippocampus and amygdala. Long-term changes in synaptic strength in these brain regions after drug exposure may be importantly…

  3. Exposure to ambient concentrations of particulate air pollution does not influence vascular function or inflammatory pathways in young healthy individuals

    DEFF Research Database (Denmark)

    Bräuner, E. V.; Møller, P.; Barregård, L.

    2008-01-01

    Background: Particulate air pollution is associated with increased risk of cardiovascular events although the involved mechanisms are poorly understood. The objective of the present study was to investigate the effects of controlled exposure to ambient air fine and ultrafine particles on microvas...... with detectable systemic inflammation, lipid or protein oxidation, altered haemostasis or microvascular function in young healthy participants....

  4. Modelling effects of chemical exposure on birds wintering in agricultural landscapes: The western burrowing owl (Athene cunicularia hypugaea) as a case study

    Science.gov (United States)

    Engelman, Catherine A.; Grant, William E.; Mora, Miguel A.; Woodin, Marc

    2012-01-01

    We describe an ecotoxicological model that simulates the sublethal and lethal effects of chronic, low-level, chemical exposure on birds wintering in agricultural landscapes. Previous models estimating the impact on wildlife of chemicals used in agro-ecosystems typically have not included the variety of pathways, including both dermal and oral, by which individuals are exposed. The present model contains four submodels simulating (1) foraging behavior of individual birds, (2) chemical applications to crops, (3) transfers of chemicals among soil, insects, and small mammals, and (4) transfers of chemicals to birds via ingestion and dermal exposure. We demonstrate use of the model by simulating the impacts of a variety of commonly used herbicides, insecticides, growth regulators, and defoliants on western burrowing owls (Athene cunicularia hypugaea) that winter in agricultural landscapes in southern Texas, United States. The model generated reasonable movement patterns for each chemical through soil, water, insects, and rodents, as well as into the owl via consumption and dermal absorption. Sensitivity analysis suggested model predictions were sensitive to uncertainty associated with estimates of chemical half-lives in birds, soil, and prey, sensitive to parameters associated with estimating dermal exposure, and relatively insensitive to uncertainty associated with details of chemical application procedures (timing of application, amount of drift). Nonetheless, the general trends in chemical accumulations and the relative impacts of the various chemicals were robust to these parameter changes. Simulation results suggested that insecticides posed a greater potential risk to owls of both sublethal and lethal effects than do herbicides, defoliants, and growth regulators under crop scenarios typical of southern Texas, and that use of multiple indicators, or endpoints provided a more accurate assessment of risk due to agricultural chemical exposure. The model should prove

  5. A model of the ethylene signaling pathway and its gene response in Arabidopsis thaliana: Pathway cross-talk and noise-filtering properties

    Science.gov (United States)

    Díaz, José; Álvarez-Buylla, Elena R.

    2006-06-01

    Dynamic models of molecular networks and pathways enable in silico evaluations of the consistency of proposed interactions and the outcomes of perturbations as well as of hypotheses on system-level structure and function. We postulate a continuous model of the activation dynamics of the ethylene response factor 1 (ERF1) gene in response to ethylene signaling. This activation elicits the response of the plant defensin 1 (PDF1) gene, which also responds to jasmonic acid, and the inhibition of the putative auxin responsive factor 2 (ARF2) gene, that also responds to auxin. Our model allows the effect of different ethylene concentrations in eliciting contrasting genetic and phenotypic responses to be evaluated allows the effect of different ethylene concentrations in eliciting contrasting genetic and phenotypic responses to be evaluated and seems to consider key components of the ethylene pathway because the ERF1 dose-response curve that we predict has the same qualitative form as the phenotypic dose-response curves obtained experimentally. Therefore, our model suggests that the phenotypic dose-response curves obtained experimentally could be due, at least in part, to ERF1 changes to different ethylene concentrations. Stability analyses show that the model's results are robust to parameter estimates. Of interest is that our model predicts that the ethylene pathway may filter stochastic and rapid chaotic fluctuations in ethylene availability. This novel approach may be applied to any cellular signaling and response pathway in plants and animals.

  6. Environmental tobacco smoke in designated smoking areas in the hospitality industry: exposure measurements, exposure modelling and policy assessment.

    Science.gov (United States)

    McNabola, A; Eyre, G J; Gill, L W

    2012-09-01

    Tobacco control policy has been enacted in many jurisdictions worldwide banning smoking in the workplace. In the hospitality sector many businesses such as bars, hotels and restaurants have installed designated smoking areas on their premises and allowance for such smoking areas has been made in the tobacco control legislation of many countries. An investigation was carried out into the level of exposure to environmental tobacco smoke (ETS) present in 8 pubs in Ireland which included designated smoking areas complying with two different definitions of a smoking area set out in Irish legislation. In addition, ETS exposure in a pub with a designated smoking area not in compliance with the legislation was also investigated. The results of this investigation showed that the two differing definitions of a smoking area present in pubs produced similar concentrations of benzene within smoking areas (5.1-5.4 μg/m(3)) but differing concentrations within the 'smoke-free' areas (1.42-3.01 μg/m(3)). Smoking areas in breach of legislative definitions were found to produce the highest levels of benzene in the smoking area (49.5 μg/m(3)) and 'smoke-free' area (7.68 μg/m(3)). 3D exposure modelling of hypothetical smoking areas showed that a wide range of ETS exposure concentrations were possible in smoking areas with the same floor area and same smoking rate but differing height to width and length to width ratios. The results of this investigation demonstrate that significant scope for improvement of ETS exposure concentrations in pubs and in smoking areas may exist by refining and improving the legislative definitions of smoking areas in law. Copyright © 2012 Elsevier Ltd. All rights reserved.

  7. Propofol exposure during late stages of pregnancy impairs learning and memory in rat offspring via the BDNF-TrkB signalling pathway.

    Science.gov (United States)

    Zhong, Liang; Luo, Foquan; Zhao, Weilu; Feng, Yunlin; Wu, Liuqin; Lin, Jiamei; Liu, Tianyin; Wang, Shengqiang; You, Xuexue; Zhang, Wei

    2016-10-01

    The brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) (BDNF-TrkB) signalling pathway plays a crucial role in regulating learning and memory. Synaptophysin provides the structural basis for synaptic plasticity and depends on BDNF processing and subsequent TrkB signalling. Our previous studies demonstrated that maternal exposure to propofol during late stages of pregnancy impaired learning and memory in rat offspring. The purpose of this study is to investigate whether the BDNF-TrkB signalling pathway is involved in propofol-induced learning and memory impairments. Propofol was intravenously infused into pregnant rats for 4 hrs on gestational day 18 (E18). Thirty days after birth, learning and memory of offspring was assessed by the Morris water maze (MWM) test. After the MWM test, BDNF and TrkB transcript and protein levels were measured in rat offspring hippocampus tissues using real-time PCR (RT-PCR) and immunohistochemistry (IHC), respectively. The levels of phosphorylated-TrkB (phospho-TrkB) and synaptophysin were measured by western blot. It was discovered that maternal exposure to propofol on day E18 impaired spatial learning and memory of rat offspring, decreased mRNA and protein levels of BDNF and TrkB, and decreased the levels of both phospho-TrkB and synaptophysin in the hippocampus. Furthermore, the TrkB agonist 7,8-dihydroxyflavone (7,8-DHF) reversed all of the observed changes. Treatment with 7,8-DHF had no significant effects on the offspring that were not exposed to propofol. The results herein indicate that maternal exposure to propofol during the late stages of pregnancy impairs spatial learning and memory of offspring by disturbing the BDNF-TrkB signalling pathway. The TrkB agonist 7,8-DHF might be a potential therapy for learning and memory impairments induced by maternal propofol exposure. © 2016 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular

  8. Size-dependent characterisation of historical gold mine wastes to examine human pathways of exposure to arsenic and other potentially toxic elements.

    Science.gov (United States)

    Martin, Rachael; Dowling, Kim; Pearce, Dora C; Florentine, Singarayer; Bennett, John W; Stopic, Attila

    2016-10-01

    Abandoned historical gold mining wastes often exist as geographically extensive, unremediated, and poorly contained deposits that contain elevated levels of As and other potentially toxic elements (PTEs). One of the key variables governing human exposure to PTEs in mine waste is particle size. By applying a size-resolved approach to mine waste characterisation, this study reports on the proportions of mine waste relevant to human exposure and mobility, as well as their corresponding PTE concentrations, in four distinct historical mine wastes from the gold province in Central Victoria, Australia. To the best of our knowledge, such a detailed investigation and comparison of historical mining wastes has not been conducted in this mining-affected region. Mass distribution analysis revealed notable proportions of waste material in the readily ingestible size fraction (≤250 µm; 36.1-75.6 %) and the dust size fraction (≤100 µm; 5.9-45.6 %), suggesting a high potential for human exposure and dust mobilisation. Common to all mine waste types were statistically significant inverse trends between particle size and levels of As and Zn. Enrichment of As in the finest investigated size fraction (≤53 µm) is of particular concern as these particles are highly susceptible to long-distance atmospheric transport. Human populations that reside in the prevailing wind direction from a mine waste deposit may be at risk of As exposure via inhalation and/or ingestion pathways. Enrichment of PTEs in the finer size fractions indicates that human health risk assessments based on bulk contaminant concentrations may underestimate potential exposure intensities.

  9. Modeling the nonlinear dynamic interactions of afferent pathways in the dentate gyrus of the hippocampus.

    Science.gov (United States)

    Dimoka, Angelika; Courellis, Spiros H; Marmarelis, Vasilis Z; Berger, Theodore W

    2008-05-01

    The dentate gyrus is the first region of the hippocampus that receives and integrates sensory information (e.g., visual, auditory, and olfactory) via the perforant path, which is composed of two distinct neuronal pathways: the Lateral Perforant Path (LPP) and the Medial Perforant Path (MPP). This paper examines the nonlinear dynamic interactions among arbitrary stimulation patterns at these two afferent pathways and their combined effect on the resulting response of the granule cells at the dentate gyrus. We employ non-parametric Poisson-Volterra models that serve as canonical quantitative descriptors of the nonlinear dynamic transformations of the neuronal signals propagating through these two neuronal pathways. These Poisson-Volterra models are estimated in the so-called "reduced form" with experimental data from in vitro hippocampal slices and provide excellent predictions of the electrophysiological activity of the granule cells in response to arbitrary stimulation patterns. The data are acquired through a custom-made multi-electrode-array system, which stimulated simultaneously the two pathways with random impulse trains and recorded the neuronal postsynaptic activity at the granule cell layer. The results of this study show that significant nonlinear interactions exist between the LPP and the MPP that may be critical for the integration of sensory information performed by the dentate gyrus of the hippocampus.

  10. Improving Metabolic Pathway Efficiency by Statistical Model-Based Multivariate Regulatory Metabolic Engineering.

    Science.gov (United States)

    Xu, Peng; Rizzoni, Elizabeth Anne; Sul, Se-Yeong; Stephanopoulos, Gregory

    2017-01-20

    Metabolic engineering entails target modification of cell metabolism to maximize the production of a specific compound. For empowering combinatorial optimization in strain engineering, tools and algorithms are needed to efficiently sample the multidimensional gene expression space and locate the desirable overproduction phenotype. We addressed this challenge by employing design of experiment (DoE) models to quantitatively correlate gene expression with strain performance. By fractionally sampling the gene expression landscape, we statistically screened the dominant enzyme targets that determine metabolic pathway efficiency. An empirical quadratic regression model was subsequently used to identify the optimal gene expression patterns of the investigated pathway. As a proof of concept, our approach yielded the natural product violacein at 525.4 mg/L in shake flasks, a 3.2-fold increase from the baseline strain. Violacein production was further increased to 1.31 g/L in a controlled benchtop bioreactor. We found that formulating discretized gene expression levels into logarithmic variables (Linlog transformation) was essential for implementing this DoE-based optimization procedure. The reported methodology can aid multivariate combinatorial pathway engineering and may be generalized as a standard procedure for accelerating strain engineering and improving metabolic pathway efficiency.

  11. Aerosol penetration of leak pathways : an examination of the available data and models.

    Energy Technology Data Exchange (ETDEWEB)

    Powers, Dana Auburn

    2009-04-01

    Data and models of aerosol particle deposition in leak pathways are described. Pathways considered include capillaries, orifices, slots and cracks in concrete. The Morewitz-Vaughan criterion for aerosol plugging of leak pathways is shown to be applicable only to a limited range of particle settling velocities and Stokes numbers. More useful are sampling efficiency criteria defined by Davies and by Liu and Agarwal. Deposition of particles can be limited by bounce from surfaces defining leak pathways and by resuspension of particles deposited on these surfaces. A model of the probability of particle bounce is described. Resuspension of deposited particles can be triggered by changes in flow conditions, particle impact on deposits and by shock or vibration of the surfaces. This examination was performed as part of the review of the AP1000 Standard Combined License Technical Report, APP-GW-GLN-12, Revision 0, 'Offsite and Control Room Dose Changes' (TR-112) in support of the USNRC AP1000 Standard Combined License Pre-Application Review.

  12. Pathways of Change Explaining the Effect of Smoke-Free Legislation on Smoking Cessation in the Netherlands. An Application of the International Tobacco Control Conceptual Model

    Science.gov (United States)

    de Vries, Hein; Fong, Geoffrey T.; Candel, Math J. J. M.; Thrasher, James F.; van den Putte, Bas; Thompson, Mary E.; Cummings, K. Michael; Willemsen, Marc C.

    2012-01-01

    Introduction: This study aims to test the pathways of change from individual exposure to smoke-free legislation on smoking cessation, as hypothesized in the International Tobacco Control (ITC) Conceptual Model. Methods: A nationally representative sample of Dutch smokers aged 15 years and older was surveyed during 4 consecutive annual surveys. Of the 1,820 baseline smokers, 1,012 participated in the fourth survey. Structural Equation Modeling was employed to test a model of the effects of individual exposure to smoke-free legislation through policy-specific variables (support for smoke-free legislation and awareness of the harm of [secondhand] smoking) and psychosocial mediators (attitudes, subjective norm, self-efficacy, and intention to quit) on quit attempts and quit success. Results: The effect of individual exposure to smoke-free legislation on smoking cessation was mediated by 1 pathway via support for smoke-free legislation, attitudes about quitting, and intention to quit smoking. Exposure to smoke-free legislation also influenced awareness of the harm of (secondhand) smoking, which in turn influenced the subjective norm about quitting. However, only attitudes about quitting were significantly associated with intention to quit smoking, whereas subjective norm and self-efficacy for quitting were not. Intention to quit predicted quit attempts and quit success, and self-efficacy for quitting predicted quit success. Conclusions: Our findings support the ITC Conceptual Model, which hypothesized that policies influence smoking cessation through policy-specific variables and psychosocial mediators. Smoke-free legislation may increase smoking cessation, provided that it succeeds in influencing support for the legislation. PMID:22491892

  13. Global transcriptome analysis of Atlantic cod (Gadus morhua) liver after in vivo methylmercury exposure suggests effects on energy metabolism pathways.

    Science.gov (United States)

    Yadetie, Fekadu; Karlsen, Odd Andre; Lanzén, Anders; Berg, Karin; Olsvik, Pål; Hogstrand, Christer; Goksøyr, Anders

    2013-01-15

    Methylmercury (MeHg) is a widely distributed contaminant polluting many aquatic environments, with health risks to humans exposed mainly through consumption of seafood. The mechanisms of toxicity of MeHg are not completely understood. In order to map the range of molecular targets and gain better insights into the mechanisms of toxicity, we prepared Atlantic cod (Gadus morhua) 135k oligonucleotide arrays and performed global analysis of transcriptional changes in the liver of fish treated with MeHg (0.5 and 2 mg/kg of body weight) for 14 days. Inferring from the observed transcriptional changes, the main pathways significantly affected by the treatment were energy metabolism, oxidative stress response, immune response and cytoskeleton remodeling. Consistent with known effects of MeHg, many transcripts for genes in oxidative stress pathways such as glutathione metabolism and Nrf2 regulation of oxidative stress response were differentially regulated. Among the differentially regulated genes, there were disproportionate numbers of genes coding for enzymes involved in metabolism of amino acids, fatty acids and glucose. In particular, many genes coding for enzymes of fatty acid beta-oxidation were up-regulated. The coordinated effects observed on many transcripts coding for enzymes of energy pathways may suggest disruption of nutrient metabolism by MeHg. Many transcripts for genes coding for enzymes in the synthetic pathways of sulphur containing amino acids were also up-regulated, suggesting adaptive responses to MeHg toxicity. By this toxicogenomics approach, we were also able to identify many potential biomarker candidate genes for monitoring environmental MeHg pollution. These results based on changes on transcript levels, however, need to be confirmed by other methods such as proteomics. Copyright © 2012 Elsevier B.V. All rights reserved.

  14. Observed and modeled pathways of the Iceland Scotland Overflow Water in the eastern North Atlantic

    Science.gov (United States)

    Zou, Sijia; Lozier, Susan; Zenk, Walter; Bower, Amy; Johns, William

    2017-12-01

    The spreading of Iceland Scotland Overflow Water (ISOW) in the eastern North Atlantic has largely been studied in an Eulerian frame using numerical models or with observations limited to a few locations. No study to date has provided a comprehensive description of the ISOW spreading pathways from both Eulerian and Lagrangian perspectives. In this paper, we use a combination of previously unreported current meter data, hydrographic data, RAFOS float data, and a high resolution (1/12°) numerical ocean model to study the spreading pathways of ISOW from both of these perspectives. We identify three ISOW transport cores in the central Iceland Basin (∼59°N), with the major core along the eastern boundary of the Reykjanes Ridge (RR) and the other two in the basin interior. Based on trajectories of observed and/or numerical floats seeded along 59°N, we also describe the ISOW spreading pathways and quantify their relative importance. Within 10 years, 7-11% of ISOW from 59°N escapes into the Irminger Sea via gaps in the RR north of the Charlie Gibbs Fracture Zone (CGFZ); the water that moves through these gaps principally originates from the shallower ISOW layer along the RR eastern boundary. 10-13% travels further southward until the CGFZ, where it crosses westward into the western subpolar gyre. 18-21% of ISOW spreads southward along the eastern flank of the Mid-Atlantic Ridge into the Western European Basin (WEB). Most of the remaining water stays in the Iceland Basin over the 10-year period. A model-based investigation provides a first look at the temporal variability of these ISOW pathways. We find that the fraction of southward water exported into the WEB is anti-correlated with the export through the CGFZ, a result assumed to reflect these pathways' interactions with the North Atlantic Current in magnitude and/or position shift.

  15. Pathway-based approaches for assessment of real-time exposure to an estrogenic wastewater treatment plant effluent on fathead minnow reproduction

    Science.gov (United States)

    Cavallin, Jenna E.; Jensen, Kathleen M.; Kahl, Michael D.; Villeneuve, Daniel L.; Lee, Kathy E.; Schroeder, Anthony L.; Mayasich, Joe; Eid, Evan P.; Nelson, Krysta R.; Milsk, Rebecca Y.; Blackwell, Brett R.; Berninger, Jason P.; LaLone, Carlie A.; Blanskma, Chad; Jicha, Terri M.; Elonen, Colleen M.; Johnson, Rodney C.; Ankley, Gerald T.

    2016-01-01

    Wastewater treatment plant (WWTP) effluents are known contributors of chemical mixtures into the environment. Of particular concern are endocrine-disrupting compounds, such as estrogens, which can affect the hypothalamic-pituitary-gonadal axis function in exposed organisms. The present study examined reproductive effects in fathead minnows exposed for 21 d to a historically estrogenic WWTP effluent. Fathead minnow breeding pairs were held in control water or 1 of 3 effluent concentrations (5%, 20%, and 100%) in a novel onsite, flow-through system providing real-time exposure. The authors examined molecular and biochemical endpoints representing key events along adverse outcome pathways linking estrogen receptor activation and other molecular initiating events to reproductive impairment. In addition, the authors used chemical analysis of the effluent to construct a chemical-gene interaction network to aid in targeted gene expression analyses and identifying potentially impacted biological pathways. Cumulative fecundity was significantly reduced in fish exposed to 100% effluent but increased in those exposed to 20% effluent, the approximate dilution factor in the receiving waters. Plasma vitellogenin concentrations in males increased in a dose-dependent manner with effluent concentration; however, male fertility was not impacted. Although in vitro analyses, analytical chemistry, and biomarker responses confirmed the effluent was estrogenic, estrogen receptor agonists were unlikely the primary driver of impaired reproduction. The results provide insights into the significance of pathway-based effects with regard to predicting adverse reproductive outcomes.

  16. [Development of a model diets for consumers with high exposure to food chemicals].

    Science.gov (United States)

    Zhang, Lei; Liu, Ai-dong; Liu, Zhao-ping; Yang, Da-jin

    2013-06-01

    To develop and verify a model diet for consumers with high exposure to food chemicals. Based on the assumption that a person might consume average amounts of several different foods but only two or three at high levels, a model diet were put forward to calculate the high exposures to certain food chemical.Important parameters of this model were selected by comparing the outputs of this model with those of a reference model-semi-probabilistic model that is based on individual data. The concentration data of lead, cadmium and mercury (45 832, 43 862 and 25 243 samples respectively) from the national risk surveillance for chemical contaminations and harmful factors (2011), and the consumption data from the national survey on nutrition and health status in Chinese population (2002) were used in this model optimization process. The final model was verified using concentration data of eight chemical contaminations from national surveillance database of 2010. When 90, 95 and 97.5 percentile exposure being calculated under the conditions that 7, 12, 20 and 30 food categories was used respectively, the model containing two high consumption foods (2+x model) got results lower than the reference values (the relative deviation foods (3+x model) got results higher than the reference values (the relative deviation > 0 ),but the relative deviation of the two models were both within 20%. The verification results showed that the dietary exposure results of 8 food contaminations got from 3+x model were all higher than and(or) close to those got from semi-probabilistic model, and the relative deviations were between -5% and 25%. The 3+x model diet can fulfill the demands of "conservative" and "accurate" on exposure assessment model, and can give reliable estimations of high exposure to food chemicals occurred in various food categories.

  17. Integrating both interaction pathways between warming and pesticide exposure on upper thermal tolerance in high- and low-latitude populations of an aquatic insect.

    Science.gov (United States)

    Op de Beeck, Lin; Verheyen, Julie; Stoks, Robby

    2017-05-01

    Global warming and chemical pollution are key anthropogenic stressors with the potential to interact. While warming can change the impact of pollutants and pollutants can change the sensitivity to warming, both interaction pathways have never been integrated in a single experiment. Therefore, we tested the effects of warming and multiple pesticide pulses (allowing accumulation) of chlorpyrifos on upper thermal tolerance (CTmax) and associated physiological traits related to aerobic/anaerobic energy production in the damselfly Ischnura elegans. To also assess the role of latitude-specific thermal adaptation in shaping the impact of warming and pesticide exposure on thermal tolerance, we exposed larvae from replicated high- and low-latitude populations to the pesticide in a common garden rearing experiment at 20 and 24 °C, the mean summer water temperatures at high and low latitudes. As expected, exposure to chlorpyrifos resulted in a lower CTmax. Yet, this pesticide effect on CTmax was lower at 24 °C compared to 20 °C because of a lower accumulation of chlorpyrifos in the medium at 24 °C. The effects on CTmax could partly be explained by reduction of the aerobic scope. Given that these effects did not differ between latitudes, gradual thermal evolution is not expected to counteract the negative effect of the pesticide on thermal tolerance. By for the first time integrating both interaction pathways we were not only able to provide support for both of them, but more importantly demonstrate that they can directly affect each other. Indeed, the warming-induced reduction in pesticide impact generated a lower pesticide-induced climate change sensitivity (in terms of decreased upper thermal tolerance). Our results indicate that, assuming no increase in pesticide input, global warming might reduce the negative effect of multiple pulse exposures to pesticides on sensitivity to elevated temperatures. Copyright © 2016 Elsevier Ltd. All rights reserved.

  18. The chemical exposure toxicity space (CETS) model: Displaying exposure time, aqueous and organic concentration, activity, and onset of toxicity.

    Science.gov (United States)

    Mackay, Donald; Celsie, Alena K D; Parnis, J Mark; McCarty, Lynn S; Arnot, Jon A; Powell, David E

    2017-05-01

    A 1-compartment toxicokinetic model is used to characterize the chemical exposure toxicity space (CETS), providing a novel graphic tool that can aid in the design of aquatic toxicity tests for fish and for interpreting their results. The graph depicts the solution to the differential equation describing the uptake kinetics of a chemical by a modeled fish under conventional bioassay conditions. The model relates the exposure concentration in the water to a dimensionless time and the onset of toxicity as determined by an estimated or assumed critical body residue or incipient lethal aqueous concentration. These concentration graphs are specific to each chemical and exposure and organism parameters and clearly demonstrate differences in toxicity between chemicals and how factors such as hydrophobicity influence the toxic endpoint. The CETS plots can also be used to assess bioconcentration test conditions to ensure that concentrations are well below toxic levels. Illustrative applications are presented using a recent set of high-quality toxicity data. Conversion of concentrations to chemical activities in the plots enables results for different baseline toxicants to be superimposed. For chemicals that have different modes of toxic action, the increased toxicity then becomes apparent. Implications for design and interpretation of aquatic toxicity tests are discussed. The model, and pictorial visualization of the time-course of aquatic toxicity tests, may contribute to improvements in test design, implementation, and interpretation, and to reduced animal usage. Environ Toxicol Chem 2017;36:1389-1396. © 2016 The Authors. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc. on behalf of SETAC. © 2016 The Authors. Environmental Toxicology and Chemistry Published by Wiley Periodicals, Inc. on behalf of SETAC.

  19. A pedagogical walkthrough of computational modeling and simulation of Wnt signaling pathway using static causal models in MATLAB.

    Science.gov (United States)

    Sinha, Shriprakash

    2016-12-01

    Simulation study in systems biology involving computational experiments dealing with Wnt signaling pathways abound in literature but often lack a pedagogical perspective that might ease the understanding of beginner students and researchers in transition, who intend to work on the modeling of the pathway. This paucity might happen due to restrictive business policies which enforce an unwanted embargo on the sharing of important scientific knowledge. A tutorial introduction to computational modeling of Wnt signaling pathway in a human colorectal cancer dataset using static Bayesian network models is provided. The walkthrough might aid biologists/informaticians in understanding the design of computational experiments that is interleaved with exposition of the Matlab code and causal models from Bayesian network toolbox. The manuscript elucidates the coding contents of the advance article by Sinha (Integr. Biol. 6:1034-1048, 2014) and takes the reader in a step-by-step process of how (a) the collection and the transformation of the available biological information from literature is done, (b) the integration of the heterogeneous data and prior biological knowledge in the network is achieved, (c) the simulation study is designed, (d) the hypothesis regarding a biological phenomena is transformed into computational framework, and (e) results and inferences drawn using d -connectivity/separability are reported. The manuscript finally ends with a programming assignment to help the readers get hands-on experience of a perturbation project. Description of Matlab files is made available under GNU GPL v3 license at the Google code project on https://code.google.com/p/static-bn-for-wnt-signaling-pathway and https: //sites.google.com/site/shriprakashsinha/shriprakashsinha/projects/static-bn-for-wnt-signaling-pathway. Latest updates can be found in the latter website.

  20. [Applying temporally-adjusted land use regression models to estimate ambient air pollution exposure during pregnancy].

    Science.gov (United States)

    Zhang, Y J; Xue, F X; Bai, Z P

    2017-03-06

    The impact of maternal air pollution exposure on offspring health has received much attention. Precise and feasible exposure estimation is particularly important for clarifying exposure-response relationships and reducing heterogeneity among studies. Temporally-adjusted land use regression (LUR) models are exposure assessment methods developed in recent years that have the advantage of having high spatial-temporal resolution. Studies on the health effects of outdoor air pollution exposure during pregnancy have been increasingly carried out using this model. In China, research applying LUR models was done mostly at the model construction stage, and findings from related epidemiological studies were rarely reported. In this paper, the sources of heterogeneity and research progress of meta-analysis research on the associations between air pollution and adverse pregnancy outcomes were analyzed. The methods of the characteristics of temporally-adjusted LUR models were introduced. The current epidemiological studies on adverse pregnancy outcomes that applied this model were systematically summarized. Recommendations for the development and application of LUR models in China are presented. This will encourage the implementation of more valid exposure predictions during pregnancy in large-scale epidemiological studies on the health effects of air pollution in China.

  1. Pathway-Consensus Approach to Metabolic Network Reconstruction for Pseudomonas putida KT2440 by Systematic Comparison of Published Models.

    Directory of Open Access Journals (Sweden)

    Qianqian Yuan

    Full Text Available Over 100 genome-scale metabolic networks (GSMNs have been published in recent years and widely used for phenotype prediction and pathway design. However, GSMNs for a specific organism reconstructed by different research groups usually produce inconsistent simulation results, which makes it difficult to use the GSMNs for precise optimal pathway design. Therefore, it is necessary to compare and identify the discrepancies among networks and build a consensus metabolic network for an organism. Here we proposed a process for systematic comparison of metabolic networks at pathway level. We compared four published GSMNs of Pseudomonas putida KT2440 and identified the discrepancies leading to inconsistent pathway calculation results. The mistakes in the models were corrected based on information from literature so that all the calculated synthesis and uptake pathways were the same. Subsequently we built a pathway-consensus model and then further updated it with the latest genome annotation information to obtain modelPpuQY1140 for P. putida KT2440, which includes 1140 genes, 1171 reactions and 1104 metabolites. We found that even small errors in a GSMN could have great impacts on the calculated optimal pathways and thus may lead to incorrect pathway design strategies. Careful investigation of the calculated pathways during the metabolic network reconstruction process is essential for building proper GSMNs for pathway design.

  2. A Chain Modeling Approach To Estimate the Impact of Soil Cadmium Pollution on Human Dietary Exposure

    National Research Council Canada - National Science Library

    Franz, Eelco; Romkens, Paul; van Raamsdonk, Leo; van der Fels-Klerx, Ine

    2008-01-01

    .... The extent of accumulation depends strongly on soil type and the degree of pollution. The objective of the present study was to develop a predictive model to estimate human dietary cadmium exposure from soil characteristics...

  3. Organizational Statement for EPA-sponsored Public Meetings to Discuss Pesticide Exposure Modeling

    Science.gov (United States)

    Information about EMPM meetings: Vision, Mission Statement, Organization, Meeting Administration and Public Meeting Attendance. Purpose is to discuss and exchange information regarding technical model-related pesticide exposure issues.

  4. A structured approach to modelling the effects of binary exposure variables over the life course

    National Research Council Canada - National Science Library

    Mishra, Gita; Nitsch, Dorothea; Black, Stephanie; De Stavola, Bianca; Kuh, Diana; Hardy, Rebecca

    2009-01-01

    .... This accumulation hypothesis is usually tested by summing indicators of binary variables across the life span to form an overall score that is then used as the exposure in regression models for health outcomes...

  5. Brain-Region-Specific Organoids Using Mini-bioreactors for Modeling ZIKV Exposure

    National Research Council Canada - National Science Library

    Qian, Xuyu; Nguyen, Ha Nam; Song, Hongjun; Song, Mingxi M; Hadiono, Christopher; Ogden, Sarah C; Hammack, Christy; Yao, Bing; Hamersky, Gregory R; Jacob, Fadi; Zhong, Chun; Yoon, Ki-jun; Jeang, William; Lin, Li; Li, Yujing; Thakor, Jai; Berg, Daniel A; Zhang, Ce; Kang, Eunchai; Chickering, Michael; Nauen, David; Ho, Cheng-Ying; Wen, Zhexing; Christian, Kimberly M; Shi, Pei-Yong; Maher, Brady J; Wu, Hao; Jin, Peng; Tang, Hengli; Ming, Guo-li

    2016-01-01

    .... Finally, we employed the forebrain organoid platform to model Zika virus (ZIKV) exposure. Quantitative analyses revealed preferential, productive infection of neural progenitors with either African or Asian ZIKV strains...

  6. Airborne particulate matter in vitro exposure induces cytoskeleton remodeling through activation of the ROCK-MYPT1-MLC pathway in A549 epithelial lung cells.

    Science.gov (United States)

    Chirino, Yolanda I; García-Cuellar, Claudia María; García-García, Carlos; Soto-Reyes, Ernesto; Osornio-Vargas, Álvaro Román; Herrera, Luis A; López-Saavedra, Alejandro; Miranda, Javier; Quintana-Belmares, Raúl; Pérez, Irma Rosas; Sánchez-Pérez, Yesennia

    2017-04-15

    Airborne particulate matter with an aerodynamic diameter ≤10μm (PM 10 ) is considered a risk factor for the development of lung cancer. Little is known about the cellular mechanisms by which PM 10 is associated with cancer, but there is evidence that its exposure can lead to an acquired invasive phenotype, apoptosis evasion, inflammasome activation, and cytoskeleton remodeling in lung epithelial cells. Cytoskeleton remodeling occurs through actin stress fiber formation, which is partially regulated through ROCK kinase activation, we aimed to investigate if this protein was activated in response to PM 10 exposure in A549 lung epithelial cells. Results showed that 10μg/cm 2 of PM 10 had no influence on cell viability but increased actin stress fibers, cytoplasmic ROCK expression, and phosphorylation of myosin phosphatase-targeting 1 (MYPT1) and myosin light chain (MLC) proteins, which are targeted by ROCK. The inhibition of ROCK prevented actin stress fiber formation and the phosphorylation of MYPT1 and MLC, suggesting that PM 10 activated the ROCK-MYPT1-MLC pathway in lung epithelial cells. The activation of ROCK1 has been involved in the acquisition of malignant phenotypes, and its induction by PM 10 exposure could contribute to the understanding of PM 10 as a risk factor for cancer development through the mechanisms associated with invasive phenotype. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Biological correlates of child and adolescent responses to disaster exposure: a bio-ecological model.

    Science.gov (United States)

    Weems, Carl F

    2015-07-01

    Exposure to both human-caused and natural disasters is associated with a number of postevent reactions in youth including the experience of symptoms of several mental disorders. There is wide variability in these responses, with some youth having very intense exposure to the disaster and yet showing resilience or even personal growth, while others with low exposure sometimes show intensely negative reactions. Research findings are reviewed in this article to identify biological correlates of risk and resilience focusing on potential genetic, neurobiological, and physiological factors linked to the reactions of children exposed to disasters. A bio-ecological model is presented to couch this review of biological correlates of disaster exposure. The model predicts susceptibility to negative reactions after disaster exposure, and the biological correlates of disaster reactions can be understood in terms of this susceptibility as it relates to biological markers of the fear system.

  8. Using consensus bayesian network to model the reactive oxygen species regulatory pathway.

    Directory of Open Access Journals (Sweden)

    Liangdong Hu

    Full Text Available Bayesian network is one of the most successful graph models for representing the reactive oxygen species regulatory pathway. With the increasing number of microarray measurements, it is possible to construct the bayesian network from microarray data directly. Although large numbers of bayesian network learning algorithms have been developed, when applying them to learn bayesian networks from microarray data, the accuracies are low due to that the databases they used to learn bayesian networks contain too few microarray data. In this paper, we propose a consensus bayesian network which is constructed by combining bayesian networks from relevant literatures and bayesian networks learned from microarray data. It would have a higher accuracy than the bayesian networks learned from one database. In the experiment, we validated the bayesian network combination algorithm on several classic machine learning databases and used the consensus bayesian network to model the Escherichia coli's ROS pathway.

  9. Reconstruction and logical modeling of glucose repression signaling pathways in Saccharomyces cerevisiae

    DEFF Research Database (Denmark)

    Christensen, Tobias S.; Soberano de Oliveira, Ana Paula; Nielsen, Jens

    2009-01-01

    Background: In the yeast Saccharomyces cerevisiae, the presence of high levels of glucose leads to an array of down-regulatory effects known as glucose repression. This process is complex due to the presence of feedback loops and crosstalk between different pathways, complicating the use of intui......Background: In the yeast Saccharomyces cerevisiae, the presence of high levels of glucose leads to an array of down-regulatory effects known as glucose repression. This process is complex due to the presence of feedback loops and crosstalk between different pathways, complicating the use...... of intuitive approaches to analyze the system. Results: We established a logical model of yeast glucose repression, formalized as a hypergraph. The model was constructed based on verified regulatory interactions and it includes 50 gene transcripts, 22 proteins, 5 metabolites and 118 hyperedges. We computed...... and evaluating the effect of deleting regulatory elements involved in glucose repression....

  10. Using consensus bayesian network to model the reactive oxygen species regulatory pathway.

    Science.gov (United States)

    Hu, Liangdong; Wang, Limin

    2013-01-01

    Bayesian network is one of the most successful graph models for representing the reactive oxygen species regulatory pathway. With the increasing number of microarray measurements, it is possible to construct the bayesian network from microarray data directly. Although large numbers of bayesian network learning algorithms have been developed, when applying them to learn bayesian networks from microarray data, the accuracies are low due to that the databases they used to learn bayesian networks contain too few microarray data. In this paper, we propose a consensus bayesian network which is constructed by combining bayesian networks from relevant literatures and bayesian networks learned from microarray data. It would have a higher accuracy than the bayesian networks learned from one database. In the experiment, we validated the bayesian network combination algorithm on several classic machine learning databases and used the consensus bayesian network to model the Escherichia coli's ROS pathway.

  11. Exposure age and ice-sheet model constraints on Pliocene East Antarctic ice sheet dynamics

    OpenAIRE

    Yamane, Masako; Yokoyama, Yusuke; Abe-Ouchi, Ayako; Obrochta, Stephen; Saito, Fuyuki; Moriwaki, Kiichi; Matsuzaki, Hiroyuki

    2015-01-01

    The Late Pliocene epoch is a potential analogue for future climate in a warming world. Here we reconstruct Plio-Pleistocene East Antarctic Ice Sheet (EAIS) variability using cosmogenic nuclide exposure ages and model simulations to better understand ice sheet behaviour under such warm conditions. New and previously published exposure ages indicate interior-thickening during the Pliocene. An ice sheet model with mid-Pliocene boundary conditions also results in interior thickening and suggests ...

  12. Gene Expression Profiles from Disease Discordant Twins Suggest Shared Antiviral Pathways and Viral Exposures among Multiple Systemic Autoimmune Diseases.

    Science.gov (United States)

    Gan, Lu; O'Hanlon, Terrance P; Lai, Zhennan; Fannin, Rick; Weller, Melodie L; Rider, Lisa G; Chiorini, John A; Miller, Frederick W

    2015-01-01

    Viral agents are of interest as possible autoimmune triggers due to prior reported associations and widely studied molecular mechanisms of antiviral immune responses in autoimmunity. Here we examined new viral candidates for the initiation and/or promotion of systemic autoimmune diseases (SAID), as well as possible related signaling pathways shared in the pathogenesis of those disorders. RNA isolated from peripheral blood samples from 33 twins discordant for SAID and 33 matched, unrelated healthy controls was analyzed using a custom viral-human gene microarray. Paired comparisons were made among three study groups-probands with SAID, their unaffected twins, and matched, unrelated healthy controls-using statistical and molecular pathway analyses. Probands and unaffected twins differed significantly in the expression of 537 human genes, and 107 of those were associated with viral infections. These 537 differentially expressed human genes participate in overlapping networks of several canonical, biologic pathways relating to antiviral responses and inflammation. Moreover, certain viral genes were expressed at higher levels in probands compared to either unaffected twins or unrelated, healthy controls. Interestingly, viral gene expression levels in unaffected twins appeared intermediate between those of probands and the matched, unrelated healthy controls. Of the viruses with overexpressed viral genes, herpes simplex virus-2 (HSV-2) was the only human viral pathogen identified using four distinct oligonucleotide probes corresponding to three HSV-2 genes associated with different stages of viral infection. Although the effects from immunosuppressive therapy on viral gene expression remain unclear, this exploratory study suggests a new approach to evaluate shared viral agents and antiviral immune responses that may be involved in the development of SAID.

  13. Modelling self-management pathways for people with diabetes in primary care

    OpenAIRE

    Penn, ML; Kennedy, AP; Vassilev, II; Chew-Graham, CA; Protheroe, J; Rogers, A.; Monks, T

    2015-01-01

    Background: self-management support to facilitate people with type 2 diabetes to effectively manage their condition is complex to implement. Organisational and system elements operating in relation to providing optimal self-management support in primary care are poorly understood. We have applied operational research techniques to model pathways in primary care to explore and illuminate the processes and points where people struggle to find self-management support.Methods: primary care clinic...

  14. Temperament Pathways to Childhood Disruptive Behavior and Adolescent Substance Abuse: Testing a Cascade Model

    OpenAIRE

    Martel, Michelle M.; Pierce, Laura; Nigg, Joel T.; Jester, Jennifer M; Adams, Kenneth; Puttler, Leon I.; Buu, Anne; Fitzgerald, Hiram; Zucker, Robert A.

    2009-01-01

    Temperament traits may increase risk for developmental psychopathology like Attention-Deficit/Hyperactivity Disorder (ADHD) and disruptive behaviors during childhood, as well as predisposing to substance abuse during adolescence. In the current study, a cascade model of trait pathways to adolescent substance abuse was examined. Component hypotheses were that (a) maladaptive traits would increase risk for inattention/hyperactivity, (b) inattention/hyperactivity would increase risk for disrupti...

  15. Slacking off in comfort : a dual-pathway model for psychological safety climate.

    OpenAIRE

    Deng, H; K Leung; Lam, C.; Huang, X

    2017-01-01

    Research on psychological safety climate has primarily focused on its salutary effects on group risk-taking behaviors. We developed a group-level dual-pathway model in which psychological safety climate also exerts a simultaneous negative effect on risk-taking behaviors by diminishing group average work motivation. In a field survey, we found that psychological safety climate was positively related to group learning behavior and voice through a reduction in group average fear of failure but n...

  16. USING CMAQ FOR EXPOSURE MODELING AND CHARACTERIZING THE SUB-GRID VARIABILITY FOR EXPOSURE ESTIMATES

    Science.gov (United States)

    Atmospheric processes and the associated transport and dispersion of atmospheric pollutants are known to be highly variable in time and space. Current air quality models that characterize atmospheric chemistry effects, e.g. the Community Multi-scale Air Quality (CMAQ), provide vo...

  17. Modeling time-varying exposure using inverse probability of treatment weights.

    Science.gov (United States)

    Grafféo, Nathalie; Latouche, Aurélien; Geskus, Ronald B; Chevret, Sylvie

    2017-12-27

    For estimating the causal effect of treatment exposure on the occurrence of adverse events, inverse probability weights (IPW) can be used in marginal structural models to correct for time-dependent confounding. The R package ipw allows IPW estimation by modeling the relationship between the exposure and confounders via several regression models, among which is the Cox model. For right-censored data and time-dependent exposures such as treatment switches, the ipw package allows a single switch, assuming that patients are treated once and for all. However, to accommodate multiple switches, we extend this package by implementing a function that allows for multiple and intermittent exposure status in the estimation of IPW using a survival model. This extension allows for the whole exposure treatment trajectory in the estimation of IPW. The impact of the estimated weights on the estimated causal effect, with both methods, is assessed in a simulation study. Then, the function is illustrated on a real dataset from a nationwide prospective observational cohort including patients with inflammatory bowel disease. In this study, patients received one or multiple medications (thiopurines, methotrexate, and anti-TNF) over time. We used a Cox marginal structural model to assess the effect of thiopurines exposure on the cause-specific hazard for cancer incidence considering other treatments as confounding factors. To this end, we used our extended function which is available online in the Supporting Information. © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  18. Identification of mutated driver pathways in cancer using a multi-objective optimization model.

    Science.gov (United States)

    Zheng, Chun-Hou; Yang, Wu; Chong, Yan-Wen; Xia, Jun-Feng

    2016-05-01

    New-generation high-throughput technologies, including next-generation sequencing technology, have been extensively applied to solve biological problems. As a result, large cancer genomics projects such as the Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium are producing large amount of rich and diverse data in multiple cancer types. The identification of mutated driver genes and driver pathways from these data is a significant challenge. Genome aberrations in cancer cells can be divided into two types: random 'passenger mutation' and functional 'driver mutation'. In this paper, we introduced a Multi-objective Optimization model based on a Genetic Algorithm (MOGA) to solve the maximum weight submatrix problem, which can be employed to identify driver genes and driver pathways promoting cancer proliferation. The maximum weight submatrix problem defined to find mutated driver pathways is based on two specific properties, i.e., high coverage and high exclusivity. The multi-objective optimization model can adjust the trade-off between high coverage and high exclusivity. We proposed an integrative model by combining gene expression data and mutation data to improve the performance of the MOGA algorithm in a biological context. Copyright © 2016 Elsevier Ltd. All rights reserved.

  19. Hepatotoxicity prediction by systems biology modeling of disturbed metabolic pathways using gene expression data.

    Science.gov (United States)

    Carbonell, Pablo; Lopez, Oriol; Amberg, Alexander; Pastor, Manuel; Sanz, Ferran

    2017-01-01

    The present study applies a systems biology approach for the in silico predictive modeling of drug toxicity on the basis of high-quality preclinical drug toxicity data with the aim of increasing the mechanistic understanding of toxic effects of compounds at different levels (pathway, cell, tissue, organ). The model development was carried out using 77 compounds for which gene expression data for treated primary human hepatocytes is available in the LINCS database and for which rodent in vivo hepatotoxicity information is available in the eTOX database. The data from LINCS were used to determine the type and number of pathways disturbed by each compound and to estimate the extent of disturbance (network perturbation elasticity), and were used to analyze the correspondence with the in vivo information from eTOX. Predictive models were developed through this integrative analysis, and their specificity and sensitivity were assessed. The quality of the predictions was determined on the basis of the area under the curve (AUC) of plots of true positive vs. false positive rates (ROC curves). The ROC AUC reached values of up to 0.9 (out of 1.0) for some hepatotoxicity endpoints. Moreover, the most frequently disturbed metabolic pathways were determined across the studied toxicants. They included, e.g., mitochondrial beta-oxidation of fatty acids and amino acid metabolism. The process was exemplified by successful predictions on various statins. In conclusion, an entirely new approach linking gene expression alterations to the prediction of complex organ toxicity was developed and evaluated.

  20. Childhood physical abuse and midlife physical health: testing a multi-pathway life course model.

    Science.gov (United States)

    Springer, Kristen W

    2009-07-01

    Although prior research has established that childhood abuse adversely affects midlife physical health, it is unclear how abuse continues to harm health decades after the abuse has ended. In this project, I assess four life course pathways (health behaviors, cognition, mental health, and social relation) that plausibly link childhood physical abuse to three midlife physical health outcomes (bronchitis diagnosis, ulcer diagnosis, and general physical health). These three outcomes are etiologically distinct, leading to unique testable hypotheses. Multivariate models controlling for childhood background and early adversity were estimated using data from over 3000 respondents in the Wisconsin Longitudinal Study, USA. The results indicate that midlife social relations and cognition do not function as pathways for any outcome. However, smoking is a crucial pathway connecting childhood abuse with bronchitis; mental health is important for ulcers; and BMI, smoking, and mental health are paramount for general physical health. These findings suggest that abuse survivors' coping mechanisms can lead to an array of midlife health problems. Furthermore, the results validate the use of etiologically distinct outcomes for understanding plausible causal pathways when using cross-sectional data.

  1. The probabilistic aggregate consumer exposure model (PACEM): validation and comparison to a lower-tier assessment for the cyclic siloxane D5.

    Science.gov (United States)

    Dudzina, Tatsiana; Delmaar, Christiaan J E; Biesterbos, Jacqueline W H; Bakker, Martine I; Bokkers, Bas G H; Scheepers, Paul T J; van Engelen, Jacqueline G M; Hungerbuehler, Konrad; von Goetz, Natalie

    2015-06-01

    Current practice of chemical risk assessment for consumer product ingredients still rarely exercises the aggregation of multi-source exposure. However, focusing on a single dominant source/pathway combination may lead to a significant underestimation of the risk for substances present in numerous consumer products, which often are used simultaneously. Moreover, in most cases complex multi-route exposure scenarios also need to be accounted for. This paper introduces and evaluates the performance of the Probabilistic Aggregate Consumer Exposure Model (PACEM) applied in the context of a tiered approach to exposure assessment for ingredients in cosmetics and personal care products (C&PCPs) using decamethylcyclopentasiloxane (D5) as a worked example. It is demonstrated that PACEM predicts a more realistic, but still conservative aggregate exposure within the Dutch adult population when compared to a deterministic point estimate obtained in a lower tier screening assessment. An overall validation of PACEM is performed by quantitatively relating and comparing its estimates to currently available human biomonitoring and environmental sampling data. Moderate (by maximum one order of magnitude) overestimation of exposure is observed due to a justified conservatism built into the model structure, resulting in the tool being suitable for risk assessment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  2. The nano-TiO{sub 2} exposure can induce hepatic inflammation involving in a JAK–STAT signalling pathway

    Energy Technology Data Exchange (ETDEWEB)

    Hong, Jie [Soochow University, Department of Applied Biology, School of Basic Medical and Biological Sciences (China); Hong, Fashui, E-mail: hongfsh-cn@sina.com [Huaiyin Normal University, Jiangsu Collaborative Innovation Center of Regional Modern Agriculture and Environmental Protection (China); Ze, Yuguan; Zhang, Yu-Qing, E-mail: sericult@suda.edu.cn [Soochow University, Department of Applied Biology, School of Basic Medical and Biological Sciences (China)

    2016-06-15

    TiO{sub 2} nanoparticles (TiO{sub 2} NPs) have unique physiochemical properties and thus are widely used in daily life. However, these nanoparticles also have potential toxic effects in humans and animals, and the issue of the security TiO{sub 2} NPs has also gained prominence. In this article, mice were administered a gavage instillation of 2.5, 5, or 10 mg/kg body weight TiO{sub 2} NPs (5–6 nm) for 90 days. We investigated whether TiO{sub 2} NPs activate the JAK–STAT signalling pathway, causing nano-TiO{sub 2}-induced hepatic toxicity. The results demonstrated that with increasing doses of TiO{sub 2} NPs the body weights of the mice body decreased, and the liver index, liver dysfunction, infiltration of inflammatory cells, and hepatocyte apoptosis and necrosis increased. Moreover, liver inflammation was accompanied by increased expression of Janus kinase 2, the signal transducers and activators of transcription 3, interleukin-6, cyclooxygenase-2, neutrophil gelatinase-associated lipocalin, purinergic receptor-7, and epithelial neutrophil-activating protein-78 and decreased expression of suppressors of cytokine signalling-1, peroxisome proliferator-activated receptor-γ, and peroxisome proliferator-activated receptor gamma coactivator-1 alpha. In summary, the activation of the JAK–STAT pathway may be involved in the hepatic inflammation induced by chronic nano-TiO{sub 2} toxicity.

  3. Obtaining realistic exposure estimates around hot spots using probabilistic uncertainty analysis: An elk foraging model

    Energy Technology Data Exchange (ETDEWEB)

    Appling, J.W.; Pye, L.H. [Woodward-Clyde Consultants, Denver, CO (United States)

    1994-12-31

    Screening level risk assessments for both human health and ecological receptors conducted using chemical concentrations found at hot spots often overestimate exposure and risk when the exposure area is larger than the hot spot. Making reasonable remedial decisions is difficult when risk is overestimated. Alternate methods of estimating exposure concentrations such as averaging over the area of the site may over or underestimate exposure. The authors have developed a Monte Carlo application to simulate probable large herbivore exposures to stack emissions deposited on forage under different time scenarios. The method generates a distribution of probable exposure concentrations assuming the herbivore may wander off the unfenced site and combines this with literature-based distributions of forage intake and exposure area estimates. Application of the model to realistic data sets shows that under some circumstances, when hot spot concentration exceed trigger levels, it can be shown that actual exposures are not likely to exceed trigger levels, and that if exceedances occur, they are unlikely to have significant impacts on the exposed population. If risk is excessive, remedial alternatives can be evaluated to see if they achieve acceptable risk levels. The method potentially has wide application in human and ecological risk assessments when hot spots are smaller than exposure areas for either individuals or populations.

  4. Exposure to Ionizing Radiation Causes Long-Term Increase in Serum Estradiol and Activation of PI3K-Akt Signaling Pathway in Mouse Mammary Gland

    Energy Technology Data Exchange (ETDEWEB)

    Suman, Shubhankar [Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC (United States); Johnson, Michael D. [Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC (United States); Fornace, Albert J. [Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC (United States); Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC (United States); Datta, Kamal, E-mail: kd257@georgetown.edu [Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington, DC (United States)

    2012-10-01

    Purpose: Exposure to ionizing radiation is an established risk factor for breast cancer. Radiation exposure during infancy, childhood, and adolescence confers the highest risk. Although radiation is a proven mammary carcinogen, it remains unclear where it acts in the complex multistage process of breast cancer development. In this study, we investigated the long-term pathophysiologic effects of ionizing radiation at a dose (2 Gy) relevant to fractionated radiotherapy. Methods and Materials: Adolescent (6-8 weeks old; n = 10) female C57BL/6J mice were exposed to 2 Gy total body {gamma}-radiation, the mammary glands were surgically removed, and serum and urine samples were collected 2 and 12 months after exposure. Molecular pathways involving estrogen receptor-{alpha} (ER{alpha}) and phosphatidylinositol-3-OH kinase (PI3K)-Akt signaling were investigated by immunohistochemistry and Western blot. Results: Serum estrogen and urinary levels of the oncogenic estrogen metabolite (16{alpha}OHE1) were significantly increased in irradiated animals. Immunostaining for the cellular proliferative marker Ki-67 and cyclin-D1 showed increased nuclear accumulation in sections of mammary glands from irradiated vs. control mice. Marked increase in p85{alpha}, a regulatory sub-unit of the PI3K was associated with increase in Akt, phospho-Akt, phospho-BAD, phospho-mTOR, and c-Myc in irradiated samples. Persistent increase in nuclear ER{alpha} in mammary tissues 2 and 12 months after radiation exposure was also observed. Conclusions: Taken together, our data not only support epidemiologic observations associating radiation and breast cancer but also, specify molecular events that could be involved in radiation-induced breast cancer.

  5. Highly pathogenic avian influenza (H5N1: pathways of exposure at the animal-human interface, a systematic review.

    Directory of Open Access Journals (Sweden)

    Maria D Van Kerkhove

    Full Text Available BACKGROUND: The threat posed by highly pathogenic avian influenza A H5N1 viruses to humans remains significant, given the continued occurrence of sporadic human cases (499 human cases in 15 countries with a high case fatality rate (approximately 60%, the endemicity in poultry populations in several countries, and the potential for reassortment with the newly emerging 2009 H1N1 pandemic strain. Therefore, we review risk factors for H5N1 infection in humans. METHODS AND FINDINGS: Several epidemiologic studies have evaluated the risk factors associated with increased risk of H5N1 infection among humans who were exposed to H5N1 viruses. Our review shows that most H5N1 cases are attributed to exposure to sick poultry. Most cases are sporadic, while occasional limited human-to-human transmission occurs. The most commonly identified factors associated with H5N1 virus infection included exposure through contact with infected blood or bodily fluids of infected poultry via food preparation practices; touching and caring for infected poultry; [corrected] exposure to H5N1 via swimming or bathing in potentially virus laden ponds; and exposure to H5N1 at live bird markets. CONCLUSIONS: Research has demonstrated that despite frequent and widespread contact with poultry, transmission of the H5N1 virus from poultry to humans is rare. Available research has identified several risk factors that may be associated with infection including close direct contact with poultry and transmission via the environment. However, several important data gaps remain that limit our understanding of the epidemiology of H5N1 in humans. Although infection in humans with H5N1 remains rare, human cases continue to be reported and H5N1 is now considered endemic among poultry in parts of Asia and in Egypt, providing opportunities for additional human infections and for the acquisition of virus mutations that may lead to more efficient spread among humans and other mammalian species

  6. Modeling thermal responses in human subjects following extended exposure to radiofrequency energy

    Directory of Open Access Journals (Sweden)

    Foster Kenneth R

    2004-02-01

    Full Text Available Abstract Background This study examines the use of a simple thermoregulatory model for the human body exposed to extended (45 minute exposures to radiofrequency/microwave (RF/MW energy at different frequencies (100, 450, 2450 MHz and under different environmental conditions. The exposure levels were comparable to or above present limits for human exposure to RF energy. Methods We adapted a compartmental model for the human thermoregulatory system developed by Hardy and Stolwijk, adding power to the torso skin, fat, and muscle compartments to simulate exposure to RF energy. The model uses values for parameters for "standard man" that were originally determined by Hardy and Stolwijk, with no additional adjustment. The model predicts changes in core and skin temperatures, sweat rate, and changes in skin blood flow as a result of RF energy exposure. Results The model yielded remarkably good quantitative agreement between predicted and measured changes in skin and core temperatures, and qualitative agreement between predicted and measured changes in skin blood flow. The model considerably underpredicted the measured sweat rates. Conclusions The model, with previously determined parameter values, was successful in predicting major aspects of human thermoregulatory response to RF energy exposure over a wide frequency range, and at different environmental temperatures. The model was most successful in predicting changes in skin temperature, and it provides insights into the mechanisms by which the heat added to body by RF energy is dissipated to the environment. Several factors are discussed that may have contributed to the failure to account properly for sweat rate. Some features of the data, in particular heating of the legs and ankles during exposure at 100 MHz, would require a more complex model than that considered here.

  7. A health economic lifetime treatment pathway model for low back pain in Sweden.

    Science.gov (United States)

    Olafsson, Gylfi; Jonsson, Emma; Fritzell, Peter; Hägg, Olle; Borgström, Fredrik

    2017-12-01

    To develop a health economic model to evaluate the long-term costs and outcomes over the healthcare treatment pathway for patients with low back pain (LBP). A health economic model, consisting of a decision tree structure with a Markov microsimulation model at the end of each branch, was created. Patients were followed from first observed clinical presentation with LBP until the age of 100 years or death. The underlying data to populate the model were based on Swedish national and regional registry data on healthcare resource use and sickness insurance in patients presenting with LBP in the Swedish region Västra Götaland during 2008-2012. Costs (outpatient healthcare visits, inpatient bed days, pharmaceuticals, productivity loss), EUR 2016, and quality-of-life based on EQ-5D data from the registries and published estimates were summarized over the lifetime of the patients with 3% annual discount. A lost quality-adjusted life year (QALY) was valued at €70,000. Mean lifetime total cost was estimated at €47,452/patient, of which indirect costs were 57%. Total lifetime economic burden for all patients coming to clinical presentation in Sweden per year was €8.8bn. The average LBP patient was estimated to face a loss of 2.7 QALYs over their lifetime compared with the general population. For all patients in Sweden coming to clinical presentation in 1 year this gives 505,407 QALYs lost, valued at €35.3bn. Adding the economic burden, the total societal burden amounts to €44.1bn. This pathway model shows that most patients with LBP receive conservative care, and a minority consume high-cost healthcare interventions like surgery. The model could be used to see broad economic effects of different patterns of healthcare provision in sub-groups with LBP and to estimate where it is possible to influence these pathways to increase utility for patients and for society.

  8. Association Between Myopia, Ultraviolet B Radiation Exposure, Serum Vitamin D Concentrations, and Genetic Polymorphisms in Vitamin D Metabolic Pathways in a Multicountry European Study.

    Science.gov (United States)

    Williams, Katie M; Bentham, Graham C G; Young, Ian S; McGinty, Ann; McKay, Gareth J; Hogg, Ruth; Hammond, Christopher J; Chakravarthy, Usha; Rahu, Mati; Seland, Johan; Soubrane, Gisele; Tomazzoli, Laura; Topouzis, Fotis; Fletcher, Astrid E

    2017-01-01

    Myopia is becoming increasingly common globally and is associated with potentially sight-threatening complications. Spending time outdoors is protective, but the mechanism underlying this association is poorly understood. To examine the association of myopia with ultraviolet B radiation (UVB; directly associated with time outdoors and sunlight exposure), serum vitamin D concentrations, and vitamin D pathway genetic variants, adjusting for years in education. A cross-sectional, population-based random sample of participants 65 years and older was chosen from 6 study centers from the European Eye Study between November 6, 2000, to November 15, 2002. Of 4187 participants, 4166 attended an eye examination including refraction, gave a blood sample, and were interviewed by trained fieldworkers using a structured questionnaire. Myopia was defined as a mean spherical equivalent of -0.75 diopters or less. Exclusion criteria included aphakia, pseudophakia, late age-related macular degeneration, and vision impairment due to cataract, resulting in 371 participants with myopia and 2797 without. Exposure to UVB estimated by combining meteorological and questionnaire data at different ages, single-nucleotide polymorphisms in vitamin D metabolic pathway genes, serum vitamin D3 concentrations, and years of education. Odds ratios (ORs) of UVB, serum vitamin D3 concentrations, vitamin D single-nucleotide polymorphisms, and myopia estimated from logistic regression. Of the included 3168 participants, the mean (SD) age was 72.4 (5) years, and 1456 (46.0%) were male. An SD increase in UVB exposure at age 14 to 19 years (OR, 0.81; 95% CI, 0.71-0.92) and 20 to 39 years (OR, 0.7; 95% CI, 0.62-0.93) was associated with a reduced adjusted OR of myopia; those in the highest tertile of years of education had twice the OR of myopia (OR, 2.08; 95% CI, 1.41-3.06). No independent associations between myopia and serum vitamin D3 concentrations nor variants in genes associated with vitamin D

  9. Pedestrian Exposure to Air Pollution in Cities: Modeling the Effect of Roadside Trees

    Directory of Open Access Journals (Sweden)

    Jorge Humberto Amorim

    2013-01-01

    Full Text Available The exposure of students to traffic-emitted carbon monoxide (CO in their daily walk to school is evaluated, with a particular emphasis on the effect of trees and route choice. The study is focused on the city centre of Aveiro, in central Portugal. Time evolution of the georeferenced location of an individual is tracked with a GPS for different alternative walking routes to a school. Spatial distribution of CO concentration is simulated with a computational fluid dynamics (CFD model. An exposure model is developed that associates the georeferenced location of the student with the computed air quality levels (at an average breathing height for that specific grid cell. For each individual, the model calculates the instantaneous exposure at each time frame and the mean value for a given period. Results show a general benefit induced by the trees over the mean exposure of the student in each route. However, in the case of instantaneous exposure values, this is not consistent along the entire period. Also, the variability of the estimated exposure values indicates the potential error that can be committed when using a single value of air quality as a surrogate of air pollution exposure.

  10. [Interference of testosterone synthesis through HPGA and ERalpha pathway after 17beta-estradiol exposure to regulate spermatogenesis].

    Science.gov (United States)

    Ding, Sijin; Qiao, Peihuan; Zhang, Linyuan; Chang, Bing

    2013-05-01

    To evaluate the effects of 17beta-estradiol (E2) exposure on male reproductive endocrine system, and study the potential mechanism. Male Wistar rats were gavaged with E2 (1.00, 0.50, 0.10, 0.01 mg.kg(-1).d(-1)) for 8 weeks, with corn oil as control. The testes weight and testicular organ coefficient and sperm parameter were examined. Serum levels of zinc and calcium were measured by atomic absorption spectrophotometry. Serum hormone concentrations were determined by RIA. The expression of testosterone synthetase mRNA were assessed by RT-PCR. The expression of estrogen and androgen receptor protein were detected by Western blot. Testis weight and testicular coefficient were significantly declined. Serum testosterone levels were significantly decreased. Serum estradiol levels showed a significant increase in a dose-related manner (Ptestosterone biosynthesis and spermatogensis in adulthood. mechanism may be indirectly through disturbing the balance of HPGA, and directly through up-regulating the level of ERa protein consequently inhibiting testosterone synthetase. Blood zinc was involved in mediating spermatogensis by E2 exposure.

  11. Calculation of lifetime lung cancer risks associated with radon exposure, based on various models and exposure scenarios.

    Science.gov (United States)

    Hunter, Nezahat; Muirhead, Colin R; Bochicchio, Francesco; Haylock, Richard G E

    2015-09-01

    The risk of lung cancer mortality up to 75 years of age due to radon exposure has been estimated for both male and female continuing, ex- and never-smokers, based on various radon risk models and exposure scenarios. We used risk models derived from (i) the BEIR VI analysis of cohorts of radon-exposed miners, (ii) cohort and nested case-control analyses of a European cohort of uranium miners and (iii) the joint analysis of European residential radon case-control studies. Estimates of the lifetime lung cancer risk due to radon varied between these models by just over a factor of 2 and risk estimates based on models from analyses of European uranium miners exposed at comparatively low rates and of people exposed to radon in homes were broadly compatible. For a given smoking category, there was not much difference in lifetime lung cancer risk between males and females. The estimated lifetime risk of radon-induced lung cancer for exposure to a concentration of 200 Bq m(-3) was in the range 2.98-6.55% for male continuing smokers and 0.19-0.42% for male never-smokers, depending on the model used and assuming a multiplicative relationship for the joint effect of radon and smoking. Stopping smoking at age 50 years decreases the lifetime risk due to radon by around a half relative to continuing smoking, but the risk for ex-smokers remains about a factor of 5-7 higher than that for never-smokers. Under a sub-multiplicative model for the joint effect of radon and smoking, the lifetime risk of radon-induced lung cancer was still estimated to be substantially higher for continuing smokers than for never smokers. Radon mitigation-used to reduce radon concentrations at homes-can also have a substantial impact on lung cancer risk, even for persons in their 50 s; for each of continuing smokers, ex-smokers and never-smokers, radon mitigation at age 50 would lower the lifetime risk of radon-induced lung cancer by about one-third. To maximise risk reductions, smokers in high

  12. Protective role of the cholinergic anti-inflammatory pathway in a mouse model of viral myocarditis.

    Directory of Open Access Journals (Sweden)

    Zheng Cheng

    Full Text Available Activation of the cholinergic anti-inflammatory pathway, which relies on the α7nAchR (alpha 7 nicotinic acetylcholine receptor, has been shown to decrease proinflammatory cytokines. This relieves inflammatory responses and improves the prognosis of patients with experimental sepsis, endotoxemia, ischemia/reperfusion injury, hemorrhagic shock, pancreatitis, arthritis and other inflammatory syndromes. However, whether the cholinergic anti-inflammatory pathway has an effect on acute viral myocarditis has not been investigated. Here, we studied the effects of the cholinergic anti-inflammatory pathway on acute viral myocarditis.In a coxsackievirus B3 murine myocarditis model (Balb/c, nicotine and methyllycaconitine were used to stimulate and block the cholinergic anti-inflammatory pathway, respectively. Relevant signal pathways were studied to compare their effects on myocarditis, survival rate, histopathological changes, ultrastructural changes, and cytokine levels. Nicotine treatments significantly improved survival rate, attenuated myocardial lesions, and downregulated the expression of TNF-α and IL-6. Methyllycaconitine decreased survival rate, aggravated myocardial lesions, and upregulated the expression of TNF-α and IL-6. In addition, levels of the signaling protein phosphorylated STAT3 were higher in the nicotine group and lower in the methyllycaconitine group compared with the untreated myocarditis group.These results show that nicotine protects mice from CVB3-induced viral myocarditis and that methyllycaconitine aggravates viral myocarditis in mice. Because nicotine is a α7nAchR agonist and methyllycaconitine is a α7nAchR antagonist, we conclude that α7nAchR activation increases the phosphorylation of STAT3, reduces the expression of TNF-α and IL-6, and, ultimately, alleviates viral myocarditis. We also conclude that blocking α7nAchR reduces the phosphorylation of STAT3, increases the expression of TNF-α and IL-6, aggravating viral

  13. Interaction pathways between soft lipid nanodiscs and plasma membranes: A molecular modeling study.

    Science.gov (United States)

    Li, Shixin; Luo, Zhen; Xu, Yan; Ren, Hao; Deng, Li; Zhang, Xianren; Huang, Fang; Yue, Tongtao

    2017-10-01

    Lipid nanodisc, a model membrane platform originally synthesized for study of membrane proteins, has recently been used as the carrier to deliver amphiphilic drugs into target tumor cells. However, the central question of how cells interact with such emerging nanomaterials remains unclear and deserves our research for both improving the delivery efficiency and reducing the side effect. In this work, a binary lipid nanodisc is designed as the minimum model to investigate its interactions with plasma membranes by using the dissipative particle dynamics method. Three typical interaction pathways, including the membrane attachment with lipid domain exchange of nanodiscs, the partial membrane wrapping with nanodisc vesiculation, and the receptor-mediated endocytosis, are discovered. For the first pathway, the boundary normal lipids acting as ligands diffuse along the nanodisc rim to gather at the membrane interface, repelling the central bola lipids to reach a stable membrane attachment. If bola lipids are positioned at the periphery and act as ligands, they diffuse to form a large aggregate being wrapped by the membrane, leaving the normal lipids exposed on the membrane exterior by assembling into a vesicle. Finally, by setting both central normal lipids and boundary bola lipids as ligands, the receptor-mediated endocytosis occurs via both deformation and self-rotation of the nanodiscs. All above pathways for soft lipid nanodiscs are quite different from those for rigid nanoparticles, which may provide useful guidelines for design of soft lipid nanodiscs in widespread biomedical applications. Copyright © 2017 Elsevier B.V. All rights reserved.

  14. Modeling the flux of metabolites in the juvenile hormone biosynthesis pathway using generalized additive models and ordinary differential equations.

    Science.gov (United States)

    Martínez-Rincón, Raúl O; Rivera-Pérez, Crisalejandra; Diambra, Luis; Noriega, Fernando G

    2017-01-01

    Juvenile hormone (JH) regulates development and reproductive maturation in insects. The corpora allata (CA) from female adult mosquitoes synthesize fluctuating levels of JH, which have been linked to the ovarian development and are influenced by nutritional signals. The rate of JH biosynthesis is controlled by the rate of flux of isoprenoids in the pathway, which is the outcome of a complex interplay of changes in precursor pools and enzyme levels. A comprehensive study of the changes in enzymatic activities and precursor pool sizes have been previously reported for the mosquito Aedes aegypti JH biosynthesis pathway. In the present studies, we used two different quantitative approaches to describe and predict how changes in the individual metabolic reactions in the pathway affect JH synthesis. First, we constructed generalized additive models (GAMs) that described the association between changes in specific metabolite concentrations with changes in enzymatic activities and substrate concentrations. Changes in substrate concentrations explained 50% or more of the model deviances in 7 of the 13 metabolic steps analyzed. Addition of information on enzymatic activities almost always improved the fitness of GAMs built solely based on substrate concentrations. GAMs were validated using experimental data that were not included when the model was built. In addition, a system of ordinary differential equations (ODE) was developed to describe the instantaneous changes in metabolites as a function of the levels of enzymatic catalytic activities. The results demonstrated the ability of the models to predict changes in the flux of metabolites in the JH pathway, and can be used in the future to design and validate experimental manipulations of JH synthesis.

  15. Groundwater Pathway Model for the Los Alamos National Laboratory Technical Area 54, Area G, Revision 1

    Energy Technology Data Exchange (ETDEWEB)

    Stauffer, Philip H. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Chu, Shaoping [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Miller, Terry A. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Strobridge, Daniel M. [Neptune Inc., Los Alamos, NM (United States); Cole, Gregory L. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Birdsell, Kay H. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Robinson, Bruce Alan [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Gable, Carl Walter [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Broxton, David E. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Springer, Everett P. [Los Alamos National Lab. (LANL), Los Alamos, NM (United States); Schofield, Tracy [Los Alamos National Lab. (LANL), Los Alamos, NM (United States)

    2017-02-10

    This report consists of four major sections, including this introductory section. Section 2 provides an overview of previous investigations related to the development of the current sitescale model. The methods and data used to develop the 3-D groundwater model and the techniques used to distill that model into a form suitable for use in the GoldSim models are discussed in Section 3. Section 4 presents the results of the model development effort and discusses some of the uncertainties involved. Eight attachments that provide details about the components and data used in this groundwater pathway model are also included with this report. The groundwater modeling effort reported here is a revision of the work that was conducted in 2005 (Stauffer et al., 2005a) in support of the 2008 Area G performance assessment and composite analysis (LANL, 2008). The revision effort was undertaken primarily to incorporate new geologic information that has been collected since 2003 at, and in the vicinity of, Area G. The new data were used to create a more accurate geologic framework model (GFM) that forms the basis of the numerical modeling of the site’s long-term performance. The groundwater modeling uses mean hydrologic properties of the geologic strata underlying Area G; this revision includes an evaluation of the impacts that natural variability in these properties may have on the model projections.

  16. Reaction pathways of model compounds of biomass-derived oxygenates on Fe/Ni bimetallic surfaces

    Science.gov (United States)

    Yu, Weiting; Chen, Jingguang G.

    2015-10-01

    Controlling the activity and selectivity of converting biomass-derivatives to fuels and valuable chemicals is critical for the utilization of biomass feedstocks. There are primarily three classes of non-food competing biomass, cellulose, hemicellulose and lignin. In the current work, glycolaldehyde, furfural and acetaldehyde are studied as model compounds of the three classes of biomass-derivatives. Monometallic Ni(111) and monolayer (ML) Fe/Ni(111) bimetallic surfaces are studied for the reaction pathways of the three biomass surrogates. The ML Fe/Ni(111) surface is identified as an efficient surface for the conversion of biomass-derivatives from the combined results of density functional theory (DFT) calculations and temperature programmed desorption (TPD) experiments. A correlation is also established between the optimized adsorption geometry and experimental reaction pathways. These results should provide helpful insights in catalyst design for the upgrading and conversion of biomass.

  17. The p-ERK–p-c-Jun–cyclinD1 pathway is involved in proliferation of smooth muscle cells after exposure to cigarette smoke extract

    Energy Technology Data Exchange (ETDEWEB)

    Li, Tianjia [Department of Vascular surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005 (China); Song, Ting [Nursing Department of Orthopedics 3rd Ward, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005 (China); Ni, Leng; Yang, Genhuan; Song, Xitao; Wu, Lifei [Department of Vascular surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005 (China); Liu, Bao, E-mail: liubao72@yahoo.com.cn [Department of Vascular surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005 (China); Liu, Changwei, E-mail: liucw@vip.sina.com [Department of Vascular surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, 5 Dong Dan San Tiao, Beijing 100005 (China)

    2014-10-24

    Highlights: • Smooth muscle cells proliferated after exposure to cigarette smoke extract. • The p-ERK, p-c-Jun, and cyclinD1 expressions increased in the process. • The p-ERK inhibitor, U0126, can reverse these effects. • The p-ERK → p-c-Jun → cyclinD1 pathway is involved in the process. - Abstract: An epidemiological survey has shown that smoking is closely related to atherosclerosis, in which excessive proliferation of vascular smooth muscle cells (SMCs) plays a key role. To investigate the mechanism underlying this unusual smoking-induced proliferation, cigarette smoke extract (CSE), prepared as smoke-bubbled phosphate-buffered saline (PBS), was used to induce effects mimicking those exerted by smoking on SMCs. As assessed by Cell Counting Kit-8 detection (an improved MTT assay), SMC viability increased significantly after exposure to CSE. Western blot analysis demonstrated that p-ERK, p-c-Jun, and cyclinD1 expression increased. When p-ERK was inhibited using U0126 (inhibitor of p-ERK), cell viability decreased and the expression of p-c-Jun and cyclinD1 was reduced accordingly, suggesting that p-ERK functions upstream of p-c-Jun and cyclinD1. When a c-Jun over-expression plasmid was transfected into SMCs, the level of cyclinD1 in these cells increased. Moreover, when c-Jun was knocked down by siRNA, cyclinD1 levels decreased. In conclusion, our findings indicate that the p-ERK–p-c-Jun–cyclinD1 pathway is involved in the excessive proliferation of SMCs exposed to CSE.

  18. Effects of copper nanoparticle exposure on host defense in a murine pulmonary infection model

    Directory of Open Access Journals (Sweden)

    Grassian Vicki H

    2011-09-01

    Full Text Available Abstract Background Human exposure to nanoparticles (NPs and environmental bacteria can occur simultaneously. NPs induce inflammatory responses and oxidative stress but may also have immune-suppressive effects, impairing macrophage function and altering epithelial barrier functions. The purpose of this study was to assess the potential pulmonary effects of inhalation and instillation exposure to copper (Cu NPs using a model of lung inflammation and host defense. Methods We used Klebsiella pneumoniae (K.p. in a murine lung infection model to determine if pulmonary bacterial clearance is enhanced or impaired by Cu NP exposure. Two different exposure modes were tested: sub-acute inhalation (4 hr/day, 5 d/week for 2 weeks, 3.5 mg/m3 and intratracheal instillation (24 hr post-exposure, 3, 35, and 100 μg/mouse. Pulmonary responses were evaluated by lung histopathology plus measurement of differential cell counts, total protein, lactate dehydrogenase (LDH activity, and inflammatory cytokines in bronchoalveolar lavage (BAL fluid. Results Cu NP exposure induced inflammatory responses with increased recruitment of total cells and neutrophils to the lungs as well as increased total protein and LDH activity in BAL fluid. Both inhalation and instillation exposure to Cu NPs significantly decreased the pulmonary clearance of K.p.-exposed mice measured 24 hr after bacterial infection following Cu NP exposure versus sham-exposed mice also challenged with K.p (1.4 × 105 bacteria/mouse. Conclusions Cu NP exposure impaired host defense against bacterial lung infections and induced a dose-dependent decrease in bacterial clearance in which even our lowest dose demonstrated significantly lower clearance than observed in sham-exposed mice. Thus, exposure to Cu NPs may increase the risk of pulmonary infection.

  19. Creating and analyzing pathway and protein interaction compendia for modelling signal transduction networks

    Directory of Open Access Journals (Sweden)

    Kirouac Daniel C

    2012-05-01

    Full Text Available Abstract Background Understanding the information-processing capabilities of signal transduction networks, how those networks are disrupted in disease, and rationally designing therapies to manipulate diseased states require systematic and accurate reconstruction of network topology. Data on networks central to human physiology, such as the inflammatory signalling networks analyzed here, are found in a multiplicity of on-line resources of pathway and interactome databases (Cancer CellMap, GeneGo, KEGG, NCI-Pathway Interactome Database (NCI-PID, PANTHER, Reactome, I2D, and STRING. We sought to determine whether these databases contain overlapping information and whether they can be used to construct high reliability prior knowledge networks for subsequent modeling of experimental data. Results We have assembled an ensemble network from multiple on-line sources representing a significant portion of all machine-readable and reconcilable human knowledge on proteins and protein interactions involved in inflammation. This ensemble network has many features expected of complex signalling networks assembled from high-throughput data: a power law distribution of both node degree and edge annotations, and topological features of a “bow tie” architecture in which diverse pathways converge on a highly conserved set of enzymatic cascades focused around PI3K/AKT, MAPK/ERK, JAK/STAT, NFκB, and apoptotic signaling. Individual pathways exhibit “fuzzy” modularity that is statistically significant but still involving a majority of “cross-talk” interactions. However, we find that the most widely used pathway databases are highly inconsistent with respect to the actual constituents and interactions in this network. Using a set of growth factor signalling networks as examples (epidermal growth factor, transforming growth factor-beta, tumor necrosis factor, and wingless, we find a multiplicity of network topologies in which receptors couple to downstream

  20. Timing of Maternal Exposure to a High Fat Diet and Development of Obesity and Hyperinsulinemia in Male Rat Offspring: Same Metabolic Phenotype, Different Developmental Pathways?

    Directory of Open Access Journals (Sweden)

    Graham J. Howie

    2013-01-01

    Full Text Available Objective. Offspring born to mothers either fed an obesogenic diet throughout their life or restricted to pregnancy and lactation demonstrate obesity, hyperinsulinemia, and hyperleptinemia, irrespective of their postweaning diet. We examined whether timing of a maternal obesogenic diet results in differential regulation of pancreatic adipoinsular and inflammatory signaling pathways in offspring. Methods. Female Wistar rats were randomized into 3 groups: (1 control (CONT: fed a control diet preconceptionally and during pregnancy and lactation; (2 maternal high fat (MHF: fed an HF diet throughout their life and during pregnancy and lactation; (3 pregnancy and lactation HF (PLHF: fed a control diet throughout life until mating, then HF diet during pregnancy and lactation. Male offspring were fed the control diet postweaning. Plasma and pancreatic tissue were collected, and mRNA concentrations of key factors regulating adipoinsular axis signaling were determined. Results. MHF and PLHF offspring exhibited increased adiposity and were hyperinsulinemic and hyperleptinemic compared to CONT. Despite a similar anthropometric phenotype, MHF and PLHF offspring exhibited distinctly different expression for key pancreatic genes, dependent upon maternal preconceptional nutritional background. Conclusions. These data suggest that despite using differential signaling pathways, obesity in offspring may be an adaptive outcome of early life exposure to HF during critical developmental windows.

  1. Modeling position-specific isotope fractionation of organic micropollutants degradation via different reaction pathways

    DEFF Research Database (Denmark)

    Jin, Biao; Rolle, Massimo

    contaminants [2,3] are still lacking. In this study we propose an integrated modeling approach to simultaneously predict concentration as well as bulk and position-specific multi-element isotope evolution during the transformation of organic micropollutants [4]. The model simulates position......Organic compounds are produced in vast quantities for industrial and agricultural use, as well as for human and animal healthcare [1]. These chemicals and their metabolites are frequently detected at trace levels in fresh water environments, such as groundwater systems, and are referred......: dichlorobenzamide (BAM), isoproturon (IPU) and diclofenac (DCF). The model successfully reproduces the multi-element isotope data, and precisely captures the dual element isotope trends, characterizing the different degradation pathways. Besides illustrating the model capability of mechanistic evaluation...

  2. Modeling reaction front propagation from preferential flow pathways in fractured media

    Science.gov (United States)

    Myint, P. C.; Walsh, S. D.; Carroll, S.; Firoozabadi, A.

    2013-12-01

    We present analytical results and numerical models describing the growth and propagation of reaction fronts around fluid flow pathways in fractured rock, and explore how the front geometry influences both the propagation of the reaction fronts and changes in the solution chemistry. We compare model results to core-flood experiments conducted on mated wellbore cement/caprock half-cores, and demonstrate that the model accurately reproduces the observed solution chemistry. In particular the simulations provide a physical explanation for the apparent 'super-diffusive' reaction zone growth suggested by the brine chemistry. We conclude by discussing the implications of the model for long-term behavior of single and multiple reaction fronts.

  3. Effects of oral aluminum exposure on behavior and neurogenesis in a transgenic mouse model of Alzheimer's disease.

    Science.gov (United States)

    Ribes, D; Colomina, M T; Vicens, P; Domingo, J L

    2008-12-01

    The effects of a very low oral dose of Al on spatial learning and neurogenesis were evaluated in a transgenic mouse (Tg 2576) model of Alzheimer disease. At 5 months of age, wild and Tg 2576 mice received a diet supplemented with Al lactate at 0 and 1 mg/g of diet for 120 days. The experimental groups (n=7-8) were: control wild, Al-treated wild, control transgenic, and Al-treated transgenic. After 3 months of Al exposure, activity in an open-field and learning in a water maze were evaluated. At the end of the behavioral testing, in order to study cell proliferation and differentiation in the hippocampus, mice were injected with 5-bromo-2-deoxyuridine (BrdU) and sacrificed 1 or 28 days after the last BrdU injection. Tg 2576 mice were impaired in both acquisition and retention of the water maze task, showing higher amounts of beta-amyloid fragments in brain. Aluminum exposure impaired learning and memory in wild mice and increased the total number of proliferating cells in the dentate gyrus of hippocampus. The low Al doses here experimented suggest that this element might impair cognition in the general population at doses comparable to current levels of human exposure. Although these doses are not enough to interact with the amyloidogenic pathway, an increase in cell proliferation can indicate a reactive response of the brain to Al insult. Further investigations should be performed to corroborate the effects observed at very low doses of Al and to study the potential effects derived from a longer exposure period.

  4. Prediction of Relative In Vivo Metabolite Exposure from In Vitro Data Using Two Model Drugs: Dextromethorphan and Omeprazole

    Science.gov (United States)

    Lutz, Justin D.

    2012-01-01

    Metabolites can have pharmacological or toxicological effects, inhibit metabolic enzymes, and be used as probes of drug-drug interactions or specific cytochrome P450 (P450) phenotypes. Thus, better understanding and prediction methods are needed to characterize metabolite exposures in vivo. This study aimed to test whether in vitro data could be used to predict and rationalize in vivo metabolite exposures using two model drugs and P450 probes: dextromethorphan and omeprazole with their primary metabolites dextrorphan, 5-hydroxyomeprazole (5OH-omeprazole), and omeprazole sulfone. Relative metabolite exposures were predicted using metabolite formation and elimination clearances. For dextrorphan, the formation clearances of dextrorphan glucuronide and 3-hydroxymorphinan from dextrorphan in human liver microsomes were used to predict metabolite (dextrorphan) clearance. For 5OH-omeprazole and omeprazole sulfone, the depletion rates of the metabolites in human hepatocytes were used to predict metabolite clearance. Dextrorphan/dextromethorphan in vivo metabolite/parent area under the plasma concentration versus time curve ratio (AUCm/AUCp) was overpredicted by 2.1-fold, whereas 5OH-omeprazole/omeprazole and omeprazole sulfone/omeprazole were predicted within 0.75- and 1.1-fold, respectively. The effect of inhibition or induction of the metabolite's formation and elimination on the AUCm/AUCp ratio was simulated. The simulations showed that unless metabolite clearance pathways are characterized, interpretation of the metabolic ratios is exceedingly difficult. This study shows that relative in vivo metabolite exposure can be predicted from in vitro data and characterization of secondary metabolism of probe metabolites is critical for interpretation of phenotypic data. PMID:22010218

  5. Effects of Long-Term In Vivo Exposure to Di-2-Ethylhexylphthalate on Thyroid Hormones and the TSH/TSHR Signaling Pathways in Wistar Rats.

    Science.gov (United States)

    Dong, Xinwen; Dong, Jin; Zhao, Yue; Guo, Jipeng; Wang, Zhanju; Liu, Mingqi; Zhang, Yunbo; Na, Xiaolin

    2017-01-04

    Di-(2-ethylhexyl)phthalate (DEHP) was a widely used chemical with human toxicity. Recent in vivo and in vitro studies suggested that DEHP-exposure may be associated with altered serum thyroid hormones (THs) levels, but the underlying molecular mechanisms were largely unknown. To explore the possible molecular mechanisms, 128 Wistar rats were dosed with DEHP by gavage at 0, 150, 300, and 600 mg/kg/day for 3 months (M) and 6 M, respectively. After exposure, expression of genes and proteins in the thyroid, pituitary, and hypothalamus tissues of rats were analyzed by Q-PCR and western blot, while the sera and urine samples were assayed by radioimmunoassay and ELISA. Results showed that serum THs levels were suppressed by DEHP on the whole. DEHP treatment influenced the levels of rats' thyrotropin releasing hormone receptor (TRHr), Deiodinases 1 (D1), thyroid stimulating hormone beta (TSHβ), sodium iodide symporter (NIS), thyroid stimulating hormone receptor (TSHr), thyroperoxidase (TPO), thyroid transcription factor 1 (TTF-1), and thyroglobulin (TG) mRNA/protein expression in the hypothalamus-pituitary-thyroid (HPT) axis and decreased urine iodine. Taken together, observed findings indicate that DEHP could reduce thyroid hormones via disturbing the HPT axis, and the activated TSH/TSHR pathway is required to regulate thyroid function via altering TRHr, TSHβ, NIS, TSHr, TPO, TTF-1 and TG mRNA/protein expression of the HPT axis.

  6. Road traffic noise: self-reported noise annoyance versus GIS modelled road traffic noise exposure.

    Science.gov (United States)

    Birk, Matthias; Ivina, Olga; von Klot, Stephanie; Babisch, Wolfgang; Heinrich, Joachim

    2011-11-01

    self-reported road traffic noise annoyance is commonly used in epidemiological studies for assessment of potential health effects. Alternatively, some studies have used geographic information system (GIS) modelled exposure to road traffic noise as an objective parameter. The aim of this study was to analyse the association between noise exposure due to neighbouring road traffic and the noise annoyance of adults, taking other determinants into consideration. parents of 951 Munich children from the two German birth cohorts GINIplus and LISAplus reported their annoyance due to road traffic noise at home. GIS modelled road traffic noise exposure (L(den), maximum within a 50 m buffer) from the noise map of the city of Munich was available for all families. GIS-based calculated distance to the closest major road (≥10,000 vehicles per day) and questionnaire based-information about family income, parental education and the type of the street of residence were explored for their potential influence. An ordered logit regression model was applied. The noise levels (L(den)) and the reported noise annoyance were compared with an established exposure-response function. the correlation between noise annoyance and noise exposure (L(den)) was fair (Spearman correlation r(s) = 0.37). The distance to a major road and the type of street were strong predictors for the noise annoyance. The annoyance modelled by the established exposure-response function and that estimated by the ordered logit model were moderately associated (Pearson's correlation r(p) = 0.50). road traffic noise annoyance was associated with GIS modelled neighbouring road traffic noise exposure (L(den)). The distance to a major road and the type of street were additional explanatory factors of the noise annoyance appraisal.

  7. MobRISK: a model for assessing the exposure of road users to flash flood events

    Science.gov (United States)

    Shabou, Saif; Ruin, Isabelle; Lutoff, Céline; Debionne, Samuel; Anquetin, Sandrine; Creutin, Jean-Dominique; Beaufils, Xavier

    2017-09-01

    Recent flash flood impact studies highlight that road networks are often disrupted due to adverse weather and flash flood events. Road users are thus particularly exposed to road flooding during their daily mobility. Previous exposure studies, however, do not take into consideration population mobility. Recent advances in transportation research provide an appropriate framework for simulating individual travel-activity patterns using an activity-based approach. These activity-based mobility models enable the prediction of the sequence of activities performed by individuals and locating them with a high spatial-temporal resolution. This paper describes the development of the MobRISK microsimulation system: a model for assessing the exposure of road users to extreme hydrometeorological events. MobRISK aims at providing an accurate spatiotemporal exposure assessment by integrating travel-activity behaviors and mobility adaptation with respect to weather disruptions. The model is applied in a flash-flood-prone area in southern France to assess motorists' exposure to the September 2002 flash flood event. The results show that risk of flooding mainly occurs in principal road links with considerable traffic load. However, a lag time between the timing of the road submersion and persons crossing these roads contributes to reducing the potential vehicle-related fatal accidents. It is also found that sociodemographic variables have a significant effect on individual exposure. Thus, the proposed model demonstrates the benefits of considering spatiotemporal dynamics of population exposure to flash floods and presents an important improvement in exposure assessment methods. Such improved characterization of road user exposures can present valuable information for flood risk management services.

  8. Modelling Dietary Exposure to Chemical Components in Heat-Processed Meats

    DEFF Research Database (Denmark)

    Georgiadis, Stylianos; Jakobsen, Lea Sletting; Nielsen, Bo Friis

    Several chemical compounds that potentially increase the risk of developing cancer in humans are formed during heat processing of meat. Estimating the overall health impact of these compounds in the population requires accurate estimation of the exposure to the chemicals, as well as the probability.......g. the Poisson-Lognormal approach, are promising tools to address this obstacle. The exposure estimates can then be applied to dose-response models to quantify the cancer risk....

  9. In vitro and in vivo models of acute alcohol exposure.

    Science.gov (United States)

    Dolganiuc, Angela; Szabo, Gyongyi

    2009-03-14

    Alcohol abuse is a global problem due to the financial burden on society and the healthcare system. While the harmful health effects of chronic alcohol abuse are well established, more recent data suggest that acute alcohol consumption also affects human wellbeing. Thus, there is a need for research models in order to fully understand the effect of acute alcohol abuse on different body systems and organs. The present manuscript summarizes the interdisciplinary advantages and disadvantages of currently available human and non-human models of acute alcohol abuse, and identifies their suitability for biomedical research.

  10. The Validity and Applicability of Using a Generic Exposure Assessment Model for Occupational Exposure to Nano-Objects and Their Aggregates and Agglomerates

    NARCIS (Netherlands)

    Bekker, Cindy; Voogd, Eef; Fransman, Wouter; Vermeulen, Roel

    2016-01-01

    BACKGROUND: Control banding can be used as a first-tier assessment to control worker exposure to nano-objects and their aggregates and agglomerates (NOAA). In a second tier, more advanced modelling approaches are needed to produce quantitative exposure estimates. As currently no general quantitative

  11. The validity and applicability of using a generic exposure assessment model for occupational exposure to nano-objects and their aggregates and agglomerates

    NARCIS (Netherlands)

    Bekker, C.; Voogd, E.; Fransman, W.; Vermeulen, R.

    2016-01-01

    Background: Control banding can be used as a first-tier assessment to control worker exposure to nano-objects and their aggregates and agglomerates (NOAA). In a second tier, more advanced modelling approaches are needed to produce quantitative exposure estimates. As currently no general quantitative

  12. ADDRESSING HUMAN EXPOSURE TO AIR POLLUTANTS AROUND BUILDINGS IN URBAN AREAS WITH COMPUTATIONAL FLUID DYNAMICS (CFD) MODELS

    Science.gov (United States)

    Computational Fluid Dynamics (CFD) simulations provide a number of unique opportunities for expanding and improving capabilities for modeling exposures to environmental pollutants. The US Environmental Protection Agency's National Exposure Research Laboratory (NERL) has been c...

  13. Position-specific isotope modeling of organic micropollutants transformations through different reaction pathways

    Science.gov (United States)

    Jin, Biao; Rolle, Massimo

    2016-04-01

    Organic compounds are produced in vast quantities for industrial and agricultural use, as well as for human and animal healthcare [1]. These chemicals and their metabolites are frequently detected at trace levels in fresh water environments where they undergo degradation via different reaction pathways. Compound specific stable isotope analysis (CSIA) is a valuable tool to identify such degradation pathways in different environmental systems. Recent advances in analytical techniques have promoted the fast development and implementation of multi-element CSIA. However, quantitative frameworks to evaluate multi-element stable isotope data and incorporating mechanistic information on the degradation processes [2,3] are still lacking. In this study we propose a mechanism-based modeling approach to simultaneously evaluate concentration as well as bulk and position-specific multi-element isotope evolution during the transformation of organic micropollutants. The model explicitly simulates position-specific isotopologues for those atoms that experience isotope effects and, thereby, provides a mechanistic description of isotope fractionation occurring at different molecular positions. We validate the proposed approach with the concentration and multi-element isotope data of three selected organic micropollutants: dichlorobenzamide (BAM), isoproturon (IPU) and diclofenac (DCF). The model precisely captures the dual element isotope trends characteristic of different reaction pathways and their range of variation consistent with observed multi-element (C, N) bulk isotope fractionation. The proposed approach can also be used as a tool to explore transformation pathways in scenarios for which position-specific isotope data are not yet available. [1] Schwarzenbach, R.P., Egli, T., Hofstetter, T.B., von Gunten, U., Wehrli, B., 2010. Global Water Pollution and Human Health. Annu. Rev. Environ. Resour. doi:10.1146/annurev-environ-100809-125342. [2] Jin, B., Haderlein, S.B., Rolle, M

  14. Parameterization Models for Pesticide Exposure via Crop Consumption<