Investigation of Nrf2, AhR and ATF4 Activation in Toxicogenomic Databases

Toxicological responses to chemical insult are largely regulated by transcriptionally activated pathways that may be independent, correlated and partially or fully overlapping. Investigating the dynamics of the interactions between stress responsive transcription factors from toxicogenomic data and defining the signature of each of them is an additional step toward a system level understanding of perturbation driven mechanisms. To this end, we investigated the segregation of the genes belonging to the three following transcriptionally regulated pathways: the AhR pathway, the Nrf2 pathway and the ATF4 pathway. Toxicogenomic datasets from three projects (carcinoGENOMICS, Predict-IV and TG-GATEs) obtained in various experimental conditions (in human and rat in vitro liver and kidney models and rat in vivo, with bolus administration and with repeated doses) were combined and consolidated where overlaps between datasets existed. A bioinformatic analysis was performed to refine pathways' signatures and to create chemical activation capacity scores to classify chemicals by their potency and selectivity of activation of each pathway. With some refinement such an approach may improve chemical safety classification and allow biological read across on a pathway level

Effect of environmental and nutritional conditions on the formation of single and mixed-species biofilms and their efficiency in cadmium removal

Remediation of contaminated water and wastewater using biosorption methods has attracted significant attention in recent decades due to its efficiency, convenience and minimised environmental effects. Bacterial biosorbents are normally deployed as a non-living powder or suspension. Little is known about the mechanisms or rates of bacterial attachment to surfaces and effect of various conditions on the biofilm development, as well as efficiency of living biofilms in the removal of heavy metals. In the present study, the effect of environmental and nutritional conditions such as pH, temperature, concentrations of phosphate, glucose, amino acid, nitrate, calcium and magnesium, on planktonic and biofilm growth of single and mixed bacterial cultures, were measured. Actinomyces meyeri, Bacillus cereus, Escherichia coli, Pseudomonas fluorescens strains were evaluated to determine the optimum biofilm growth conditions. The Cd(II) biosorption efficiencies of the mixed-species biofilm developed in the optimum growth condition, were investigated and modelled using Langmuir, Freundlich and Dubnin Radushkevich models. The biofilm quantification techniques revealed that the optimum concentration of phosphate, glucose, amino acid, nitrate, calcium and magnesium for the biofilm development were 25, 10, 1, 1.5, 5 and 0.5 g L−1, respectively. Further increases in the nutrient concentrations resulted in less biofilm growth. The optimum pH for the biofilm growth was 7 and alkaline or acidic conditions caused significant negative effects on the bacterial attachment and development. The optimum temperatures for the bacterial attachment to the surface were between 25 and 35 °C. The maximum Cd(II) biosorption efficiency (99%) and capacity (18.19 mg g−1) of the mixed-species biofilm, occurred on day 35 (Ci = 0.1 mg L−1) and 1 (Ci = 20 mg L−1) of biofilm growth, respectively. Modelling of the biosorption data revealed that Cd(II) removal by the living biofilm was a physical process by a monolayer of biofilm. The results of present study suggested that environmental and nutritional conditions had a significant effect on bacterial biofilm formation and its efficiency in Cd(II) removal

Approches de bio-informatique et de modélisation pour une compréhension du stress oxydant au niveau systémique

New understanding of biology shows more and more that the mechanisms that underlie toxicity are complex and involve multiple biological processes and pathways. Adverse outcome pathways (AOPs) and systems biology (SB) can be appropriate tools for studying toxicology at this level of complexity. This PhD thesis focuses on the elaboration of a SB model of the role of the Nrf2 pathway in the control of oxidative stress. The model’s calibration with experimental data (obtained with RPTEC/TERT1 renal cells exposed to various doses of potassium bromate) comprised several rounds of hypotheses stating/verification, through which new reactions were progressively added to the model. Some of these new hypotheses (e.g., direct action of potassium bromate on DCF, bleaching of DCF with time, etc.) could be confirmed by future experiments. Considered in a wider framework, this SB model was then evaluated and compared to two other computational models (i.e., an empirical dose-response statistical model and a dynamic Bayesian model) for the quantification of a ‘chronic kidney disease’ AOP. All parameter calibrations were done by MCMC simulations with the GNU MCSim software with a quantification of uncertainties associated with predictions. Even though the SB model was indeed complex to conceive, it offers insight in biology that the other approaches could not afford. In addition, using multiple toxicogenomic databases; interactions and cross-talks of the Nrf2 pathway with two other toxicity pathways (i.e., AhR and ATF4) were examined. The results of this last analysis suggest adding new AhR contribution to the control of some of the Nrf2 genes in our SB model (e.g., HMOX1, SRXN1 and GCLM), and integrating in it description of the ATF4 pathway (partially at least). Despites their complexity, precise SB models are precious investments for future developments in predictive toxicology.Avec les nouvelles avancées en biologie et toxicologie, on constate de plus en plus la complexité des mécanismes et le grand nombre de voies de toxicité. Les concepts de ‘biologie systémique’ (SB) et de ‘voies des effets indésirables’ (adverse outcome pathway, AOP) pourraient être des outils appropriés pour l’étude de la toxicologie à ces niveaux de complexité élevés. Le point central du travail de cette thèse est le développement d’un modèle de SB du rôle de la voie de signalisation Nrf2 dans le contrôle du stress oxydant. Pour la calibration de ce modèle avec des données expérimentales (exposition des cellules rénales RPTEC/TERT1 à différentes doses de bromate de potassium), plusieurs cycles de proposition/vérification d’hypothèses ont progressivement contribué à l’ajout de nouvelles réactions. Ces nouvelles hypothèses (par exemple : action directe du bromate de potassium sur le DCF, atténuation de la fluorescence du DCF avec le temps, etc.) devraient être confirmées par de futures expérimentations. Ce modèle de SB a été ensuite utilisé pour la quantification d’un AOP de l’insuffisance rénale chronique et comparé à deux autres approches: l’utilisation de modèles statistiques empiriques et celle d’un réseau Bayésien dynamique. Les calibrations des paramètres ont été effectuées par chaînes de Markov simulées MCMC avec le logiciel GNU MCSim avec une quantification des incertitudes associées aux prédictions. Même si la mise au point du modèle SB a été une tâche complexe, la compréhension de la biologie qu’offre ce modèle n’est pas accessible aux deux autres approches. Nous avons aussi évalué les interactions entre Nrf2 et deux autres voies de toxicité, AhR et ATF4, dans le cadre d’une analyse utilisant des données de toxico-génomique provenant de trois projets différents. Les résultats de cette dernière analyse suggèrent d’ajouter au modèle SB de Nrf2 la co-activation par AhR de plusieurs gènes (par exemple, HMOX1, SRXN1 et GCLM) ainsi que d’associer (au moins partiellement) à ce modèle la voie ATF4. Malgré leur complexité, les modèles SB constituent un investissement intéressant pour le développement de la toxicologie prédictive

CO2 Emission and Energy Reduction Evaluations of Plug-in Hybrid Vehicles

Disponible en ligne contre 22$ à l'adresse : http://papers.sae.org/2009-01-1324ISBN: 978-0-7680-2131-8Product Code: SP-2235International audienceEnergy consumption and exhaust emissions are the most challenging issues in transportation that car makers and policy makers have to deal with. As a consequence, several technologies have been developed in order to limit fuel consumption and pollutant emissions. So far, some of the promising technologies for passenger cars are hybrid electric vehicles (HEV) and, later on, plug-in hybrid electric vehicles (PHEV). The study presents an assessment in terms of energy consumption and carbon dioxide emissions for gasoline HEV and PHEV compared to Internal Combustion Engine (ICE) conventional gasoline and diesel vehicles. This comparison intends to assess carbon dioxide and energy consumption reduction ability of PHEV for several countries or geographical region (EU 15, USA, Japan, and France). The energy consumption is computed with a detailed drive train model taking into account different driving patterns. The emissions are calculated depending on the electricity mix of the studied countries or group of countries. The study details the abatement potential of the new technology by geographical area. A detailed analysis of hourly carbon dioxide content of electricity is performed in order to study the impact of the electricity mix variation

Electrified Vehicle Penetration Scenarios in Europe: Economic and Environmental Impacts

International audienceWhat will the passenger car fleet look like over the next two decades' As most expected, affordability and convenience are the major drivers of new vehicle technology penetration into the market. Within this scope, vehicle electrification strategy to limit oil dependence and meet the European targets for CO₂ emissions should be cost-effective and convenient to the buyer.This paper will focus first, through different economic models, on the penetration of passenger electrified vehicles (Plug-in Hybrid Vehicles PHVs and Electric Vehicles EVs) in Europe (EU15: 15 European Union member countries) up to 2030. Economic models are based on real-world-use behaviors and driving patterns in order to compute fuel and energy consumption and to estimate total cost of the vehicle including incentives. The economic models use household wages in order to later make conclusions on vehicle technology market shares by vehicle classes. Later, the study investigates how user behavior, fuel cost and electric power prices would impact the electrified vehicle penetration of the car fleet. Furthermore, the impact of electrified vehicle fleet penetration on reduction of CO₂ emissions and on electricity demand is assessed

Effect of Al₂O₃, ZnO and TiO₂ Atomic Layer Deposition Grown Thin Films on the Electrochemical and Mechanical Properties of Sputtered Al-Zr Coating

The 316L stainless steels, often used in turbine blades for naval and marine applications, usually suffer from localized pitting corrosion after long exposure to chlorinated environments. The aluminum-zirconium coatings deposited by magnetron sputtering technique can be used to ensure cathodic protection for steels. In this work, we study the influence of atomic layer deposited (ALD) Al2O3, ZnO, and TiO2 thin films on the structural, mechanical, and electrochemical properties of Al-Zr (4 at.% Zr) magnetron sputtered coatings. The morphology, preferred orientation growth, mechanical properties, wettability, and corrosion resistance were investigated. The change in the sputtered Al-Zr morphology is mainly due to the insertion of the ALD layer. The Al-Zr layer deposited on ZnO and TiO2 layers presented a distinctive morphology. The agglomerate particles of AlZr/Al2O3/AlZr, AlZr/ZnO/AlZr and AlZr/TiO2/AlZr coatings exhibited a cauliflower shape. For ALD/PVD coatings, the insertion of an ALD oxide layer promoted the intensity of the peaks corresponding to the (111) crystallographic orientation. The nanoindentation measurements confirmed the enhancement in the mechanical properties, where the hardness increased by about 75%. The ALD oxide layers promoted the hydrophobicity of the coatings. The electrochemical characterization in a 3.5 wt.% NaCl solution also confirmed the role of the ALD oxides layers in delaying the pitting corrosion of the Al-Zr coating by widening the passive region and enhancing the protective efficiency of the passive film

Méthodes haut-débit en toxicologie et en évaluation des risques sanitaires

International audienceToxicology is changing its experimental approaches from animal testing to less expensive, more ethical and relevant methods. From the beginning of this century, various regulations and research programs on both sides of the Atlantic have pushed and contributed to this change. Modern toxicology relies on two main components: in vitro testing and in silico analyses. Toxicology has also entered a world of “big data” production, switching from a low-throughput to a high-throughput mode of screening. Complementary to the assessment of toxicological impact, a large effort has also been made to evaluate human exposure to chemicals: new human and field surveys, analytical measurements, computational capacities, and the use of mathematical modeling have open new possibilities for exposure assessment. Accounting for several sources and routes of exposures, estimating combined exposure to mixtures, integrating exposure variability, and simulating long-term exposure are new challenges on their way to be solved. In addition, biomonitoring data, internal exposure biomarkers, and toxicokinetics are all adding to the list of tools and techniques helping to link the pieces of the yet incomplete puzzle of high-throughput risk assessment. Yet, high-throughput applications in toxicology have been criticized, for their inadequate representation of the biological interactions at the organism level, for the experimental noise they suffer from, for the complexity of the in vivo to in vitro extrapolation and for their yet undefined validation protocols. We propose here a brief panorama of those developments.Les approches expérimentales en toxicologie sont en train de passer de l’expérimentation animale à des méthodes moins coûteuses, plus éthiques et pertinentes. Dès le début de ce siècle, différents programmes de recherche et réglementations des deux côtés de l’Atlantique ont contribué à ce changement. La toxicologie moderne repose sur deux éléments principaux: les tests in vitro et les analyses in silico. La toxicologie s’est également lancée dans la production de données à grande échelle, passant d’un faible débit à un mode de criblage haut-débit. D’une manière complémentaire à l’évaluation de l’impact toxicologique, un effort important est également fait pour évaluer l’exposition humaine aux substances chimiques. De nouvelles enquêtes de consommation, de nouveaux dosages analytiques, des capacités de calcul plus importantes, ainsi que l’utilisation de la modélisation mathématique ont ouvert de nouvelles possibilités pour l’évaluation de l’exposition. Malgré le grand nombre de sources et de voies d’exposition, l’estimation de l’exposition aux mélanges, l’intégration de sa variabilité, et la simulation des expositions à long terme sont de nouveaux défis en voie de résolution. De plus, les données de biosurveillance, les biomarqueurs d’exposition interne, et la toxicocinétique sont des outils qui aident à compléter le puzzle d’évaluation à haut débit des risques. Pourtant, les applications à haut débit en toxicologie ont été critiquées pour leur représentation inadéquate des interactions biologiques au niveau de l’organisme, les incertitudes dont elles sont entachées, la complexité de l’extrapolation in vivo-in vitro et à cause de leurs protocoles de validation encore mal définis. Nous présentons ici un bref aperçu de ces développements

Behaviour Indicators of Animal Welfare in Purebred and Crossbred Yearling Beef Reared in Optimal Environmental Conditions

The aim of this study was to monitor the behaviour of purebred and crossbred beef cattle reared in the same optimal environmental conditions according to Classyfarm®. Thirty-yearling beef 11.5 months old, including 10 Limousines (LMS), 10 Sardo-Bruna (SRB), and 10 crossbred Limousine × Sardo-Bruna (LMS × SRB), balanced for sex and body weight, were used. Animals were evaluated for five months by two trained operators by SCAN (“sternal resting”, “lateral resting”, “ central or peripheral position in the pen”, standing”, “walking”, “feeding”, “drinking”, and “ruminating) and FOCUS (“displacement for space”, “displacement for feed or water”, “play-fighting”, “self-grooming”, “allo-grooming”, “stereotyping”, and “mounting”) protocols. Feeding behaviour was monitored by a CCTV system. The application of the SCAN sampling evidenced that SRB animals preferred the “standing” activity over the LMS animals, while the LMS × SRB did not differ from them. The “standing” and “ ruminating “activities were observed mostly in females than males (p p p p p p < 0.05) in females than males. In conclusion, behaviour indicators of animal welfare did not evidence substantial differences among genetic types and between sexes reared in the same “optimal” environmental conditions. Female beef and the autochthon’s cattle breed of Sardinia, although typically hardy, showed a wide behavioural repertoire

A Wideband V-Shaped Coplanar Patch Antenna for 2-6 GHz Designed for Energy Harvesting and Wireless Communications

International audienceThis article portrays a compact wideband coplanar-fed V-shaped antenna. It has been designed for harvesting energy from wireless local area networks (IEEE 802.11) and other wireless communication systems covering the 2–6 GHz frequency band. The Structure of this antenna comprises a rectangular patch and an isosceles trapezoid. A V-shaped slot is introduced on the rectangular patch in order to perturb the surface current path which contributes to the formation of the wide-band characteristics. A trapezoid is inserted between the coplanar feed and the patch for the purpose of impedance matching and resonance shifting. A parametric study has been carried out to understand the effects of various dimensional parameters and to optimize the performance of the antenna. The measurement results which are in agreement with Ansoft HFSS simulation results, showed an agreeable bandwidth and satisfactory characteristics for omnidirectional radiation