Analysis of Time-Series Gene Expression Data to Explore Mechanisms of Chemical-Induced Hepatic Steatosis Toxicity

Non-alcoholic fatty liver disease (NAFLD) represents a wide spectrum of disease, ranging from simple fatty liver through steatosis with inflammation and necrosis to cirrhosis. One of the most challenging problems in biomedical research and within the chemical industry is to understand the underlying mechanisms of complex disease, and complex adverse outcome pathways (AOPs). Based on a set of 28 steatotic chemicals with gene expression data measured on primary hepatocytes at three times (2, 8, and 24 h) and three doses (low, medium, and high), we identified genes and pathways, defined as molecular initiating events (MIEs) and key events (KEs) of steatosis using a combination of a time series and pathway analyses. Among the genes deregulated by these compounds, the study highlighted OSBPL9, ALDH7A1, MYADM, SLC51B, PRDX6, GPAT3, TMEM135, DLGDA5, BCO2, APO10LA, TSPAN6, NEURL1B, and DUSP1. Furthermore, pathway analysis indicated deregulation of pathways related to lipid accumulation, such as fat digestion and absorption, linoleic and linolenic acid metabolism, calcium signaling pathway, fatty acid metabolism, peroxisome, retinol metabolism, and steroid metabolic pathways in a time dependent manner. Such transcription profile analysis can help in the understanding of the steatosis evolution over time generated by chemical exposure

The ATLAS3D project - XXIV. The intrinsic shape distribution of early-type galaxies

We use the ATLAS3D sample to perform a study of the intrinsic shapes of early-type galaxies, taking advantage of the available combined photometric and kinematic data. Based on our ellipticity measurements from the Sloan Digital Sky Survey Data Release 7, and additional imaging from the Isaac Newton Telescope, we first invert the shape distribution of fast and slow rotators under the assumption of axisymmetry. Theso-obtained intrinsic shape distribution for the fast rotators can be described with a Gaussian with a mean flattening of q=0.25 and standard deviation σq = 0.14, and an additional tail towards rounder shapes.The slow rotators are much rounder, and are well described with a Gaussian with mean q = 0.63 and σq =0.09. We then checked that our results were consistent when applying a different and independent method to obtain intrinsic shape distributions, by fitting the observed ellipticity distributions directly using Gaussian parametrizations for the intrinsic axis ratios. Although both fast and slow rotators are identified as early-type galaxies in morphological studies, and in many previous shape studies are therefore grouped together, their shape distributions are significantly different, hinting at different formation scenarios. The intrinsic shape distribution of the fast rotators shows similarities with the spiral galaxy population. Including the observed kinematic misalignment in our intrinsic shape study shows that the fast rotators are predominantly axisymmetric, with only very little room for triaxiality. For the slow rotators though there are very strong indications that they are (mildly) triaxial.PostprintPeer reviewe

The ATLAS3D project - XXVI : H I discs in real and simulated fast and slow rotators

One quarter of all nearby early-type galaxies (ETGs) outside Virgo host a disc/ring of H I with size from a few to tens of kpc and mass up to ∼109 M⊙. Here we investigate whether this H I is related to the presence of a stellar disc within the host making use of the classification of ETGs in fast and slow rotators (FR/SR). We find a large diversity of H I masses and morphologies within both families. Surprisingly, SRs are detected as often, host as much H I and have a similar rate of H I discs/rings as FRs. Accretion of H I is therefore not always linked to the growth of an inner stellar disc. The weak relation between H I and stellar disc is confirmed by their frequent kinematical misalignment in FRs, including cases of polar and counterrotating gas. In SRs the H I is usually polar. This complex picture highlights a diversity of ETG formation histories which may be lost in the relative simplicity of their inner structure and emerges when studying their outer regions. We find that Λ CDM hydrodynamical simulations have difficulties reproducing the H I properties of ETGs. The gas discs formed in simulations are either too massive or too small depending on the star formation feedback implementation. Kinematical misalignments match the observations only qualitatively. The main point of conflict is that nearly all simulated FRs and a large fraction of all simulated SRs host corotating H I. This establishes the H I properties of ETGs as a novel challenge to simulationsPeer reviewedFinal Accepted Versio

t4 Workshop Report: Integrated Testing Strategies (ITS) for Safety Assessment

Integrated testing strategies (ITS), as opposed to single definitive tests or fixed batteries of tests, are expected to efficiently combine different information sources in a quantifiable fashion to satisfy an information need, in this case for regulatory safety assessments. With increasing awareness of the limitations of each individual tool and the development of highly targeted tests and predictions, the need for combining pieces of evidence increases. The discussions that took place during this workshop, which brought together a group of experts coming from different related areas, illustrate the current state of the art of ITS, as well as promising developments and identifiable challenges. The case of skin sensitization was taken as an example to understand how possible ITS can be constructed, optimized and validated. This will require embracing and developing new concepts such as adverse outcome pathways (AOP), advanced statistical learning algorithms and machine learning, mechanistic validation and “Good ITS Practices”.JRC.I.5-Systems Toxicolog

DEVELOPPEMENT DE MODELES TOXICOCINETIQUES ET ANALYSE STATISTIQUE DE DONNEES D'EXPOSITION AU TETRACHLORETHYLENE

LA MODELISATION TOXICOCINETIQUE PERMET DE DECRIRE LES PROCESSUS D'ABSORPTION, DE DISTRIBUTION ET D'ELIMINATION MIS EN JEU DANS L'ORGANISME EN CAS D'EXPOSITION A UNE SUBSTANCE TOXIQUE. ELLE CONSTITUE UNE ETAPE ESSENTIELLE DE LA DETERMINATION DE LA RELATION DOSE-EFFETS DANS LE CADRE D'UNE EVALUATION QUANTITATIVE DES RISQUES TOXIQUES. CE TRAVAIL CONSIDERE L'INFERENCE BAYESIENNE DES MODELES TOXICOCINETIQUES DE POPULATION PAR LES METHODES DE SIMULATIONS MONTE CARLO PAR CHAINES DE MARKOV. CETTE APPROCHE CONSISTE A INSERER LE MODELE TOXICOCINETIQUE DETERMINISTE DANS UN MODELE STATISTIQUE HIERARCHIQUE DECRIVANT LES VARIABILITES INTERINDIVIDUELLE ET INTRAINDIVIDUELLE, AINSI QUE L'INCERTITUDE SUR LES DONNEES MESUREES. UNE APPLICATION A DES DONNEES ORIGINALES DE TOXICOCINETIQUE CHEZ L'HUMAIN D'UN IMPORTANT SOLVANT CHLORE, LE TETRACHLORETHYLENE (TETRA), EST PROPOSEE. LES DONNEES PROVIENNENT D'EXPOSITIONS REPETEES DE 6 VOLONTAIRES SAINS A 1 PPM DE TETRA PENDANT 6 HEURES. NOUS AVONS DEVELOPPE UN MODELE TOXICOCINETIQUE SEMI-PHYSIOLOGIQUE A TROIS COMPARTIMENTS POUR LA DISTRIBUTION DU TETRA ET UN COMPARTIMENT POUR LA CINETIQUE DE SON METABOLITE PRINCIPAL. SUR LES 6 SUJETS ETUDIES, LES ESTIMATIONS DE LA FRACTION DE TETRA METABOLISEE VARIENT ENTRE 1,4% ET 19% ET INDIQUENT UNE IMPORTANTE VARIABILITE INTRA-INDIVIDUELLE (70%CV) DE CETTE QUANTITE. DANS UNE POPULATION SIMULEE DE 1 000 INDIVIDUS, LA FRACTION DE TETRA METABOLISEE EST ESTIMEE A 12% EN MOYENNE (IC 9 5 : 3,9%-26,3%). CE TRAVAIL MET EN EVIDENCE QUE LE TETRA EST PLUS FORTEMENT METABOLISE AU COURS D'EXPOSITIONS A FAIBLE DOSE QU'AUX DOSES PRECEDEMMENT INVESTIGUEES. L'EXISTENCE D'UNE FORTE VARIABILITE INTRA-INDIVIDUELLE DANS LA TOXICOCINETIQUE DU TETRA CHEZ L'HOMME DEVRAIT ETRE PRISE EN COMPTE DANS LES FUTURES EVALUATIONS DE RISQUES POUR CE SOLVANT.PARIS-BIUSJ-Thèses (751052125) / SudocCentre Technique Livre Ens. Sup. (774682301) / SudocPARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Bayesian Dependency Modelling and Inference for PBPK Model Parameters: A Nimble Approach

<p>Increasing reliance on complex physiologically-based pharmacokinetic (PBPK) models instead of clinical trials for decision making in drug development calls for an improved framework able to represent a priori parameter dependencies when creating representative virtual populations and performing related statistical inference. We describe here a graph-based solution to harness such dependencies and apply it to inference on hierarchical (population) model parameters. It can model complex parameter and data dependencies, perform efficient Monte Carlo simulations to generate virtual individuals, but also rigorous Bayesian inference on parameters when observed individual covariates are available. Plasma PK data of theophylline were used as an example of application of a PBPK model with built-in covariate structure. A range of models with increasing sophistication and accuracy at describing the data generation process was considered. A stationary MCMC sampler is also described, which has lower complexity than full Bayesian inference. The use of such a sampler and the changes in inference at each stage of the process are discussed.</p&gt