770 research outputs found
Sandwich-Cultured Hepatocytes as a Tool to Study Drug Disposition and Drug-Induced Liver Injury
Sandwich-cultured hepatocytes (SCH) are metabolically competent and have proper localization of basolateral and canalicular transporters with functional bile networks. Therefore, this cellular model is a unique tool that can be used to estimate biliary excretion of compounds. SCH have been used widely to assess hepatobiliary disposition of endogenous and exogenous compounds and metabolites. Mechanistic modeling based on SCH data enables estimation of metabolic and transporter-mediated clearances, which can be employed to construct physiologically-based pharmacokinetic models for prediction of drug disposition and drug-drug interactions in humans. In addition to pharmacokinetic studies, SCH also have been employed to study cytotoxicity and perturbation of biological processes by drugs and hepatically-generated metabolites. Human SCH can provide mechanistic insights underlying clinical drug-induced liver injury (DILI). In addition, data generated in SCH can be integrated into systems pharmacology models to predict potential DILI in humans. In this review, applications of SCH in studying hepatobiliary drug disposition and bile acid-mediated DILI are discussed. An example is presented to show how data generated in the SCH model was used to establish a quantitative relationship between intracellular bile acids and cytotoxicity, and how this information was incorporated into a systems pharmacology model for DILI prediction
A two-part seabed geomorphology classification scheme : (v.2). Part 1 : morphology features glossary
This report updates the ‘Two-part Seabed Geomorphology classification scheme’ of Dove et al. (2016) and
presents a new glossary (Part 1) of Seabed Morphology features. This Morphology glossary is intended to
provide marine scientists with a robust and consistent way to characterise the seabed. Each glossary entry
includes a feature definition and a representative schematic diagram to support clear and accurate
classification. Feature terms and definitions are primarily drawn from the International Hydrographic
Organization (IHO) guide for undersea feature names, which are herein modified and augmented with
additional terms to ensure the final feature catalogue and glossary encompasses the diversity of
morphologies observed at the seabed, while also minimising duplication and/or ambiguity. This updated
classification system and new glossary are the result of a collaboration between marine geoscientists from
marine mapping programmes/networks in Norway (MAREANO), Ireland (INFOMAR), UK (MAREMAP), and
Australia (Geoscience Australia) (MIM-GA). A subsequent report will present the (Part 2) Geomorphology
feature glossar
Learning an atlas of a cognitive process in its functional geometry
Proceedings of the 22nd International Conference, IPMI 2011, Kloster Irsee, Germany, July 3-8, 2011.In this paper we construct an atlas that captures functional characteristics of a cognitive process from a population of individuals. The functional connectivity is encoded in a low-dimensional embedding space derived from a diffusion process on a graph that represents correlations of fMRI time courses. The atlas is represented by a common prior distribution for the embedded fMRI signals of all subjects. The atlas is not directly coupled to the anatomical space, and can represent functional networks that are variable in their spatial distribution. We derive an algorithm for fitting this generative model to the observed data in a population. Our results in a language fMRI study demonstrate that the method identifies coherent and functionally equivalent regions across subjects.National Science Foundation (U.S.) (IIS/CRCNS 0904625)National Science Foundation (U.S.) (CAREER grant 0642971)National Institutes of Health (U.S.) (NCRR NAC P41- RR13218)National Institute of Biomedical Imaging and Bioengineering (U.S.) (U54-EB005149)National Institutes of Health (U.S.) (U41RR019703)National Institutes of Health (U.S.) (P01CA067165)Seventh Framework Programme (European Commission) (n◦257528 (KHRESMOI)
Finite Element Convergence for the Joule Heating Problem with Mixed Boundary Conditions
We prove strong convergence of conforming finite element approximations to
the stationary Joule heating problem with mixed boundary conditions on
Lipschitz domains in three spatial dimensions. We show optimal global
regularity estimates on creased domains and prove a priori and a posteriori
bounds for shape regular meshes.Comment: Keywords: Joule heating problem, thermistors, a posteriori error
analysis, a priori error analysis, finite element metho
Variational Multiscale Stabilization and the Exponential Decay of Fine-scale Correctors
This paper addresses the variational multiscale stabilization of standard
finite element methods for linear partial differential equations that exhibit
multiscale features. The stabilization is of Petrov-Galerkin type with a
standard finite element trial space and a problem-dependent test space based on
pre-computed fine-scale correctors. The exponential decay of these correctors
and their localisation to local cell problems is rigorously justified. The
stabilization eliminates scale-dependent pre-asymptotic effects as they appear
for standard finite element discretizations of highly oscillatory problems,
e.g., the poor approximation in homogenization problems or the pollution
effect in high-frequency acoustic scattering
Application of a Mechanistic Model to Evaluate Putative Mechanisms of Tolvaptan Drug-Induced Liver Injury and Identify Patient Susceptibility Factors
Tolvaptan is a selective vasopressin V2 receptor antagonist, approved in several countries for the treatment of hyponatremia and autosomal dominant polycystic kidney disease (ADPKD). No liver injury has been observed with tolvaptan treatment in healthy subjects and in non-ADPKD indications, but ADPKD clinical trials showed evidence of drug-induced liver injury (DILI). Although all DILI events resolved, additional monitoring in tolvaptan-treated ADPKD patients is required. In vitro assays identified alterations in bile acid disposition and inhibition of mitochondrial respiration as potential mechanisms underlying tolvaptan hepatotoxicity. This report details the application of DILIsym software to determine whether these mechanisms could account for the liver safety profile of tolvaptan observed in ADPKD clinical trials. DILIsym simulations included physiologically based pharmacokinetic estimates of hepatic exposure for tolvaptan and2 metabolites, and their effects on hepatocyte bile acid transporters and mitochondrial respiration. The frequency of predicted alanine aminotransferase (ALT) elevations, following simulated 90/30 mg split daily dosing, was 7.9% compared with clinical observations of 4.4% in ADPKD trials. Toxicity was multifactorial as inhibition of bile acid transporters and mitochondrial respiration contributed to the simulated DILI. Furthermore, simulation analysis identified both pre-treatment risk factors and on-treatment biomarkers predictive of simulated DILI. The simulations demonstrated that in vivo hepatic exposure to tolvaptan and the DM-4103 metabolite, combined with these 2 mechanisms of toxicity, were sufficient to account for the initiation of tolvaptan-mediated DILI. Identification of putative risk-factors and potential novel biomarkers provided insight for the development of mechanism-based tolvaptan risk-mitigation strategies
Search for displaced vertices arising from decays of new heavy particles in 7 TeV pp collisions at ATLAS
We present the results of a search for new, heavy particles that decay at a
significant distance from their production point into a final state containing
charged hadrons in association with a high-momentum muon. The search is
conducted in a pp-collision data sample with a center-of-mass energy of 7 TeV
and an integrated luminosity of 33 pb^-1 collected in 2010 by the ATLAS
detector operating at the Large Hadron Collider. Production of such particles
is expected in various scenarios of physics beyond the standard model. We
observe no signal and place limits on the production cross-section of
supersymmetric particles in an R-parity-violating scenario as a function of the
neutralino lifetime. Limits are presented for different squark and neutralino
masses, enabling extension of the limits to a variety of other models.Comment: 8 pages plus author list (20 pages total), 8 figures, 1 table, final
version to appear in Physics Letters
Search for direct production of charginos and neutralinos in events with three leptons and missing transverse momentum in √s = 7 TeV pp collisions with the ATLAS detector
A search for the direct production of charginos and neutralinos in final states with three electrons or muons and missing transverse momentum is presented. The analysis is based on 4.7 fb−1 of proton–proton collision data delivered by the Large Hadron Collider and recorded with the ATLAS detector. Observations are consistent with Standard Model expectations in three signal regions that are either depleted or enriched in Z-boson decays. Upper limits at 95% confidence level are set in R-parity conserving phenomenological minimal supersymmetric models and in simplified models, significantly extending previous results
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