Mathematical model of uptake and metabolism of arsenic(III) in human hepatocytes - Incorporation of cellular antioxidant response and threshold-dependent behavior

<p>Abstract</p> <p>Background</p> <p>Arsenic is an environmental pollutant, potent human toxicant, and oxidative stress agent with a multiplicity of health effects associated with both acute and chronic exposures. A semi-mechanistic cellular-level toxicokinetic (TK) model was developed in order to describe the uptake, biotransformation and clearance of arsenical species in human hepatocytes. Notable features of this model are the incorporation of arsenic-glutathione complex formation and a "switch-like" formulation to describe the antioxidant response of hepatocytes to arsenic exposure.</p> <p>Results</p> <p>The cellular-level TK model applies mass action kinetics in order to predict the concentrations of trivalent and pentavalent arsenicals in hepatocytes. The model simulates uptake of arsenite (iAs^III) via aquaporin isozymes 9 (AQP9s), glutathione (GSH) conjugation, methylation by arsenic methyltransferase (AS3MT), efflux through multidrug resistant proteins (MRPs) and the induced antioxidant response via thioredoxin reductase (TR) activity. The model was parameterized by optimization of model estimates for arsenite (iAs^III), monomethylated (MMA) and dimethylated (DMA) arsenicals concentrations with time-course experimental data in human hepatocytes for a time span of 48 hours, and dose-response data at 24 hours for a range of arsenite concentrations from 0.1 to 10 μM. Global sensitivity analysis of the model showed that at low doses the transport parameters had a dominant role, whereas at higher doses the biotransformation parameters were the most significant. A parametric comparison of the TK model with an analogous model developed for rat hepatocytes from the literature demonstrated that the biotransformation of arsenite (e.g. GSH conjugation) has a large role in explaining the variation in methylation between rats and humans.</p> <p>Conclusions</p> <p>The cellular-level TK model captures the temporal modes of arsenical accumulation in human hepatocytes. It highlighted the key biological processes that influence arsenic metabolism by explicitly modelling the metabolic network of GSH-adducts formation. The parametric comparison with the TK model developed for rats suggests that the variability in GSH conjugation could have an important role in inter-species variability of arsenical methylation. The TK model can be incorporated into larger-scale physiologically based toxicokinetic (PBTK) models of arsenic for improving the estimates of PBTK model parameters.</p

Power demand control scenarios for smart grid applications with finite number of appliances

In this paper we propose novel and more realistic analytical models for the determination of the peak demand under four power demand control scenarios. Each scenario considers a finite number of appliances installed in a residential area, with diverse power demands and different arrival rates of power requests. We develop recursive formulas for the efficient calculation of the peak demand under each scenario, which take into account the finite population of the appliances. Moreover, we associate each scenario with a proper real-time pricing process in order to derive the social welfare. The proposed analysis is validated through simulations. Moreover, the performance evaluation of the proposed formulas reveals that the absence of the assumption of finite number of appliances could lead to serious peak-demand over-estimations.Grant numbers : This work has been funded by the project of the Catalan Government 2014-SGR-1551

Three-way catalytic converter modeling as a modern engineering design tool

The competition to deliver ultra low emitting vehicles at a reasonable cost is driving the automotive industry to invest significant manpower and test lab resources in the design optimization of increasingly complex exhaust aftertreatment systems. Optimization can no longer be based on traditional approaches, which are intensive in hardware use and lab testing. This paper discusses the extents and limitations of applicability of state-of-the-art mathematical models of catalytic converter performance. In-house software from the authors' lab, already in use during the last decade in design optimization studies, updated with recent, important model improvements, is employed as a reference in this discussion. Emphasis is on the engineering methodology of the computational tools and their application, which covers quality assurance of input data, advanced parameter estimation procedures, and a suggested performance measure that drives the parameter estimation code to optimum results and also allows a less subjective assessment of model prediction accuracy. Extensive comparisons between measured and computed instantaneous emissions over full cycles are presented, aiming to give a good picture of the capabilities of state of the art engineering models of automotive catalytic converter systems

Experimental investigation of the role of soot volatile organic fraction in the regeneration of diesel filters

This paper involves an experimental investigation of the role of the volatile organic fraction (VOF) adsorbed on the diesel particulate, in the initiation of regeneration of a SiC diesel filter installed on a modern diesel engine, run on catalytic additive-doped fuel. VOF adsorption-desorption and oxidation behaviour is mainly determined by performing a thermogravimetric analysis (TGA) of samples collected directly from a SiC filter installed on the engine running under low- and medium-speed and low- and medium-load conditions, as more representative of city driving. Based on the TGA analysis results, the percentage VOF content in soot was calculated and mapped as a function of engine speed and load in the range of investigation. The effect of adsorbed hydrocarbons on the regeneration behaviour was assessed by comparing regeneration experiments with the stepwise load increase for a filter loaded with soot at different VOF concentration levels. The appearance of a number of incidents of stochastic regeneration behaviour during loading at low exhaust temperatures with a relative high VOF content was observed and discussed. An effort was made to correlate regeneration rate with the VOF content in soot and the prevailing engine operation point during loading. This work aims at better understanding of diesel filter behaviour with modern diesel engines and also aims to support improved modelling of fuel-additive assisted regeneration by use of fuel additives at low temperatures (150-400degreesC)

Tumor Ensemble-Based Modeling and Visualization of Emergent Angiogenic Heterogeneity in Breast Cancer

Abstract There is a critical need for new tools to investigate the spatio-temporal heterogeneity and phenotypic alterations that arise in the tumor microenvironment. However, computational investigations of emergent inter- and intra-tumor angiogenic heterogeneity necessitate 3D microvascular data from ‘whole-tumors’ as well as “ensembles” of tumors. Until recently, technical limitations such as 3D imaging capabilities, computational power and cost precluded the incorporation of whole-tumor microvascular data in computational models. Here, we describe a novel computational approach based on multimodality, 3D whole-tumor imaging data acquired from eight orthotopic breast tumor xenografts (i.e. a tumor ‘ensemble’). We assessed the heterogeneous angiogenic landscape from the microvascular to tumor ensemble scale in terms of vascular morphology, emergent hemodynamics and intravascular oxygenation. We demonstrate how the abnormal organization and hemodynamics of the tumor microvasculature give rise to unique microvascular niches within the tumor and contribute to inter- and intra-tumor heterogeneity. These tumor ensemble-based simulations together with unique data visualization approaches establish the foundation of a novel ‘cancer atlas’ for investigators to develop their own in silico systems biology applications. We expect this hybrid image-based modeling framework to be adaptable for the study of other tissues (e.g. brain, heart) and other vasculature-dependent diseases (e.g. stroke, myocardial infarction)

* * Presently with Harris Corporation Broadband Wireless Access Business Unit

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