Mesoscopic simulation of diffusive contaminant spreading in gas flows at low pressure

Many modern production and measurement facilities incorporate multiphase systems at low pressures. In this region of flows at small, non-zero Knudsen- and low Mach numbers the classical mesoscopic Monte Carlo methods become increasingly numerically costly. To increase the numerical efficiency of simulations hybrid models are promising. In this contribution, we propose a novel efficient simulation approach for the simulation of two phase flows with a large concentration imbalance in a low pressure environment in the low intermediate Knudsen regime. Our hybrid model comprises a lattice-Boltzmann method corrected for the lower intermediate Kn regime proposed by Zhang et al. for the simulation of an ambient flow field. A coupled event-driven Monte-Carlo-style Boltzmann solver is employed to describe particles of a second species of low concentration. In order to evaluate the model, standard diffusivity and diffusion advection systems are considered.Comment: 9 pages, 8 figure

On Tackling the Limits of Resolution in SAT Solving

The practical success of Boolean Satisfiability (SAT) solvers stems from the CDCL (Conflict-Driven Clause Learning) approach to SAT solving. However, from a propositional proof complexity perspective, CDCL is no more powerful than the resolution proof system, for which many hard examples exist. This paper proposes a new problem transformation, which enables reducing the decision problem for formulas in conjunctive normal form (CNF) to the problem of solving maximum satisfiability over Horn formulas. Given the new transformation, the paper proves a polynomial bound on the number of MaxSAT resolution steps for pigeonhole formulas. This result is in clear contrast with earlier results on the length of proofs of MaxSAT resolution for pigeonhole formulas. The paper also establishes the same polynomial bound in the case of modern core-guided MaxSAT solvers. Experimental results, obtained on CNF formulas known to be hard for CDCL SAT solvers, show that these can be efficiently solved with modern MaxSAT solvers

Current Industrial Practices in Assessing CYP450 Enzyme Induction: Preclinical and Clinical

Induction of drug metabolizing enzymes, such as the cytochromes P450 (CYP) is known to cause drug-drug interactions due to increased elimination of co-administered drugs. This increased elimination may lead to significant reduction or complete loss of efficacy of the co-administered drug. Due to the significance of such drug interactions, many pharmaceutical companies employ screening and characterization models which predict CYP enzyme induction to avoid or attenuate the potential for drug interactions with new drug candidates. The most common mechanism of CYP induction is transcriptional gene activation. Activation is mediated by nuclear receptors, such as AhR, CAR, and PXR that function as transcription factors. Early high throughput screening models utilize these nuclear hormone receptors in ligand binding or cell-based transactivation/reporter assays. In addition, immortalized hepatocyte cell lines can be used to assess enzyme induction of specific drug metabolizing enzymes. Cultured primary human hepatocytes, the best established in vitro model for predicting enzyme induction and most accepted by regulatory agencies, is the predominant assay used to evaluate induction of a wide variety of drug metabolizing enzymes. These in vitro models are able to appropriately predict enzyme induction in patients when compared to clinical drug-drug interactions. Finally, transgenic animal models and the cynomolgus monkey have also been shown to recapitulate human enzyme induction and may be appropriate in vivo animal models for predicting human drug interactions

Studying protein–protein affinity and immobilized ligand–protein affinity interactions using MS-based methods

This review discusses the most important current methods employing mass spectrometry (MS) analysis for the study of protein affinity interactions. The methods are discussed in depth with particular reference to MS-based approaches for analyzing protein–protein and protein–immobilized ligand interactions, analyzed either directly or indirectly. First, we introduce MS methods for the study of intact protein complexes in the gas phase. Next, pull-down methods for affinity-based analysis of protein–protein and protein–immobilized ligand interactions are discussed. Presently, this field of research is often called interactomics or interaction proteomics. A slightly different approach that will be discussed, chemical proteomics, allows one to analyze selectivity profiles of ligands for multiple drug targets and off-targets. Additionally, of particular interest is the use of surface plasmon resonance technologies coupled with MS for the study of protein interactions. The review addresses the principle of each of the methods with a focus on recent developments and the applicability to lead compound generation in drug discovery as well as the elucidation of protein interactions involved in cellular processes. The review focuses on the analysis of bioaffinity interactions of proteins with other proteins and with ligands, where the proteins are considered as the bioactives analyzed by MS

Recent Progress in the Use of Glucagon and Glucagon Receptor Antagonists in the Treatment of Diabetes Mellitus

Glucagon is an important pancreatic hormone, released into blood circulation by alpha cells of the islet of Langerhans. Glucagon induces gluconeogenesis and glycogenolysis in hepatocytes, leading to an increase in hepatic glucose production and subsequently hyperglycemia in susceptible individuals. Hyperglucagonemia is a constant feature in patients with T2DM. A number of bioactive agents that can block glucagon receptor have been identified. These glucagon receptor antagonists can reduce the hyperglycemia associated with exogenous glucagon administration in normal as well as diabetic subjects. Glucagon receptor antagonists include isoserine and beta-alanine derivatives, bicyclic 19-residue peptide BI-32169, Des-His1-[Glu9] glucagon amide and related compounds, 5-hydroxyalkyl-4-phenylpyridines, N-[3-cano-6- (1,1 dimethylpropyl)-4,5,6,7-tetrahydro-1-benzothien-2-yl]-2-ethylbutamide, Skyrin and NNC 250926. The absorption, dosage, catabolism, excretion and medicinal chemistry of these agents are the subject of this review. It emphasizes the role of glucagon in glucose homeostasis and how it could be applied as a novel tool for the management of diabetes mellitus by blocking its receptors with either monoclonal antibodies, peptide and non-peptide antagonists or gene knockout techniques