ACAT inhibitors derived from hetero-Diels-Alder cycloadducts of thioaldehydes

Acyl-CoA:cholesterol acyltransferase (ACAT) is the enzyme largely responsible for intracellular cholesterol esterification. A systemic inhibitor of ACAT is believed to be able to slow or even reverse the atherosclerotic process. Towards that goal, a series of cyclic sulfides, derived from the hetero-Diels-Alder reaction of thioaldehydes with 1,3-dienes, and bearing carboxamide substituents, were prepared and evaluated for in vitro (in several tissues and species) and ex vivo ACAT inhibition. Minor changes in subsequent structure were found to have a significant effect in optimization of the biological activity of this series of compounds.     

Experimental study of NiO electrical conductivity changes under low oxygen pressures

The electrical conductivity of NiO was measured at 740°C in an oxygen pressure range of 10^–2 –1.3 Torr. By means of continuous recording, longtime experiments were performed. The results show that for any admittance of oxygen, the electrical conductivity initially increased and then decreased to its initial value. For pressures higher than 0.1 Torr the decrease of the signal was reduced and the time required to attain the initial value sometimes reached several days. These results suggest that the electrical conductivity changes may be considered as a transitory phenomenon connected to attaining gassolid equilibrium.     

Recovery of the refractive-index profile from the wigner distribution of an optical waveguide

We propose a new method for the recovery of the refractive-index profile of a single-mode or multimode optical guided structure. We solve the inverse problem using the Wigner distribution and reduce it to the solution of a linear system of equations.     

Study of the dead layer in germanium for the CDMS detectors

We present new measurements on a Cryogenic Dark Matter Search (CDMS) detector with electron, neutron, and gamma sources. The measurements have been performed to investigate the dead layer of one of the CDMS Z-dependent Ionization Phonon germanium detectors. The dead layer has been studied at both charge electrodes and at different electric field intensities. We also present a method to remove the dependence of athermal phonon measurements on event position.     

Hepatotoxicity of Drugs Used in Multiple Sclerosis,Diagnostic Challenge,and the Role of HLA Genotype Susceptibility

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system and the association with other autoimmune diseases is well-documented. There are many therapeutic options for the treatment of MS. Most of the available drugs cause drug-induced liver injury (DILI) to variable extents with heterogeneous clinical and biological manifestations, including liver injury with or without signs of hypersensitivity and autoimmunity. The diagnosis of DILI may be particularly difficult because MS is frequently associated with idiopathic autoimmune hepatitis. Recent advances suggest that MS and immune-mediated DILI could be promoted by genetic factors, including HLA genotype. In addition, some of these drugs may promote hepatitis B virus reactivation. This review explores the potential hepatotoxicity of drugs used to treat MS and the criteria to distinguish DILI from idiopathic autoimmune hepatitis associated with MS. The role of susceptible genes both promoting MS and causing the hepatotoxicity of the drug used for MS treatment is also discussed.     

Distributed Coordination and Workflow on the World Wide Web

This paper describes WebFlow, an environment thatsupports distributed coordination services on theWorld Wide Web. WebFlow leverages the HTTP Webtransport protocol and consists of a number of toolsfor the development of applications that require thecoordination of multiple, distributed servers.Typical applications of WebFlow include distributeddocument workspaces, inter/intra-enterprise workflow,and electronic commerce. In this paper we describe thegeneral WebFlow architecture for distributedcoordination, and then focus on the environment fordistributed workflow.     

Synchrony in heterogeneous networks of spiking neurons

The emergence of synchrony in the activity of large, heterogeneous networks of spiking neurons is investigated. We define the robustness of synchrony by the critical disorder at which the asynchronous state becomes linearly unstable. We show that at low firing rates, synchrony is more robust in excitatory networks than in inhibitory networks, but excitatory networks cannot display any synchrony when the average firing rate becomes too high. We introduce a new regime where all inputs, external and internal, are strong and have opposite effects that cancel each other when averaged. In this regime, the robustness of synchrony is strongly enhanced, and robust synchrony can be achieved at a high firing rate in inhibitory networks. On the other hand, in excitatory networks, synchrony remains limited in frequency due to the intrinsic instability of strong recurrent excitation.     

Binding of the tautomeric forms of isoniazid-NAD adducts to the active site of the Mycobacterium tuberculosis enoyl-ACP reductase (InhA): a theoretical approach

The front-line antituberculosis drug isoniazid (INH) inhibits InhA, the NADH-dependent fatty acid biosynthesis enoyl ACP-reductase from Mycobacterium tuberculosis, via formation of covalent adducts with NAD (INH-NAD adducts). While ring tautomers were found the main species formed in solution, only the 4S chain INH-NAD tautomer was evidenced in the crystallized InhA:INH-NAD complex. In this study we attempted to explore the modes of interaction and energy binding of the different isomers placed in the active site of InhA with the help of various molecular modelling techniques. Ligand and enzyme models were generated with the help of the Vega ZZ program package. Resulting ligands were then docked into the InhA active site individually using computational automated docking package AUTODOCK 3.0.5. The more relevant docked conformations were then used to compute the interaction energy between the ligands and the InhA cavity. The AM1 Hamiltonian and the QM/MM ONIOM methodologies were used and the results compared. The various tautomers were found docked in almost the same place where INH-NAD was present as predicted by earlier X-ray crystallographic studies. However, some changes of ligand conformation and of the interactions ligand-protein were evidenced. The lower binding energy was observed for the 4S chain adduct that probably represents the effective active form of the INH-NAD adducts, as compared to the 4R epimer. The two 4S,7R and 4R,7S ring tautomers show intermediate and similar binding energies contrasting with their different experimental inhibitory potency on InhA. As a possible explanation based on calculated conformations, we formulated the hypothesis of an initial binding of the two ring tautomers to InhA followed by opening of only the ring hemiamidal 4S,7R tautomer (possibly catalyzed by Tyr158 phenolate basic group) to give the 4S chain INH-NAD tight-binding inhibitor. The predictions of ligand-protein interactions at the molecular level can be of primary importance in elucidating the mechanisms of action of isoniazid and InhA-related resistances, in identifying the effective mycobactericidal entities and, in further step, in the design of a new generation of antitubercular drugs.     

3-D high frequency computation of transformer R, L parameters

High frequency electrical machine modeling based on lumped parameter equivalent circuit requires that eddy currents effects be taken into account for R and L coefficient derivation. Substituting hysteretic materials (complex permeability) to conductive materials makes it possible to accurately approximate proximity losses and shielding effect while considering realistic meshes for finite element methods computation. Three-dimensional magnetodynamic simulations of transformer test-cases using anisotropic complex permeability for magnetic core and windings have shown a good agreement with the standard model results.