Structure-based design of inhibitors of NS3 serine protease of hepatitis C virus

We have designed small focused combinatorial library of hexapeptide inhibitors of NS3 serine protease of the hepatitis C virus (HCV) by structure-based molecular design complemented by combinatorial optimisation of the individual residues. Rational residue substitutions were guided by the structure and properties of the binding pockets of the enzyme's active site. The inhibitors were derived from peptides known to inhibit the NS3 serine protease by using unusual amino acids and alpha-ketocysteine or difluoroaminobutyric acid, which are known to bind to the S1 pocket of the catalytic site. Inhibition constants (Ki) of the designed library of inhibitors were predicted from a QSAR model that correlated experimental Ki of known peptidic inhibitors of NS3 with the enthalpies of enzyme-inhibitor interaction computed via molecular mechanics and the solvent effect contribution to the binding affinity derived from the continuum model of solvation. The library of the optimised inhibitors contains promising drug candidates-water-soluble anionic hexapeptides with predicted Ki* in the picomolar range.     

Computational simulation methods for fiber reinforced composites

Trefftz-finite element method (Trefftz-FEM), adaptive cross approximation BEM (ACA BEM) and continuous source function method (CSFM) are used for the simulation of composites reinforced by short fibers (CRSF) with the aim of showing the possibilities of reducing the problem of complicated and important interactions in such composite materials.     

Acid-catalyzed decomposition of stable 1-(2,1-benzisothiazol-3-yl)-3-phenyltriazenes

The acid-catalyzed decomposition of unusually stable 1-(2,1-benzisothiazol-3-yl)-3-phenyltriazenes in either aqueous perchloric acid or an aqueous mixture of perchloric and acetic acid was studied under pseudo-first order reaction conditions at 25 °C. Different products were obtained according to substitution on nitrogen N-3. For a triazene carrying hydrogen, the corresponding 3-amino-2,1-benzisothiazole and benzenediazonium salts were formed whereas in the case of substitution by an alkyl group (methyl and n-butyl) the 2,1-benzisothiazole-3-diazonium salt and N-alkylaniline were obtained. The observed rate constant (k_obs) of the acid-catalyzed decomposition increased, initially, nonlinearly with increasing concentration of acid. Subsequently, k_obs decreased slightly and at high acid concentration, increased steeply once again. An A-S_E2 mechanism in which protonation of the triazene nitrogen proceeds simultaneously with cleavage of the N–N bond is proposed. Tautomerism of 1-(2,1-benzisothiazol-3-yl)-3-phenyltriazene was investigated using ¹H NMR spectroscopy.     

Determination of Heat of Adsorption on Clean Solid Surfaces

One of the basic parameters characterizing the bond between a chemisorbed atom (or molecule) and the surface is its dissociation energy. It is difficult, however, to determine the bond energy and therefore it becomes necessary to turn to some other quantity, which is sufficiently close to the bond energy and which can be determined without much difficulty. Such a quantity is the heat of adsorption. Heat of adsorption is defined as the difference between the total energy of the adsorption system prior to and after the adsorption process, i.e., it equals the sum of all energy changes connected with adsorption. Thus the experimentally determined value for the heat of adsorption is obviously closely related to the bond energy of the chemisorbed particle, though this relation is not quite simple [1,2].     

Antifungal activity of lauric acid derivatives against Aspergillus niger

The antifungal effects of lauric acid and four lauric acid derivatives (monolauroylglycerol, D-laurate A, T-laurate A, 6-O-lauroysucrose) were tested on the spore germination and the growth rate of Aspergillus niger DMF 0801. The results showed that the tested substances varied in their antifungal activity and they also confirmed the relation of the structure of tested substances and their antifungal effects. Monolauroylglycerol at concentration level between 0.2 and 1.8 mmol l^-1 caused the highest inhibition of spore outgrowths whereas 6-O-lauroysucrose at concentration between 0.05 and 1.8 mmol l^-1 did not exhibit inhibition of spore germination. The inhibition of colony growth rate was detected mainly at presence of 6-O-lauroysucrose.     

Description of Quantum Dynamics of Open Systems Based on Collision-Like Models

Master equations in the Lindblad form describe evolution of open quantum systems that are completely positive and simultaneously have a semigroup property. We analyze the possibility to derive this type of master equations from an intrinsically discrete dynamics that is modelled as a sequence of collisions between a given quantum system (a qubit) with particles that form the environment. In order to illustrate our approach we analyze in detail how the process of an exponential decay and the process of decoherence can be derived from a collision-like model in which particular collisions are described by SWAP and controlled-NOT interactions, respectively.Presented at the 36th Symposium on Mathematical Physics, “Open Systems & Quantum Information”, Toruń, Poland, June 9-12, 2004.     

Measurement of beam intensity of electrically charged particles in superconductive accelerators using SQM

This paper is aimed at theoretical aspects of the application of superconducting quantum magnetometers in measurement of beam intensity of electrically charged particles in superconductive accelerators. The parameters of antenna system, which picks up the magnetic field induced by unidirectional component of the accelerated particles current, are examined. From the analysis it follows that for accelerators with a beam trajectory radius of the order of10 ¹ m the spectral sensitivity limit is of the order of (10 ²–10³) elementary particles/(cycleHz ^1/2).     

Poly[N-(2-hydroxypropyl)methacrylamide]-based tissue-embedding medium compatible with MALDI mass spectrometry imaging experiments

Traditional tissue-sectioning techniques for histological samples utilize various embedding media to stabilize the tissue on a sectioning target and to provide a smooth cutting surface. Due to the ion suppression effect in MALDI ionization and number of background peaks in the low-mass region, these media are not suitable for mass spectrometry imaging (MSI) experiments. To overcome this, droplets of water are often used to mount the tissue on a sectioning target, but the ice block formed around the tissue does not provide a good support for sectioning of fragile samples. In this work, we propose a novel embedding media, compatible with MALDI ionization and MSI experiments, based on poly[N-(2-hydroxypropyl)methacrylamide] (pHPMA). Using a reversible addition-fragmentation chain transfer polymerization technique, well-defined pHPMA polymer with narrow mass distribution was prepared. Benefits of the resulted pHPMA-based embedding media were tested on different tissue samples.     

Fast point-based 3-D alignment of live cells.

Typical time intervals between acquisitions of three-dimensional (3-D) images of the same cell in live cell imaging are in the orders of minutes. In the meantime, the live cell can move in a water basin on the stage. This movement can hamper the studies of intranuclear processes. We propose a fast point-based image registration method for the suppression of the movement of a cell as a whole in the image data. First, centroids of certain intracellular objects are computed for each image in a time-lapse series. Then, a matching between the centroids, which have the maximal number of pairs, is sought between consecutive point sets by a 3-D extension of a two-dimensional fast point pattern matching method, which is invariant to rotation, translation, local distortion, and extra/missing points. The proposed 3-D extension assumes rotations only around the z axis to retain the complexity of the original method. The final step involves computing the optimal fully 3-D transformation between images from corresponding points in the least-squares manner. The robustness of the method was evaluated on generated data. The results of the simulations show that the method is very precise and its correctness can be estimated. This article also presents two practical application examples, namely the registration of images of HP1 domains and the registration of images of telomeres. More than 97% of time-consecutive images were successfully registered. The results show that the method is very well suited to live cell imaging.