Search

Here, we describe the first systematic study on the mechanism of substrate-selective inhibition of mammalian ALOX15 orthologs. For this purpose, we prepared a series of N-substituted 5-(1H-indol-2-yl)anilines and found that (N-(5-(1H-indol-2-yl)-2-methoxyphenyl)sulfamoyl)carbamates and their monofluorinated analogues are potent and selective inhibitors of the linoleate oxygenase activity of rabbit and human ALOX15. Introduction of a 2-methoxyaniline moiety into the core pharmacophore plays a crucial role in substrate-selective inhibition of ALOX15-catalyzed oxygenation of linoleic acid at submicromolar concentrations without affecting arachidonic acid oxygenation. Steady-state kinetics, mutagenesis studies, and molecular dynamics (MD) simulations suggested an allosteric mechanism of action. Using a dimer model of ALOX15, our MD simulations suggest that the binding of the inhibitor at the active site of one monomer induces conformational alterations in the other monomer so that the formation of a productive enzyme-linoleic acid complex is energetically compromised.

Single-ion and exchange anisotropy effects in equal-spin $s^{(1)}=s^{(2)}$ dimeric single molecule magnets exhibiting C 2 point group symmetry have been studied. The Hamiltonian which is written in two-spin $4\times 4$ Pauli matrixes representation in the appropriate local coordinates has been used to derive energy levels and eigen spin states. The anomalous variation of the average spin system in dependence of non-collinear misalignment of the local anisotropy axes has been found. Particularly a fully non magnetic state of an $\mathrm{s}=1/2$ spin dimer was predicted.

For more than a decade, atherosclerosis has been one of the leading causes of death in developed countries. The issue of treatment and prevention of the disease is especially acute. Despite the huge amount of basic and clinical research, a significant number of gaps remain in our understanding of the pathogenesis of atherosclerosis, and only their closure will bring us closer to understanding the causes of the disease at the cellular and molecular levels and, accordingly, to the development of an effective treatment. One of the seemingly well-studied elements of atherogenesis is the mTOR signaling pathway. However, more and more new details are still being clarified. Therapeutic strategies associated with rapamycin have worked well in a number of different diseases, and there is every reason to believe that targeting components of the mTOR pathway may pay off in atherosclerosis as well.

His596 of human ALOX12 has been suggested to interact with the COO--group of arachidonic acid during ALOX catalysis. In mammalian ALOX15 orthologs Gln596 occupies this position and this amino acid exchange might contribute to the functional differences between the two ALOX-isoforms. To explore the role of Gln596 for ALOX15 functionality we mutated this amino acid to different residues in rabbit and human ALOX15 and investigated the impact of these mutations on structural, catalytic and allosteric enzyme properties. To shed light on the molecular basis of the observed functional alterations we performed in silico substrate docking studies and molecular dynamics simulations and also explored the impact of Gln596 exchange on the protein structure. The combined theoretical and experimental data suggest that Gln596 may not directly interact with the COO--group of arachidonic acid. In contrast, mutations at Gln596 destabilize the secondary and tertiary structure of ALOX15 orthologs, which may be related to a disturbance of the electrostatic interaction network with other amino acids in the immediate surrounding. Moreover, our MD-simulations suggest that the geometry of the dimer interface depends on the structure of substrate bound inside the substrate-binding pocket and that Gln596Ala exchange impairs the allosteric properties of the enzyme. Taken together, these data indicate the structural and functional importance of Gln596 for ALOX15 catalysis.

Ommidirectional in azimuth plane antennas with horizontal polarization are used in communication systems of McWILL standard, digital television systems of DVB-T2 standard, radio monitoring systems, semi-active ranging using the target illumination with the television broadcast signal, and many other cases. In many cases, radar and radio monitoring systems use phase methods to determine the azimuth and elevation angle of the target. To view all azimuthal angles, ring arrays consisting of omnidirectional emitters, usually also represented by ring arrays, are used. This paper studies the characteristics of an omnidirectional radiating element of electrically small horizontal dipole elements. An expression is derived that relates the radius of the dipole ring array to the number of dipoles and the variation of the resulting radiation pattern. The results are confirmed by experimental studies.

Three analytical methods, namely, inductively coupled plasma sector field mass spectrometry (ICP-SFMS); inductively coupled plasma quadrupole mass spectrometry (ICP-QMS) and filter-furnace electrothermal atomic-absorption spectroscopy (FF-ET-AAS) for the determination of V, Mn, Ni, Cu, As, Sr, Mo, Cd and Pb in ground natural water samples were compared and evaluated for their capacity to provide reliable and precise results. Two certified reference materials (SLEW-3 Estuarine Water; SLRS-4 River Water) were analysed to prove that accurate results could be obtained by using all the listed methods with properly optimised parameters. The limit of detection (LOD) for V, Mn, Ni, Cu, As, Sr, Mo, Cd and Pb provided by the ICP-MS methods ranged from 0.001 to 0.05 µg L-1. Such LOD proved sufficient for the reliable determination of the listed elements in ground natural waters. However, the LOD of the FF-ET-AAS was approximately two orders of magnitude higher than that of ICP-MS, which made it impossible to quantify V, Mn, Ni, Mo and Pb. The effects of the usage of the collision cell mode in ICP-QMS and of the desolvation system Apex for ICP-SFMS to eliminate oxide ions levels were investigated. For all three analytical methods, the influence of the matrix effect on the results of the determination of the investigated elements using matrix model solution, external calibration and standard addition methods was evaluated. A comparison using a paired Student's t-test between the results obtained by both ICP-MS methods for V, Mn, Ni, Cu, As, Sr, Mo, Cd and Pb concentrations in ground natural waters showed that there was no significant difference on a 95% confidence level. The precision of the results for ICP-SFMS, ICP-QMS and FF-ET-AAS varied between ~0.5 and 11; 2.5 and 12.5; 3 and 13.5%, respectively. Moreover, ICP-SFMS equipped with the desolvation system APEX proved a better choice for As, Cu and Mn analysis due to its better LOD (0.008, 0.03 and 0.02 µg L-1, respectively) and precision (Sr

The paper deals with the problem of calculating the rod structure of a two-tier dome for stability. Such structures consisting of straight rod elements are widely used in practice and have a number of significant advantages. First of all, it is a high rigidity with a low mass. Also, this type of construction is well resistant to dynamic loads. At the same time, the dome model allows for the bifurcation of points on the equilibrium state curve of the system. The problem of the dynamic stability of double dome is solved by the principle of stationarity of total potential energy of the system. The analysis of the obtained solution is carried out, and the equilibrium state diagram for a two-tier core dome is constructed.

This paper deals with a number of problems that occur most frequently in the course of scientific research during the process of conceptualization and categorization of the world around us by means of natural language. The main subject is to consider the origins of certain issues and difficulties concerning the process of conceptualization and categorization, as well as to explain their nature or, at least, work out some speculations. The methodology of the research is analysis of the most common problems that occur in the process of conceptualization and categorization of the world by means of natural language. Results of the research are determination of a number of problems concerning conceptualization and categorization, explanation of certain reasons for them to occur. A scope of results is various kinds of scientific research works, concerning the features and issues occurring in the course of conceptualization and categorization during the process of creating and analyzing different linguistic world images.