High-Resolution Three-Dimensional NMR Structure Of The KRAS Proto-Oncogene Promoter Reveals Key Features Of A G-Quadruplex Involved In Transcriptional Regulation

Non-canonical base pairing within guanine-rich DNA and RNA sequences can produce G-quartets, whose stacking leads to the formation of a G-quadruplex (G4). G4s can coexist with canonical duplex DNA in the human genome and have been suggested to suppress gene transcription, and much attention has therefore focused on studying G4s in promotor regions of disease-related genes. For example, the human KRAS proto-oncogene contains a nuclease-hypersensitive element located upstream of the major transcription start site. The KRAS nuclease-hypersensitive element (NHE) region contains a G-rich element (22RT; 5′-AGGGCGGTGTGGGAATAGGGAA-3′) and encompasses a Myc-associated zinc finger-binding site that regulates KRAS transcription. The NEH region therefore has been proposed as a target for new drugs that control KRAS transcription, which requires detailed knowledge of the NHE structure. In this study, we report a high-resolution NMR structure of the G-rich element within the KRAS NHE. We found that the G-rich element forms a parallel structure with three G-quartets connected by a four-nucleotide loop and two short one-nucleotide double-chain reversal loops. In addition, a thymine bulge is found between G8 and G9. The loops of different lengths and the presence of a bulge between the G-quartets are structural elements that potentially can be targeted by small chemical ligands that would further stabilize the structure and interfere or block transcriptional regulators such as Myc-associated zinc finger from accessing their binding sites on the KRAS promoter. In conclusion, our work suggests a possible new route for the development of anticancer agents that could suppress KRAS expression

Development of personnel technologies in the customs system of the Russian Federation

In the paper, the authors study the main reasons for introducing economic sanctions against the Russian Federation and how to counteract them. At the same time, the current situation requires intensified development of the international business to modernize the Russian economy. For this, it has become imperative to understand the role and place of the customs of the Russian Federation in this process and to further improve the approaches to staffing a federal executive body – the Federal Customs Service (FCS of Russia) in terms of selecting highly skilled personnel. In the end, a unified methodology for evaluating candidates taking civil service postsin the customs bodies is propose

Comparative first-principles molecular dynamics study of TiN(001)/SiN/TiN(001) and TiN(001)/SiC/TiN(001) interfaces in superhard nanocomposites

Heterostructures TiN(001)/SiN/TiN(001) and TiN(001)/SiC/TiN(001), with one monolayer (ML) of interfacial SiN and SiC, respectively, inserted between five monolayer thick B1-TiN, were investigated using first-principles quantum molecular dynamics (QMD) calculations. The temperature dependent QMD simulations at 300 K in combination with subsequent variable-cell structural relaxation revealed that the TiN(001)/SiN/TiN(001) interface exists as pseudomorphic B1-SiN layer only at 0 K, and as a superposition of distorted octahedral SiN6 and tetrahedral SiN4 units aligned along the (110) direction at a finite temperature. Thus, at 300 K, the interfacial layer is not epitaxial. Instead it consists of aggregates of the B1-SiN-like and Si3N4-like distorted clusters. However, in the the TiN(001)/SiC/TiN(001) heterostructures, the interfacial layer remains epitaxial B1-SiC at 0 K as well as at 300 K, with only a small shift of nitrogen atoms on both sides of the interface towards the silicon atoms. A comparison with the results obtained by earlier "static" ab initio DFT calculations at 0 K shows the great advantage of the QMD calculations that allow us to reveal structural reconstructions caused by thermal activation. When you are citing the document, use the following link http://essuir.sumdu.edu.ua/handle/123456789/2054

First-Principles Quantum Molecular Dynamics Study of TixZr1-xN(111)/SiNy Heterosrtructures

Heterostructures with 1 monolayer of Si3N4-like Si2N3 interfacial layer between five monolayers thick B1-TixZr1-xN(111), x 1.0, 0.6, 0.4 and 0.0, slabs were investigated by means of first-principles quantum molecular dynamics and structure optimization procedure using the Quantum ESPRESSO code. Slabs consisting of stoichiometric TiN and ZrN and random, as well as segregated B1-TixZr1-xN(111) solutions were considered. The calculations of the B1-TixZr1-xN solid solutions as well as of the heterostructures showed that the pseudo-binary TiN-ZrN system exhibits a miscibility gap. The segregated heterostructures in which the Zr atoms surround the SiyNz interface were found to be most stable. For the Zr-rich heterostructures, the total energy of the random solid solution was lower compared to that of the segregated one, whereas for the Ti-rich heterostructures the opposite tendency was observed. When you are citing the document, use the following link http://essuir.sumdu.edu.ua/handle/123456789/3518

Percolation in deposits for competitive models in (1+1)-dimensions

The percolation behaviour during the deposit formation, when the spanning cluster was formed in the substrate plane, was studied. Two competitive or mixed models of surface layer formation were considered in (1+1)-dimensional geometry. These models are based on the combination of ballistic deposition (BD) and random deposition (RD) models or BD and Family deposition (FD) models. Numerically we find, that for pure RD, FD or BD models the mean height of the percolation deposit $\bar h$ grows with the substrate length $L$ according to the generalized logarithmic law $\bar h\propto (\ln (L))^\gamma$, where $\gamma=1.0$ (RD), $\gamma=0.88\pm 0.020$ (FD) and $\gamma=1.52\pm 0.020$ (BD). For BD model, the scaling law between deposit density $p$ and its mean height $\bar h$ at the point of percolation of type $p-p_\infty \propto \bar h^{-1/\nu_h}$ are observed, where $\nu_h =1.74\pm0.02$ is a scaling coefficient. For competitive models the crossover, %in $h$ versus $L$ corresponding to the RD or FD -like behaviour at small $L$ and the BD-like behaviour at large $L$ are observed.Comment: 8 pages,4 figures, Latex, uses iopart.cl

Cosmological scalar fields that mimic the ΛCDM\Lambda CDM cosmological model

We look for cosmologies with a scalar field (dark energy without cosmological constant), which mimic the standard $\Lambda CDM$ cosmological model yielding exactly the same large-scale geometry described by the evolution of the Hubble parameter (i.e. photometric distance and angular diameter distance as functions on $z$). Asymptotic behavior of the field solutions is studied in the case of spatially flat Universe with pressureless matter and separable scalar field Lagrangians (power-law kinetic term + power-law potential). Exact analytic solutions are found in some special cases. A number of models have the field solutions with infinite behavior in the past or even singular behavior at finite redshifts. We point out that introduction of the cosmological scalar field involves some degeneracy leading to lower precision in determination of $\Omega_m$. To remove this degeneracy additional information is needed beyond the data on large-scale geometry.Comment: VIII International Conference "Relativistic Astrophysics, Gravitation and Cosmology": May 21-23, 2008, Kyiv, Ukrain

Gravitational Ionization: A Chaotic Net in the Kepler System

The long term nonlinear dynamics of a Keplerian binary system under the combined influences of gravitational radiation damping and external tidal perturbations is analyzed. Gravitational radiation reaction leads the binary system towards eventual collapse, while the external periodic perturbations could lead to the ionization of the system via Arnold diffusion. When these two opposing tendencies nearly balance each other, interesting chaotic behavior occurs that is briefly studied in this paper. It is possible to show that periodic orbits can exist in this system for sufficiently small damping. Moreover, we employ the method of averaging to investigate the phenomenon of capture into resonance.Comment: REVTEX Style, Submitte