Combinatorial–computational–chemoinformatics (C3) approach to finding and analyzing low-energy tautomers

Finding the most stable tautomer or a set of low-energy tautomers of molecules is critical in many aspects of molecular modelling or virtual screening experiments. Enumeration of low-energy tautomers of neutral molecules in the gas-phase or typical solvents can be performed by applying available organic chemistry knowledge. This kind of enumeration is implemented in a number of software packages and it is relatively reliable. However, in esoteric cases such as charged molecules in uncommon, non-aqueous solvents there is simply not enough available knowledge to make reliable predictions of low energy tautomers. Over the last few years we have been developing an approach to address the latter problem and we successfully applied it to discover the most stable anionic tautomers of nucleic acid bases that might be involved in the process of DNA damage by low-energy electrons and in charge transfer through DNA. The approach involves three steps: (1) combinatorial generation of a library of tautomers, (2) energy-based screening of the library using electronic structure methods, and (3) analysis of the information generated in step (2). In steps 1–3 we employ combinatorial, computational and chemoinformatics techniques, respectively. Therefore, this hybrid approach is named “Combinatorial*Computational*Chemoinformatics”, or just abbreviated as C3 (or C-cube) approach. This article summarizes our developments and most interesting methodological aspects of the C3 approach. It can serve as an example how to identify the most stable tautomers of molecular systems for which common chemical knowledge had not been sufficient to make definite predictions

RNAi-Mediated c-Rel Silencing Leads to Apoptosis of B Cell Tumor Cells and Suppresses Antigenic Immune Response In Vivo

c-Rel is a member of the Rel/NF-κB transcription factor family and is predominantly expressed in lymphoid and myeloid cells, playing a critical role in lymphocyte proliferation and survival. Persistent activation of the c-Rel signal transduction pathway is associated with allergies, inflammation, autoimmune diseases, and a variety of human malignancies. To explore the potential of targeting c-Rel as a therapeutic agent for these disorders, we designed a small interfering RNA (siRNA) to silence c-Rel expression in vitro and in vivo. C-Rel-siRNA expression via a retroviral vector in a B cell tumor cell line leads to growth arrest and apoptosis of the tumor cells. Silencing c-Rel in primary B cells in vitro compromises their proliferative and survival response to CD40 activation signals, similar to the impaired response of c-Rel knockout B cells. Most important, in vivo silencing of c-Rel results in significant impairment in T cell-mediated immune responses to antigenic stimulation. Our study thus validates the efficacy of c-Rel-siRNA, and suggests the development of siRNA-based therapy, as well as small molecular inhibitors for the treatment of B cell tumors as well as autoimmune diseases

Features of adaptation of new employees in the education sector for example the Municipal budgetary educational institution of secondary school № 127

The article is devoted to the peculiarities of employees adaptation in education. Adaptation is a process of employees adaption to work and to the social environment of the organization. This process usually takes place in educational institutions spontaneously and difficult, as there is no set of measures to adapt personnel. Many organizations - small and / or having a specific nature - often neglected adaptation procedure. The article contained research of school staff adaptation. The results of scrutiny give an idea about the features of this procedure and its effectiveness in educational institutions.Статья посвящена особенностям адаптации сотрудников в сфере образования. Адаптация — это процесс приспособления сотрудников к трудовой деятельности и к социальной среде организации. В образовательных учреждениях данный процесс обычно проходит затруднительно и стихийно, так как отсутствует комплекс мероприятий по адаптации персонала. Во многих организациях – маленьких и/или имеющих особую специфику – часто пренебрегают процедурой адаптации. В статье содержатся результаты исследования адаптации сотрудников школы, которые дают представление об особенностях проведения данной процедуры и ее эффективности в образовательных учреждениях

N NMR of tetrapropylammonium based crystals

We have investigated using 14N NMR different types of materials containing tetrapropylammonium cations. We consider the tetrapropylammonium bromide crystal as well as two different microporous materials silicalite-1 and AlPO-5, with MFI and AFI topology respectively, where the tetrapropylammonium cation plays the role of structure directing agent. 14N NMR quadrupolar coupling parameters were determined experimentally for all the crystals. In addition calculations based on Density Functional Theory with empirical dispersion (DFT-D) were performed on the MFI type zeolite. The sensitivity of the 14N quadrupolar coupling parameters to the spatial distribution of the anions in the zeolite's framework is emphasized

Transformation of state policy for regulating labor and education markets in the digital reality of modern society

Global penetration of digital tools into everyday life dictates a significant change in approaches to defining requirements for specialists of the present and future. High speed of technological changes and total algorithmization of typical tasks significantly reduce the list of traditional professions and create conditions for the emergence of technological unemployment. A significant problem for all subjects of the labor market is the natural transformation of models of their interaction with each other. Reducing the time lag of a technological wave duration plays an important role here. This affects directly the development trends of the real economy, education, and labor markets. In addition, the paradigm of state management of labor and education markets is expected to undergo radical changes. High transparency of the borders of national labor markets and development of on-line education dictate the need to synchronize approaches to models of public administration in these areas. In the framework of this article we have identified the prerequisites for transforming the existing paradigm of interaction between labor market actors and have proposed measures for immediate synchronous work of governments of different states in order to offset possible negative consequences of digitalization of the economy

Comparison of density functionals for energy and structural differences between the high-[5T2g:(t2g)4(eg)2] and low-[1A1g:(t2g)6(eg)0] spin states of the hexaquoferrous cation [Fe(H2O)6]2+

A comparison of density functionals is made for the calculation of energy and geometry differences for the high- [5T2g: (t2g)4(eg)2] and low- [1A1g: (t2g)6(eg)0] spin states of the hexaquoferrous cation [Fe(H2O)6]2+. Since very little experimental results are available (except for crystal structures involving the cation in its high-spin state), the primary comparison is with our own complete active-space self-consistent field (CASSCF), second-order perturbation theory-corrected complete active-space self-consistent field (CASPT2), and spectroscopy-oriented configuration interaction (SORCI) calculations. We find that generalized gradient approximations (GGAs) and the B3LYP hybrid functional provide geometries in good agreement with experiment and with our CASSCF calculations provided sufficiently extended basis sets are used (i.e., polarization functions on the iron and polarization and diffuse functions on the water molecules). In contrast, CASPT2 calculations of the low-spin–high-spin energy difference DeltaELH = ELS–EHS appear to be significantly overestimated due to basis set limitations in the sense that the energy difference of the atomic asymptotes (5D-->1I excitation of Fe2+) are overestimated by about 3000 cm–1. An empirical shift of the molecular DeltaELH based upon atomic calculations provides a best estimate of 12 000–13 000 cm–1. Our unshifted SORCI result is 13 300 cm–1, consistent with previous comparisons between SORCI and experimental excitation energies which suggest that no such empirical shift is needed in conjunction with this method. In contrast, after estimation of incomplete basis set effects, GGAs with one exception underestimate this value by 3000–4000 cm–1 while the B3LYP functional underestimates it by only about 1000 cm–1. The exception is the GGA functional RPBE which appears to perform as well as or better than the B3LYP functional for the properties studied here. In order to obtain a best estimate of the molecular DeltaELH within the context of density functional theory (DFT) calculations we have also performed atomic excitation energy calculations using the multiplet sum method. These atomic DFT calculations suggest that no empirical correction is needed for the DFT calculations