Abstract
Background
The development and clinical implementation of the cap-dependent endonuclease (CEN) inhibitor baloxavir marboxil was a breakthrough in influenza therapy, but it was associated ...with the emergence of drug-resistant variants.
Objectives
To design and synthesize structural analogues of CEN inhibitors and evaluate their safety, pharmacokinetics and antiviral potency in vitro and in vivo.
Methods
The drug candidate AV5124 and its active metabolite AV5116 were synthesized based on pharmacophore modelling. Stability in plasma and microsomes, plasma protein binding, cytotoxicity and antiviral activities were assessed in vitro. Pharmacokinetics after IV or oral administration were analysed in CD-1 mice. Acute toxicity and protective efficacy against lethal A(H1N1)pdm09 influenza virus challenge were examined in BALB/c mice.
Results
Pharmacophore model-assisted, 3D molecular docking predicted key supramolecular interactions of the metal-binding group and bulky hydrophobic group of AV5116 with the CEN binding site (Protein Data Bank code: 6FS6) that are essential for high antiviral activity. AV5116 inhibited influenza virus polymerase complexes in cell-free assays and replication of oseltamivir-susceptible and -resistant influenza A and B viruses at nanomolar concentrations. Notably, AV5116 was equipotent or more potent than baloxavir acid (BXA) against WT (I38-WT) viruses and viruses with reduced BXA susceptibility carrying an I38T polymerase acidic (PA) substitution. AV5116 exhibited low cytotoxicity in Madin–Darby canine kidney cells and lacked mitochondrial toxicity, resulting in favourable selective indices. Treatment with 20 or 50 mg/kg AV5124 prevented death in 60% and 100% of animals, respectively.
Conclusions
Overall, AV5124 and A5116 are promising inhibitors of the influenza virus CEN and warrant further development as potent anti-influenza agents.
The hybrid model for analyzing distortions of a laser beam passed through a moderately scattering medium with the number of scattering events up to 10 is developed and investigated. The model ...implemented the Monte Carlo technique to simulate the beam propagation through a scattering layer, a ray-tracing technique to propagate the scattered beam to the measurements plane, and the Shack–Hartmann technique to calculate the scattered laser beam distortions. The results obtained from the developed model were confirmed during the laboratory experiment. Both the numerical model and laboratory experiment showed that with an increase of the concentration value of scattering particles in the range from 105 to 106 mm−3, the amplitude of distortions of laser beam propagated through the layer of the scattering medium increases exponentially.
MicroRNAs (miRNA) are a recently discovered class of noncoding RNAs that negatively regulate gene expression. Recent evidence indicates that miRNAs may play an important role in cancer. However, the ...mechanism of their deregulation in neoplastic transformation has only begun to be understood. To elucidate the role of tumor suppressor p53 in regulation of miRNAs, we have analyzed changes in miRNA microarray expression profile immediately after conditional inactivation of p53 in primary mouse ovarian surface epithelium cells. Among the most significantly affected miRNAs were miR-34b and miR-34c, which were down-regulated 12-fold according to quantitative reverse transcription-PCR analysis. Computational promoter analysis of the mir-34b/mir-34c locus identified the presence of evolutionarily conserved p53 binding sites approximately 3 kb upstream of the miRNA coding sequence. Consistent with evolutionary conservation, mir-34b/mir-34c were also down-regulated in p53-null human ovarian carcinoma cells. Furthermore, as expected from p53 binding to the mir-34b/c promoter, doxorubicin treatment of wild-type, but not p53-deficient, cells resulted in an increase of mir-34b/mir-34c expression. Importantly, miR-34b and miR-34c cooperate in suppressing proliferation and soft-agar colony formation of neoplastic epithelial ovarian cells, in agreement with the partially overlapping spectrum of their predicted targets. Taken together, these results show the existence of a novel mechanism by which p53 suppresses such critical components of neoplastic growth as cell proliferation and adhesion-independent colony formation.
The problem of nucleation and development for the fatigue fracture process in element of aircraft structure is solved using previously developed cyclic damage model. The model contains the evolution ...equation for the damage function depending on stress state and amplitudes of the cyclic loads. On this basis, calculations of the initiation and development of crack-like fracture zones are carried out for an aircraft structure element of a disk with a blade in a flight loading cycle (HCF mode). The damage function was calculated based on the elastic solution for the element of structure loaded by centrifugal forces in disk and blade and aerodynamical pressure on blade. An alternative cyclic loading regime associated with high-frequency vibrations of the blades was investigated. Fatigue fracture in this process corresponds to the VHCF mode. Simulation of the combined cyclic loading mode was also carried out. In all these modes, the real time of the nucleation and development of quasi-cracks was estimated up to reaching the observed disk surface.
A combined steam-gas plant with in-cycle steam gasification of coal and hot gas purification is considered as a promising technology for increasing the efficiency of energy production with ...simultaneous reduction in environmental impact. To intensify steam-air gasification, mechanical activation of fuel is used; it consists in high-stress grinding in a mill-disintegrator. The supply of steam to the gasifier allows an increase in reactivity of fuel, suppression of sorbent decomposition in the unit of hot desulfurization, reduction in the steam load on the shift reactor, increase in useful external work of gas turbine expansion, reduction in nitrogen oxide formation, and general increase in the efficiency and ecological compatibility of energy generation. On the other hand, a significant amount of steam can deteriorate the heat balance and efficiency of the gasifier. In this work, the influence of the steam/fuel ratio on steam-air gasification of mechanically activated Kuznetsk coal in a flow reactor was studied experimentally. The excess air coefficient was maintained constant and equal to 0.51, which corresponded to a temperature at the reactor outlet of about 1100?C. When steam was supplied, the fuel and air-flow rates were adjusted to ensure a constant gas-dynamic regime. To evaluate the obtained regimes, the heat and material balances were compiled. A positive effect of steam on characteristics of the gasification process was revealed. For the studied coal, the maximum degree of coal conversion and the calorific value of synthesis gas are achieved with a steam/fuel ratio of about 0.4 kg/kg.
The application of titanium and its alloys under friction conditions is severely restricted, owing to their poor wear resistance. The paper presents the results of studies of the composition, ...microstructure, and tribological properties of Ti-TiC-based composite coatings formed on titanium alloys by the electroarc treatment in an aqueous electrolyte using a graphite anode. It has been found that TiC grains have a different stoichiometry and do not contain oxygen. The grain size varies from hundreds of nanometers to tens of micrometers, and the micro-hardness of the treated surface reached the value of 29.5 GPa. The wear resistance of the treated surface increased approximately 40-fold, and the friction coefficient with steel decreased to 0.08-0.3 depending on the friction conditions. The formation of a composite material based on Ti-TiC will contribute to the effective protection of titanium alloys from frictional loads in engineering.
An Old Persian Inscription from Phanagoria Kuznetsov, Vladimir D; Nikitin, Alexander B
Ancient civilizations from Scythia to Siberia,
06/2019, Letnik:
25, Številka:
1
Journal Article
Recenzirano
Abstract
This article is a publication of the fragmentary Old Persian inscription from the ancient Greek city of Phanagoria (the Taman Peninsula, Russia). The inscription was found in a private house ...built over the ruins of the city's fortifications, which perished in a fire in the late first or the early second quarter of the 5th century BC. The fragment of the stele bears six partially preserved lines of the text. The signs at the beginning and the end of each line are missing. Due to the fragmentary nature of the inscription, its contents can not be determined. However, the archaeological context of the find allows us to attribute its authorship to King Xerxes. The new document attests that the Persian Empire took an active interest in the northern coast of the Black Sea.
The paper is devoted to the problem of fatigue failure of two-phase titanium alloy VT3-1 under the action of high-frequency cyclic loading. Samples for the tests were made from the compressor disk of ...aviation engine D30-Ku installed on Tupolev Tu-154 planes. Repeated alternating loading was carried out by displacements of small amplitude at 20 kHz, coinciding with the first harmonic of longitudinal elastic vibrations of the sample. Analysis of specimen fracture surfaces shows predominant subsurface fracture. Analysis of areas of fatigue nucleation allows identifying elements of microstructure associated with crack nucleation. The results of the study can be used in the interpretation of fracture scenarios of structural elements in operation. Increasing the resource of products under such loads is possible through the use of damping layers or tapes, where possible.
Currently, the technology of microelectromechanical systems is widely used in the development of high-frequency and ultrahigh-frequency devices. The most important requirements for modern and ...advanced devices of the ultra-high-frequency range are the reduction of weight and size characteristics, power consumption with an increase in their functionality, operating frequency and level of integration. Radio frequency microelectromechanical switches are developed using the technology of the manufacture of CMOS-integrated circuits. Integrated radio frequency control circuits require low control voltages, the high ratio of losses to the isolation in the open and closed condition, high performance and reliability. This review is devoted to the analytical approach based on the knowledge of materials, basic performance indices and mechanisms of failure, which can be used in the development of radio-frequency microelectromechanical switches.
The paper is focused on the very high cycle fatigue (VHCF) properties of aluminum alloys proceeded in two different technological procedures. The hot-rolled D16T alloy is compared with the selected ...laser melting (SLM) AlSi10Mg alloy. The fatigue tests were performed at a high frequency (20 kHz) in the laboratory air environment at room temperature. The experimental results showed a significant difference in fatigue strength between hot-rolled and SLM materials. The VHCF properties of AlSi10Mg were more than two times lower than those of D16T in spite of the comparable quasi-static tensile properties. The difference in fatigue properties was explained based on fractographic analysis of fracture surfaces. The morphology of the fracture pattern was qualitatively different. In the case of the hot-rolled alloy, the three clear zones of crack growth could be outlined. The main part of the pattern was covered by quasi-brittle facets that are typical for VHCF fractures in Al alloys. In the case of the SLM material, unregulated structures were found in the microstructure. In some local zones, numerous non-melted particles were observed on the fracture surface. The boundaries of certain layers also played an important role in the fracture. Large, separated surfaces were observed on the fracture pattern. It is important to note that these boundaries were not associated with the layer-by-layer building of the specimen. The distance between such features was significantly larger than the thickness of an individual layer.
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