Chemically engineering ligand selectivity at the free fatty acid receptor 2 based on pharmacological variation between species orthologs

When it is difficult to develop selective ligands within a family of related G-protein-coupled receptors (GPCRs), chemically engineered receptors activated solely by synthetic ligands (RASSLs) are useful alternatives for probing receptor function. In the present work, we explored whether a RASSL of the free fatty acid receptor 2 (FFA2) could be developed on the basis of pharmacological variation between species orthologs. For this, bovine FFA2 was characterized, revealing distinct ligand selectivity compared with human FFA2. Homology modeling and mutational analysis demonstrated a single mutation in human FFA2 of C4.57G resulted in a human FFA2 receptor with ligand selectivity similar to the bovine receptor. This was exploited to generate human FFA2-RASSL by the addition of a second mutation at a known orthosteric ligand interaction site, H6.55Q. The resulting FFA2-RASSL displayed a >100-fold loss of activity to endogenous ligands, while responding to the distinct ligand sorbic acid with pEC(50) values for inhibition of cAMP, 5.83 ± 0.11; Ca(2+) mobilization, 4.63 ± 0.05; ERK phosphorylation, 5.61 ± 0.06; and dynamic mass redistribution, 5.35 ± 0.06. This FFA2-RASSL will be useful in future studies on this receptor and demonstrates that exploitation of pharmacological variation between species orthologs is a powerful method to generate novel chemically engineered GPCRs

Віталітетна структура популяцій деяких видів бур’янів у посівах зернових культур

Features of development of populations of weed species (Cirsium arvense (L.) Scop., Sonchus arvensis L., Melandium album (Mill.) Garke, Setaria glauca (L.) Beauv., Fallopia convolvulus (L.) А. Lоve) in most typical crops in the forest-steppe zone of the Sumy region. It was studied the crop sowings (winter wheat, rye, barley, buckwheat, pea) which was not subjected to the herbicide treatment. Исследованы особенности развития популяций сегетальных видов (Cirsium arvense (L.) Scop., Sonchus arvensis L., Melandium album (Mill.) Garke, Setaria glauca (L.) Beauv., Fallopia convolvulus (L.) А. Lоve) в посевах зерновых культур (пшеницы озимой, ржи, ячменя, гречихи, гороха), которые не подвергались обработке гербицидами в хозяйствах лесостепной зоны на территории Сумской области. Досліджено особливості розвитку популяцій сегетальних видів (Cirsium arvense (L.) Scop., Sonchus arvensis L., Melandium album (Mill.) Garke, Setaria glauca (L.) Beauv., Fallopia convolvulus (L.) А. Lоve) у посівах зернових культур (пшениці озимої, жита, ячменю, гречки, гороху), які не оброблялися гербіцидами у господарствах лісостепової зони на території Сумської області.

Optical Monitoring in Elaboration of Metal Matrix Composites by Direct Metal Deposition

AbstractDevelopment of composites with multi-functional properties is a challenging problem that could be solved by laser cladding. The objective of the present work is to demonstrate the advantages of optical monitoring in optimizing deposition of carbide-reinforced metal matrix composites. Multi-wavelength pyrometer and infrared camera are applied to analyse high temperature heat – and mass transfer in the cladding zone. The influence of laser power, laser cladding speed and powder feeding rate on the brightness temperature are studied. The thermal images of the molten pool obtained by infrared camera for different TiC contents in the powder blend are analysed as well as the beads geometry, microstructure and microhardness

Tensile behavior of an austenitic stainless steel subjected to multidirectional forging

The mechanical behavior of a chromium -nickel austenitic stainless steel with submicrocrystalline structures produced by multidirectional forging (MDF) to a total strain of ∼ 4 at temperatures of 700 and 600° C was studied. This processing resulted in the formation of uniform ultrafine grained structure with an average crystallite size of 360 and 300 nm, respectively, and high dislocation density. The tensile tests were carried out in a wide temperature range 20 -650° C. At ambient temperature, the yield stress (YS) comprised 900 MPa and 730 MPa in the samples subjected to MDF at 600 and 700° C, respectively. It should be noted that this strength was achieved along with elongations of 16% and 22% in the samples subjected to MDF at 600 and 700° C. The YS decreased and elongati on-to-failure tends to increase with increasing test temperature and approaching 235 MPa and 51%, respectively, at 650° C. Effect of temperature on mechanical behavior of stainless steel with submicrocrystalline structure is discusse

Analysis of approaches to sterility testing of COVID-19 prevention vaccines

Preventive vaccination against SARS-CoV-2 infection is currently receiving close attention in the Russian Federation. Improving public confidence in immunisation with new vaccines largely depends on a guarantee of the absence of side effects caused by contamination. A high risk of contamination is inherent to biological products, including coronavirus prevention vaccines, due to their properties and the nature of raw materials used. This risk adds to the need for using effective contaminant detection approaches.The aim of the study was to evaluate the possibility to improve sterility testing of preventive vaccines against SARS-CoV-2 infection.This article presents an analysis of the procedures proposed by pharmaceutical developers for sterility testing of ten Russian vaccines approved in the country for COVID-19 prevention. The authors considered specific characteristics of these vaccines, including their physical and chemical properties, the presence of antimicrobial components, and other critical factors affecting the correctness of the experimental setup. The results suggest that it is possible to improve sterility testing. According to the authors, the main directions for its improvement are the proposal to develop an alternative procedure based on compendial method 2 (OFS.1.2.4.0003.15, Ph. Rus. XIV), as well as the use of a universal culture medium. If used for refining the established procedures and developing new ones, the authors’ recommendations will improve the reliability and applicability of sterility testing during both manufacturing and pre-approval regulatory assessment of updated coronavirus vaccines for subsequent release to the market. The proposed approaches can be applied to testing other medicinal products for sterility

Professional discourse: the verbal and visual semiosis interplay

The goal of this paper is to identify the dominating semiotic system in the formation of meaning and knowledge transfer in popular science discourse. The authors have carried out the semiotic analysis of verbal-visual relations in journal articles headlines belonging to the sphere of popular science, their correlation in the process of semiosis, representation of scientific knowledge in popular science discours

Detection of the possible "acute" toxicity of a suspension of magnetic nanoparticles modified with iron glycerolate in the glycerin Fe3O4 • Glyc (~10 mg / ml) AMD-1092 in an experiment on non-pedigreed mice

The article deals with the manifestations of toxic effects on the body of magnetic nanoparticles Fe3O4 on the example of white non-pedigreed mice with different methods of introduction.В статье рассмотрены проявления токсического действия на организм магнитных наночастиц Fe3O4 на примере белых беспородных мышей при различных способах его введения

Anthocyanins as functional food components

Among the natural pigments, anthocyanins are assumed to represent one of the most studied groups. Starting with the first studies on the physicochemical properties of anthocyanins carried out in the 17th century by British naturalist Robert Boyle, the science about these unique compounds has progressed substantially. To date, the structure and functions of anthocyanins in plant cells have been well studied, and the pathway of their biosynthesis is one of the most fully characterized pathways of secondary metabolite biosynthesis at both the biochemical and genetic levels. Along with these fundamental achievements, we are beginning to realize the potential of anthocyanins as compounds of industrial importance, as pigments themselves, as well as components of functional food that contribute to the prevention and reduction of risk of chronic diseases. For a long time, the biological activity of anthocyanins has been underestimated, in particular, due to the data on their low bioavailability. However, studies showed that in humans and animals, these compounds are actively metabolized and the bioavailability, estimated taking into account their metabolites, exceeded 12 %. It has been experimentally shown that anthocyanins have antioxidant, anti-inflammatory, hypoglycemic, antimutagenic, antidiabetic, anti-cancer, neuroprotective properties, and they are beneficial for eye health. However, the studies conducted cannot always explain the molecular mechanism of action of anthocyanins in the human body. According to some reports, the observed effects are not due to the action of anthocyanins themselves, but to their metabolites, which can be more biologically active because of their increased bioavailability. Other data ascribe the positive effect on human health not to individual anthocyanins, but to the whole complex of polyphenolic compounds consumed. The review summarizes the results of the studies of anthocyanins as components of functional food. Special attention is paid to genetic control of the pigment synthesis. These data are of particular importance in respect to the initiated breeding programs aimed at increasing the content of anthocyanins in cultural plants

VASCULAR ENDOTHELIAL GROWTH FACTOR RECEPTOR-1 SIGNALING AS A NOVEL MECHANISM OF T CELL SUPPRESSION IN TUMOR NEOANGIOGENESIS

The immunomodulatory activity of vascular endothelial growth factors (VEGFs) reveals a new role of neoangiogenesis in tumor development. Most of VEGF effects on T cells are mediated through the VEGF-R2 receptors. Placental growth factor (PlGF) belongs to the VEGFs family and is a selective ligand for VEGF-R1. In order to study the role of VEGF-R1-signaling in the regulation of T-cell functions, the effect of PlGF on the proliferation of donor T cell has been investigated. PlGF has been shown to inhibit the proliferation of T-lymphocytes in cultures of anti-CD3-stimulated mononuclear cells in a wide dose range, suppressing the proliferative response of both CD4 + and CD8 + T cells. The suppressive effect of PlGF was mediated through the direct interaction with VEGFR-1 on T-cells that was evidenced by the expression of VEGFR-1 by T-lymphocytes (especially after their activation) and by blocking the suppressive effect of PlGF with neutralizing anti-VEGFR-1 antibodies. Given the increased levels of PlGF in many tumors, this factor may play an important role in immunomodulation during tumor growth, mediating its effect through the VEGFR-1 signaling pathway

Expression of arginase 1 and tyrosine kinase Mer by blood monocytes in the dynamics of physiological pregnancy

During pregnancy, the maternal immune system must maintain tolerance to paternal antigens, at the same time being able to eliminate pathogens, which is achieved by the weakening of adoptive immunity and the activation of innate immunity, in particular, monocytes. However, the question about the functional phenotype of monocytes, having not only pro-inflammatory, but also anti-inflammatory activity, remains open. In the given work, we have investigated the expression of M2-associated suppressive markers Arg1 and MerTK in monocyte subpopulations during uncomplicated pregnancy. Fifty-three pregnant women with uncomplicated gestation were recruited, including 14 pregnant in the 1st trimester, 20 – in the 2nd and 19 – in the third pregnancy trimester. The comparison group consisted of 15 fertile unpregnant women without aggravated somatic anamnesis, with a history of at least one childbirth. The findings showed that in the unpregnant group circulating Mo express Arg1 and MerTK, and the most relative number of Arg1+ and MerTK+ cells is concentrated in intermediate and nonclassic monocytes. During pregnancy the expression of researched molecules in monocytes reliably increases. An increase in MerTK expression is manifested by a simultaneous increase in the number of MerTK+ cells and the mean fluorescence intensity of this marker; it is observed in the 1st and 2nd trimesters and registered in all three monocyte subpopulations. At the same time, an increase in Arg1 expression is manifested either by an enhancement of Arg1+ cells, or an increase in receptor density; it is registered throughout pregnancy, including the 3rd trimester, and is maximally expressed in classic monocytes. There is a direct correlation between the number of Arg1+ and MerTK+ cells in intermediate Mo, which increases with the progression of pregnancy, and in the 3rd trimester is also detected in classical and non-classical Mo. In general, the revealed increase in the expression of Arg1 and MerTK by monocytes indicates an increase in the anti-inflammatory potential of monocytes during pregnancy, and the involvement of monocytes in the regulation of the inflammatory process at the system level. Moreover, the features of Arg1 and MerTK expression in various monocyte subpopulations during pregnancy suggest that monocytes expressing Arg1 and MerTK can mediate different mechanisms of immune adaptation during pregnancy