Laboratory of Senses

It is reported about a series of scientific and research events “Laboratory of Senses” organized in October and December 2016 at the Philological faculty of Samara State Socio-Pedagogical University. The content and purpose of “Laboratory of Senses” are characterized - teaching the analysis of literary text in literary, philological and linguistic methodology aspects with the achievements of various methodologies and scientific schools. Constructive performance of this series of activities carried out by teachers of the University with the bachelors and undergraduates is described

The efficiency of telerehabilitation in patients with multiple sclerosis

The aim of the study - to evaluate the possibilities and efficacy of telerehabilitation in patients with MS.Цель исследования – оценка возможностей и эффективности телереабилитации у пациентов с РС

A glimpse of the ERM proteins

In all eukaryotes, the plasma membrane is critically important as it maintains the architectural integrity of the cell. Proper anchorage and interaction between the plasma membrane and the cytoskeleton is critical for normal cellular processes. The ERM (ezrin-radixin-moesin) proteins are a class of highly homologous proteins involved in linking the plasma membrane to the cortical actin cytoskeleton. This review takes a succinct look at the biology of the ERM proteins including their structure and function. Current reports on their regulation that leads to activation and deactivation was examined before taking a look at the different interacting partners. Finally, emerging roles of each of the ERM family members in cancer was highlighted

Selective small molecule induced degradation of the BET bromodomain protein BRD4

The Bromo- and Extra-Terminal (BET) proteins BRD2, BRD3, and BRD4 play important roles in transcriptional regulation, epigenetics, and cancer and are the targets of pan-BET selective bromodomain inhibitor JQ1. However, the lack of intra-BET selectivity limits the scope of current inhibitors as probes for target validation and could lead to unwanted side effects or toxicity in a therapeutic setting. We designed Proteolysis Targeted Chimeras (PROTACs) that tether JQ1 to a ligand for the E3 ubiquitin ligase VHL, aimed at triggering the intracellular destruction of BET proteins. Compound MZ1 potently and rapidly induces reversible, long-lasting, and unexpectedly selective removal of BRD4 over BRD2 and BRD3. The activity of MZ1 is dependent on binding to VHL but is achieved at a sufficiently low concentration not to induce stabilization of HIF-1α. Gene expression profiles of selected cancer-related genes responsive to JQ1 reveal distinct and more limited transcriptional responses induced by MZ1, consistent with selective suppression of BRD4. Our discovery opens up new opportunities to elucidate the cellular phenotypes and therapeutic implications associated with selective targeting of BRD4

Construction of 3D models of the CYP11B family as a tool to predict ligand binding characteristics

Aldosterone is synthesised by aldosterone synthase (CYP11B2). CYP11B2 has a highly homologous isoform, steroid 11β-hydroxylase (CYP11B1), which is responsible for the biosynthesis of aldosterone precursors and glucocorticoids. To investigate aldosterone biosynthesis and facilitate the search for selective CYP11B2 inhibitors, we constructed three-dimensional models for CYP11B1 and CYP11B2 for both human and rat. The models were constructed based on the crystal structure of Pseudomonas Putida CYP101 and Oryctolagus Cuniculus CYP2C5. Small steric active site differences between the isoforms were found to be the most important determinants for the regioselective steroid synthesis. A possible explanation for these steric differences for the selective synthesis of aldosterone by CYP11B2 is presented. The activities of the known CYP11B inhibitors metyrapone, R-etomidate, R-fadrazole and S-fadrazole were determined using assays of V79MZ cells that express human CYP11B1 and CYP11B2, respectively. By investigating the inhibitors in the human CYP11B models using molecular docking and molecular dynamics simulations we were able to predict a similar trend in potency for the inhibitors as found in the in vitro assays. Importantly, based on the docking and dynamics simulations it is possible to understand the enantioselectivity of the human enzymes for the inhibitor fadrazole, the R-enantiomer being selective for CYP11B2 and the S-enantiomer being selective for CYP11B1

Dynamic relocalization of NHERF1 mediates chemotactic migration of ovarian cancer cells toward lysophosphatidic acid stimulation

NHERF1/EBP50 (Na+/H+ exchanger regulating factor 1; Ezrin-binding phosphoprotein of 50 kDa) organizes stable protein complexes beneath the apical membrane of polar epithelial cells. By contrast, in cancer cells without any fixed polarity, NHERF1 often localizes in the cytoplasm. The regulation of cytoplasmic NHERF1 and its role in cancer progression remain unclear. In this study, we found that, upon lysophosphatidic acid (LPA) stimulation, cytoplasmic NHERF1 rapidly translocated to the plasma membrane, and subsequently to cortical protrusion structures, of ovarian cancer cells. This movement depended on direct binding of NHERF1 to C-terminally phosphorylated ERM proteins (cpERMs). Moreover, NHERF1 depletion downregulated cpERMs and further impaired cpERM-dependent remodeling of the cell cortex, suggesting reciprocal regulation between these proteins. The LPA-induced protein complex was highly enriched in migratory pseudopodia, whose formation was impaired by overexpression of NHERF1 truncation mutants. Consistent with this, NHERF1 depletion in various types of cancer cells abolished chemotactic cell migration toward a LPA gradient. Taken together, our findings suggest that the high dynamics of cytosolic NHERF1 provide cancer cells with a means of controlling chemotactic migration. This capacity is likely to be essential for ovarian cancer progression in tumor microenvironments containing LPA

Response and resistance to BET bromodomain inhibitors in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is a heterogeneous and clinically aggressive disease for which there is no targeted therapy. BET bromodomain inhibitors, which have shown efficacy in several models of cancer, have not been evaluated in TNBC. These inhibitors displace BET bromodomain proteins such as BRD4 from chromatin by competing with their acetyl-lysine recognition modules, leading to inhibition of oncogenic transcriptional programs. Here we report the preferential sensitivity of TNBCs to BET bromodomain inhibition in vitro and in vivo, establishing a rationale for clinical investigation and further motivation to understand mechanisms of resistance. In paired cell lines selected for acquired resistance to BET inhibition from previously sensitive TNBCs, we failed to identify gatekeeper mutations, new driver events or drug pump activation. BET-resistant TNBC cells remain dependent on wild-type BRD4, which supports transcription and cell proliferation in a bromodomain-independent manner. Proteomic studies of resistant TNBC identify strong association with MED1 and hyper-phosphorylation of BRD4 attributable to decreased activity of PP2A, identified here as a principal BRD4 serine phosphatase. Together, these studies provide a rationale for BET inhibition in TNBC and present mechanism-based combination strategies to anticipate clinical drug resistance

Technological Properties of Grain Varieties of Strong and Valuable Wheat in the Northern Forest-steppe of the Tyumen Region

The article presents the results of the technological properties of grain of strong wheat varieties Novosibirskaya 15, Novosibirskaya 29, SKENT-1 and valuable Iren, Krasnoufimskaya 100, Lutescens 70, Tyumenskaya 25. The results of the evaluation of the mixing ability of flour of varieties of strong wheat are presented. The varieties of spring soft wheat were grown in 2010–2012 on the experimental field of Agrotechnological Institute of the SAU of the Northern Trans-Urals (the zone of the northern forest-steppe of the Tyumen region). The soil of the experimental field is leached chernozem, heavy loam in granulometric composition. The predecessor is annual herbs. The fertilizers were applied in the amount of 4 t/ha per grain yield. Soil cultivation is generally accepted for the culture in the zone. Laboratory studies were performed in the laboratories of the Agrobiotechnological Center of State Agrarian University of Northern Trans-Urals and Kurgan Research Institute of Agriculture. The results showed that by type of grain Tyumenskaya 25 showed the best results: high rates in 2010 and 2011 (781 and 787 g/l) and higher rates compared to the other varieties in arid period in 2012 (723 g/l). By the number of gluten, strong wheat varieties Novosibirskaya 15 and Novosibirskaya 29, valuable wheat varieties Iren and Tyumen 25 corresponded to the standards of the first class of GOST (at least 32 %). The same varieties were distinguished by the highest physical properties of the test when evaluated on a pharynograph and alveograph. The standards for strong wheat corresponded to the volume of bread from flour varieties Novosibirskaya 15 (1355 cm3) and Novosibirskaya 29 (1207 cm3). The mixing ability of flour of a strong wheat variety of Novosibirskaya 15 was manifested to a greater extent in the variant with a share of 50 % in a mixture with weak wheat. The improvement effect was 20–24 %. Under the conditions of production experience, the mixing ability of flour of strong wheat variety Novosibirskaya 29 when added to flour from grain of Ikar grade was also the highest in the variant with a ratio of 50: 50 %. The improvement effect was 29 %