Репозиторий Университета

© Copyright © 2019 Klochkov, Pukhov, Afanasieva, Neganova, Ananiev, Avila-Rodriguez, Tarasov and Aliev. Natural sesquiterpene lactones which contain an exocyclic methylene group in the β-position of the lactone ring react readily with N-nucleophiles. When studying the reaction of the natural epoxyalantolactone with the primary amines we demonstrate the formation of a new heterocyclic system—the hydrogenated benzo[g]furo[4,3,2-cd]indol-3(1H)-one. Spectral data on the characteristics of the synthesized compounds are presented. The data on the reaction mechanisms and its applicability for the preparation are discussed.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. WWP2 is an E3 ubiquitin ligase that differentially regulates the contextual tumour suppressor/progressor TGFβ signalling pathway by alternate isoform expression. WWP2 isoforms select signal transducer Smad2/3 or inhibitor Smad7 substrates for degradation through different compositions of protein-protein interactionWWdomains. The WW4 domain-containing WWP2-C induces Smad7 turnover in vivo and positively regulates the metastatic epithelial-mesenchymal transition programme. This activity and the overexpression of these isoforms in human cancers make them candidates for therapeutic intervention. Here, we use NMR spectroscopy to solve the solution structure of the WWP2 WW4 domain and observe the binding characteristics of Smad7 substrate peptide. We also reveal that WW4 has an enhanced affinity for a Smad7 peptide phosphorylated at serine 206 adjacent to the PPxY motif. Using the same approach, we show that the WW3 domain also binds Smad7 and has significantly enhanced Smad7 binding affinity when expressed in tandem with the WW4 domain. Furthermore, and relevant to these biophysical findings, we present evidence for a novel WWP2 isoform (WWP2C-DHECT) comprising WW3-WW4 tandem domains and a truncated HECT domain that can inhibit TGFβ signalling pathway activity, providing a further layer of complexity and feedback to the WWP2 regulatory apparatus. Collectively, our data reveal a structural platform for Smad substrate selection by WWP2 isoform WW domains that may be significant in the context of WWP2 isoform switching linked to tumorigenesis.

Heart failure is a complex syndrome whose phenotypic presentation and disease progression depends on a complex network of adaptive and maladaptive responses. One of these responses is the endothelial release of NRG (neuregulin)-1-a paracrine growth factor activating ErbB2 (erythroblastic leukemia viral oncogene homolog B2), ErbB3, and ErbB4 receptor tyrosine kinases on various targets cells. NRG-1 features a multitasking profile tuning regenerative, inflammatory, fibrotic, and metabolic processes. Here, we review the activities of NRG-1 on different cell types and organs and their implication for heart failure progression and its comorbidities. Although, in general, effects of NRG-1 in heart failure are compensatory and beneficial, translation into therapies remains unaccomplished both because of the complexity of the underlying pathways and because of the challenges in the development of therapeutics (proteins, peptides, small molecules, and RNA-based therapies) for tyrosine kinase receptors. Here, we give an overview of the complexity to be faced and how it may be tackled.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Calcium ions (Ca2+) influx to mitochondrial matrix is crucial for the life of a cell. Mitochondrial calcium uniporter (mtCU) is a protein complex which consists of the pore-forming subunit (MCU) and several regulatory subunits. MtCU is the main contributor to inward Ca2+ currents through the inner mitochondrial membrane. Extensive investigations of mtCU involvement into normal and pathological molecular pathways started from the moment of discovery of its molecular components. A crucial role of mtCU in the control of these pathways is now recognized in both health and disease. In particular, impairments of mtCU function have been demonstrated for cardiovascular and skeletal muscle-associated pathologies. This review summarizes the current state of knowledge on mtCU structure, regulation, and function in different types of muscle tissues in health and disease.

© 2019 Elsevier Inc. Purpose: To identify preoperative risk factors for disease recurrence, following radical nephroureterectomy (RNU) for upper tract urothelial carcinoma (UTUC), and to create a predictive nomogram. Materials and methods: Based on a multicenter database, we identified patients who underwent RNU due to high grade UTUC. Urothelial carcinoma of the bladder or contralateral UTUC was not considered as recurrence. Cox regression model was used to determine the effect of different preoperative variables as predictors of recurrence. Results: Two hundred and forty-five patients were included in the analysis. The 2 and 5 years recurrence rates were 16.3% and 19.2%, respectively. Factors associated with recurrence on univariable analysis were sessile architecture hazard ratio (HR) 3.16 (95% CI, 1.38–7.26, P = 0.006), ≥cT3 disease HR 2.30 (95% CI, 1.12–4.72, P= 0.023), age >65 HR 2.02 (95% CI, 1.00–4.05, P= 0.048), Eastern Cooperative Group > 0 HR 1.98 (95% CI, 1.09–3.57, P= 0.023), hydronephrosis HR 1.93 (95% CI, 1.04–3.57, P= 0.035). Higher hemoglobin levels HR 0.81 (95% CI, 0.69–0.96, P= 0.013) and preoperative estimated glomerular filtration rate ≥ 50 HR 0.48 (95% CI, 0.25–0.92, P = 0.028) were associated with lower probability for recurrence. Multivariable analysis identified sessile architecture as the only independent predictor of recurrence HR 2.52 (95% CI, 1.09–5.86, P= 0.0308). C-index of 0.71 was calculated for a predictive model including all variables in the multivariable analysis, indicating good predictive accuracy. A nomogram predicting 2 and 5 year recurrence free probability was developed accordingly. Conclusions: Based on a multicenter database, we developed a nomogram with good predictive accuracy for recurrence following RNU. This may serve as an aid in decision-making regarding the use of neoadjuvant chemotherapy.

© 2019 Federation of European Biochemical Societies Neurotoxins are among the main components of scorpion and snake venoms. Scorpion neurotoxins affect voltage-gated ion channels, while most snake neurotoxins target ligand-gated ion channels, mainly nicotinic acetylcholine receptors (nAChRs). We report that scorpion venoms inhibit α-bungarotoxin binding to both muscle-type nAChR from Torpedo californica and neuronal human α7 nAChR. Toxins inhibiting nAChRs were identified as OSK-1 (α-KTx family) from Orthochirus scrobiculosus and HelaTx1 (κ-KTx family) from Heterometrus laoticus, both being blockers of voltage-gated potassium channels. With an IC50 of 1.6 μm, OSK1 inhibits acetylcholine-induced current through mouse muscle-type nAChR heterologously expressed in Xenopus oocytes. Other well-characterized scorpion toxins from these families also bind to Torpedo nAChR with micromolar affinities. Our results indicate that scorpion neurotoxins present target promiscuity.

© 2019 Elsevier B.V. This study demonstrates a hollow structure constructed by Au nanoparticles decorated on the surface of the In2O3 hollow nanospheres. This structure is prepared via calcination of solid organic precursors and in-situ reduction of Au nanoparticles on the metal oxide surface. The In2O3 hollow nanospheres are with the diameter of ˜200 nm and the shell thickness of 30 nm, while the Au nanoparticles on the surface of In2O3 hollow spheres are with the size of ˜10 nm. XPS indicates that the Au modification can increase the deficient oxygen vacancy ratio, and the presence of the positive Au ions (Auδ+) in the composites helps to trap the electrons and further improve the sensing performance. The gas sensing tests indicate that the Au decorated In2O3 hollow nanocomposites show excellent sensitivity (26.3 of 100 ppm) and selectivity toward 1-butylamine at the optimized temperature of 340 °C. The decoration of Au nanoparticles can lower the optimized working temperature and shorten the response/recovery times. The enhanced sensing mechanism can be attributed to electronic and chemical sensitization. The decoration of Au nanoparticles on the In2O3 surface can cause the Schottky barrier at the interface. The existence of positive Au ions can boost the barrier by trapping extra electrons. These results tender the promising hollow structure for sensing organic amine vapor in field-based use.

© 2018, Springer Nature B.V. No matter how sophisticated the structures are and on what length scale the pore sizes are, fluid displacement in porous media can be visualized, captured, mimicked and optimized using microfluidics. Visualizing transport processes is fundamental to our understanding of complex hydrogeological systems, petroleum production, medical science applications and other engineering applications. Microfluidics is an ideal tool for visual observation of flow at high temporal and spatial resolution. Experiments are typically fast, as sample volume is substantially low with the use of miniaturized devices. This review first discusses the fabrication techniques for generating microfluidics devices, experimental setups and new advances in microfluidic fabrication using three-dimensional printing, geomaterials and biomaterials. We then address multiphase transport in subsurface porous media, with an emphasis on hydrology and petroleum engineering applications in the past few decades. We also cover the application of microfluidics to study membrane systems in biomedical science and particle sorting. Lastly, we explore how synergies across different disciplines can lead to innovations in this field. A number of problems that have been resolved, topics that are under investigation and cutting-edge applications that are emerging are highlighted.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Sterols change the biophysical properties of lipid membranes. Here, we analyzed how sterols affect the activity of widely used antimicrobial membrane-active compounds, sodium dodecyl sulfate (SDS) and benzalkonium chloride (BAC). We also tested a novel benzalkonium-like substance, Kor105. Our data suggest that benzalkonium and Kor105 disturb the ordering of the membrane lipid packaging, and this disturbance is dampened by cholesterol. The disturbance induced by Kor105 is stronger than that induced by BAC because of the higher rigidity of the Kor105 molecule due to a shorter linker between the phenyl group and quaternary nitrogen. On the contrary, individual SDS molecules do not cause the disturbance. Thus, in the tested range of concentrations, SDS-membrane interaction is not influenced by cholesterol. To study how sterols influence the biological effects of these chemicals, we used yeast strains lacking Lam1-4 proteins. These proteins transport sterols from the plasma membrane into the endoplasmic reticulum. We found that the mutants are resistant to BAC and Kor105 but hypersensitive to SDS. Together, our findings show that sterols influence the interaction of SDS versus benzalkonium chloride and Kor105 with the membranes in a completely different manner.

© 2019 by the authors. In today's analytical trends, there is an ever-increasing importance of polymeric materials for low molecular weight compounds including amines and drugs because they can act as carriers or capture amines or drugs. The use of this type of materials will allow the development of modern materials for the chromatographic column beds and the substrates of selective sensors. Moreover, these kinds of materials could be used as a drug carrier. Therefore, the aim of this study is presenting the synthesis and complexing properties of star-shaped oxiranes as a new sensor for the selective complexation of low molecular weight compounds. Propylene oxide and selected oxirane monomers with carbazolyl in the substituent were selected as the monomers in this case and tetrahydrofuran as its solvent. The obtained polymer structures were characterized using the MALDI-TOF. It was found that in the initiation step potassium hydride deprotonates the monomer molecule and takes also part in the nucleophilic substitution. The resulting polymeric material preferably cross-linked with selected di-oxiranes (1,2,7,8-diepoksyoktan in respect ratio 3:1 according to active center) was then used as a stationary phase in the column and thin layer chromatography for amine separation and identification. Sorption ability of the resulting deposits was determined using a quartz microbalance (QCMB). The study was carried out in stationary mode and flow cells to simulate actual operating phase conditions. Based on changes in electrode vibration frequency, the maximum amount of adsorbed analyte and the best conditions for its sorption were determined. 2019 by the authors.

© 2019 The Authors. Alcoholism: Clinical  &  Experimental Research published by Wiley Periodicals, Inc. on behalf of Research Society on Alcoholism Background: The Alcohol Use Disorders Identification Test (AUDIT) was developed for use in primary health care settings to identify hazardous and harmful patterns of alcohol consumption, and is often used to screen for alcohol use disorders (AUDs). This study examined the AUDIT as a screening tool for AUDs. Methods: A systematic literature search was performed of electronic bibliographic databases (CINAHL, Embase, ERIC, MEDLINE, PsycINFO, Scopus, and Web of Science) without language or geographic restrictions for original quantitative studies published before September 1, 2018, that assess the AUDIT's ability to screen for AUDs. Random-effects meta-regression models were constructed by sex to assess the potential determinants of the AUDIT's specificity and sensitivity. From these models and ecological data from the Global Information System on Alcohol and Health, the true- and false-positive and true- and false-negative proportions were determined. The number of people needed to be screened to treat 1 individual with an AUD was estimated for all countries globally where AUD data exist, using a specificity of 0.95. Results: A total of 36 studies met inclusion criteria for the meta-regression. The AUDIT score cut-point was significantly associated with sensitivity and specificity. Standard drink size was found to affect the sensitivity and specificity of the AUDIT for men, but not among women. The AUDIT performs less well in identifying women compared to men, and countries with a low prevalence of AUDs have higher false-positive rates compared to countries with a higher AUD prevalence. Conclusions: The AUDIT does not perform well as a screening tool for identifying individuals with an AUD, especially in countries and among populations with a low AUD prevalence (e.g., among women), and thus should not be used for this purpose.

© 2019 Elsevier GmbH Here, we report the first confirmed autochthonous tick-borne encephalitis case diagnosed in Moscow in 2016 and describe the detection of tick-borne encephalitis virus (TBEV) in ticks and small mammals in a Moscow park. The paper includes data from two patients who were bitten by TBEV-infected ticks in Moscow city; one of these cases led to the development of the meningeal form of TBE. Both TBEV-infected ticks attacked patients in the same area. We collected ticks and trapped small mammals in this area in 2017. All samples were screened for the presence of pathogens causing tick-borne diseases by PCR. The TBEV-positive ticks and small mammals’ tissue samples were subjected to virus isolation. The sequencing of the complete polyprotein gene of the positive samples was performed. A total of 227 questing ticks were collected. TBEV was detected in five specimens of Ixodes ricinus. We trapped 44 small mammals, mainly bank voles (Myodes glareolus) and pygmy field mice (Apodemus uralensis). Two samples of brain tissue from bank voles yielded a positive signal in RT-PCR for TBEV. We obtained six virus isolates from the ticks and brain tissue of a bank vole. Complete genome sequencing showed that the obtained isolates belong to the European subtype and have low diversity with sequence identities as high as 99.9%. GPS tracking showed that the maximum distance between the exact locations where the TBEV-positive ticks were collected was 185 m. We assume that the forest park had been free of TBEV and that the virus was recently introduced.

© 2019 Elsevier Inc. In order to investigate the prevalence and prognostic value of the polymorphic variant (1245A>C) of the HSD3B1 gene, in the tumors of patients with castration-resistant prostate cancer, we retrospectively analyzed a small number of tumor samples from 44 patients by genomic sequencing. We noticed a relatively high prevalence in the overall study group (n = 23; 52.2%) as well as in the subgroup of patients undergoing second systemic treatment (n = 20; 51.2%) where we assessed for survival outcomes. However, this alteration was neither associated with the time to progression nor with survival.

© 2019 British Society for Neuroendocrinology The growth hormone secretagogue receptor (GHSR) is a G protein-coupled receptor that is highly expressed in the central nervous system. GHSR acts as a receptor for ghrelin and for liver-expressed antimicrobial peptide 2 (LEAP2), which blocks ghrelin-evoked activity. GHSR also displays ligand-independent activity, including a high constitutive activity that signals in the absence of ghrelin and is reduced by LEAP2. GHSR activity modulates a variety of food intake-related behaviours, including binge eating. Previously, we reported that GHSR-deficient mice daily and time-limited exposed to a high-fat (HF) diet display an attenuated binge-like HF intake compared to wild-type mice. In the present study, we aimed to determine whether ligand-independent GHSR activity affects binge-like HF intake in a 4-day binge-like eating protocol. We found that plasma levels of ghrelin and LEAP2 were not modified in mice exposed to this binge-like eating protocol. Moreover, systemic administration of ghrelin or LEAP2 did not alter HF intake in our experimental conditions. Interestingly, we found that central administration of LEAP2 or K-(D-1-Nal)-FwLL-NH2, which are both blockers of constitutive GHSR activity, reduced binge-like HF intake, whereas central administration of ghrelin or the ghrelin-evoked GHSR activity blockers [D-Lys3]-GHRP-6 and JMV2959 did not modify binge-like HF intake. Taken together, current data indicate that GHSR activity in the brain affects binge-like HF intake in mice independently of plasma levels of ghrelin and LEAP2.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. Vitamin D (25(OH)D) insufficiency and deficiency are highly prevalent in adult soccer players and can exceed 80% even in regions with high insolation; however, the treatment of this condition is often complicated. The aim of the present study was to examine the prevalence of vitamin D insufficiency and deficiency in youth Russian soccer players and the efficacy of its treatment. Participants were 131 young male football players (age 15.6 ± 2.4 years). Low vitamin D levels (below 30 ng/mL) were observed in 42.8% of the analyzed participants. These athletes were split in two groups composed of persons with vitamin D deficiency (serum vitamin D below 21 ng/mL) and insufficiency (serum vitamin D in range of 21-29 ng/mL). A dietary supplement of 5000 IU cholecalciferol per day was administered for two months. After the treatment, an average 92% increase in vitamin D concentration was observed (before treatment—19.7 ± 5.4 ng/mL, after treatment—34.7 ± 8.6 ng/mL, p < 0.001) and 74% of the post-treatment values were within the reference range (30-60 ng/mL). Serum concentration of vitamin D increased by 200% ± 98% (p < 0.001) during the first month of treatment with vitamin D deficiency and insufficiency being successfully treated in 83% of the football players. In summary, the prevalence of vitamin D insufficiency and deficiency was high in young Russian soccer players. Furthermore, it was indicated that the daily usage of cholecalciferol in a dose 5000 IU was an effective and well-tolerated treatment for vitamin D insufficiency. No linear dependency between the duration of treatment and increase in vitamin 25(OH) D concentration was observed.

© 2019 by the authors. Licensee MDPI, Basel, Switzerland. The object of this contribution based on a systematic review of the literature is to examine to what degree the level of use and potency play a role in regulatory policies for alcohol, other psychoactive substances and gambling, and whether there is an evidence base for this role. Level of use is usually defined around a behavioural pattern of the user (for example, cigarettes smoked per day, or average ethanol use in grams per day), while potency is defined as a property or characteristic of the substance. For all substances examined (alcohol, tobacco, opioids, cannabis) and gambling, both dimensions were taken into consideration in the formulation of most regulatory policies. However, the associations between both dimensions and regulatory policies were not systematic, and not always based on evidence. Future improvements are suggested.

© 2019 Wolters Kluwer Health, Inc. Purpose of reviewThe current review summarizes contemporary decellularization and hydrogel manufacturing strategies in the field of tissue engineering and regenerative medicine.Recent findingsDecellularized extracellular matrix (ECM) bioscaffolds are a valuable biomaterial that can be purposed into various forms of synthetic tissues such as hydrogels. ECM-based hydrogels can be of animal or human origin. The use of human tissues as a source for ECM hydrogels in the clinical setting is still in its infancy and current literature is scant and anecdotal, resulting in inconclusive results.SummaryThus far the methods used to obtain hydrogels from human tissues remains a work in progress. Gelation, the most complex technique in obtaining hydrogels, is challenging due to remarkable heterogeneity of the tissues secondary to interindividual variability. Age, sex, ethnicity, and preexisting conditions are factors that dramatically undermine the technical feasibility of the gelation process. This is contrasted with animals whose well defined anatomical and histological characteristics have been selectively bred for the goal of manufacturing hydrogels.

© 2019 The Authors International Journal for Numerical Methods in Biomedical Engineering Published by John Wiley  &  Sons Ltd Non-invasive coronary computed tomography (CT) angiography-derived fractional flow reserve (cFFR) is an emergent approach to determine the functional relevance of obstructive coronary lesions. Its feasibility and diagnostic performance has been reported in several studies. It is unclear if differences in sensitivity and specificity between these studies are due to study design, population, or "computational methodology." We evaluate the diagnostic performance of four different computational workflows for the prediction of cFFR using a limited data set of 10 patients, three based on reduced-order modelling and one based on a 3D rigid-wall model. The results for three of these methodologies yield similar accuracy of 6.5% to 10.5% mean absolute difference between computed and measured FFR. The main aspects of modelling which affected cFFR estimation were choice of inlet and outlet boundary conditions and estimation of flow distribution in the coronary network. One of the reduced-order models showed the lowest overall deviation from the clinical FFR measurements, indicating that reduced-order models are capable of a similar level of accuracy to a 3D model. In addition, this reduced-order model did not include a lumped pressure-drop model for a stenosis, which implies that the additional effort of isolating a stenosis and inserting a pressure-drop element in the spatial mesh may not be required for FFR estimation. The present benchmark study is the first of this kind, in which we attempt to homogenize the data required to compute FFR using mathematical models. The clinical data utilised in the cFFR workflows are made publicly available online.

© 2019 American Headache Society Background: The International Classification of Headache Disorders lists different subtypes of medication overuse headache (MOH), according to the medication overused. The aim of this study is to evaluate whether the different subtypes correspond to clinically distinguishable phenotypes in a large population. Method: This descriptive cross-sectional observational study included 660 patients with MOH referred to headache centers in Europe and Latin America as a part of the COMOESTAS project. Information about clinical features was collected with structured patient interviews and with self-administered questionnaires for measuring disability, anxiety, and depression. Results: Female/male ratio, body mass index, marital status, and level of education were similar among in subjects enrolled in the 5 centers. The mean age was higher among subjects overusing triptans (T-MOH) with respect to subjects overusing simple analgesic (A-MOH). Duration of headache before chronification was longer in T-MOH (19.2 ± 11.9 years) and in subjects overusing ergotamines (E-MOH, 17.8 ± 11.7 years) with respect to the A-MOH group (13.1 ± 10.9; P <.001 and P =.017, respectively) and in T-MOH with respect multiple drug classes (M-MOH, 14.9 ± 11.7; P =.030). Migraine Disability Assessment (MIDAS) score was significantly lower in E-MOH group (33.6 ± 41.6), while T-MOH group (56.8 ± 40.6) had a significant lower MIDAS score with respect to M-MOH (67.2 ± 62.5; P =.016 and P =.037, respectively). Prevalence of depression and anxiety was lower in patients overusing T with respect to other groups of patients (χ2 = 10.953, P =.027 and χ2 = 25.725, P <.001, respectively). Conclusion: In this study on a large and very well characterized population of MOH, we describe the distinctive clinical characteristics of MOH subtypes. These findings contribute to more clearly define the clinical picture of a poorly delineated headache disorder. They also provide some insights in the possible trajectories leading to this highly disabling chronic headache, that is classified as a secondary form, but whose occurrence is entirely dependent on an underlying primary headache.