Конформація пропоксазепаму та його орієнтація у центрі зв’язування ГАМКА-рецептора

Introduction. One of 1.4-benzodiazepine 3-alcoxy derivatives – propoxazepam, possessing high analgetic action, also effectively suppressed different experimental seizures types. Unexpected combination of pharmacological spectrum components suggests its different binding sites of GABAA receptor.The aim of the work was to determine the geometry of the ligand-receptor complexes of GABA-RC using experimental data of the propoxazepam conformation and calculated data for the three-dimensional structure of the ligandbinding site and subsequent docking to characterize its binding to this receptor.Materials and methods. X-ray diffraction studies of the compound were performed using Xcalibur 3 single crystal X-ray diffractometer. Calculation of the molecular docking parameters was performed using the iGEMDOCK v2.1 program for the GABA receptor (GABA (A) R-beta3 homopentamer, 4COF), the molecular structures of propoxazepam conformers were prepared using ChemAxon (MarvinSketch 17.11.0).Results and discussion. Based on the X-ray diffraction analysis, the coordinates of the atoms, bond lengths and valence angles in the propoxazepam molecule were calculated, it is found that it form crystallographic twins as racemate. The molecular docking method showed that propoxazepam several binding sites with the energy of complex formation from -78.64 to -85.29 kcal/mol exist on the isolated site of the GABA-receptor.Conclusions. The highest contribution to the formation of the bond of the complex is carried out by residues of polar amino acids (serine, asparagine, methionine and arginine in polar binding sub-center). However, also for individual conformers, aromatic amino acids, predominantly phenylalanine (Phe-31, Ala-135 – hydrophobic binding sub-center) make a significant contribution.Актуальность. Одно из 3-алкоксипроизводных 1,4-бенздиазепина – пропоксазепам – продемонстрировал высокую анальгетическую активность, а также эффективно блокировал разные типы экспериментальных судорог. Нестандартная комбинация компонентов фармакологического спектра предусматривает разные места его связывания на ГАМКА-рецепторе.Цель исследования состояла в определении геометрии лигандрецепторных комплексов ГАМК-РК на основе использования экспериментальных данных о конформации пропоксазепама и расчетных данных о трехмерном строении лигандсвязывающего центра и последующее проведение докинга для характеристики его связывания с данным рецептором.Материалы и методы. Рентгеноструктурное исследование соединения выполнено на монокристальном рентгеновском дифрактометре Xcalibur 3, Расчет параметров молекулярного докинга был осуществлен с использованием программы iGEMDOCK v2.1, для ГАМК-рецептора (GABA(A) R-beta3 гомопентамер, 4COF), молекулярные структуры конформеров пропоксазепама были подготовлены в программе ChemAxon (MarvinSketch 17.11.0).                                                                                              Результаты и их обсуждение. На основании данных рентгеноструктурного анализа рассчитаны координаты атомов, длины связей и валентные углы в молекуле пропоксазепама, установлено, что он существует в виде кристаллографического двойника в виде рацемата.                                      Выводы. Методом молекулярного докинга показано, что на выделенном участке ГАМКА-рецептора существует несколько мест связывания пропоксазепама с энергией образования комплекса от -78,64 до -85,29 ккал/моль. Наибольший вклад в формирование связи комплекса осуществляют остатки полярных аминокислот (серин, аспарагин, метионин и аргинин – полярный подцентр связывания). Однако также для отдельных конформеров значительный вклад имеют ароматические аминокислоты, преимущественно фенилаланин (Phe-31, Ala-135 – гидрофобный подцентр связывания).Актуальність. Одне з 3-алкоксипохідних 1,4-бенздіазепіну – пропоксазепам, який продемонстрував високу аналгетичну активність, а також ефективно блокував різні типи експериментальних судом. Нестандартна комбінація компонентів фармакологічного спектра передбачає різні місця його зв’язування на ГАМКА-рецепторі.Мета дослідження полягала у визначенні геометрії ліганд-рецепторних комплексів ГАМК-РК на підставі використання експериментальних даних про конформацію пропоксазепаму та розрахункових даних тривимірної будови лігандзв’язуючого центра та подальше проведення докінгу для характеристики його зв’язування з даним рецептором.Матеріали та методи. Рентгеноструктурне дослідження сполуки було виконано на монокристальному рентгенівському дифрактометрі Xcalibur 3, розрахунок параметрів молекулярного докінгу буз здійснений у програмі GEMDOCK v2.1, для ГАМК-рецептора (GABA(A) R-beta3 пентамер); молекулярні структури конформерів пропоксазепаму були підготовлені у програмі ChemAxon (MarvinSketch 17.11.0).Результати та їх обговорення. На підставі даних рентгеноструктурного аналізу розраховані координати атомів, довжини зв’язків та валентні кути у молекулі пропоксазепаму, встановлено, що він існує у вигляді кристалографічного двійника як рацемат.Висновки. Методом молекулярного докінгу показано, що на виділеній частині ГАМКА-рецептора існує декілька місць зв’язування пропоксазепаму з енергією утворення комплексів від -78,64 до -85,29 ккал/моль. Найбільший внесок у формування зв’язку комплексу здійснюють залишки полярних амінокислот (серин, аспарагін, метіонін та аргінін – полярний підцентр зв’язування). Однак також для окремих конформерів значний внесок мають ароматичні амінокислоти, переважно фенілаланін (Phe-31, Ala-135 – гідрофобний підцентр зв’язування)

Nutritional Evaluation and Physicochemical Properties of Fermented Shirezh Dairy Product

Many of the Kurdish traditional dairy products have not been studied thoroughly so far though are still produced at small scale. Dow (sour butter milk) and Shirezh are among these products. Shirezh known to Iraqi Kurds as sour concentrated Dow. The characteristics of Shirezh and Dow were: pH (5.5, 4.05), acidity (2.13%, 1.10%), total solids (18.70%, 5.32%), ash (0.62%, 0.45%), fat (2.57%, 0.8%) and total protein (13.59%, 3.28%) respectively, furthermore the amino acids of Shirezh’s protein found in balanced and acceptable quality. The aim of this research is to introduce Shirezh and Dow to scientific literature and to determine their characterization and nutritional values. Keywords: Shirezh, Dow, Dairy, Fermented, Nutrition, Physicochemical, Amino acids

Early MRI results and odds of attaining 'no evidence of disease activity' status in MS patients treated with interferon β-1a in the EVIDENCE study

Abstract Introduction 'No evidence of disease activity' (NEDA) is increasingly used as a treatment target with disease-modifying drugs for relapsing multiple sclerosis. Methods This post-hoc analysis of the randomised EVIDENCE trial compared interferon beta-1a injected subcutaneously three times weekly (IFN β-1a SC tiw) with interferon β-1a injected intramuscularly once weekly (IFN β-1a IM qw) on NEDA and clinical activity-free (CAF) status. The influence of the frequency of magnetic resonance imaging (MRI) scanning on NEDA and the effect of baseline T1 gadolinium-enhancing (Gd +) lesions on NEDA and CAF were also investigated. Results More patients in the IFN β-1a SC tiw group achieved NEDA compared with the IFN β-1a IM qw group, although rates were lower when monthly MRI scans through 24 weeks were included (35.0% vs. 21.6%, respectively; p p p = 0.022), and CAF through Week 48 in patients receiving IFN β-1a SC tiw ( p = 0.024). Conclusions IFN β-1a SC tiw was associated with significantly higher rate of NEDA status compared with IFN β-1a IM qw. Baseline Gd + lesions augured less frequent CAF or NEDA status. Inclusion of more MRI scans in the analysis reduced rates of NEDA status

Optimisation of Data Acquisition in Wind Turbines with Data-Driven Conversion Functions for Sensor Measurements

Operation and Maintenance (O&M) is an important cost driver of modern wind turbines. Condition monitoring (CM) allows the implementation of predictive O&M strategies helping to reduce costs. In this work a novel approach for wind turbine condition monitoring is proposed focusing on synergistic effects of coexisting sensing technologies. The main objective is to understand the predictability of signals using information from other measurements recorded at different locations of the turbine. The approach is based on a multi-step procedure to pre-process data, train a set of conversion functions and evaluate their performance. A subsequent sensitivity analysis measuring the impact of the input variables on the predicted response reveals hidden relationships between signals. The concept feasibility is tested in a case study using Supervisory Control And Data Acquisition (SCADA) data from an offshore turbine

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Transitions of care from child and adolescent mental health services to adult mental health services (TRACK Study) : a study of protocols in Greater London

Background: Although young people's transition from Child and Adolescent Mental Health Services (CAMHS) to Adult Mental Health Services (AMHS) in England is a significant health issue for service users, commissioners and providers, there is little evidence available to guide service development. The TRACK study aims to identify factors which facilitate or impede effective transition from CAHMS to AMHS. This paper presents findings from a survey of transition protocols in Greater London. Methods: A questionnaire survey (Jan-April 2005) of Greater London CAMHS to identify transition protocols and collect data on team size, structure, transition protocols, population served and referral rates to AMHS. Identified transition protocols were subjected to content analysis. Results: Forty two of the 65 teams contacted (65%) responded to the survey. Teams varied in type (generic/targeted/in-patient), catchment area (locality-based, wider or national) and transition boundaries with AMHS. Estimated annual average number of cases considered suitable for transfer to AMHS, per CAMHS team (mean 12.3, range 0–70, SD 14.5, n = 37) was greater than the annual average number of cases actually accepted by AMHS (mean 8.3, range 0–50, SD 9.5, n = 33). In April 2005, there were 13 active and 2 draft protocols in Greater London. Protocols were largely similar in stated aims and policies, but differed in key procedural details, such as joint working between CAHMS and AMHS and whether protocols were shared at Trust or locality level. While the centrality of service users' involvement in the transition process was identified, no protocol specified how users should be prepared for transition. A major omission from protocols was procedures to ensure continuity of care for patients not accepted by AMHS. Conclusion: At least 13 transition protocols were in operation in Greater London in April 2005. Not all protocols meet all requirements set by government policy. Variation in protocol-sharing organisational units and transition process suggest that practice may vary. There is discontinuity of care provision for some patients who 'graduate' from CAMHS services but are not accepted by adult services

Assessing variations of extreme indices inducing weather-hazards on critical infrastructures over Europe?the INTACT framework

Extreme weather events are projected to be more frequent and severe across the globe because of global warming. This poses challenging problems for critical infrastructures, which could be dramatically affected (or disrupted), and may require adaptation plans to the changing climate conditions. The INTACT FP7-European project evaluated the resilience and vulnerability of critical infrastructures to extreme weather events in a climate change scenario. To identify changes in the hazard induced by climate change, appropriate extreme weather indicators (EWIs), as proxies of the main atmospheric features triggering events with high impact on the infrastructures, were defined for a number of case studies and different approaches were analyzed to obtain local climate projections. We considered the influence of weighting and bias correction schemes on the delta approach followed to obtain the resulting projections, considering data from the Euro-CORDEX ensemble of regional future climate scenarios over Europe. The aim is to provide practitioners, decision-makers, and administrators with appropriate methods to obtain actionable and plausible results on local/regional future climate scenarios. Our results show a small sensitivity to the weighting approach and a large sensitivity to bias correcting the future projections.This work has been carried out within the activities of INTACT project, receiving funding from the European Union Seventh Framework Programme (FP7/2007-2013) under grant agreement n° FP7-SEC-2013-1-606799. The information and views set out in this paper are those of the authors and do not necessarily reflect the opinion of the European Union. We acknowledge the World Climate Research Programme's Working Group on Regional Climate, and the Working Group on Coupled Modelling, former coordinating body of CORDEX and responsible panel for CMIP5

Functional Imaging of Pheochromocytoma with 68Ga-DOTATOC and 68C-HED in a Genetically Defined Rat Model of Multiple Endocrine Neoplasia

Rats affected by the MENX multitumor syndrome develop pheochromocytoma (100%). Pheochromocytomas are uncommon tumors and animal models are scarce, hence the interest in MENX rats to identify and preclinically evaluate novel targeted therapies. A prerequisite for such studies is a sensitive and noninvasive detection of MENXassociated pheochromocytoma. We performed positron emission tomography (PET) to determine whether rat pheochromocytomas are detected by tracers used in clinical practice, such as 68Ga-DOTATOC (somatostatin analogue) or 11C-Hydroxyephedrine (HED), a norepinephrine analogue. We analyzed four affected and three unaffected rats. The PET scan findings were correlated to histopathology and immunophenotype of the tumors, their proliferative index, and the expression of genes coding for somatostatin receptors or the norepinephrine transporter. We observed that mean 68Ga-DOTATOC standard uptake value (SUV) in adrenals of affected animals was 23.3 ± 3.9, significantly higher than in control rats (15.4 ± 7.9; P = .03). The increase in mean tumor-to-liver ratio of 11C-HED in the MENX-affected animals (1.6 ± 0.5) compared to controls (0.7 ± 0.1) was even more significant (P = .0016). In a unique animal model, functional imaging depicting two pathways important in pheochromocytoma biology discriminated affected animals from controls, thus providing the basis for future preclinical work with MENX rats