Genetic Inactivation of ANGPTL4 Improves Glucose Homeostasis and Reduces Risk of Type 2 Diabetes

Abstract Angiopoietin-like 4 (ANGPTL4) is an endogenous inhibitor of lipoprotein lipase that modulates lipid levels, coronary atherosclerosis risk, and nutrient partitioning. We hypothesize that loss of ANGPTL4 function might improve glucose homeostasis and decrease risk of type 2 diabetes (T2D). We investigate protein-altering variants in ANGPTL4 among 58,124 participants in the DiscovEHR human genetics study, with follow-up studies in 82,766 T2D cases and 498,761 controls. Carriers of p.E40K, a variant that abolishes ANGPTL4’s ability to inhibit lipoprotein lipase, have lower odds of T2D (odds ratio 0.89, 95% confidence interval 0.85-0.92, p=6.3x10-10), lower fasting glucose, and greater insulin sensitivity. Predicted loss-of-function variants are associated with lower odds of T2D among 32,015 cases and 84,006 controls (odds ratio 0.71, 95% confidence interval 0.49-0.99, p=0.041). Functional studies in Angptl4-deficient mice confirm improved insulin sensitivity and glucose homeostasis. In conclusion, genetic inactivation of ANGPTL4 is associated with improved glucose homeostasis and reduced risk of T2D

SIMULATION OF INFORMATION INFRASTRUCTURE FOR SMALL PEDAGOGICAL SYSTEM

The model of information infrastructure control for small pedagogical system including virtual machines is presented. Particular models of pedagogical system parameters are defined within the control model; the usage of risk model and application possibility of software technical quality model are justified. The key events (decision points) are highlighted in describing the life cycle of infrastructure control. The set of methods and algorithms supporting decision-making in the framework of a small pedagogical system is proposed. In order to illustrate the applicability of the generated solutions the main results of the experiments are presented

Comparative evaluation of therapy results in mild acne

Introduction. Mild acne is the most underestimated form of the disease.The aim of the study was to compare the results of external combination therapy with 15% azelaic acid gel + 1% clindamycin gel and benzoyl peroxide + clindamycin for mild papulopustular acne.Material and methods. An open comparative prospective observational study in parallel groups (12 weeks) included 96 people, 65 patients with mild papulo-pustular acne and a control group of 30 healthy individuals. Group I received 15% azelaic acid gel +1% clindamycin gel, group II – benzoyl peroxide gel + clindamycin. The number of acne elements, morphofunctional indicators of the facial skin, side effects were recorded.Results. As a result of treatment, the indicators of sebumetry significantly decreased: in group I in the T-zone 47.5 ± 11.3 units (p = 0.043) and in the U-zone 57.5 ± 6.3 units (p = 0.037), and in group II in the T-zone 37.1 ± 5.8 units (p = 0.015) and in the U-zone 48.7 ± 5.6 units (p = 0.027). The pore sizes decreased significantly: in group I in the T-zone 0.052 ± 0.010 mm (p = 0.046) and in the U-zone 0.054 ± 0.009 mm (p = 0.049), and in group II in the T-zone 0.039 ± 0.011 mm (p = 0.064) and in the U-zone 0.047 ± 0.013 mm (p = 0.041). In patients in group I, pigmentation indicators in the T-zone of 17.0 ± 2.8 units (p < 0.001) and the U-zone of 17.0 ± 2.8 units (p = 0.048) were normalized. In patients in both groups, there was a significant (p >< 0.05) decrease in the number of papulopustules.>˂ 0.001) and the U-zone of 17.0 ± 2.8 units (p = 0.048) were normalized. In patients in both groups, there was a significant (p ˂ 0.05) decrease in the number of papulopustules.Conclusion. When comparing the results of therapy with 15% azelaic acid gel + 1% clindamycin gel and benzoyl peroxide + adapalene for mild papulopustular acne, comparable efficacy and safety were revealed

МЕТОД ОЦЕНКИ ЭФФЕКТИВНОСТИ ДЕЯТЕЛЬНОСТИ ПРОМЫШЛЕННЫХ ПРЕДПРИЯТИЙ КАК ИНСТРУМЕНТ АНТИКРИЗИСНОГО УПРАВЛЕНИЯ (РЕГИОНАЛЬНЫЙ АСПЕКТ)

An original approach of the author to the assessment of efficiency of activities of industrial organizations, based on the comparison of key performance indicators of industrial organizations with industry average indexes, is presented. Stimulation methods of the efficiency improvement are developed in the form of benefits and preferences for effective enterprises and in the form of economic coercion to improve the efficiency for unfair participants of the economic turnover.Представлен оригинальный авторский подход к оценке эффективности деятельности промышленных предприятий, основанный на сравнении ключевых показателей эффективности со среднеотраслевыми значениями. Разработаны методы стимулирования повышения эффективности в виде системы льгот и преференций для эффективных предприятий и экономического принуждения к повышению эффективности для недобросовестных участников хозяйственного оборота

Structure formation features of large block-shaped samples from the copper and aluminum alloy produced by the wire-feed electron-beam additive technology

In this work the study of the structure of samples made by the wire-feed electronbeam 3D printing from copper C11000 and aluminum alloy AA5056 was carried out. The presence of a dendritic structure typical of this method was revealed, as well as the presence of pores, cracks and other defects that occurred during printing. Mechanical properties of samples cut in the planar section are at a rather low level. The ultimate tensile strength of copper block samples varies between 165 and 187 MPa. The relative elongation of samples without pores is at 18%, but with the presence of pores it decreases sharply to 7%, while the strength is practically not decreased. The samples of alloy AA5056 demonstrate slightly higher mechanical properties: the strength is at the level of 190-192 MPa and the relative elongation is about 16-18%. In samples with defects such as large pores or discontinuities, the strength drops to almost zero

Using topological data analysis for building Bayesan neural networks

For the first time, a simplified approach to constructing Bayesian neural networks is proposed, combining computational efficiency with the ability to analyze the learning process. The proposed approach is based on Bayesianization of a deterministic neural network by randomizing parameters only at the interface level, i.e., the formation of a Bayesian neural network based on a given network by replacing its parameters with probability distributions that have the parameters of the original model as the average value. Evaluations of the efficiency metrics of the neural network were obtained within the framework of the approach under consideration, and the Bayesian neural network constructed through variation inference were performed using topological data analysis methods. The Bayesianization procedure is implemented through graded variation of the randomization intensity. As an alternative, two neural networks with identical structure were used — deterministic and classical Bayesian networks. The input of the neural network was supplied with the original data of two datasets in versions without noise and with added Gaussian noise. The zero and first persistent homologies for the embeddings of the formed neural networks on each layer were calculated. To assess the quality of classification, the accuracy metric was used. It is shown that the barcodes for embeddings on each layer of the Bayesianized neural network in all four scenarios are between the corresponding barcodes of the deterministic and Bayesian neural networks for both zero and first persistent homologies. In this case, the deterministic neural network is the lower bound, and the Bayesian neural network is the upper bound. It is shown that the structure of data associations within a Bayesianized neural network is inherited from a deterministic model, but acquires the properties of a Bayesian one. It has been experimentally established that there is a relationship between the normalized persistent entropy calculated on neural network embeddings and the accuracy of the neural network. For predicting accuracy, the topology of embeddings on the middle layer of the neural network model turned out to be the most revealing. The proposed approach can be used to simplify the construction of a Bayesian neural network from an already trained deterministic neural network, which opens up the possibility of increasing the accuracy of an existing neural network without ensemble with additional classifiers. It becomes possible to proactively evaluate the effectiveness of the generated neural network on simplified data without running it on a real dataset, which reduces the resource intensity of its development

Thermodynamic properties of myo-inositol

© 2017 Elsevier Ltd In the present work, the temperature dependence of heat capacity of vitamin B8 (myo-inositol) has been measured for the first time over the range from 8 K to 340 K by precision adiabatic vacuum calorimetry. Based on the experimental data, the thermodynamic functions of the vitamin B8, namely, the heat capacity, enthalpy H°(T)–H°(0), entropy S°(T)–S°(0) and Gibbs function G°(T)–H°(0) have been determined for the range from T → 0 K to 340 K. The value of the fractal dimension D in the function of multifractal generalization of Debye's theory of the heat capacity of solids was estimated and the character of heterodynamics of structure was detected. The enthalpy of combustion (−2747.0 ± 2.1) kJ·mol−1 of the vitamin B8 was measured for the first time using high-precision combustion calorimeter. The standard molar enthalpy of formation in the crystalline state (−1329.3 ± 2.3) kJ·mol−1 of B8 at 298.15 K was derived from the combustion experiments. Using combination of the adiabatic and combustion calorimetry results the thermodynamic functions of formation of the myo-inositol at T = 298.15 K and p = 0.1 MPa have been calculated. The low-temperature X-ray diffraction was used for the determination of coefficients of thermal expansion

Alirocumab, evinacumab, and atorvastatin triple therapy regresses plaque lesions and improves lesion composition in mice[S]

Atherosclerosis-related CVD causes nearly 20 million deaths annually. Most patients are treated after plaques develop, so therapies must regress existing lesions. Current therapies reduce plaque volume, but targeting all apoB-containing lipoproteins with intensive combinations that include alirocumab or evinacumab, monoclonal antibodies against cholesterol-regulating proprotein convertase subtilisin/kexin type 9 and angiopoietin-like protein 3, may provide more benefit. We investigated the effect of such lipid-lowering interventions on atherosclerosis in APOE*3-Leiden.CETP mice, a well-established model for hyperlipidemia. Mice were fed a Western-type diet for 13 weeks and thereafter matched into a baseline group (euthanized at 13 weeks) and five groups that received diet alone (control) or with treatment [atorvastatin; atorvastatin and alirocumab; atorvastatin and evinacumab; or atorvastatin, alirocumab, and evinacumab (triple therapy)] for 25 weeks. We measured effects on cholesterol levels, plaque composition and morphology, monocyte adherence, and macrophage proliferation. All interventions reduced plasma total cholesterol (37% with atorvastatin to 80% with triple treatment; all P < 0.001). Triple treatment decreased non-HDL-C to 1.0 mmol/l (91% difference from control; P < 0.001). Atorvastatin reduced atherosclerosis progression by 28% versus control (P < 0.001); double treatment completely blocked progression and diminished lesion severity. Triple treatment regressed lesion size versus baseline in the thoracic aorta by 50% and the aortic root by 36% (both P < 0.05 vs. baseline), decreased macrophage accumulation through reduced proliferation, and abated lesion severity. Thus, high-intensive cholesterol-lowering triple treatment targeting all apoB-containing lipoproteins regresses atherosclerotic lesion area and improves lesion composition in mice, making it a promising potential approach for treating atherosclerosis.Cardiolog

РЕГУЛИРОВАНИЕ ОТНОШЕНИЙ МЕЖДУ ЗАКАЗЧИКОМ И ИСПОЛНИТЕЛЕМ ГОСУДАРСТВЕННОГО ОБОРОННОГО ЗАКАЗА

Below is the original author's method of assessment of financial and economic sustainability of enterprises-performers of the state defense order. This method takes into account the financial and economic performance of the enterprise. The proposed comprehensive indicator of financial and economic sustainability can be used by the state customer at the stage of analyzing the possibility of the state contract execution by potential contractors.Предложен оригинальный авторский метод оценки финансово-экономической устойчивости предприятий – исполнителей государственного оборонного заказа. Метод учитывает финансовые и экономические показатели деятельности предприятия. Предлагаемый комплексный показатель оценки финансово-экономической устойчивости может быть использован государственным заказчиком на этапе анализа возможностей выполнения государственного контракта потенциальными исполнителями