Statin-induced myopathic changes in primary human muscle cells and reversal by a prostaglandin F2 alpha analogue

Statin-related muscle side effects are a constant healthcare problem since patient compliance is dependent on side effects. Statins reduce plasma cholesterol levels and can prevent secondary cardiovascular diseases. Although statin-induced muscle damage has been studied, preventive or curative therapies are yet to be reported. We exposed primary human muscle cell populations (n = 22) to a lipophilic (simvastatin) and a hydrophilic (rosuvastatin) statin and analyzed their expressome. Data and pathway analyses included GOrilla, Reactome and DAVID. We measured mevalonate intracellularly and analyzed eicosanoid profiles secreted by human muscle cells. Functional assays included proliferation and differentiation quantification. More than 1800 transcripts and 900 proteins were differentially expressed after exposure to statins. Simvastatin had a stronger effect on the expressome than rosuvastatin, but both statins influenced cholesterol biosynthesis, fatty acid metabolism, eicosanoid synthesis, proliferation, and differentiation of human muscle cells. Cultured human muscle cells secreted ω-3 and ω-6 derived eicosanoids and prostaglandins. The ω-6 derived metabolites were found at higher levels secreted from simvastatin-treated primary human muscle cells. Eicosanoids rescued muscle cell differentiation. Our data suggest a new aspect on the role of skeletal muscle in cholesterol metabolism. For clinical practice, the addition of omega-n fatty acids might be suitable to prevent or treat statin-myopathy

Проект мини-ТЭЦ на базе отопительной котельной ж/д станции Полосухинская г. Новокузнецк

Дипломный проект выполнен в объеме 95 страниц. Содержит 7 схем, 4 иллюстрации, 27 таблиц, 18 источников, 3 приложения, 6 л. графического материала. Объектом исследования являются тепловые нагрузки существующей котельной и целесообразность генерации электрической энергии для покрытия потребностей. Цель работы – проект реконструкции отопительной котельной ж/д Полосухинская г.Новокузнецк с целью создания мини-ТЭЦ и перехода на комбинированное производство тепловой и электрической энергии. В процессе исследования проводился выбор тепловой схемы мини-ТЭЦ и её проектирование на базе отопительной котельной. Результат расчета показывает экономическую эффективность и технологическую целесообразность эксплуатации газопоршневой установки и внедрение газификатора в схеме ТЭЦ.The degree project carried out in a volume of 95 pages. 7 contains diagrams, illustrations, 4, 27 tables, 18 sources three applications 6L. graphic material. The object of research is the thermal load of the existing boiler and feasibility of generating electricity to cover the needs. The purpose of the work - the project of reconstruction of the heating boiler w / d Polosukhinskaya Novokuznetsk to create a mini-CHP and the transition to the combined production of heat and electricity. The study was conducted selection of the thermal circuit CHP and its design based on the heating boiler. The result of calculation shows the cost-effectiveness and technological feasibility of operating a gas piston installation and implementation of the scheme the gasifier in CHP

Процесс импортозамещения на предприятиях ВЭД в условиях экономических санкций и эмбарго

Дипломная работа на тему "Процесс импортозамещения на предприятиях ВЭД в условиях внешнеэкономических санкций и эмбарго". Целью исследования является раскрытие импортозамещющих процессов в условиях санкций и эмбарго на предприятиях разных отраслей промышленности. В работе рассматриваются проблемные места государственной программы импортозамещения в разных отраслях, такие как недостаточность правовой базы процесса, недоступность финансовых ресурсов для развития компаний, а также использование научного и инновационного потенциала России не в полной мере. В основной части рассмотрены проблемы и перспективы внедрения отечественных компаний аграрной, легкой и фармацевтической промышленности в импортозамещение.Diploma work on the topic "The process of import substitution in foreign trade enterprises in terms of foreign economic sanctions and embargoes." The purpose of this diploma is to disclose import-substituting processes in conditions of sanctions and embargoes at enterprises of different industries. The paper examines the problems of the state program of import substitution in various sectors, such as the lack of a legal framework for the process, the inaccessibility of financial resources for the development of companies, and the use of Russia's scientific and innovative potential is not fully realized. In the main part, problems and prospects for introducing domestic companies of the agrarian, light and pharmaceutical industries into import substitution are discussed

ЗАЛЕЖНІСТЬ ПРИРОСТУ ПРИБУТКУ ШАХТИ ВІД ПРИРОСТУ ВИДОБУТКУ ВУГІЛЛЯ ПРИ ПРОВЕДЕННІ ШТРЕКІВ ШИРОКИМ ВИБОЄМ

Розглянуто питання впливу чинників на ефективність проведення виробок широким вибоєм. Визначено приріст видобутку вугілля на прибуток шахти.; Influence of factors on efficiency of leadthrough of making a wide b ackwall is considered. Increase of coal production on the income of mine is analyzed

Altered splicing of the BIN1 muscle-specific exon in humans and dogs with highly progressive centronuclear myopathy

Amphiphysin 2, encoded by BIN1, is a key factor for membrane sensing and remodelling in different cell types. Homozygous BIN1 mutations in ubiquitously expressed exons are associated with autosomal recessive centronuclear myopathy (CNM), a mildly progressive muscle disorder typically showing abnormal nuclear centralization on biopsies. In addition, misregulation of BIN1 splicing partially accounts for the muscle defects in myotonic dystrophy (DM). However, the muscle-specific function of amphiphysin 2 and its pathogenicity in both muscle disorders are not well understood. In this study we identified and characterized the first mutation affecting the splicing of the muscle-specific BIN1 exon 11 in a consanguineous family with rapidly progressive and ultimately fatal centronuclear myopathy. In parallel, we discovered a mutation in the same BIN1 exon 11 acceptor splice site as the genetic cause of the canine Inherited Myopathy of Great Danes (IMGD). Analysis of RNA from patient muscle demonstrated complete skipping of exon 11 and BIN1 constructs without exon 11 were unable to promote membrane tubulation in differentiated myotubes. Comparative immunofluorescence and ultrastructural analyses of patient and canine biopsies revealed common structural defects, emphasizing the importance of amphiphysin 2 in membrane remodelling and maintenance of the skeletal muscle triad. Our data demonstrate that the alteration of the muscle-specific function of amphiphysin 2 is a common pathomechanism for centronuclear myopathy, myotonic dystrophy, and IMGD. The IMGD dog is the first faithful model for human BIN1-related CNM and represents a mammalian model available for preclinical trials of potential therapies

Unusual multisystemic involvement and a novel BAG3 mutation revealed by NGS screening in a large cohort of myofibrillar myopathies

Myofibrillar myopathies (MFM) are a group of phenotypically and genetically heterogeneous neuromuscular disorders, which are characterized by protein aggregations in muscle fibres and can be associated with multisystemic involvement.Methods We screened a large cohort of 38 index patients with MFM for mutations in the nine thus far known causative genes using Sanger and next generation sequencing (NGS). We studied the clinical and histopathological characteristics in 38 index patients and five additional relatives (n = 43) and particularly focused on the associated multisystemic symptoms.Results We identified 14 heterozygous mutations (diagnostic yield of 37%), among them the novel p.Pro209Gln mutation in the BAG3 gene, which was associated with onset in adulthood, a mild phenotype and an axonal sensorimotor polyneuropathy, in the absence of giant axons at the nerve biopsy. We revealed several novel clinical phenotypes and unusual multisystemic presentations with previously described mutations: hearing impairment with a FLNC mutation, dysphonia with a mutation in DES and the first patient with a FLNC mutation presenting respiratory insufficiency as the initial symptom. Moreover, we described for the first time respiratory insufficiency occurring in a patient with the p.Gly154Ser mutation in CRYAB. Interestingly, we detected a polyneuropathy in 28% of the MFM patients, including a BAG3 and a MYOT case, and hearing impairment in 13%, including one patient with a FLNC mutation and two with mutations in the DES gene. In four index patients with a mutation in one of the MFM genes, typical histological findings were only identified at the ultrastructural level (29%).Conclusions We conclude that extraskeletal symptoms frequently occur in MFM, particularly cardiac and respiratory involvement, polyneuropathy and/or deafness. BAG3 mutations should be considered even in cases with a mild phenotype or an adult onset. We identified a genetic defect in one of the known genes in less than half of the MFM patients, indicating that more causative genes are still to be found. Next generation sequencing techniques should be helpful in achieving this aim

Expanding the importance of HMERF titinopathy : new mutations and clinical aspects

ObjectiveHereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and considered quite rare. Respiratory insufficiency is an early symptom. A collection of families and patients with muscle disease suggestive of HMERF was clinically and genetically studied.MethodsAltogether 12 new families with 19 affected patients and diverse nationalities were studied. Most of the patients were investigated using targeted next-generation sequencing; Sanger sequencing was applied in some of the patients and available family members. Histological data and muscle MRI findings were evaluated.ResultsThree families had several family members studied while the rest were single patients. Most patients had distal and proximal muscle weakness together with respiratory insufficiency. Five heterozygous TTN A-band mutations were identified of which two were novel. Also with the novel mutations the muscle pathology and imaging findings were compatible with the previous reports of HMERF.ConclusionsOur collection of 12 new families expands mutational spectrum with two new mutations identified. HMERF is not that rare and can be found worldwide, but maybe underdiagnosed. Diagnostic process seems to be complex as this study shows with mostly single patients without clear dominant family history.Peer reviewe

Differential cross section measurements for the production of a W boson in association with jets in proton–proton collisions at √s = 7 TeV

Measurements are reported of differential cross sections for the production of a W boson, which decays into a muon and a neutrino, in association with jets, as a function of several variables, including the transverse momenta (pT) and pseudorapidities of the four leading jets, the scalar sum of jet transverse momenta (HT), and the difference in azimuthal angle between the directions of each jet and the muon. The data sample of pp collisions at a centre-of-mass energy of 7 TeV was collected with the CMS detector at the LHC and corresponds to an integrated luminosity of 5.0 fb[superscript −1]. The measured cross sections are compared to predictions from Monte Carlo generators, MadGraph + pythia and sherpa, and to next-to-leading-order calculations from BlackHat + sherpa. The differential cross sections are found to be in agreement with the predictions, apart from the pT distributions of the leading jets at high pT values, the distributions of the HT at high-HT and low jet multiplicity, and the distribution of the difference in azimuthal angle between the leading jet and the muon at low values.United States. Dept. of EnergyNational Science Foundation (U.S.)Alfred P. Sloan Foundatio

Search for stop and higgsino production using diphoton Higgs boson decays

Results are presented of a search for a "natural" supersymmetry scenario with gauge mediated symmetry breaking. It is assumed that only the supersymmetric partners of the top-quark (stop) and the Higgs boson (higgsino) are accessible. Events are examined in which there are two photons forming a Higgs boson candidate, and at least two b-quark jets. In 19.7 inverse femtobarns of proton-proton collision data at sqrt(s) = 8 TeV, recorded in the CMS experiment, no evidence of a signal is found and lower limits at the 95% confidence level are set, excluding the stop mass below 360 to 410 GeV, depending on the higgsino mass