New Dystrophin/Dystroglycan interactors control neuron behavior in Drosophila eye

<p>Abstract</p> <p>Background</p> <p>The Dystrophin Glycoprotein Complex (DGC) is a large multi-component complex that is well known for its function in muscle tissue. When the main components of the DGC, Dystrophin (Dys) and Dystroglycan (Dg) are affected cognitive impairment and mental retardation in addition to muscle degeneration can occur. Previously we performed an array of genetic screens using a <it>Drosophila </it>model for muscular dystrophy in order to find novel DGC interactors aiming to elucidate the signaling role(s) in which the complex is involved. Since the function of the DGC in the brain and nervous system has not been fully defined, we have here continued to analyze the DGC modifiers' function in the developing <it>Drosophila </it>brain and eye.</p> <p>Results</p> <p>Given that disruption of <it>Dys </it>and <it>Dg </it>leads to improper photoreceptor axon projections into the lamina and eye neuron elongation defects during development, we have determined the function of previously screened components and their genetic interaction with the DGC in this tissue. Our study first found that mutations in <it>chif, CG34400, Nrk</it>, <it>Lis1, capt </it>and <it>Cam </it>cause improper axon path-finding and loss of <it>SP2353, Grh, Nrk, capt, CG34400, vimar, Lis1 </it>and <it>Cam </it>cause shortened rhabdomere lengths. We determined that <it>Nrk</it>, <it>mbl</it>, <it>capt </it>and <it>Cam </it>genetically interact with <it>Dys </it>and/or <it>Dg </it>in these processes. It is notable that most of the neuronal DGC interacting components encountered are involved in regulation of actin dynamics.</p> <p>Conclusions</p> <p>Our data indicate possible DGC involvement in the process of cytoskeletal remodeling in neurons. The identification of new components that interact with the DGC not only helps to dissect the mechanism of axon guidance and eye neuron differentiation but also provides a great opportunity for understanding the signaling mechanisms by which the cell surface receptor Dg communicates via Dys with the actin cytoskeleton.</p

The Advantages of Remote Work as an Efficient Form of Employment of Staff in Modern Conditions

The article is aimed at researching the theoretical and practical aspects of organization kinds of remote work and considering its advantages as an efficient form of employment of staff. Information and communication technologies (ICTs) have a direct impact on the economy through the creation of new jobs and the transformation of the labor force. This transformation has led to a number of atypical forms of employment, one of which is remote work. The categories of employees who are most interested in the remote work form are provided. The advantages and disadvantages of remote work are analyzed for all interested parties: employers, employees, and the State. The emphasis is placed on the fact that, despite certain shortcomings, remote work is demanded and promising in view of tendencies in the development of the labor market

ГЕНДЕРНІ ОСОБЛИВОСТІ ЖИРНОКИСЛОТНОГО ТА ЛІПІДНОГО СПЕКТРА ПЛАЗМИ КРОВІ В МЕШКАНЦІВ РІВНИННИХ НАСЕЛЕНИХ ПУНКТІВ ЗАКАРПАТСЬКОЇ ОБЛАСТІ З РІЗНИМ ТРОФОЛОГІЧНИМ СТАТУСОМ

Introduction. In the human body, about half of all energy is formed by oxidation of higher fatty acids. At present, the number of studies that are studying changes in the fatty acid and lipid plasma spectrum, depending on altitude of living and body mass index (BMI), is limited. The aim of the study – to identify the gender characteristics of the fatty acid and lipid plasma spectrum in the inhabitants of flat inhabited areas of the Transcarpathian region with overweight and obesity. Research Methods. 107 persons with different trophological status, inhabitants of Uzhhorod district of Zakarpattia region (plain settlements) were investigated, in which indicators of fatty acid and lipid spectrum were determined. Results and Discussion. Lipid spectrum levels in women were worse than in men due to the higher level of TC and LDL cholesterol. Women showed higher levels of saturated fatty acid due to palmitic ((765.00±30.60) μg/ml versus (644.50±40.00) μg/ml among men, p=0.02) and stearinic fatty acid (214.80±10.30) μg/ml versus (175.70±9.00) μg/ml for men, p=0.01). In addition, women had significantly higher total polyunsaturated fatty acid levels compared to men (1546.40±39.90) μg/ml versus (1214.00±53.10) μg/ml, p&lt;0.01), primarily due to a higher level of ω6- polyunsaturated fatty acid (1446.60±37.20) μg/ml versus (1132.90±49.10); p&lt;0.01). Conclusions. Women had the worst lipid plasma parameters, higher levels of individual saturated fatty acids, higher total polyunsaturated fatty acid levels, and higher levels of ω6-polyunsaturated fatty acid, indicating a higher predisposition for atherogenesis and development of proinflammatory vascular changes. Such results can be partially explained by premenopausal and early menopause in the examined women.Вступление. В организме человека около половины всей энергии образуется путем окисления высших жирных кислот. На сегодня количество исследований, во время которых изучали бы изменения жирнокислотного и липидного спектра плазмы крови в зависимости от высоты проживания и индекса массы тела, ограничено. Цель исследования – выявить гендерные особенности жирнокислотного и липидного спектра плазмы крови у жителей равнинных населенных пунктов Закарпатской области с избыточным весом и ожирением. Методы исследования. Обследовано 107 человек с разным трофологическим статусом – жителей Ужгородского района Закарпатской области (равнинные населенные пункты), у которых определяли показатели жирнокислотного и липидного спектра плазмы крови. Результаты и обсуждение. Показатели липидограммы у женщин оказались хуже, чем у мужчин, из-за более высокого уровня общего холестерола и холестерола липопротеинов низкой плотности. У женщин содержание насыщенных жирных кислот было больше за счет пальмитиновой ((765,00±30,60) мкг/мл против (644,50±40,00) мкг/мл среди мужчин, р=0,02) и стеариновой кислот ((214,80±10,30) мкг/мл против (175,70±9,00) мкг/мл среди мужчин, р&lt;0,01). Кроме того, женщины имели значительно более высокий суммарный уровень полиненасыщенных жирных кислот по сравнению с мужчинами ((1546,40±39,90) мкг/мл против (1214,00±53,10) мкг/мл, р&lt;0,01), в первую очередь из-за большего содержания ω-6 полиненасыщенных жирных кислот ((1446,60±37,20) мкг/мл против (1132,90±49,10) мкг/мл, р&lt;0,01). Выводы. Показатели липидного спектра плазмы крови у женщин были хуже, чем у мужчин. У женщин определялось большее содержание как отдельных насыщенных жирных кислот, так и суммарных ω-6 полиненасыщенных жирных кислот, что указывает на более высокую склонность к атерогенезу и развитию провоспалительных сосудистых изменений. Полученные результаты частично можна объяснить предменопаузой и начальной менопаузой у обследованных женщин.Вступ. В організмі людини близько половини всієї енергії утворюється шляхом окиснення вищих жирних кислот. На сьогодні кількість досліджень, під час яких вивчали б зміни жирнокислотного і ліпідного спектра плазми крові залежно від висоти проживання та індексу маси тіла, є обмеженою. &nbsp;&nbsp; Мета дослідження – виявити гендерні особливості жирнокислотного і ліпідного спектра плазми крові в мешканців рівнинних населених пунктів Закарпатської області з надмірною масою тіла та ожирінням. Методи дослідження. Обстежено 107 осіб з різним трофологічним статусом – мешканців Ужгородського району Закарпатської області (рівнинні населені пункти), в яких визначали показники жирнокислотного і ліпідного спектра плазми крові. Результати й обговорення. Показники ліпідограми в жінок виявилися гіршими, ніж у чоловіків, через вищий рівень загального холестеролу та холестеролу ліпопротеїнів низької щільності. У жінок вміст насичених жирних кислот був більшим за рахунок пальмітинової ((765,00±30,60) мкг/мл проти (644,50±40,00) мкг/мл серед чоловіків, р=0,02) та стеаринової кислот ((214,80±10,30) мкг/мл проти (175,70±9,00) мкг/мл серед чоловіків, р&lt;0,01). Крім того, жінки мали значно вищий сумарний рівень поліненасичених жирних кислот порівняно з чоловіками ((1546,40±39,90) мкг/мл проти (1214,00±53,10) мкг/мл, р&lt;0,01), насамперед через більший вміст ω-6 поліненасичених жирних кислот ((1446,60±37,20) мкг/мл проти (1132,90±49,10) мкг/мл, р&lt;0,01). Висновки. Показники ліпідного спектра плазми крові в жінок були гіршими, ніж у чоловіків. У жінок визначався більший вміст як окремих насичених жирних кислот, так і сумарних ω-6 поліненасичених жирних кислот, що вказує на вищу схильність до атерогенезу та розвитку прозапальних судинних змін. Отримані результати частково можна пояснити пременопаузою та початковою менопаузою в обстежених жінок

Paraffin-Embedded and Frozen Sections of Drosophila Adult Muscles

The molecular characterization of muscular dystrophies and myopathies in humans has revealed the complexity of muscle disease and genetic analysis of muscle specification, formation and function in model systems has provided valuable insight into muscle physiology. Therefore, identifying and characterizing molecular mechanisms that underlie muscle damage is critical. The structure of adult Drosophila multi-fiber muscles resemble vertebrate striated muscles 1 and the genetic tractability of Drosophila has made it a great system to analyze dystrophic muscle morphology and characterize the processes affecting muscular function in ageing adult flies 2. Here we present the histological technique for preparing paraffin-embedded and frozen sections of Drosophila thoracic muscles. These preparations allow for the tissue to be stained with classical histological stains and labeled with protein detecting dyes, and specifically cryosections are ideal for immunohistochemical detection of proteins in intact muscles. This allows for analysis of muscle tissue structure, identification of morphological defects, and detection of the expression pattern for muscle/neuron-specific proteins in Drosophila adult muscles. These techniques can also be slightly modified for sectioning of other body parts

SCREENING FOR DYSLIPIDEMIA AND EXPEDIENCE OF STATIN THERAPY FOR THE CITIZENS OF TRANSCARPATHIA VALLEY REGIONS WITH OVERWEIGHT AND OBESITY

Background. The lipid profiles of patients with overweight, obesity and healthy individuals, the citizens of Transcarpathia valley regions were analysed.Objective. The study was aimed at evaluation of dyslipidaemia frequency in patients with overweight and obesity, determination of expedience of statins prescription.Methods. All patients were divided into 2 groups: group 1 – patients with overweight; group 2 – patients with obesity of I and II degree. Estimation of lipid profile parameters was conducted by means of spectrophotometric device SIEMENS Dimension RxL Max. Statistical analysis of the data was conducted using Microsoft Excel 2007.Results. The patients with obesity had higher level of total cholesterol (6.03±0.53 mmol/l), lower HDL-C (1.15±0.07 mmol/l) and higher level of LDL-C (4.19±0.46 mmol/l) compare with overweight patients.In 46% of patients with overweight, dyslipidaemia was evidenced and required correction, 27% of them had high CVR and needed statin therapy, 19% of people with obesity had moderate CVR and didn’t need statins.77% of obese patients needed lipid correction, 54% of them with very high and averagely high level of CVR required statin therapy; 23% of people with obesity had moderate CVR and did not need statins.Conclusions. In the studied overweight and obese patients, atherogenic dyslipidaemia was established in 46% and 77% of cases respectively. Correction of dyslipidaemia with statin was compulsory for 27% of patients with overweight and for 54% with obesity

Naïve-like pluripotency to pave the way for saving the northern white rhinoceros from extinction

The northern white rhinoceros (NWR) is probably the earth's most endangered mammal. To rescue the functionally extinct species, we aim to employ induced pluripotent stem cells (iPSCs) to generate gametes and subsequently embryos in vitro. To elucidate the regulation of pluripotency and differentiation of NWR PSCs, we generated iPSCs from a deceased NWR female using episomal reprogramming, and observed surprising similarities to human PSCs. NWR iPSCs exhibit a broad differentiation potency into the three germ layers and trophoblast, and acquire a naïve-like state of pluripotency, which is pivotal to differentiate PSCs into primordial germ cells (PGCs). Naïve culturing conditions induced a similar expression profile of pluripotency related genes in NWR iPSCs and human ESCs. Furthermore, naïve-like NWR iPSCs displayed increased expression of naïve and PGC marker genes, and a higher integration propensity into developing mouse embryos. As the conversion process was aided by ectopic BCL2 expression, and we observed integration of reprogramming factors, the NWR iPSCs presented here are unsuitable for gamete production. However, the gained insights into the developmental potential of both primed and naïve-like NWR iPSCs are fundamental for in future PGC-specification in order to rescue the species from extinction using cryopreserved somatic cells.Toxicolog

Effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial

Aims  The third Universal Definition of Myocardial Infarction (MI) Task Force classified MIs into five types: Type 1, spontaneous; Type 2, related to oxygen supply/demand imbalance; Type 3, fatal without ascertainment of cardiac biomarkers; Type 4, related to percutaneous coronary intervention; and Type 5, related to coronary artery bypass surgery. Low-density lipoprotein cholesterol (LDL-C) reduction with statins and proprotein convertase subtilisin–kexin Type 9 (PCSK9) inhibitors reduces risk of MI, but less is known about effects on types of MI. ODYSSEY OUTCOMES compared the PCSK9 inhibitor alirocumab with placebo in 18 924 patients with recent acute coronary syndrome (ACS) and elevated LDL-C (≥1.8 mmol/L) despite intensive statin therapy. In a pre-specified analysis, we assessed the effects of alirocumab on types of MI. Methods and results  Median follow-up was 2.8 years. Myocardial infarction types were prospectively adjudicated and classified. Of 1860 total MIs, 1223 (65.8%) were adjudicated as Type 1, 386 (20.8%) as Type 2, and 244 (13.1%) as Type 4. Few events were Type 3 (n = 2) or Type 5 (n = 5). Alirocumab reduced first MIs [hazard ratio (HR) 0.85, 95% confidence interval (CI) 0.77–0.95; P = 0.003], with reductions in both Type 1 (HR 0.87, 95% CI 0.77–0.99; P = 0.032) and Type 2 (0.77, 0.61–0.97; P = 0.025), but not Type 4 MI. Conclusion  After ACS, alirocumab added to intensive statin therapy favourably impacted on Type 1 and 2 MIs. The data indicate for the first time that a lipid-lowering therapy can attenuate the risk of Type 2 MI. Low-density lipoprotein cholesterol reduction below levels achievable with statins is an effective preventive strategy for both MI types.For complete list of authors see http://dx.doi.org/10.1093/eurheartj/ehz299</p

Cardiovascular Risk Reduction with Icosapent Ethyl for Hypertriglyceridemia

BACKGROUND Patients with elevated triglyceride levels are at increased risk for ischemic events. Icosapent ethyl, a highly purified eicosapentaenoic acid ethyl ester, lowers triglyceride levels, but data are needed to determine its effects on ischemic events. METHODS We performed a multicenter, randomized, double-blind, placebo-controlled trial involving patients with established cardiovascular disease or with diabetes and other risk factors, who had been receiving statin therapy and who had a fasting triglyceride level of 135 to 499 mg per deciliter (1.52 to 5.63 mmol per liter) and a low-density lipoprotein cholesterol level of 41 to 100 mg per deciliter (1.06 to 2.59 mmol per liter). The patients were randomly assigned to receive 2 g of icosapent ethyl twice daily (total daily dose, 4 g) or placebo. The primary end point was a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina. The key secondary end point was a composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke. RESULTS A total of 8179 patients were enrolled (70.7% for secondary prevention of cardiovascular events) and were followed for a median of 4.9 years. A primary end-point event occurred in 17.2% of the patients in the icosapent ethyl group, as compared with 22.0% of the patients in the placebo group (hazard ratio, 0.75; 95% confidence interval [CI], 0.68 to 0.83; P<0.001); the corresponding rates of the key secondary end point were 11.2% and 14.8% (hazard ratio, 0.74; 95% CI, 0.65 to 0.83; P<0.001). The rates of additional ischemic end points, as assessed according to a prespecified hierarchical schema, were significantly lower in the icosapent ethyl group than in the placebo group, including the rate of cardiovascular death (4.3% vs. 5.2%; hazard ratio, 0.80; 95% CI, 0.66 to 0.98; P=0.03). A larger percentage of patients in the icosapent ethyl group than in the placebo group were hospitalized for atrial fibrillation or flutter (3.1% vs. 2.1%, P=0.004). Serious bleeding events occurred in 2.7% of the patients in the icosapent ethyl group and in 2.1% in the placebo group (P=0.06). CONCLUSIONS Among patients with elevated triglyceride levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower among those who received 2 g of icosapent ethyl twice daily than among those who received placebo. (Funded by Amarin Pharma; REDUCE-IT ClinicalTrials.gov number, NCT01492361

Effect of alirocumab on mortality after acute coronary syndromes. An analysis of the ODYSSEY OUTCOMES randomized clinical trial

Background: Previous trials of PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitors demonstrated reductions in major adverse cardiovascular events, but not death. We assessed the effects of alirocumab on death after index acute coronary syndrome. Methods: ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was a double-blind, randomized comparison of alirocumab or placebo in 18 924 patients who had an ACS 1 to 12 months previously and elevated atherogenic lipoproteins despite intensive statin therapy. Alirocumab dose was blindly titrated to target achieved low-density lipoprotein cholesterol (LDL-C) between 25 and 50 mg/dL. We examined the effects of treatment on all-cause death and its components, cardiovascular and noncardiovascular death, with log-rank testing. Joint semiparametric models tested associations between nonfatal cardiovascular events and cardiovascular or noncardiovascular death. Results: Median follow-up was 2.8 years. Death occurred in 334 (3.5%) and 392 (4.1%) patients, respectively, in the alirocumab and placebo groups (hazard ratio [HR], 0.85; 95% CI, 0.73 to 0.98; P=0.03, nominal P value). This resulted from nonsignificantly fewer cardiovascular (240 [2.5%] vs 271 [2.9%]; HR, 0.88; 95% CI, 0.74 to 1.05; P=0.15) and noncardiovascular (94 [1.0%] vs 121 [1.3%]; HR, 0.77; 95% CI, 0.59 to 1.01; P=0.06) deaths with alirocumab. In a prespecified analysis of 8242 patients eligible for ≥3 years follow-up, alirocumab reduced death (HR, 0.78; 95% CI, 0.65 to 0.94; P=0.01). Patients with nonfatal cardiovascular events were at increased risk for cardiovascular and noncardiovascular deaths (P<0.0001 for the associations). Alirocumab reduced total nonfatal cardiovascular events (P<0.001) and thereby may have attenuated the number of cardiovascular and noncardiovascular deaths. A post hoc analysis found that, compared to patients with lower LDL-C, patients with baseline LDL-C ≥100 mg/dL (2.59 mmol/L) had a greater absolute risk of death and a larger mortality benefit from alirocumab (HR, 0.71; 95% CI, 0.56 to 0.90; Pinteraction=0.007). In the alirocumab group, all-cause death declined wit h achieved LDL-C at 4 months of treatment, to a level of approximately 30 mg/dL (adjusted P=0.017 for linear trend). Conclusions: Alirocumab added to intensive statin therapy has the potential to reduce death after acute coronary syndrome, particularly if treatment is maintained for ≥3 years, if baseline LDL-C is ≥100 mg/dL, or if achieved LDL-C is low. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01663402

Omecamtiv mecarbil in chronic heart failure with reduced ejection fraction, GALACTIC‐HF: baseline characteristics and comparison with contemporary clinical trials

Aims: The safety and efficacy of the novel selective cardiac myosin activator, omecamtiv mecarbil, in patients with heart failure with reduced ejection fraction (HFrEF) is tested in the Global Approach to Lowering Adverse Cardiac outcomes Through Improving Contractility in Heart Failure (GALACTIC‐HF) trial. Here we describe the baseline characteristics of participants in GALACTIC‐HF and how these compare with other contemporary trials. Methods and Results: Adults with established HFrEF, New York Heart Association functional class (NYHA) ≥ II, EF ≤35%, elevated natriuretic peptides and either current hospitalization for HF or history of hospitalization/ emergency department visit for HF within a year were randomized to either placebo or omecamtiv mecarbil (pharmacokinetic‐guided dosing: 25, 37.5 or 50 mg bid). 8256 patients [male (79%), non‐white (22%), mean age 65 years] were enrolled with a mean EF 27%, ischemic etiology in 54%, NYHA II 53% and III/IV 47%, and median NT‐proBNP 1971 pg/mL. HF therapies at baseline were among the most effectively employed in contemporary HF trials. GALACTIC‐HF randomized patients representative of recent HF registries and trials with substantial numbers of patients also having characteristics understudied in previous trials including more from North America (n = 1386), enrolled as inpatients (n = 2084), systolic blood pressure &lt; 100 mmHg (n = 1127), estimated glomerular filtration rate &lt; 30 mL/min/1.73 m2 (n = 528), and treated with sacubitril‐valsartan at baseline (n = 1594). Conclusions: GALACTIC‐HF enrolled a well‐treated, high‐risk population from both inpatient and outpatient settings, which will provide a definitive evaluation of the efficacy and safety of this novel therapy, as well as informing its potential future implementation