Evolution of Highly Polymorphic T Cell Populations in Siblings with the Wiskott-Aldrich Syndrome

Population level evolutionary processes can occur within a single organism when the germ line contains a mutation that confers a cost at the level of the cell. Here we describe how multiple compensatory mutations arose through a within-individual evolutionary process in two brothers with the immune deficiency Wiskott-Aldrich Syndrome (WAS). As a result, both brothers have T lymphocyte populations that are highly polymorphic at the locus of the germ line defect, and no single allele achieves fixation. WASP, the gene product affected in this disease, is specific to white blood cells where it is responsible for regulating actin cytoskeleton dynamics in a wide range of cellular responses. The brothers inherited a rare allele predicted to result in truncated WASP lacking the carboxy-terminal VCA domains, the region that directly catalyzes actin filament generation. Although the brothers' T cell populations are highly polymorphic, all share a corrective effect relative to the inherited allele in that they restore the VCA domain. This indicates massive selection against the truncated germ line allele. No single somatic allele becomes fixed in the circulating T cell population of either brother, indicating that a regulated step in maturation of the affected cell lineage is severely compromised by the germ line allele. Based on the finding of multiple somatic mutations, the known maturation pathway for T-lineage cells and the known defects of T cells and precursor thymocytes in mice with truncated WASP, we hypothesize that the presence of truncated WASP (WASPΔVCA) confers an extreme disadvantage in early developing thymocytes, above and beyond the known cost of absence of full-length WASP, and that the disadvantage likely occurs through dominant negative competition of WASPΔVCA with N-WASP, a protein that otherwise partially compensates for WASP absence in developing thymocytes

Ocrelizumab versus Interferon Beta-1a in Relapsing Multiple Sclerosis

Supported by F. Hoffmann–La Roche

КОНЦЕПЦІЯ IТ ОСВІТИ В УКРАЇНІ

Large corporations and IT-companies are considered as the pioneers of conception of «double education»: obligatory base preparation and additional certificated education at the applied courses. This ideology allows students to gain an university diploma within the special educational IT-courses. Co-operation between an university and IT-companies directed on advancement of practical disciplines and specialized courses for the complete higher education getting is a necessary requirement for development of information security (IS). In article the conceptual solutions of questions of preparation, retraining and in-plant training of staff in information security field are discussed in the conditions of their accordance to international standards. Questions that must be defined by this conception: circle of problems and proper purpose of educational field «Information security» introduction, and also comparative analysis and ways of solution of this problem in obedience to international standards and requirements. Derivatives from the adopted conception are a level, functions and maintenance of teaching of specialist in information security field.Большие корпорации и IT-компании по праву считаются пионерами концепции «двойного образования»: обязательная базовая подготовка и дополнительное сертификационное образование на прикладных курсах. Данная идеология позволяет студентам получить университетский диплом в рамках специальных образовательных IT-курсов. Взаимодействие между университетом и IT-компаниями, направленное на продвижение практических дисциплин и специализированных курсов для получения полного высшего образования, является необходимым условием, для развития информационной безопасности. В статье предложена концепция решения проблемы подготовки, переподготовки и повышения квалификации кадров в сфере информационной безопасности в условиях их соответствия международным стандартам. Рассмотренные вопросы, которые должны быть освещены данной концепцией: круг проблем и цель введения образовательной сферы «Информационная безопасность», также определены пути решения данной задачи в соответствии с международными стандартами и требованиями. Определены производные от предложенной концепции – уровень, функции и содержание обучения специалиста в области информационной безопасности.Великі корпорації та IT-компанії по праву вважаються піонерами концепції «подвійної освіти»: обов'язкова базова підготовка і додаткове сертифікаційна освіта на прикладних курсах. Дана ідеологія дозволяє студентам отримати університетський диплом в рамках спеціальних освітніх IT-курсів. Взаємодія між університетом та IT-компаніями, спрямована на просування практичних дисциплін та спеціалізованих курсів для отримання повної вищої освіти є необхідною умовою, для розвитку інформаційної безпеки. У статті запропонована концепція рішення проблеми підготовки, перепідготовки та підвищення кваліфікації кадрів у галузі інформаційної безпеки в умовах їх відповідності міжнародним стандартам. Розглянуті питання, які повинні бути висвітлені даною концепцією: коло проблем і мета введення освітньої сфери «Інформаційна безпека», також визначені шляхи вирішення даної задачі у відповідності з міжнародними стандартами та вимогами. Визначені похідні від запропонованої концепції – рівень, функції і зміст навчання фахівця в області інформаційної безпек

Spinal muscular atrophy: a perspective outlook

Background. Recent decades have witnessed a leap in understanding the molecular genetic bases of spinal muscular atrophy for a considerable improvement in diagnosis and treatment of this disease and development of innovative therapies for correcting genetic deficiencies. Given scarcity of etiotropic therapies for spinal muscular atrophy, traditional effective approaches remain relevant to target pathophysiological mechanisms of the disease progression and demand further development and improvement.Objectives. Efficacy assessment of proactive therapy to spinal muscular atrophy based on electromyographic techniques using verifiable patient-specific functional scales.Methods. The study is designed as a prospective cohort study conducted at the Republican Clinical Centre for Neurorehabilitation. We used a 15-year monitoring data on 95 children (66 boys and 29 girls) with genetically confirmed proximal spinal muscular atrophy. Patients were divided in two cohorts. The main cohort (65 children) received personalised therapy based on a proactive comprehensive stepwise approach to isolate a stem pathological pattern with clinical and electromyographic data. The comparison cohort (30 children) received conventional symptomatic therapy, including neurometabolic, cholinotropic drugs, classical massage and physiotherapy. In the study design, functional capacities and electromyographic data were estimated in a standardised time scheme with reference points («baseline», «1 year», «3 years», «5 years»).Results. The proposed methodology for clinical and electromyographic data sampling at different points of the disease progression has yielded results. We registered a weaker pathological progression in the main cohort reflected by less pronounced motor deficiency and electromyographic pathology compared to the comparison group receiving conventional symptomatic therapy.Conclusion. Dynamic monitoring of clinical and neurological disorders using modern assessment scales and extended electromyography of morbid motor markers enables a personalised proactive clinically justified treatment to suppress complications and manifestation of pathology

Ways to Improve Speed GaAs-Transistor Schottky and Selective Doped Heterotranzystors for the Formation of Modern Microwave Circuits

There is no doubt that the use of technology with field-effect transistors on GaAs Schottky to form a high-speed LSI has a great future. No fewer prospects facing unique in its properties SLHT - technology for the design of modern LSI / VLSI. In the case of SLHT can satisfy three main technological criteria: performance, low power consumption and hichnist technological and manufacturing process of complex structures BI

DIAGNOSIS OF OCCIPITAL LOBE EPILEPSY

Objective. The study aimed to investigate the significance of MRI and video electro-encephalography (EEG) monitoring in diagnosis of occipital lobe epilepsy.Materials and methods. The study involved 103 patients aged 2-17 years old who were diagnosed with occipital lobe epilepsy. All patients underwent brain MRI scans using a CT scanner 1.5 TL in the T1 and T2 modes in the axial, sagittal and frontal planes. For video electro-encephalography monitoring the EEG-recorder Encephalan 9 was used.Results. For the analysis of MRI studies in patients with occipital epilepsy, we grouped the patients as follows: with signs of perinatal brain lesions – 39 patients (38%), with congenital abnormalities of brain development – 26 patients (25%), and those with no pathological findings in the brain structures – 38 (37%). The EEG monitoring results revealed no deviations from the normal background rhythm in 27 patients (26%). Fifty patients (49%) demonstrated abnormalities of the alpha rhythm. In 26 patients (25%) a slowdown of the background rhythm was detected. The results demonstrated that a slowdown and abnormalities of the background rhythm occurred more often in children with symptomatic occipital lobe epilepsy, while these EEG changes occurred the least in patients with Lennox-Gastaut Syndrome. All patients showed the epileptiform activities manifested by the “peak – slow wave” complexes similar to the benign epileptiform rhythm patterns.Conclusion. The results obtained from the brain MRI studies in patients with occipital lobe epilepsy indicate that the perinatal brain damage has a role in the pathogenesis of the disease. The EEG results show that the EEG patterns in Panayiotopoulos Syndrome are more variable as compared to Lennox-Gastaut Syndrome and symptomatic occipital lobe epilepsy

Wiskott–Aldrich syndrome protein is required for NK cell cytotoxicity and colocalizes with actin to NK cell-activating immunologic synapses

The Wiskott–Aldrich syndrome (WAS) is a primary immunodeficiency disorder caused by a mutation in WAS protein (WASp) that results in defective actin polymerization. Although the function of many hematopoietic cells requires WASp, the specific expression and function of this molecule in natural killer (NK) cells is unknown. Here, we report that WAS patients have increased percentages of peripheral blood NK cells and that fresh enriched NK cells from two patients with a WASp mutation have defective cytolytic function. In normal NK cells, WASp was expressed and localized to the activating immunologic synapse (IS) with filamentous actin (F-actin). Perforin also localized to the NK cell-activating IS but at a lesser frequency than F-actin and WASp. The accumulation of F-actin and WASp at the activating IS was decreased significantly in NK cells that had been treated with the inhibitor of actin polymerization, cytochalasin D. NK cells from WAS patients lacked expression of WASp and accumulated F-actin at the activating IS infrequently. Thus, WASp has an important function in NK cells. In patients with WASp mutations, the resulting NK cell defects are likely to contribute to their disease