Blood flow controls coagulation onset via the positive feedback of factor VII activation by factor Xa

<p>Abstract</p> <p>Background</p> <p>Blood coagulation is a complex network of biochemical reactions, which is peculiar in that it is time- and space-dependent, and has to function in the presence of rapid flow. Recent experimental reports suggest that flow plays a significant role in its regulation. The objective of this study was to use systems biology techniques to investigate this regulation and to identify mechanisms creating a flow-dependent switch in the coagulation onset.</p> <p>Results</p> <p>Using a detailed mechanism-driven model of tissue factor (TF)-initiated thrombus formation in a two-dimensional channel we demonstrate that blood flow can regulate clotting onset in the model in a threshold-like manner, in agreement with existing experimental evidence. Sensitivity analysis reveals that this is achieved due to a combination of the positive feedback of TF-bound factor VII activation by activated factor X (Xa) and effective removal of factor Xa by flow from the activating patch depriving the feedback of "ignition". The level of this trigger (i.e. coagulation sensitivity to flow) is controlled by the activity of tissue factor pathway inhibitor.</p> <p>Conclusions</p> <p>This mechanism explains the difference between red and white thrombi observed <it>in vivo </it>at different shear rates. It can be speculated that this is a special switch protecting vascular system from uncontrolled formation and spreading of active coagulation factors in vessels with rapidly flowing blood.</p

Increased proteasomal activity supports photoreceptor survival in inherited retinal degeneration

Inherited retinal degenerations, affecting more than 2 million people worldwide, are caused by mutations in over 200 genes. This suggests that the most efficient therapeutic strategies would be mutation independent, i.e., targeting common pathological conditions arising from many disease-causing mutations. Previous studies revealed that one such condition is an insufficiency of the ubiquitin–proteasome system to process misfolded or mistargeted proteins in affected photoreceptor cells. We now report that retinal degeneration in mice can be significantly delayed by increasing photoreceptor proteasomal activity. The largest effect is observed upon overexpression of the 11S proteasome cap subunit, PA28α, which enhanced ubiquitin-independent protein degradation in photoreceptors. Applying this strategy to mice bearing one copy of the P23H rhodopsin mutant, a mutation frequently encountered in human patients, quadruples the number of surviving photoreceptors in the inferior retina of 6-month-old mice. This striking therapeutic effect demonstrates that proteasomes are an attractive target for fighting inherited blindness

Loss of Arf4 causes severe degeneration of the exocrine pancreas but not cystic kidney disease or retinal degeneration

Arf4 is proposed to be a critical regulator of membrane protein trafficking in early secretory pathway. More recently, Arf4 was also implicated in regulating ciliary trafficking, however, this has not been comprehensively tested in vivo. To directly address Arf4\u27s role in ciliary transport, we deleted Arf4 specifically in either rod photoreceptor cells, kidney, or globally during the early postnatal period. Arf4 deletion in photoreceptors did not cause protein mislocalization or retinal degeneration, as expected if Arf4 played a role in protein transport to the ciliary outer segment. Likewise, Arf4 deletion in kidney did not cause cystic disease, as expected if Arf4 were involved in general ciliary trafficking. In contrast, global Arf4 deletion in the early postnatal period resulted in growth restriction, severe pancreatic degeneration and early death. These findings are consistent with Arf4 playing a critical role in endomembrane trafficking, particularly in the pancreas, but not in ciliary function

Increased proteasomal activity supports photoreceptor survival in inherited retinal degeneration

Inherited retinal degenerations, affecting more than 2 million people worldwide, are caused by mutations in over 200 genes. This suggests that the most efficient therapeutic strategies would be mutation independent, i.e., targeting common pathological conditions arising from many disease-causing mutations. Previous studies revealed that one such condition is an insufficiency of the ubiquitin–proteasome system to process misfolded or mistargeted proteins in affected photoreceptor cells. We now report that retinal degeneration in mice can be significantly delayed by increasing photoreceptor proteasomal activity. The largest effect is observed upon overexpression of the 11S proteasome cap subunit, PA28α, which enhanced ubiquitin-independent protein degradation in photoreceptors. Applying this strategy to mice bearing one copy of the P23H rhodopsin mutant, a mutation frequently encountered in human patients, quadruples the number of surviving photoreceptors in the inferior retina of 6-month-old mice. This striking therapeutic effect demonstrates that proteasomes are an attractive target for fighting inherited blindness

Определение возможности применения неметаллических контрольных образцов для оценки работоспособности дефектоскопических материалов и оценки чувствительности капиллярного контроля

INTRODUCTION. Liquid penetrant testing (PT) is one of the most widely used non-destructive testing methods for detecting surface discontinuities in nonporous solid materials. This method has shown good results when looking for defects in details made of any nonporous materials including glass, ceramics, plastic, magnetic or nonmagnetic metals or alloys. Penetrant materials and check samples are the main tools for PT. The samples are used to estimate the performance of penetrant materials and to evaluate the sensitivity of the testing technology. AIM OF THE PAPER. The paper aims to evaluate the discontinuity parameters, such as cracks, in non-metal samples to determine the feasibility of using these samples to assess the sensitivity of the testing technology. METHODS. Discontinuity parameters in non-metallic check samples were determined using a microscope, and then the data was statistically processed in accordance with GOST 8.736-2011"Multiple direct measurements. Methods of measurement results processing. Main principles". RESULTS. The conducted study has showed that samples made of non-metallic material can be used to estimate the performance of penetrant families, as well as to assess penetrant testing sensitivity since the cracks in samples are virtually straight.Введение. Капиллярный метод неразрушающего контроля является одним из наиболее широко используемых методов для выявления поверхностных несплошностей в твердых непористых материалах. Данный метод хорошо зарекомендовал себя при поиске дефектов в деталях из любых непористых материалов, в том числе стекла, керамики, пластмассы, магнитных и немагнитных металлах и сплавах. Дефектоскопические материалы и контрольные образцы являются основными средствами капиллярного контроля. Образцы служат для определения работоспособности дефектоскопических материалов и оценки чувствительности технологии контроля. Цель работы - оценка влияния параметров несплошностей типа трещин в образцах из неметалла для определения возможности применения таких образцов для оценки чувствительности технологии контроля. Методы исследования. Параметры несплошностей в неметаллических контрольных образцах определяли с помощью микроскопа, затем полученные данные подвергали статистической обработке в соответствии с ГОСТ 8.736-2011 «Измерения прямые многократные. Методы обработки результатов измерений. Основные положения». Результаты. По результатам исследования выявлено, что образцы из неметаллического материала пригодны для определения работоспособности наборов дефектоскопических материалов, а также возможности применения данных образцов для оценки чувствительности капиллярного контроля, так как трещины в образцах получаются практически прямолинейными

ОТКРЫТЫЕ ОБРАЗОВАТЕЛЬНЫЕ РЕСУРСЫ: МЕЖДУНАРОДНЫЙ ОПЫТ И СИТУАЦИЯ В РОССИИ

The main objective of this paper is to study and evaluate the use of andprospects for the development of open educational resources in Russia andin the international context of the historical and legal point of view, and presentthe example of the integration of open educational resources of universitiesin the digital library portal ‘Single Window’ with opportunities for information exchange in the educational environment.Главной задачей данной статьи является изучение и оценка использования и перспектив развития открытых образовательных ресурсов в России и в международном контексте с исторической и правовой точек зрения, а также представить на примере интеграции открытых образовательных ресурсов вузов в электронной библиотеке портала «Единое окно» возможностиинформационногообменавобразовательнойсреде

Possibility of using non-metallic check samples to assess the performance of penetrant materials and the sensitivity of penetrant testing

INTRODUCTION. Liquid penetrant testing (PT) is one of the most widely used non-destructive testing methods for detecting surface discontinuities in nonporous solid materials. This method has shown good results when looking for defects in details made of any nonporous materials including glass, ceramics, plastic, magnetic or nonmagnetic metals or alloys. Penetrant materials and check samples are the main tools for PT. The samples are used to estimate the performance of penetrant materials and to evaluate the sensitivity of the testing technology. AIM OF THE PAPER. The paper aims to evaluate the discontinuity parameters, such as cracks, in non-metal samples to determine the feasibility of using these samples to assess the sensitivity of the testing technology. METHODS. Discontinuity parameters in non-metallic check samples were determined using a microscope, and then the data was statistically processed in accordance with GOST 8.736-2011"Multiple direct measurements. Methods of measurement results processing. Main principles". RESULTS. The conducted study has showed that samples made of non-metallic material can be used to estimate the performance of penetrant families, as well as to assess penetrant testing sensitivity since the cracks in samples are virtually straight

OPEN EDUCATIONAL RESOURCES: INTERNATIONAL EXPERIENCE AND THE SITUATION IN RUSSIA

The main objective of this paper is to study and evaluate the use of andprospects for the development of open educational resources in Russia andin the international context of the historical and legal point of view, and presentthe example of the integration of open educational resources of universitiesin the digital library portal ‘Single Window’ with opportunities for information exchange in the educational environment