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

Modeling of liquid flow in surface discontinuities

Polymer composite and metallic materials have found wide application in various industries such as aviation, rocket, car manufacturing, ship manufacturing, etc. Many design elements need permanent quality control. Ensuring high quality and reliability of products is impossible without effective nondestructive testing methods. One of these methods is penetrant testing using penetrating substances based on liquid penetration into defect cavities. In this paper, we propose a model of liquid flow to determine the rates of filling the defect cavities with various materials and, based on this, to choose optimal control modes

Clinical characteristics of patients with COVID-19 depending on the treatment received and the presence of type 2 diabetes mellitus

BACKGROUND. Type 2 diabetes mellitus (T2DM) is an independent risk factor for adverse clinical outcomes in patients with Covid-19. There is currently insufficient data evaluating the efficacy and safety of drugs for the treatment of COVID-19, especially in patients with T2DM.AIM. The aim of study was to identify an associative relationship between the drugs used and the clinical outcomes of patients with Covid-19 and T2DM.MATERIALS AND METHODS. A retrospective analysis of the clinical outcomes of 1753 patients with COVID-19 who were hospitalized to the redesignated departments of multidisciplinary city clinical hospital in the period from 23.03.2020 to 01.06.2020.RESULTS. The total number of patients is 1,753, of which 311 (17.7%) are patients with DM2. 92.6% of patients received treatment for COVID-19. At the same time, 91.4% of patients received antibiotics (a/b), 61.5% — bronchodilators, 56.6% — injectable anticoagulants (a/c), 45.2% — hydroxychloroquine, 6.3% — antiviral drugs, 5.4% — oral a/c, 4.6% — glucocorticosteroids (GCS), 1.9% — Tocilizumab.Decrease of risk of death among patients with COVID-19 was as the therapy of a/b (OR 0.07, 95% CI 0.05–0.11, p&lt;0.05), bronchodilators (OR 0.12, 95% CI 0.08–0.18, p&lt;0.05) and injection a/c (OR 0.47, 95% CI 0.34–0.67, p&lt;0.05). At the same time, among patients with DM2, compared with patients without DM2, there was a more pronounced reduction in the risk of death during injectable a/c therapy: among patients with DM2, the risk of death decreased by 2.6 times (OR 0.39, 95% CI 0.21–0.73, p&lt;0.05), among patients without DM2 — by 2.1 times (OR 0.47, 95% CI 0.31–0.71, p&lt;0.05). Antiviral drugs was associated with an increased chance of death among patients without DM2 (OR 2.64, 95% CI 1.44–4.86, p&lt;0.05) and among patients with DM2 (OR 4.98, 95% CI 2.11–11.75, p&lt;0.05).CONCLUSION. A significant decrease of the risk of death among patients with COVID-19 was as the therapy of a/b, bronchodilators, and injectable a/c. An increase of the risk of death was observed during therapy with antiviral drugs

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

One simulation, different conclusions—the baseline period makes the difference!

The choice of the baseline period, intentionally chosen or not, as a reference for assessing future changes of any projected variable can play an important role for the resulting statement. In regional climate impact studies, well-established or arbitrarily chosen baselines are often used without being questioned. Here we investigated the effects of different baseline periods on the interpretation of discharge simulations from eight river basins in the period 1960–2099. The simulations were forced by four bias-adjusted and downscaled Global Climate Modelsunder two radiative forcing scenarios (RCP 2.6 and RCP 8.5). To systematically evaluate how far the choice of different baselines impacts the simulation results, we developed a similarity index that compares two time series of projected changes. The results show that 25% of the analyzed simulations are sensitive to the choice of the baseline period under RCP 2.6 and 32% under RCP 8.5. In extreme cases, change signals of two time series show opposite trends. This has serious consequences for key messages drawn from a basin-scale climate impact study. To address this problem, an algorithm was developed to identify flexible baseline periods for each simulation individually, which better represent the statistical properties of a given historical period

The Crystallization Of Low-Carbon Steel Simulation

В работе описано моделирование процессов равновесной и неравновесной кристаллизации для определения наиболее оптимального химического состава и температурного интервала горячей прокатки низкоуглеродистой стали. Моделирование заключалось в использовании термодинамических расчетов с помощью программного обеспечения Thermo-Calc.The paper describes the modeling of processes of equilibrium and non-equilibrium crystallization to determine the most optimal chemical composition and temperature range for hot rolling of low-carbon steel. The simulation consisted of thermodynamic calculations using Thermo-Calc software.Работа выполнена при финансовой поддержке стипендии Президента Российской Федерации (проект СП-3775.2021.1).The work was carried out with the financial support of the scholarship of the President of the Russian Federation (project No. SP-3775.2021.1)