Browsing by Subject "threshold"

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    Blood flow controls coagulation onset via the positive feedback of factor VII activation by factor Xa
    (2010) Shibeko, Alexey M; Lobanova, Ekaterina S; Panteleev, Mikhail A; Ataullakhanov, Fazoil I
    Background: 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. Results: 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. Conclusions: This mechanism explains the difference between red and white thrombi observed in vivo 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.
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    The impact of lowering the study design significance threshold to 0.005 on sample size in randomized cancer clinical trials.
    (Journal of clinical and translational science, 2024-01) Leung, Tiffany H; Ho, James C; Wang, Xiaofei; Lam, Wendy W; Pang, Herbert H
    The proposal of improving reproducibility by lowering the significance threshold to 0.005 has been discussed, but the impact on conducting clinical trials has yet to be examined from a study design perspective. The impact on sample size and study duration was investigated using design setups from 125 phase II studies published between 2015 and 2022. The impact was assessed using percent increase in sample size and additional years of accrual with the medians being 110.97% higher and 2.65 years longer respectively. The results indicated that this proposal causes additional financial burdens that reduce the efficiency of conducting clinical trials.
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    Ultraviolet Absorption Coefficients of Melanosomes Containing Eumelanin As Related to the Relative Content of DHI and DHICA
    (2010) Peles, Dana N; Lin, Erica; Wakamatsu, Kazumasa; Ito, Shosuke; Simon, John D
    Central to understanding the photochemical function(s) of melanosomes is the determination of their absorption properties and an understanding of how the absorption varies with the molecular composition of melanin. Herein, the absorption coefficients for melanosomes containing predominantly eumelanin, a polymeric pigment derived from the molecular precursors 5,6-dihydroxyindole (DHI) and 5,6-dihydroxyindole-2-carboxylic acid (DHICA), are reported for) lambda = 244 nm. The absorption coefficient varies with the DHICA/DHI ratio, determined from chemical degradation analyses. With increasing DHICA content, the absorption coefficient of the melanosome increases. This observation is consistent with reported extinction coefficients, which reveal that at 244 nm, the extinction coefficient of DHICA is a factor of similar to 2.1 greater than that of DHI. The melanosome absorption coefficients are compared to predicted values based on a linear combination of the absorption of the constituent monomers.