7 research outputs found
Computational Modeling and Analysis of Insulin Induced Eukaryotic Translation Initiation
Insulin, the primary hormone regulating the level of glucose in the bloodstream, modulates a variety of cellular and enzymatic processes in normal and diseased cells. Insulin signals are processed by a complex network of biochemical interactions which ultimately induce gene expression programs or other processes such as translation initiation. Surprisingly, despite the wealth of literature on insulin signaling, the relative importance of the components linking insulin with translation initiation remains unclear. We addressed this question by developing and interrogating a family of mathematical models of insulin induced translation initiation. The insulin network was modeled using mass-action kinetics within an ordinary differential equation (ODE) framework. A family of model parameters was estimated, starting from an initial best fit parameter set, using 24 experimental data sets taken from literature. The residual between model simulations and each of the experimental constraints were simultaneously minimized using multiobjective optimization. Interrogation of the model population, using sensitivity and robustness analysis, identified an insulin-dependent switch that controlled translation initiation. Our analysis suggested that without insulin, a balance between the pro-initiation activity of the GTP-binding protein Rheb and anti-initiation activity of PTEN controlled basal initiation. On the other hand, in the presence of insulin a combination of PI3K and Rheb activity controlled inducible initiation, where PI3K was only critical in the presence of insulin. Other well known regulatory mechanisms governing insulin action, for example IRS-1 negative feedback, modulated the relative importance of PI3K and Rheb but did not fundamentally change the signal flow
Mechanical performance of zirconia-silica bilayer coating on aluminum alloys with varying porosities: Deep learning and microstructure-based FEM
Evolution of the Quorum network and the mobilome (plasmids and bacteriophages) in clinical strains of Acinetobacter baumannii during a decade
Thrombin-receptor antagonist vorapaxar in acute coronary syndromes
BACKGROUND
Vorapaxar is a new oral protease-activated–receptor 1 (PAR-1) antagonist that inhibits
thrombin-induced platelet activation.
METHODS
In this multinational, double-blind, randomized trial, we compared vorapaxar with
placebo in 12,944 patients who had acute coronary syndromes without ST-segment
elevation. The primary end point was a composite of death from cardiovascular causes,
myocardial infarction, stroke, recurrent ischemia with rehospitalization, or urgent
coronary revascularization.
RESULTS
Follow-up in the trial was terminated early after a safety review. After a median follow-up
of 502 days (interquartile range, 349 to 667), the primary end point occurred in 1031
of 6473 patients receiving vorapaxar versus 1102 of 6471 patients receiving placebo
(Kaplan–Meier 2-year rate, 18.5% vs. 19.9%; hazard ratio, 0.92; 95% confidence interval
[CI], 0.85 to 1.01; P = 0.07). A composite of death from cardiovascular causes,
myocardial infarction, or stroke occurred in 822 patients in the vorapaxar group
versus 910 in the placebo group (14.7% and 16.4%, respectively; hazard ratio, 0.89;
95% CI, 0.81 to 0.98; P = 0.02). Rates of moderate and severe bleeding were 7.2% in the
vorapaxar group and 5.2% in the placebo group (hazard ratio, 1.35; 95% CI, 1.16 to 1.58;
P<0.001). Intracranial hemorrhage rates were 1.1% and 0.2%, respectively (hazard
ratio, 3.39; 95% CI, 1.78 to 6.45; P<0.001). Rates of nonhemorrhagic adverse events
were similar in the two groups.
CONCLUSIONS
In patients with acute coronary syndromes, the addition of vorapaxar to standard
therapy did not significantly reduce the primary composite end point but significantly
increased the risk of major bleeding, including intracranial hemorrhage