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BackgroundPatients with diabesity have a significantly increased risk of developing cardiovascular disease. Therefore, therapy addressing the multiple metabolic abnormalities linked with diabesity and leading to further reduction of cardiovascular risk is highly desirable. Activation of the TGR5 receptor holds therapeutic potential for diabesity. In the present study, we evaluated the efficacy of TRC210258, a novel TGR5 agonist, in clinically relevant animal models of diabesity.MethodsA novel small molecule, TRC210258 (N-(4-chlorophenyl)-2-(4-fluorophenoxy)-N-methylimidazo (1, 2-a) pyrimidine-3-carboxamide), was synthesized. The in vitro TGR5 receptor activation potential of TRC210258 was assessed by cyclic adenosine monophosphate (cAMP) assay and cAMP-responsive element reporter assay using cells overexpressing the human TGR5 receptor. The effect of TRC210258 on glucagon-like peptide-1 release was evaluated in vitro using a human enteroendocrine cell line. The effect of TRC210258 on energy expenditure and glycemic control was evaluated in high-fat diet-induced obese mice. Additionally, the effect of TRC210258 on dyslipidemic parameters was determined in high fat-fed hamsters.ResultsTRC210258 demonstrated potent TGR5 agonist activity, with enhanced glucagon-like peptide-1 release and energy expenditure. Treatment with TRC210258 resulted in better glycemic control and improved parameters of dyslipidemia such as plasma triglyceride, low-density lipoprotein cholesterol, and non-high-density lipoprotein cholesterol levels. Treatment with TRC210258 also improved emerging dyslipidemic cardiovascular risk parameters, including remnant cholesterol and triglyceride clearance.ConclusionThis study highlights the potential of TRC210258, a novel TGR5 agonist, to improve dyslipidemic cardiovascular risk beyond glycemic control in patients with type 2 diabetes.

We model the dynamics of solar thermal plants-the first model covering all processes between market demand through power output at millisecond resolution-for the purpose of control design. Our model integrates solar reflectors, power tower, salt tank, boiler, turbine, generator, piping, and pumps along with the flows of energy and information between them. We show how our detailed model permits control designs that can potentially enhance the life of the power tower, and thereby aid in reducing generation costs of solar power to a level competitive to current electricity price. Our modeling also opens up several problems of control and optimization of concentrated solar power (CSP) plants that can quickly bring the maturity of CSPs near that of traditional coal-fired plants and aid their integration with the other power sources. We show some of this potential via simulations. Index Terms-Concentrated solar power (CSP), controloriented model. 1063-6536

The optical performance of a novel solar concentrator consisting of a 400 spherical heliostat array and a linked two-axis tracking system is analyzed using the Monte Carlo ray-tracing technique. The optical efficiency and concentration ratio are compared for four different heliostat linkage configurations, including linkages of 1 × 1, 1 × 2, 2 × 2, 4 × 4, and 5 × 5 heliostats for 7-hour operation and the selected months of June and December. The optical performance of the concentrator decreases with the increasing number of heliostats in the individual groups due to increasing optical inaccuracies. In June, the best-performing linked configuration, in which 1 heliostat in the east-west direction and 2 heliostats in the north-south direction are linked, provides a monthly-averaged 7-hour optical efficiency and average concentration ratio of 79% and 511 suns, respectively. In December, the optical efficiency and the average concentration ratio decreases to 61% and 315 suns, respectively.