Synthesis of GPR119 Interacting Drugs for Treatment of Type II Diabetes

Type II Diabetes is one of the leading causes of death in the United States and is categorized by high blood glucose levels, insulin deficiencies, and inhibition. Located in the pancreas and intestine, the G-Protein Receptor 119 (GPR119) was noted to have an important effect on insulin secretion. Previous studies found that when the receptor is activated, insulin secretion was upregulated which is vital for type II diabetes treatment. Compounds AR437735 and AR437948 are the proposed agonist and inverse agonist pair that will be synthesized and tested for bioactivity to the receptor. It is theorized that the different double-bonded atoms on the two compounds will help determine which ligand on the receptor should be targeted for drug binding to help promote insulin secretion. The synthesis of compounds AR437735 and AR437948 failed, however, a new pair of agonists and inverse agonist were synthesized using the base structure of the two initial compounds. The agonist version of the compound had an overall yield of 18.051%, while its counterpart had an overall yield of 6.259%. All compounds are characterized by Nuclear Magnetic Radiation Spectroscopy (NMR)

Transport properties in Simplified Double Exchange model

Transport properties of the manganites by the double-exchange mechanism are considered. The system is modeled by a simplified double-exchange model, i.e. the Hund coupling of the itinerant electron spins and local spins is simplified to the Ising-type one. The transport properties such as the electronic resistivity, the thermal conductivity, and the thermal power are calculated by using Dynamical mean-field theory. The transport quantities obtained qualitatively reproduce the ones observed in the manganites. The results suggest that the Simplified double exchange model underlies the key properties of the manganites.Comment: 5 pages, 5 eps figure

Catalytic Enantioselective Birch–Heck Sequence for the Synthesis of Tricyclic Structures with All-Carbon Quaternary Stereocenters

A new enantioselective desymmetrizing Mizoroki–Heck reaction is reported. The process affords high yields and enantioselectivities of tricyclic structures containing all-carbon quaternary stereocenters. The substrates for the reaction are efficiently synthesized from Birch reduction–alkylation of benzoic acid and benzoate esters

Catalytic Enantioselective Birch–Heck Sequence for the Synthesis of Tricyclic Structures with All-Carbon Quaternary Stereocenters

A new enantioselective desymmetrizing Mizoroki–Heck reaction is reported. The process affords high yields and enantioselectivities of tricyclic structures containing all-carbon quaternary stereocenters. The substrates for the reaction are efficiently synthesized from Birch reduction–alkylation of benzoic acid and benzoate esters

Hook3 is a scaffold for the opposite-polarity microtubule-based motors cytoplasmic dynein-1 and KIF1C.

The unidirectional and opposite-polarity microtubule-based motors, dynein and kinesin, drive long-distance intracellular cargo transport. Cellular observations suggest that opposite-polarity motors may be coupled. We recently identified an interaction between the cytoplasmic dynein-1 activating adaptor Hook3 and the kinesin-3 KIF1C. Here, using in vitro reconstitutions with purified components, we show that KIF1C and dynein/dynactin can exist in a complex scaffolded by Hook3. Full-length Hook3 binds to and activates dynein/dynactin motility. Hook3 also binds to a short region in the "tail" of KIF1C, but unlike dynein/dynactin, this interaction does not activate KIF1C. Hook3 scaffolding allows dynein to transport KIF1C toward the microtubule minus end, and KIF1C to transport dynein toward the microtubule plus end. In cells, KIF1C can recruit Hook3 to the cell periphery, although the cellular role of the complex containing both motors remains unknown. We propose that Hook3's ability to scaffold dynein/dynactin and KIF1C may regulate bidirectional motility, promote motor recycling, or sequester the pool of available dynein/dynactin activating adaptors

War-Gaming Applications for Achieving Optimum Acquisition of Future Space Systems

This chapter describes an innovative modeling and simulation approach using newly proposed Advanced Game-based Mathematical Framework (AGMF), Unified Game-based Acquisition Framework (UGAF) and a set of War-Gaming Engines (WGEs) to address future space systems acquisition challenges. Its objective is to assist the DoD Acquisition Authority (DAA) to understand the contractor’s perspective and to seek optimum Program-and-Technical-Baseline (PTB) solution and corresponding acquisition strategy under both the perspectives of the government and the contractors. The proposed approach calls for an interdisciplinary research that involves game theory, probability and statistics, and non-linear programming. The goal of this chapter is to apply the proposed war-gaming frameworks to develop and evaluate PTB solutions and associated acquisition strategies in the context of acquisition of future space systems. Our simulation results suggest that our optimization problem for the acquisition of future space systems meets the affordability and innovative requirements with minimum acquisition risk

A numerical study of compact approximations based on flat integrated radial basis functions for second-order differential equations

In this paper, we propose a simple but effective preconditioning technique to improve the numerical stability of Integrated Radial Basis Function (IRBF) methods. The proposed preconditioner is simply the inverse of a well-conditioned matrix that is constructed using non-flat IRBFs. Much larger values of the free shape parameter of IRBFs can thus be employed and better accuracy for smooth solution problems can be achieved. Furthermore, to improve the accuracy of local IRBF methods, we propose a new stencil, namely Combined Compact IRBF (CCIRBF), in which (i) the starting point is the fourth-order derivative; and (ii) nodal values of first- and second-order derivatives at side nodes of the stencil are included in the computation of first- and second-order derivatives at the middle node in a natural way. The proposed stencil can be employed in uniform/nonuniform Cartesian grids. The preconditioning technique in combination with the CCIRBF scheme employed with large values of the shape parameter are tested with elliptic equations and then applied to simulate several fluid flow problems governed by Poisson, Burgers, convection-diffusion, and Navier-Stokes equations. Highly accurate and stable solutions are obtained. In some cases, the preconditioned schemes are shown to be several orders of magnitude more accurate than those without preconditioning

High-order fluid solver based on a combined compact integrated RBF approximation and its fluid structure interaction applications

In this study, we present a high-order numerical method based on a combined compact integrated RBF (IRBF) approximation for viscous flow and fluid structure interaction (FSI) problems. In the method, the fluid variables are locally approximated by using the combined compact IRBF, and the incompressible Navier-Stokes equations are solved by using the velocity-pressure formulation in a direct fully coupled approach. The fluid solver is verified through various problems including heat, Burgers, convection-diffusion equations, Taylor-Green vortex and lid driven cavity flows. It is then applied to simulate some FSI prob- lems in which an elastic structure is immersed in a viscous incompressible fluid. For FSI simulations, we employ the immersed boundary framework using a regular Eulerian computational grid for the fluid mechanics together with a Lagrangian representation of the immersed boundary. For the immersed fibre/membrane FSI problems, although the order of accuracy of the present scheme is generally similar to FDM approaches reported in the literature, the present approach is nonetheless more accurate than FDM approaches at comparable grid spacings. The numerical results obtained by the present scheme are highly accurate or in good agreement with those reported in earlier studies of the same problems

Charge-ordered ferromagnetic phase in manganites

A mechanism for charge-ordered ferromagnetic phase in manganites is proposed. The mechanism is based on the double exchange in the presence of diagonal disorder. It is modeled by a combination of the Ising double-exchange and the Falicov-Kimball model. Within the dynamical mean-field theory the charge and spin correlation function are explicitely calculated. It is shown that the system exhibits two successive phase transitions. The first one is the ferromagnetic phase transition, and the second one is a charge ordering. As a result a charge-ordered ferromagnetic phase is stabilized at low temperature.Comment: To appear in Phys. Rev.