A Dual Inhibitor of DYRK1A and GSK3β for β-Cell Proliferation: Aminopyrazine Derivative GNF4877

Loss of β-cell mass and function can lead to insufficient insulin levels and ultimately to hyperglycemia and diabetes mellitus. The mainstream treatment approach involves regulation of insulin levels; however, approaches intended to increase β-cell mass are less developed. Promoting β-cell proliferation with low-molecular-weight inhibitors of dual-specificity tyrosine-regulated kinase 1A (DYRK1A) offers the potential to treat diabetes with oral therapies by restoring β-cell mass, insulin content and glycemic control. GNF4877, a potent dual inhibitor of DYRK1A and glycogen synthase kinase 3β (GSK3β) was previously reported to induce primary human β-cell proliferation in vitro and in vivo. Herein, we describe the lead optimization that lead to the identification of GNF4877 from an aminopyrazine hit identified in a phenotypic high-throughput screening campaign measuring β-cell proliferation.     

Experimentation and the evaluation of energy efficiency programs

The use of experiments— particularly randomized controlled trials (RCTs) where subjects are randomly assigned to treatment and control conditions—has rarely been applied to the process of improving the design of energy efficiency programs and, more fundamentally, to determining the net savings from energy efficiency programs. This paper discusses the use of experimentation in the energy efficiency program field with the hope of explaining how these experiments can be used, and identifying the barriers to their use will cause more experimentation to occur. First, a brief overview of experimental methods is presented. This discussion describes the advantages and disadvantages of conducting experiments in the context of the development and evaluation of energy efficiency programs. It then discusses barriers to the use of experimental methods (including cost and equity issues) and suggests some ways of overcoming these barriers. Finally, recommendations are made for implementing key social experiments, discussing the types of energy efficiency programs and issues that can make use of experimentation and variables that one might use for selecting treatments.     

Modeling spent TRISO fuel for geological disposal: corrosion and failure under oxidizing conditions in the presence of water

High temperature gas reactors (HTGRs) are being considered for near term deployment in the United States under the GNEP program and farther term deployment under the Gen IV reactor design (U.S. DOE Nuclear Energy Research Advisory Committee, 2002). A common factor among current HTGR (prismatic or pebble) designs is the use of TRISO coated particle fuel. TRISO refers to the three types of coating layers (pyrolytic carbon, porous carbon, and silicon carbide) around the fuel kernel, which is both protected and contained by the layers. While there have been a number of reactors operated with coated particle fuel, and extensive amount of research has gone into designing new HTGRs, little work has been done on modeling and analysing the degradation rates of spent TRISO fuel for permanent geological disposal. An integral part of developing a spent fuel degradation modeling was to analyze the waste form without taking any consideration for engineering barriers. A basic model was developed to simulate the time to failure of spent TRISO fuel in a repository environment. Preliminary verification of the model was performed with comparison to output from a proprietary model called GARGOYLE that was also used to model degradation rates of TRISO fuel. A sensitivity study was performed to determine which fuel and repository parameters had the most significant effect on the predicted time to fuel particle failure. Results of the analysis indicate corrosion rates and thicknesses of the outer pyrolytic carbon and silicon carbide layers, along with the time dependent temperature of the spent fuel in the repository environment, have a significant effect on the time to particle failure. The thicknesses of the kernel, buffer, and IPyC layers along with the strength of the SiC layer and the pressure in the TRISO particle did not significantly alter the results from the model. It can be concluded that a better understanding of the corrosion rates of the OPyC and SiC layers, along with increasing the quality control of the OPyC and SiC layer thicknesses, can significantly reduce uncertainty in estimates of the time to failure of spent TRISO fuel in a repository environment.     

Effectual dispersion of carbon nanofibers in polyetherimide composites and their mechanical and tribological properties

The use of proliferation of nanotechnology in commercial applications is driving requirements for minimal chemical processing and simple processes in industry. Carbon nanofiber (CNF) products possess very high purity levels without the need of purification processing before use and are in growing demand for this quality. Polyetherimide (PEI) has excellent mechanical and thermal performance, but its high viscosity makes its nanocomposites processing very challenging. In this study, a facile melt‐mixing method was used to fabricate PEI nanocomposites with as received and physically treated CNFs. The dispersion of CNFs was characterized by scanning electron microscopy, transmitted optical microscopy, and electrometer with large‐area electrodes. The results showed that the facile and powerful melt‐mixing method is effective in homogeneously dispersing CNFs in the PEI matrix. The flexural and tribological characteristics were investigated and the formation of spatial networks of CNFs and weak interfacial bonding were considered as competitive factors to enhanced flexural properties. The composites with 1.0 wt% CNFs showed flexural strength and toughness increased by more than 50 and 550%, respectively, but showed very high wear rate comparable with that of pure PEI. The length of the CNFs also exerted great influences on both mechanical and tribological behaviors. POLYM. ENG. SCI., 50:1914–1922, 2010. © 2010 Society of Plastics Engineers     

A NUMERICAL SOLUTION FOR THE ANOMALOUS SEDIMENTATION OF A SMALL BROWNIAN SPHERE IN A VERTICAL CYLINDER OF PERIODICALLY VARYING RADIUS

We consider the long-time asymptotic transport of a small Brownian sphere that is sedimenting through a viscous fluid within an infinite vertical cylinder whose radius changes periodically and abruptly between two values. Use of generalized Taylor dispersion theory gives rise to a set of steady-state differential equations that govern the long-time mean velocity. We prove that these equations possess a unique solution. Finite difference discretization of all governing equations and boundary conditions, except for the normalization condition, leads to a homogeneous system of equations that possesses an infinite number of solutions. Application of the normalization condition selects the particular solution of the set that satisfies all conditions. Despite the absence of classical wall effects, the long-time mean velocity of the particle through the pore is generally less than the Stokes sedimentation velocity that applies at every point within the fluid. This anomalous behavior could be used to enhance force-driven separation of Brownian particles that possess identical Stokes velocities but different diffusivities. Furthermore, this numerical approach may be applied to similar problems.     

A comparative analysis of an MRP lot-for-lot system and a Kanban system for a multistage production operation

Japanese production methods and operational control techniques have been the subject of much recent attention from American production managers and the media. In this paper the Kanban aspect of the 'just-in-time' concept is analysed in order to ascertain the potential for scheduling in an ill-structured production operation and to compare its effectiveness with the traditional MRP lot-for-lot scheduling and control procedure. The analysis will be conducted using a hypothetical production operation that includes multiple workcentres, machines and product structures, and serial and assembly operations. Simulation model results are discussed and principles for selecting the more cost-effective system are outlined for the general MRP lot-for-lot versus Kanban scenarios.     

电子邮件营销:因资源与投资回报失衡而被低估

博客和业内专家认为,电子邮件营销面临的最大挑战非常复杂,如收件箱传输能力或渲染。这是真的吗?一名博学的市场人员、设计师或程序员都可以轻易解决上述两个问题,而对于其他大多数人来说,问题就不是那么简单了。这才是真正的问题。大多数公司并不知道电子邮件营销的最佳实践,同时他们内部也缺少相关的专业资源。然而,却很少有公司意识到这个问题,因为即使是写得很糟糕的电子邮件似乎仍表现不错。未造成伤害,也没有犯错,不是吗?     

Multi-Camera Human Activity Monitoring

With the proliferation of security cameras, the approach taken to monitoring and placement of these cameras is critical. This paper presents original work in the area of multiple camera human activity monitoring. First, a system is presented that tracks pedestrians across a scene of interest and recognizes a set of human activities. Next, a framework is developed for the placement of multiple cameras to observe a scene. This framework was originally used in a limited X, Y, pan formulation but is extended to include height (Z) and tilt. Finally, an active dual-camera system for task recognition at multiple resolutions is developed and tested. All of these systems are tested under real-world conditions, and are shown to produce usable results. This work has been supported by the NSF through grants #IIS-0219863, #CNS-0224363, #CNS-0324864, #IIP-0443945, #CNS-0420836, #IIP-0726109, and #CNS-0708344.