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.     

Prediction of psychoticlike symptoms in hypothetically psychosis-prone college students.

Correlates of psychotic and psychoticlike symptoms were examined in 60 college students who scored deviantly high on the Perceptual Aberration Scale. High scorers on this scale who also scored high on both the Impulsive Nonconformity Scale and the Depression subscale of the General Behavior Inventory (GBI) showed the most deviant psychotic and psychoticlike symptoms. Moreover, performance on a task of referential communication, the Password Task, was significantly related to such symptoms. The Perceptual Aberration Scale, the Impulsive Nonconformity Scale, and the GBI Depression subscale are recommended for concurrent use in mass screening to select individuals likely to exhibit psychotic or psychoticlike symptoms. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Decision support for Cybersecurity risk planning

Security countermeasures help ensure the confidentiality, availability, and integrity of information systems by preventing or mitigating asset losses from Cybersecurity attacks. Due to uncertainty, the financial impact of threats attacking assets is often difficult to measure quantitatively, and thus it is difficult to prescribe which countermeasures to employ. In this research, we describe a decision support system for calculating the uncertain risk faced by an organization under cyber attack as a function of uncertain threat rates, countermeasure costs, and impacts on its assets. The system uses a genetic algorithm to search for the best combination of countermeasures, allowing the user to determine the preferred tradeoff between the cost of the portfolio and resulting risk. Data collected from manufacturing firms provide an example of results under realistic input conditions.     

The employment of strontium to activate mouse oocytes: effects on spermatid-injection outcome

The present research investigated the effects of various strontium concentrations, in combination with different incubation periods, on mouse parthenogentic oocyte activation and blastocyst development. The results for blastocyst development showed a trend indicating that 10 mM strontium for 3 h was the optimal strontium protocol. Ethanol, an agent that incites oocyte activation via a monotonic rise in calcium, was employed as a control. The outcome of blastocyst formation arising from parthenogenic ethanol activation was significantly less (P < 0.001) than that achieved by the optimal strontium protocol. To assess the impact of strontium oocyte activation on embryo viability following fertilization with immature germ cells, the protocol of 10 mM strontium for 3 h was applied to oocytes injected with round spermatids and then compared with other protocols. The results indicate that following round-spermatid injection the benefits derived from strontium artificial oocyte activation are evident during both pre- and post-implantation development. However, in order to adjust the protocol to the most effective round-spermatid injection in relation to the oocyte cell cycle, injection was done 1.5 h after strontium activation followed by another 1.5 h activation in strontium. The implementation of round-spermatid injection in combination with this oocyte-activation protocol led to live-birth outcomes not significantly different to those outcomes obtained by mature spermatozoa.     

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.     

Kinetics of desulfurization of hydrogen sulfide using metallic copper as a desulfurizer

The kinetics of desulfurization of hydrogen sulfide, using metallic copper as desulfurizer, have been investigated over a range of temperatures and pressures of hydrogen sulfide. Our results indicate that there are two stages of reaction; activation energies for the first and second stages are 63 kJ/mol and 38 kJ/mol, respectively. Possible reaction mechanisms in which the initial rate is controlled by interface reaction and the later stage is controlled by diffusion through or in the Cu₂S layer are consistent with the experimental data.     

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?     

Force-Commutated Reactive-Power Compensator

A reactive-power compensator (RPC) is a type of static var compensator (SVC) that is used to dynamically correct power factor to prevent voltage variation (flicker) in ac power sources due to large dynamic loads. It also minimizes total source current. Thus the application of an RPC or SVC to a load may allow addition of substantial new load to existing feeders or substations. A reactive-power compensator suited to industrial ratings (1.0-25 MVA) is described. It utilizes a force-commutated current-source bridge to provide both leading and lagging reactive power. The ability to operate both leading and lagging can reduce by 2:1 the ratings of the RPC itself and the capacitors and magnetics associated with it. The characteristics of the power circuit, the means used to control it, and the resulting dynamic performance is described. Speed of response compares favorably to the thyristor-controlled reactors now in common use as SVC's at higher MVA ratings. This RPC is suited to compensate any balanced three-phase dynamic load.     

Design and Control Techniques for Extending High Frequency Operation of a CSI Induction Motor Drive

An investigation of the maximum speed capability of a current source inverter (CSI) drive in both a three-and a six-phase connection is presented. It is shown that a six-phase configuration has distinct advantages over a three-phase connection in high speed capability for the same peak motor spike voltages. In addition, with proper control of the firing pulses fed to the inverters supplying the six-phase machine, the speed range can be substantially extended beyond the maximum limit predicted using conventional control. Predicted analytical results are correlated with results obtained by a detailed hybrid computer simulation.