Discovery of GPR183 Agonists Based on an Antagonist Scaffold

The G protein-coupled receptor GPR183/EBI2, which is activated by oxysterols, is a therapeutic target for inflammatory and metabolic diseases where both antagonists and agonists are of potential interest. Using the piperazine diamide core of the known GPR183 antagonist (E)-3-(4-bromophenyl)-1-(4-(4-methoxybenzoyl)piperazin-1-yl)prop-2-en-1-one (NIBR189) as starting point, we identified and sourced 79 structurally related compounds that were commercially available. In vitro screening of this compound collection using a Ca²⁺ mobilization assay resulted in the identification of 10 compounds with agonist properties. To enable establishment of initial structure-activity relationship trends, these were supplemented with five in-house compounds, two of which were also shown to be GPR183 agonists. Taken together, our findings suggest that the agonist activity of this compound series is dictated by the substitution pattern of one of the two distal phenyl rings, which functions as a molecular efficacy-switch.     

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.     

Modeling aviation baggage screening security systems: a case study

Aviation security protects vital national interests, as well as passengers and aircraft. Key components of an aviation security system include baggage and passenger screening devices and operations. Determining how and where to assign (deploy) such devices can be quite challenging. Moreover, even after such systems are in place, it can be difficult to measure their effectiveness. This paper describes how discrete optimization models can be used to address these questions, based on three performance measures that quantify the effectiveness of airport baggage screening security device systems. These models are used to solve for optimal airport baggage screening security device deployments considering the number of passengers on a set of flights who have not been cleared using a security risk assessment system in use by the Federal Aviation Administration (i.e., passengers whose baggage is subjected to screening), the number of flights in this set, and the size of the aircraft for such flights. Several examples are provided to illustrate these results, including an example that uses data available from the Official Airline Guide.     

一种高效的硬布线控制CPU的设计方法

文章提出了一种硬布线逻辑CPU的设计流程，即以CPU设计工具软件LDF为核心的设计方法，其主要目的的提高硬布线逻辑CPU的设计效率。定义了一种用于描述硬布线控制逻辑的语言-MCDL，对总线优化问题进行了研究，并且给出了解决总线优化问题的近似算法。     

三峡地下电站变顶高尾水洞水动力特性

在国内首次应用模型水轮发电机组对三峡地下电站变顶高尾水洞方案进行水力过渡过程试验研究。对水轮机导叶实行分段关闭 ,并求出了二段关闭的最佳拐点 ,试验证实了二段关闭对减小尾水管进口的负压和机组转速上升有明显的作用。通过有关水力参数的测试 ,认为变顶高尾水洞可以满足各项技术要求 ,是一个减少山体开挖、节省投资的新型设计方案。在地下电站中具有广泛的应用前景     

The hot blow forming of AZ31 Mg sheet: Formability assessment and application development

The hot blow forming of magnesium sheet offers significant opportunity for forming complex, lightweight parts for automotive applications. This paper characterizes the elevated-temperature formability of AZ31 magnesium sheet materials and the effect of processing conditions on the performance of these materials. In addition, magnesium sheet application development at General Motors Corporation is reviewed.     

Note on ‘Construction of Double Sampling s‐Control Charts for Agile Manufacturing’

He and Grigoryan (Quality and Reliability Engineering International 2002; 18 :343–355) formulated the design of a double‐sampling (DS) s control chart as an optimization problem and solved it with a genetic algorithm. They concluded that the DS s control charts can be a more economically preferable alternative in detecting small shifts than traditional s control charts. We explain that, since they only considered the average sample size when the process is in control, their conclusion is questionable. Copyright © 2006 John Wiley & Sons, Ltd.     

分置式牛津型斯特林制冷机的数值分析与实验验证

对分置式牛津型斯特林制冷机进行了数值计算 ,介绍了计算模型考虑到的众多不可逆因素。通过对计算结果与实验结果的对比 ,验证了本文数值计算的准确性 ,说明本文计算模型与数值处理方法是切实可行的     

COMMENTS ON THE DETERMINATION OF FRIABILITY AND UNMODIFIED GRAINS

The Analysis Committee of the European Brewery Convention is aware that the Friabilimeter sometimes is used on samples that do not comply with the field of application. The precision of the method is also overlooked by some users. The field of application, precision of the method as well as the need for frequent testing of the instrument is therefore stressed in more detail than in the earlier published method by the EBC Analysis Committee.