Azasugar inhibitors as pharmacological chaperones for Krabbe disease

Krabbe disease is a devastating neurodegenerative disorder characterized by rapid demyelination of nerve fibers. This disease is caused by defects in the lysosomal enzyme β-galactocerebrosidase (GALC), which hydrolyzes the terminal galactose from glycosphingolipids. These lipids are essential components of eukaryotic cell membranes: substrates of GALC include galactocerebroside, the primary lipid component of myelin, and psychosine, a cytotoxic metabolite. Mutations of GALC that cause misfolding of the protein may be responsive to pharmacological chaperone therapy (PCT), whereby small molecules are used to stabilize these mutant proteins, thus correcting trafficking defects and increasing residual catabolic activity in cells. Here we describe a new approach for the synthesis of galacto-configured azasugars and the characterization of their interaction with GALC using biophysical, biochemical and crystallographic methods. We identify that the global stabilization of GALC conferred by azasugar derivatives, measured by fluorescence-based thermal shift assays, is directly related to their binding affinity, measured by enzyme inhibition. X-ray crystal structures of these molecules bound in the GALC active site reveal which residues participate in stabilizing interactions, show how potency is achieved and illustrate the penalties of aza/iminosugar ring distortion. The structure–activity relationships described here identify the key physical properties required of pharmacological chaperones for Krabbe disease and highlight the potential of azasugars as stabilizing agents for future enzyme replacement therapies. This work lays the foundation for new drug-based treatments of Krabbe disease.     

Stereocontrolled spirocyclic bislactams derived from pyroglutamic acid

The synthesis of rigid spirocyclic bislactams derived from pyroglutamic acid has been established.     

基于自适应预测滤波理论的模数转换器设计方法

基于自适应差分量化理论，提出了在不增加转换位数的情况下提高模数转换器(ADC)动态范围的一种设计方法。该方法通过量化输入与预测的差值来获得预测增益，从而扩大ADC的动态范围；通过差分量化值与预测值相加得到输出信号，并将该分别采用LMS和RLS算法进行处理．得到输入信号的预测值．计算机模拟结果证实，上述两种算法均能使模数转换器的动态范围提高约25dB．比较而言，RLS算法收敛速度更快，收敛性更好，但计算量较大．     

高温超导体Josephson阵列在磁场中的微波响应与磁通涡旋激发

本文从分析相变电阻率 ρP 和磁通蠕动电阻率 ρF 出发 ,指出当T小于某一温度T0 时 ,ρF>ρP,而当T >T0 时 ,ρF 远小于 ρP,并进一步分析了 ρF 与 ρP 随温度的变化率分布图 ,得出磁通蠕动电阻率 ρF 随温度的变化率分布图跟微波响应曲线具有相似的分布特征 ,结果表明 :高温超导体的非平衡微波响应机制可能与磁通涡旋的激发有关 .     

An Application of Branch and Cut to Open Pit Mine Scheduling

The economic viability of the modern day mine is highly dependent upon careful planning and management. Declining trends in average ore grades, increasing mining costs and environmental considerations will ensure that this situation will remain in the foreseeable future. The operation and management of a large open pit mine having a life of several years is an enormous and complex task. Though a number of optimization techniques have been successfully applied to resolve some important problems, the problem of determining an optimal production schedule over the life of the deposit is still very much unresolved. In this paper we will critically examine the techniques that are being used in the mining industry for production scheduling indicating their limitations. In addition, we present a mixed integer linear programming model for the scheduling problems along with a Branch and Cut solution strategy. Computational results for practical sized problems are discussed.     

THE STUDY OF SERS EFFECT AND ADSORPTION PROPERTY ON Cu SURFACE FOR PNBA

With different amounts of KCl added in the PNBA(p- nitro benzoic acid) aqueous solution, the factors affecting the SERS (Surface Enhanced Raman Scattering) are studied systematically on the surface of Copper. The results show that in PNBA aqueous solution the occurrence of SERS effect stongly depends on the existence of Cl^-. The amount of KCl added affects not only the emergence and the intensity of SERS effect, but also the adsorption properties such as the adsorption manner,etc.     

Allocating Warehouse Stock in a Retail Chain

The context is that of a retail chain where stock is purchased into a central warehouse from which branch stocks are replenished. This paper considers possible methods of allocating limited warehouse stock to branches, and uses simulation to quantify the resulting benefits.     

Maximin share and minimax envy in fair-division problems

For fair-division or cake-cutting problems with value functions which are normalized positive measures (i.e., the values are probability measures) maximin-share and minimax-envy inequalities are derived for both continuous and discrete measures. The tools used include classical and recent basic convexity results, as well as ad hoc constructions. Examples are given to show that the envy-minimizing criterion is not Pareto optimal, even if the values are mutually absolutely continuous. In the discrete measure case, sufficient conditions are obtained to guarantee the existence of envy-free partitions.