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1.
Chris H. Hill Agnete H. Viuff Samantha J. Spratley Stéphane Salamone Stig H. Christensen Randy J. Read Nigel W. Moriarty Henrik H. Jensen Janet E. Deane 《Chemical science》2015,6(5):3075-3086
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. 相似文献
2.
在1100℃制备了钙钛矿型非计量系列物Sr_(1-x)Bi_xFeO_(3-y),与文献相比,明显具有温度低、时间短、能耗少的特点。用化学分析方法测得其化学式及Fe离子的平均价态,用XRD、交流阻抗、IR、Mossbauer谱等方法研究了其结构与性质,该类化合物具有Pm3m对称性和半导体性质,铁离子会产生电荷歧化现象。 相似文献
3.
The synthesis of rigid spirocyclic bislactams derived from pyroglutamic acid has been established. 相似文献
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5.
甲基对硫磷的快速测定及电化学性质 总被引:3,自引:2,他引:1
研究了杀虫剂甲基对硫磷的电化学性质。在pH10.38的Bdtton—Robinson缓冲溶液中,采用微分脉冲溶出伏安法在悬汞电极上得到一个还原峰,峰电位为-0.5V(vs.Ag/AgCl),本工作对实验条件进行了深入的研究,结合线性扫描伏安法等手段。研究了体系的电化学行为。实验表明,甲基对硫磷在汞电极上具有吸附性,电极反应具有不可逆性。该法用于水果及水样中甲基对硫磷残余量的测定,结果满意。 相似文献
6.
An Application of Branch and Cut to Open Pit Mine Scheduling 总被引:5,自引:0,他引:5
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. 相似文献
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8.
Roger M. Hill 《The Journal of the Operational Research Society》1989,40(11):983-992
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. 相似文献
9.
The nonradiative recombination effect on carrier dynamics in GalnNAs/GaAs quantum wells is studied by timeresolved photoluminescence (TRPL) and polarization-dependent TRPL at various excitation intensities. It is found that both recombination dynamics and spin relaxation dynamics strongly depend on the excitation intensity. Under moderate excitation intensities the PL decay curves exhibit unusual non-exponential behaviour. This result is well simulated by a rate equation involving both the radiative and non-radiative recombinations via the introduction of a new parameter of the effective concentration of nonradiative recombination centres in the rate equation. In the spin dynamics study, the spin relaxation also shows strong excitation power dependence. Under the high excitation power an increase of spin polarization degree with time is observed. This new finding provides a useful hint that the spin process can be controlled by excitation power in GaInNAs systems. 相似文献
10.
用微分脉冲溶出伏安法研究了镍(11)与酸性铬兰K(ACBK)所生成的络合物在悬汞电极上的电化学特性及电化学反应机理,发现电极反应为镍与酸性铬兰K所生成的络合物吸附在电极表面后发生的不可逆还原。在HCl-硼砂介质中(pH8.67),络合物在-316mV处有一吸附还原峰,其峰电流与镍浓度在0.001~0.010μ/mL范围内呈现良好的线性关系,其最低检出浓度为0.0005μg/mL。 相似文献