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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.
The synthesis of rigid spirocyclic bislactams derived from pyroglutamic acid has been established. 相似文献
3.
Sven Walter 《Acta Analytica》2005,20(3):32-47
Frank Jackson and Philip Pettit have defended a non-reductive account of causal relevance known as the ‘program explanation
account’. Allegedly, irreducible mental properties can be causally relevant in virtue of figuring in non-redundant program explanations which convey information not conveyed by explanations in terms of the physical properties that actually do the ‘causal work’.
I argue that none of the possible ways to spell out the intuitively plausible idea of a program explanation serves its purpose,
viz., defends non-reductive physicalism against Jaegwon Kim’s Causal Exclusion Argument according to which non-reductive physicalism is committed to epiphenomenalism because irreducible mental properties are ‘screened
off’ from causal relevance by their physical realizers. Jackson and Pettit’s most promising explication of a program explanation
appeals to the idea of invariance of effect under variation of realization, but I show that invariance of effect under variation of realization is neither necessary nor sufficient for causal relevance. 相似文献
4.
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
5.
6.
7.
Received December 31, 2001 / Published online May 21, 2002 相似文献
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.
Velislava A Ignatova Sven Van Den Berghe Steven Van Dyck Vladimir N Popok 《Microscopy and microanalysis》2006,12(5):432-437
The oxide scales of AISI 304 formed in boric acid solutions at 300 degrees C and pH = 4.5 have been studied using X-ray photoelectron spectroscopy (XPS) depth profiling. The present focus is depth profile quantification both in depth and chemical composition on a molecular level. The roughness of the samples is studied by atomic force microscopy before and after sputtering, and the erosion rate is determined by measuring the crater depth with a surface profilometer and vertical scanning interferometry. The resulting roughness (20-30 nm), being an order of magnitude lower than the crater depth (0.2-0.5 microm), allows layer-by-layer profiling, although the ion-induced effects result in an uncertainty of the depth calibration of a factor of 2. The XPS spectrum deconvolution and data evaluation applying target factor analysis allows chemical speciation on a molecular level. The elemental distribution as a function of the sputtering time is obtained, and the formation of two layers is observed-one hydroxide (mainly iron-nickel based) on top and a second one deeper, mainly consisting of iron-chromium oxides. 相似文献
10.
Marco Dall'Aglio Theodore P. Hill 《Journal of Mathematical Analysis and Applications》2003,281(1):346-361
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. 相似文献