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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
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We present in this paper an efficient approach for solving the problem of planning the long-term (multiyear) operation of a multireservoir hydroelectric power system for the critical period with a monthly variable load. This load is equal to a certain percentage of the total generation at the end of the year, subject to satisfying a number of constraints on the hydrosystem, using the minimum norm formulation.The proposed method is efficient in computing time and in calculating the total expected benefits from the system during the critical period. Numerical results are reported for a real system in operation consisting of two rivers. Each river has two series reservoirs.This work was supported by the Natural Science and Engineering Research Council of Canada, Grant No. A4146. 相似文献
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Morten Nielsen 《Advances in Computational Mathematics》2007,27(2):195-209
Given a dilation matrix A :ℤd→ℤd, and G a complete set of coset representatives of 2π(A
−Tℤd/ℤd), we consider polynomial solutions M to the equation ∑
g∈G
M(ξ+g)=1 with the constraints that M≥0 and M(0)=1. We prove that the full class of such functions can be generated using polynomial convolution kernels. Trigonometric
polynomials of this type play an important role as symbols for interpolatory subdivision schemes. For isotropic dilation matrices,
we use the method introduced to construct symbols for interpolatory subdivision schemes satisfying Strang–Fix conditions of
arbitrary order.
Research partially supported by the Danish Technical Science Foundation, Grant No. 9701481, and by the Danish SNF-PDE network. 相似文献
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T Christensen E B Jensen F Junker H Dalb?ge F Abildgaard J J Led 《Acta chemica Scandinavica (Copenhagen, Denmark : 1989)》1992,46(1):97-99
Biosynthetic human growth hormone specifically 13C-labelled in the carbonyl positions of all 26 leucine residues has been obtained by recombinant DNA techniques using 13C-labelled leucine and an E. coli strain that requires leucine. It is shown that, on the whole, the labelling is specific with no significant mislabelling as would have been the case had the 13C-labelled leucine been metabolized. 相似文献
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Peter G. Casazza Ole Christensen Alexander M. Lindner Roman Vershynin 《Proceedings of the American Mathematical Society》2005,133(4):1025-1033
We show that the conjectured generalization of the Bourgain-Tzafriri restricted-invertibility theorem is equivalent to the conjecture of Feichtinger, stating that every bounded frame can be written as a finite union of Riesz basic sequences. We prove that any bounded frame can at least be written as a finite union of linearly independent sequences. We further show that the two conjectures are implied by the paving conjecture. Finally, we show that Weyl-Heisenberg frames over rational lattices are finite unions of Riesz basic sequences.
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Morten S. Risager 《Journal of Number Theory》2004,109(1):96-119
We define the counting function for Maass newforms of Hecke congruence groups and calculate the three main terms of this counting function. We then give necessary and sufficient conditions for this expansion to have the same shape as if it were counting eigenvalues related to cocompact surfaces. We relate the result to classical instances of the Jacquet-Langlands correspondence. 相似文献
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A WDM compatible Edge-to-Edge Self-Routed optical packet switched network that simplifies the optical processing is proposed. The system employs all-optical packet label generation and recognition using coded superstructured Fiber Bragg gratings. 相似文献