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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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In this Note, we present a result concerning the non existence of linear monotone schema with fixed stencil on regular meshes for some linear parabolic equation in two dimensions. The parabolic equations of interest arise from non isotropic diffusion modelling. A corollary is that no linear monotone 9 points-schemes can be designed for the one-dimensional heat equation emerged in the plane with an arbitrary direction of diffusion. Some applications of this result are provided: for the Fokker–Planck–Lorentz model for electrons in the context of plasma physics; all linear monotone scheme for the one-dimensional hyperbolic heat equation treated as a two-dimensional problem are not consistent in the diffusion limit for an arbitrary direction of propagation. We also examine the case of the Landau equation. To cite this article: C. Buet, S. Cordier, C. R. Acad. Sci. Paris, Ser. I 340 (2005). 相似文献
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Trond Stølen Gustavsen 《Compositio Mathematica》2003,138(2):199-231
We relate the equisingular deformation theory of plane curve singularities and sandwiched surface singularities. We show the existence of a smooth map between the two corresponding deformation functors and study the kernel of this map. In particular we show that the map is an isomorphism when a certain invariant is large enough. 相似文献
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Kerstin Paech Adrian Dumitru Jürgen Schaffner-Bielich Stefan Schramm Horst Stöcker Gebhard Zeeb Detlef Zschiesche 《Acta Physica Hungarica A》2004,21(2-4):151-156
The measured particle ratios in central heavy-ion collisions are investigated within a chemical and thermal equilibrium chiral SU(3) σ?ω approach. Contrary to the commonly adopted non-interacting gas calculations, the chiral SU(3) model predicts modified effective hadron masses and effective chemical potentials in the medium and a transition to a chirally restored phase at high temperatures or chemical potentials. the influence of three different types of phase transitions is investigated. We show that the deduced freeze-out values considerably depend on the underlying model while the quality of the fit is approximately the same. 相似文献
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T. Engel M. Würtz S. Borneis St. Becker I. Klaft A. Kohl T. Kühl F. Laeri D. Marx K. Meier R. Neumann F. Schmitt P. Seelig L. Völker 《Hyperfine Interactions》1997,108(1-3):251-258
Laser spectroscopy at storage rings often suffers from a limited resolution due to Doppler-broadened resonances. Broadening
is caused by the velocity spread of the ions stored in the beam. In the following, the present status of our work on laser
systems specialized on the specific needs of laser spectroscopy at storage rings is reported.
Two pulsed laser systems were developed. One is a dye laser whose spectral bandwidth can be switched by inserting different
Littrow-prisms into the resonator. An increase in bandwidth up to a factor of 45 was achieved. This laser was used for fast
qualitative scans and high resolution measurements. The other laser system is a Nd : YAG laser pumped optical parametric oscillator.
It is a tunable laser system covering the spectral range from 410 to 4000 nm. Furthermore, a continuous wave laser with a
frequency shifted feedback cavity is described. It shows broadband emission with an adjustable bandwidth of up to 4.5 GHz.
This laser can be advantageous for laser cooling of ion beams.
This revised version was published online in August 2006 with corrections to the Cover Date. 相似文献
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