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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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TGA, DTA and DSC analyses indicate that benzotriazole is significantly more stable thermally than 1,2,3-triazole. 相似文献
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Charles J. Colbourn Sosina S. Martirosyan Gary L. Mullen Dennis Shasha George B. Sherwood Joseph L. Yucas 《组合设计杂志》2006,14(2):124-138
A covering array CA(N;t,k, v is an N × k array such that every N × t subarray contains all t‐tuples from v symbols at least once, where t is the strength of the array. Covering arrays are used to generate software test suites to cover all t‐sets of component interactions. The particular case when t = 2 (pairwise coverage) has been extensively studied, both to develop combinatorial constructions and to provide effective algorithmic search techniques. In this paper, a simple “cut‐and‐paste” construction is extended to covering arrays in which different columns (factors) admit different numbers of symbols (values); in the process an improved recursive construction for covering arrays with t = 2 is derived. © 2005 Wiley Periodicals, Inc. J Combin Designs 14: 124–138, 2006 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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Morey Timothy E. Varshney Manoj Flint Jason A. Seubert Christoph N. Smith W. Brit Bjoraker David G. Shah Dinesh O. Dennis Donn M. 《Journal of nanoparticle research》2004,6(2):159-170
Background: Although microemulsion-based nanoparticles (MEs) may be useful for drug delivery or scavenging, these benefits must be balanced against potential nanotoxicological effects in biological tissue (bio-nano interface). We investigated the actions of assembled MEs and their individual components at the bio-nano interface of thrombosis and hemolysis in human blood.
Methods: Oil-in-water MEs were synthesized using ethylbutyrate, sodium caprylate, and pluronic F-68 (ME4) or F-127 (ME6) in 0.9% NaClw/v. The effects of MEs or components on thrombosis were determined using thrombo-elastography, platelet contractile force, clot elastic modulus, and platelet counting. For hemolysis, ME or components were incubated with erythrocytes, centrifuged, and washed for measurement of free hemoglobin by spectroscopy.
Results and conclusions: The mean particle diameters (polydispersity index) for ME6 and ME4 were 23.6 ± 2.5 nm (0.362) and 14.0 ± 1.0 nm (0.008), respectively. MEs (0, 0.03, 0.3, 3 mM) markedly reduced the thromboelastograph maximal amplitude in a concentration-dependent manner (49.0 ± 4.2, 39.0 ± 5.6, 15.0 ± 8.7, 3.8 ± 1.3 mm, respectively), an effect highly correlated (r2 = 0.94) with similar changes caused by pluronic surfactants (48.7 ± 10.9, 30.7 ± 15.8, 20.0 ± 11.3, 2.0 ± 0.5) alone. Neither oil nor sodium caprylate alone affected the thromboelastograph. The clot contractile force was reduced by ME (27.3 ± 11.1–6.7 ± 3.4 kdynes/cm2, P = 0.02, n = 5) whereas the platelet population not affected (175 ± 28–182 ± 23 106/ml, P = 0.12, n = 6). This data suggests that MEs reduced platelet activity due to associated pluronic surfactants, but caused minimal changes in protein function necessary for coagulation. Although pharmacological concentrations of sodium caprylate caused hemolysis (EC50 = 213 mM), MEs and pluronic surfactants did not disrupt erythrocytes. Knowledge of nanoparticle activity and potential associated nanotoxicity at this bio-nano interface enables rational ME design for in vivo applications. 相似文献
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Reduced rank regression assumes that the coefficient matrix in a multivariate regression model is not of full rank. The unknown rank is traditionally estimated under the assumption of normal responses. We derive an asymptotic test for the rank that only requires the response vector have finite second moments. The test is extended to the nonconstant covariance case. Linear combinations of the components of the predictor vector that are estimated to be significant for modelling the responses are obtained. 相似文献