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排序方式: 共有802条查询结果,搜索用时 15 毫秒
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
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Oil migration in filled chocolates limits shelf life due to texture changes and loss of visual appeal. Spatial and temporal
oil concentration changes of a two-layer chocolate and peanut butter filling system, which models a filled chocolate, were
monitored by magnetic resonance imaging. Formulations of chocolate varied with respect to particle size, milk fat content
and emulsifier level. Sorption-time experimental data was used to establish the best fit diffusion coefficient for a Fickian
diffusion model. On the basis of the comparison of spatial experimental data to the model, Fickian diffusion alone does not
account for oil migration.
Authors' address: Michael J. McCarthy, Department of Food Science and Technology, University of California, One Shields Avenue,
Davis, CA 95616, USA 相似文献
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Using the Ward-Takahashi identity, on-shell condition, bound Dirac equation and off-shell expansion, a reduced version of half off-shell virtual photon nucleon vertex has been suggested. The vertex are decomposed into several different order terms: the on-shell terms, first and second off-shell terms. The off-shell behaviour of the form factors is discussed in the one meson loop model. Using the reduced vertex and parametrized off-shell form factors the quasielastic response functions are calculated for several nuclei at ¦q¦–kf and for56Fe at large ¦q¦ up to 1.14 GeV/c and at ?q2=0.9 (GeV/c)2. The Coulomb sums are evaluated and a comparison of the theoretical prediction with data is given. The off-shell electron nucleon cross section is calculated and compared with the “cc1” off-shell extrapolation. 相似文献
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Jaffe DE Straub PB Adams MR Brown CN Charpak G Cooper WE Crittenden JA Finley DA Glass HD Gray R Hemmi Y Hsiung YB Hubbard JR Jonckheere AM Jöstlein H Kaplan DM Lederman LM Luk KB Maki A Mangeot P McCarthy RL Miyake K Plaag RE Rutherfoord JP Sakai Y Santiard JC Sauli F Smith SR Yoshida T Young KK 《Physical review D: Particles and fields》1989,40(9):2777-2795
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The fluxional molecule Os3(CO)7[P(OMe)3]5 has been prepared from OS3(CO)12 and P(OMe)3 by a combination of thermal and UV irradiation synthetic methods. An investigation by 31P and 13C NMR spectroscopy indicated that the mechanism of fluxionality in this compound probably involves the P(OMe)3 ligand of the Os(CO)3[P(OMe)3] unit moving from one equatorial site to the other via a trigonal twist mechanism. 相似文献
10.
Supercritical fluid chromatography using flameless sulfur chemiluminescence detection has been investigated for the analysis of sulfur compounds in petroleum products. The chromatography and detection system was easy to implement and exhibited good precision, linearity, selectivity, and sensitivity. A minimum detectable limit of 0.3 pg sulfur/s was obtained, and response to sulfur in different sulfur species was nearly equimolar. 相似文献