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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.
Emulsions of perfluorotributylamine (FTBA) and perflubron were evaluated for their utility in 19F echo planar imaging. Fluorine images of the emulsions were obtained in a phantom and two mice that had been predosed. Both agents, but particularly perflubron, show potential for fluorine echo planar studies because of the long spin-spin relaxation times of the CF3 resonances. High resolution thin slice images obtained in as little as 26.6 ms are presented. 相似文献
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B. M. Forster J. M. Bailey G. A. Beer J. L. Beveridge J. H. Brewer W. N. Hardy T. M. Huber K. R. Kendall A. R. Kunselman J. A. Macdonald G. M. Marshall G. R. Mason A. Olin M. Senba J. B. Warren 《Hyperfine Interactions》1991,65(1-4):1007-1013
Muonic hydrogen isotopes (μ− p, μ− d, and μ−t) are simple quantum mechanical systems ideally suited for studies of numerous fundamental phenomena in electroweak and strong
interactions as well as in applied areas such as muon chemistry or muon catalyzed fusion.
Emission of muonic hydrogen isotopes into vacuum helps to overcome the limitations which are normally imposed on conventional
investigations with gaseous and liquid targets. A proof of principle experiment for this new technique was performed at TRIUMF
last year. Negative muons with 30 MeV/c momentum were stopped in a thin film of solid hydrogen and produced very low energy μ−d in vacuum. The distribution center of the normal velocity components of emitted μ−d atoms was measured to be ∼1 cm/μs. The yield of μ−d in vacuum is an increasing function of H2 film thickness δ up to a value of δ≥1 mm. 相似文献
6.
We discuss equivalent definitions of holomorphic second-order cusp forms and prove bounds on their Fourier coefficients. We
also introduce their associated L-functions, prove functional equations for twisted versions of these L-functions and establish a criterion for a Dirichlet series to originate from a second order form. In the last section we
investigate the effect of adding an assumption of periodicity to this criterion.
2000 Mathematics Subject Classification Primary—11F12, 11F66
G. Mason: Research supported in part by NSF Grant DMS 0245225.
C. O’Sullivan: Research supported in part by PSC CUNY Research Award No. 65453-00 34. 相似文献
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M. Markytan P. Mason H. Muirhead G. D. Patel 《Zeitschrift fur Physik C Particles and Fields》1989,43(4):557-568
Evidence is presented that \(\bar p\) p annihilation proceeds via the formation of two jets, with average transverse momentum of the order of the nucleon mass. The implications of this behaviour is linked to the measured cross sections and multiplicities, and explanations for it have been sought in the underlying gluon and quark constituents of the \(\bar p\) p system. The confrontation of the suggested constituent mechanisms and experimental data lead to the concept that charm meson production may play a significant role in the \(\bar p\) p experiments at the highest available energies. 相似文献
10.
Gregory N. Coppin Andrew Hudson Richard A. Jackson Nigel P.C. Simmons 《Journal of organometallic chemistry》1977,131(3):371-375
The formation of the compound RSnX(acac)2 (acac = 2,4-pentanedionato) by reaction of bis(2,4-pentanedionato)tin(II) on a halide RX with R = CH3, C2H5, C4H9, C6H5, CH2I, (C6H5)3SnCH2, (C2H5)3SnCH2 and X = I, Br has been studied by polarography. At 25°C, it is in fact an equilibrium whose constant has been measured. The intermediate formation of the ion-pair [RSn(acac)2+X?] has allowed us to explain the experimental results. 相似文献