Azasugar inhibitors as pharmacological chaperones for Krabbe disease

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.     

Long-term optimal operation of series parallel reservoirs for critical period with specified monthly generation and average monthly storage

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.     

低频室内声散射计算机模拟方法

近年来,声散射的模拟成为室内声场计算机模拟研究的重点。现有的方法一般是依据壁面性质(结构、粗糙度等),利用经验确定散射系数,并基于该系数来模拟室内散射声能的分布。这种方法在低频情况下的精度较差,主要原因是忽略了在低频声场中起重要作用的波动现象。为此,本文提出一种新的计算壁面散射的模型,该模型既可考虑壁面上产生的散射声能,又可计算因壁面边缘衍射而产生的散射声能。文中通过模拟和实测数据的对比,分析验证了该模型的有效性,并给出了表面散射系数的取值规则。     

Microelectromagnet for magnetic manipulation in lab-on-a-chip systems

We demonstrate a simple scheme for fabrication of microelectromagnets consisting of planar spiral coils semi-encapsulated in soft magnetic yokes using conventional microfabrication techniques. The microelectromagnets are suitable for applications operating at frequencies below 250 kHz. Conventional fabrication schemes for planar microelectromagnets typically rely on five mask steps. We allow the current to flow in the soft magnetic yoke and thereby two mask steps are eliminated. We have characterized the electromagnets electrically, the results agree well with theory, and the implications arising from current flowing in the magnetic yoke are discussed. We have integrated the microelectromagnets with microfluidic channels, and demonstrated separation of commercially available magnetic beads from a fluid in a microfluidic system, i.e. a lab-on-a-chip system.     

Atomistic packing models for experimentally investigated swelling states induced by CO2 in glassy polysulfone and poly(ether sulfone)

Atomistic packing models have been created, which help to better understand the experimentally observed swelling behavior of glassy polysulfone and poly (ether sulfone), under CO₂ gas pressures up to 50 bar at 308 K. The experimental characterization includes the measurement of the time‐dependent volume dilation of the polymer samples after a pressure step and the determination of the corresponding gas concentrations by gravimetric gas‐sorption measurements. The models obtained by force‐field‐based molecular mechanics and molecular dynamics methods allow a detailed atomistic analysis of representative swelling states of polymer/gas systems, with respect to the dilation of the matrix. Also, changes of free volume distribution and backbone mobility are accessible. The behavior of gas molecules in unswollen and swollen polymer matrices is characterized in terms of sorption, diffusion, and plasticization. © 2006 Wiley Periodicals, Inc. J Polym Sci Part B: Polym Phys 44: 1874–1897, 2006     

Methane activation on Ni(1 1 1): Effects of poisons and step defects

We have, theoretically and experimentally, investigated the dissociation of methane on the terraces and steps of a Ni(1 1 1) surface. Using Density Functional Theory (DFT) total energy calculations combined with Ultra High Vacuum (UHV) experiments, we find that the steps exhibit a higher activity than the terraces. We have, furthermore, investigated how carbon and sulfur present on the surface will deactivate the steps, leaving only the terraces active. We find the intrinsic sticking probabilities of methane on the steps and terraces at 500 K to be 2.8 × 10⁻⁷ for the steps and 2.1 × 10⁻⁹ for the terraces, in complete agreement with our calculated difference in activation energy of 17 kJ/mol.     

Specific carbon-13 labelling of leucine residues in human growth hormone.

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.     

Frames and the Feichtinger conjecture

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.