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.     

Resonances in Three-Body Systems Studied by a Full Angular-Momentum, Smooth-Exterior Complex-Scaling Finite-Element Method

 The development of a tool for calculating resonances and bound states in three-body systems described by a single-potential energy surface is reported. The method has been applied to the antiprotonic helium, doubly excited states in helium, the ¹¹Li nuclear halo, the NeICl van der Waals molecule, and the recently found FHD reaction complex. Received November 26, 2001; accepted for publication November 28, 2001     

A highly selective solid phase extraction sorbent for pre-concentration of sameridine made by molecular imprinting

Summary A novel approach to solid phase extraction, based on the use of a highly selective molecularly imprinted polymer, is presented. The versatility of this type of sorbent for solid phase extraction was demonstrated in a model batch-wise pre-concentration of sameridine prior to gas chromatography. Problems associated with leakage of remaining imprint molecules during the desorption phase could be eliminated by the use of a close structural analogue of sameridine as the imprint species. It was found that a major benefit of the imprinted polymer was its specificity, which lead to distinctly cleaner chromatographic traces and ability to improve sensitivity by extracting sameridine from larger sample volumes.     

Decision support tools for ambulance dispatch and relocation

In this paper, the development of decision support tools for dynamic ambulance relocation and automatic ambulance dispatching is described. The ambulance dispatch problem is to choose which ambulance to send to a patient. The dynamic ambulance relocation problem occurs in the operational control of ambulances. The objective is to find new locations for some of the ambulances, to increase the preparedness in the area of responsibility. Preparedness is a way of evaluating the ability to serve potential patients with ambulances now and in the future. Computational tests using a simulation model show that the tools are beneficial in reducing the waiting periods for the patients.     

On the treatment of the pairing interaction in the particle-rotor model

Different ways of treating the pairing interaction in the particle-rotor model are discussed and compared in a model which can be solved exactly. Special attention is paid to the interaction between the yrast and yrare bands as function of the shell filling.     

Modeling plane turbulent Couette flow

Among the salient features of shear-driven plane Couette flow is the constancy of the total shear stress (viscous and turbulent) across the flow. This constancy gives rise to a quasi-homogenous core region, which makes the bulk of the flow substantially different from pressure-driven Poiseuille flow. The present second-moment closure study addresses the conflicting hypotheses relating to turbulent Couette flow. The inclusion of a new wall-proximity function in the wall-reflection part of the pressure-strain model seems mandatory, and the greement with recent experimental and direct numerical simulation (DNS) results is encouraging. Analysis of model computations in the range 750 ≤ Re ≤ 35,000 and comparisons with low-Re DNS data suggest that plane Couette flow exhibits a local-equilibrium core region, in which anisotropic, homogeneous turbulence prevails. However, the associated variation of the mean velocity in the core, as obtained by the model, conflicts with the intuitively appealing assumption of homogeneous mean shear. The constancy of the velocity gradient exhibited by the DNS therefore signals a deficiency in the modeled transport equation for the energy dissipation rate.     

Manifestation of biquadratic coupling in the smectic C* phase soft mode dielectric response

The soft mode dielectric response of three ferroelectric chiral smectic C* substances is studied in the vicinity of the smectic C*-smectic A* phase transition. For some substances the soft mode dielectric strength exhibits a pronounced anomaly in the C* phase just below the phase transition. We show how this anomaly can be systematically correlated with a corresponding anomaly in the experimentally determined ratio of spontaneous polarization over tilt. By comparing the experimental results with the theoretical predictions of an extended Landau model, we demonstrate how the crossover behaviour of the system can be interpreted as being the consequence of the presence of a biquadratic coupling between tilt and polarization in the Landau free-energy of the system.     

Functional calculus for non-commuting operators with real spectra via an iterated Cauchy formula

We define a smooth functional calculus for a non-commuting tuple of (unbounded) operators A_j on a Banach space with real spectra and resolvents with temperate growth, by means of an iterated Cauchy formula. The construction is also extended to tuples of more general operators allowing smooth functional calculii. We also discuss the relation to the case with commuting operators.