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.     

Rapid convergence of a Galerkin projection of the KdV equation

In this Note, it is shown that a Fourier Galerkin approximation of the Korteweg–de Vries equation with periodic boundary conditions converges exponentially fast if the initial data can be continued analytically to a strip about the real axis. To cite this article: H. Kalisch, C. R. Acad. Sci. Paris, Ser. I 341 (2005).     

Solutions of the WDVV Equations and Integrable Hierarchies of KP Type

We show that reductions of KP hierarchies related to the loop algebra of SL_n with homogeneous gradation give solutions of the Darboux-Egoroff system of PDE's. Using explicit dressing matrices of the Riemann-Hilbert problem generalized to include a set of commuting additional symmetries, we construct solutions of the Witten– Dijkgraaf–E. Verlinde–H. Verlinde equations.     

Representations, convolution square roots and spherical vectors

We extend results on square integrable representations of a locally compact group to subrepresentations of a representations induced from a character of a closed subgroup. We do so working in the framework of quotient representations of ∗-algebras.     

Slow-light enhanced optical detection in liquid-infiltrated photonic crystals

Slow-light enhanced optical detection in liquid-infiltrated photonic crystals is theoretically studied. Using a scattering-matrix approach and the Wigner–Smith delay time concept, we show that optical absorbance benefits both from slow-light phenomena as well as a high filling factor of the energy residing in the liquid. Utilizing strongly dispersive photonic crystal structures, we numerically demonstrate how liquid-infiltrated photonic crystals facilitate enhanced light–matter interactions, by potentially up to an order of magnitude. The proposed concept provides strong opportunities for improving existing miniaturized absorbance cells for optical detection in lab-on-a-chip systems.     

The Remainder in Ruijsenaars’ Asymptotic Expansion of Barnes Double Gamma Function

We show that the remainder in Ruijsenaars’ asymptotic expansion of the logarithm of Barnes double gamma function gives rise to a completely monotone function. Fourier expansions of the multiple Bernoulli polynomials are also obtained. Research supported by the Carlsberg Foundation.     

Self-organized critical pinball machine

The nature of self-organized criticality (SOC) is pin-pointed with a simple mechanical model: a pinball machine. Its phase space is fully parameterized by two integer variables, one describing the state of an on-going game, the other describing the state of the machine. This is the simplest possible SOC system, having only two degrees of freedom and no spatial correlations, yet is not solvable by analytical means.     

Optimal Inventory Policies with Service-Level Constraints

In a practical situation it is often difficult to determine the value of the shortage costs for use in in ventory-control systems. However, in cost-minimization problems including service-level constraints, shortage costs are implicitly prevailing. With the purpose of exploring these relations, a continuous review (Q, r) stock-control system is considered, where the order points and lot sizes are computed simultaneously. Instead of explicitly expressing the shortage cost in the objective function, it is taken into consideration through a service-level constraint. The shadow price of this constraint can in some sense be interpreted as the shortage cost corresponding to the requested service level. By changing the value of the service level, interesting relations between shortage costs and service levels can be viewed for different sets of other inventory parameters. In order to investigate the sensitivity for probabilistic variations in the input data, two different probability distributions are used to describe the lead-time demand.