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.     

Stereocontrolled spirocyclic bislactams derived from pyroglutamic acid

The synthesis of rigid spirocyclic bislactams derived from pyroglutamic acid has been established.     

An Application of Branch and Cut to Open Pit Mine Scheduling

The economic viability of the modern day mine is highly dependent upon careful planning and management. Declining trends in average ore grades, increasing mining costs and environmental considerations will ensure that this situation will remain in the foreseeable future. The operation and management of a large open pit mine having a life of several years is an enormous and complex task. Though a number of optimization techniques have been successfully applied to resolve some important problems, the problem of determining an optimal production schedule over the life of the deposit is still very much unresolved. In this paper we will critically examine the techniques that are being used in the mining industry for production scheduling indicating their limitations. In addition, we present a mixed integer linear programming model for the scheduling problems along with a Branch and Cut solution strategy. Computational results for practical sized problems are discussed.     

Solid Lipid Nanoparticles (SLNs): Preparation and Properties of Calix[4]resorcinarene Derived Systems.

Solid Lipid Nanoparticles (SLNs) have been prepared fromc-2,c-8,c-14,c-20-tetraundecyl-4,6,10,12,16,18,22,24-octahydroxyresorc[4]areneas colloidal suspensions. Photon Correlation Spectroscopy studies revealed aparticle hydrodynamic diameter of 150 nm. Non-contact mode Atomic ForceMicroscopy allows observation of the particles as slightly flattened sphericalobjects of 236 (±40) nm diameter and 145 (±40) nm height. Thestudy of the preparation parameters showed that shear force does not affectthe hydrodynamic size of the SLNs. In contrast, the viscosity and the pH ofthe aqueous phase, the amphiphile concentration in the organic phase and thevolume of organic phase used, all lead to variation in the size of the particles.In term of post preparation parameters only the ionic strength has been shownto affect significantly the particle size; while the pH of the storing solution,microwave, ultrasonic and thermal treatments do not. Short and long-termstability studies have been performed to measure the effect of the ionic strengthon the stability of the particles. The use of carbohydrate cryoprotectants does notallow re-dispersion of the colloidal suspension after freeze-drying.     

Enumeration of three-dimensional convex polygons

A self-avoiding polygon (SAP) on a graph is an elementary cycle. Counting SAPs on the hypercubic lattice ℤ ^d withd≥2, is a well-known unsolved problem, which is studied both for its combinatorial and probabilistic interest and its connections with statistical mechanics. Of course, polygons on ℤ ^d are defined up to a translation, and the relevant statistic is their perimeter. A SAP on ℤ ^d is said to beconvex if its perimeter is “minimal”, that is, is exactly twice the sum of the side lengths of the smallest hyper-rectangle containing it. In 1984, Delest and Viennot enumerated convex SAPs on the square lattice [6], but no result was available in a higher dimension. We present an elementar approach to enumerate convex SAPs in any dimension. We first obtain a new proof of Delest and Viennot's result, which explains combinatorially the form of the generating function. We then compute the generating function for convex SAPs on the cubic lattice. In a dimension larger than 3, the details of the calculations become very cumbersome. However, our method suggests that the generating function for convex SAPs on ℤ ^d is always a quotient ofdifferentiably finite power series.     

Latin Squares without Orthogonal Mates

In 1779 Euler proved that for every even n there exists a latin square of order n that has no orthogonal mate, and in 1944 Mann proved that for every n of the form 4k + 1, k ≥ 1, there exists a latin square of order n that has no orthogonal mate. Except for the two smallest cases, n = 3 and n = 7, it is not known whether a latin square of order n = 4k + 3 with no orthogonal mate exists or not. We complete the determination of all n for which there exists a mate-less latin square of order n by proving that, with the exception of n = 3, for all n = 4k + 3 there exists a latin square of order n with no orthogonal mate. We will also show how the methods used in this paper can be applied more generally by deriving several earlier non-orthogonality results.