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.     

Dendrimers as scaffolds for multifunctional reversible addition–fragmentation chain transfer agents: Syntheses and polymerization

The synthesis and characterization of novel first‐ and second‐generation true dendritic reversible addition–fragmentation chain transfer (RAFT) agents carrying 6 or 12 pendant 3‐benzylsulfanylthiocarbonylsulfanylpropionic acid RAFT end groups with Z‐group architecture based on 1,1,1‐hydroxyphenyl ethane and trimethylolpropane cores are described in detail. The multifunctional dendritic RAFT agents have been used to prepare star polymers of poly(butyl acrylate) (PBA) and polystyrene (PS) of narrow polydispersities (1.4 < polydispersity index < 1.1 for PBA and 1.5 < polydispersity index < 1.3 for PS) via bulk free‐radical polymerization at 60 °C. The novel dendrimer‐based multifunctional RAFT agents effect an efficient living polymerization process, as evidenced by the linear evolution of the number‐average molecular weight (M_n) with the monomer–polymer conversion, yielding star polymers with molecular weights of up to M_n = 160,000 g mol^?1 for PBA (based on a linear PBA calibration) and up to M_n = 70,000 g mol^?1 for PS (based on a linear PS calibration). A structural change in the chemical nature of the dendritic core (i.e., 1,1,1‐hydroxyphenyl ethane vs trimethylolpropane) has no influence on the observed molecular weight distributions. The star‐shaped structure of the generated polymers has been confirmed through the cleavage of the pendant arms off the core of the star‐shaped polymeric materials. © 2004 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 42: 5877–5890, 2004     

Allocating Warehouse Stock in a Retail Chain

The context is that of a retail chain where stock is purchased into a central warehouse from which branch stocks are replenished. This paper considers possible methods of allocating limited warehouse stock to branches, and uses simulation to quantify the resulting benefits.     

Fluoride effect on the palladium–phenanthroline catalyzed carbonylation of nitroarenes to carbamates

Fluorides promote the palladium–phenanthroline catalyzed carbonylation of nitroarenes to carbamates. The effect is more evident on the rate of the reaction at short reaction times, but a positive effect on selectivity is also observed under certain conditions. The effect is observed even under conditions under which chloride inhibits the reaction. Tetraethylammonium is a better countercation than sodium. Copyright © 2007 John Wiley & Sons, Ltd.     

Maximin share and minimax envy in fair-division problems

For fair-division or cake-cutting problems with value functions which are normalized positive measures (i.e., the values are probability measures) maximin-share and minimax-envy inequalities are derived for both continuous and discrete measures. The tools used include classical and recent basic convexity results, as well as ad hoc constructions. Examples are given to show that the envy-minimizing criterion is not Pareto optimal, even if the values are mutually absolutely continuous. In the discrete measure case, sufficient conditions are obtained to guarantee the existence of envy-free partitions.     

Determination of the spin-spin centrifugal distortion parameters for deuterated selenoformaldehyde in its first excited triplet state

Recently-formulated centrifugal distortion corrections to the spin-spin Hamiltonian have been used to analyse the first excited triplet state (ã³A₂) of deuterated selenoformaldehyde. By including six spin-spin centrifugal distortion parameters, it is possible to account for the energy levels of this state using a single set of three rotational constants, A, B, and C, where previously nine spin-dependent parameters were required.