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.     

Equilibrium point damage prognosis models for structural health monitoring

Most structural dynamic systems are of high order; however, they often exhibit phenomena that can be dealt with effectively using low order models. This paper presents a method for describing certain kinds of damage evolution in mechanical systems. The method relies on a simple principle that as damage evolves in a structural dynamic system, the damage indicator (i.e., diagnostic feature) behaves like a stable quasi-stationary equilibrium point in a subsidiary non-linear bifurcating system within the so-called damage center manifold. It is shown that just as linear normal modes govern the behavior of linear structures with idealized damping, so too do non-linear normal forms govern the evolution of damage within structures in many instances. The method is justified with citations from the literature on certain types of mechanical failure and then applied in an experimental case involving reversible damage in a bolted fastener. Off-line experiments on a rotorcraft fuselage show that the evolution of damage is sensitive to both temporal and spatial bifurcation parameters. A diagnostic sensing strategy whereby output-only transmissibility features are used to decrease the order of high order structural dynamic measurements is also described.     

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.     

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.     

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.