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.     

Crosstalk between microstrip transmission lines

Methods for prediction of crosstalk between microstrip transmission lines are reviewed and simplified for the weak-coupling case. Classical coupled transmission line theory is used for uniform lines, and potential and induced EMF methods are used for crosstalk between nonuniform lines. It is shown that the potential method is equivalent to classical coupled transmission line theory for the case of uniform lines. An experiment was performed for uniform coupled microstrip lines for frequencies from 50 MHz to 5 GHz, and good agreement between theory and measurement was obtained for both near- and far-end crosstalk     

Stereocontrolled spirocyclic bislactams derived from pyroglutamic acid

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

Global Asymptotical Synchronization of Chaotic Lur'e Systems Using Sampled Data: A Linear Matrix Inequality Approach

Sampled-data feedback control for master-slave synchronization schemes that consist of identical chaotic Lur'e systems is studied. Sufficient conditions for global asymptotic synchronization of such chaotic Lur'e systems are obtained using the free-weighting matrix approach and expressed in terms of linear matrix inequalities (LMIs). With the help of the LMI solvers, the sampled-data feedback control law can easily be obtained to globally asymptotically synchronize Lur'e chaotic systems. The effectiveness of the proposed method is finally illustrated via numerical simulations of chaotic Chua's circuits.     

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.     

Intermittent Phenomena in Switched Systems With High Coupling Strengths

In this paper, one kind of intermittency generated by a discontinuous system is studied. Although this system, which is composed of two switched subsystems coupled with a high strength, is nonsmooth, the mechanism of this kind of intermittency can be analyzed with several explicit relations between the intermittency characteristics and the system control parameters. In particular, estimates of "steady-state" values of the system (in the laminar phases) and a critical value for this intermittency can be derived, which are helpful in relevant control systems design. Moreover, some power laws for the observed intermittency are obtained and discussed