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.     

A convenient synthetic route to new bis(arenediazo) complexes of molybdenum and tungsten

Complexes of the type [(C₅H₅)Mo(N₂Ar)(N₂Ar′)(PPh₃)] [PF₆] have been prepared and shown to be useful starting materials for the synthesis of a variety of neutral, cationic or anionic compounds containing [cis-Mo(N₂Ar)(N₂Ar′)]²⁺ units.     

The Relationship Between Stock Markets Of Major Developed Countries And Asian Emerging Markets

With the emergence of new capital markets and liberalization of stock markets in recent years, there has been an increase in investors' interest in international diversification. This is so because international diversification allows investors to have a larger basket of foreign securities to choose from as part of their portfolio assets, so as to enhance the reward-to-volatility ratio. This benefit would be limited if national equity markets tend to move together in the long run. This paper thus studies the issue of co-movement between stock markets in major developed countries and those in Asian emerging markets using the concept of cointegration. We find that there is co-movement between some of the developed and emerging markets, but some emerging markets do differ from the developed markets with which they share a long-run equilibrium relationship. Furthermore, it has been observed that there has been increasing interdependence between most of the developed and emerging markets since the 1987 Stock Market Crash. This interdependence intensified after the 1997 Asian Financial Crisis. With this phenomenon of increasing co-movement between developed and emerging stock markets, the benefits of international diversification become limited.     

Arnol’d tongues for a resonant injection-locked frequency divider: Analytical and numerical results

In this paper we consider a resonant injection-locked frequency divider which is of interest in electronics, and we investigate the frequency locking phenomenon when varying the amplitude and frequency of the injected signal. We study both analytically and numerically the structure of the Arnol’d tongues in the frequency–amplitude plane. In particular, we provide exact analytical formulae for the widths of the tongues, which correspond to the plateaux of the devil’s staircase picture. The results account for numerical and experimental findings presented in the literature for special driving terms and, additionally, extend the analysis to a more general setting.     

Self-injection length in La0.7Ca0.3MnO3-YBa2Cu3O7-δ ferromagnet-superconductor multilayer thin films

We have carried out extensive studies on the self-injection problem in barrierless heterojunctions between La_0.7Ca_0.3MnO₃ (LCMO) and YBa₂Cu₃O_7-δ (YBCO) thin films. The heterojunctions were formed in situ by sequentially growing LCMO and YBCO films on 〈100〉 LaAlO₃ (LAO) substrate using a pulsed laser deposition (PLD) system. YBCO micro-bridges with 64 μm width were patterned both on the LAO (control) and LCMO side of the substrate. Critical current, I _c, was measured at 77 K on both the control side as well as the LCMO side for different YBCO film thickness. It was observed that while the control side showed a J _c of ∼ 2 × 10⁶ A/cm², the LCMO side showed about half the value for the same thickness (1800 ?). The difference in J _c indicates that a certain thickness of YBCO has become ‘effectively’ normal due to self-injection. From the measurement of J _c at two different thicknesses (1800 ? and 1500 ?) of YBCO films both on the LAO as well as the LCMO side, the value of self-injection length (at 77 K) was estimated to be ∼ 900 ?. To the authors’ best knowledge, this is the first time that self-injection length has been quantified. A control experiment carried out with LaNiO₃ deposited by PLD on YBCO did not show any evidence of self-injection.     

The acoustic signature of bubbles fragmenting in sheared flow

Measurements of the sound of bubbles fragmenting in fluid shear are presented and analyzed. The frequency, amplitude, and decay rate of the acoustic emissions from 1.8-mm-radius bubbles fragmenting between opposed fluid jets have been determined. A broad band of frequencies (1.8 to 30 kHz) is observed with peak pressure amplitudes in the range of 0.03 to 2 Pa. While the peak pressure amplitudes show no significant scaling with frequency, the frequency dependence of the decay rates is consistent with the sum of thermal and acoustic radiation losses.     

Orlicz projection bodies

Minkowski's projection bodies have evolved into Lp projection bodies and their asymmetric analogs. These all turn out to be part of a far larger class of Orlicz projection bodies. The analog of the classical Petty projection inequality is established for the new Orlicz projection bodies.     

NeuroGenetic approach for combinatorial optimization: an exploratory analysis

Given the NP-Hard nature of many optimization problems, it is often impractical to obtain optimal solutions to large-scale problems in reasonable computing time. For this reason, heuristic and metaheuristic search approaches are used to obtain good solutions fast. However, these techniques often struggle to develop a good balance between local and global search. In this paper we propose a hybrid metaheuristic approach which we call the NeuroGenetic approach to search for good solutions for these large scale optimization problems by at least partially overcoming this challenge. The proposed NeuroGenetic approach combines the Augmented Neural Network (AugNN) and the Genetic Algorithm (GA) search approaches by interleaving the two. We chose these two approaches to hybridize, as they offer complementary advantages and disadvantages; GAs are very good at searching globally, while AugNNs are more proficient at searching locally. The proposed hybrid strategy capitalizes on the strong points of each approach while avoiding their shortcomings. In the paper we discuss the issues associated with the feasibility of hybridizing these two approaches and propose an interleaving algorithm. We also provide empirical evidence demonstrating the effectiveness of the proposed approach.