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.     

Reply to “Comment on papers by K. Shanahan that propose to explain anomalous heat generated by cold fusion”, E. Storms, Thermochim. Acta, 2006

Dr. E. Storms has published a Letter [E. Storms, Comment on papers by K. Shanahan that propose to explain anomalous heat generated by cold fusion, Thermochim. Acta, 2006] in which he argues that in a sequence of recent papers, the apparent excess heat signal claimed by Dr. Shanahan to arise from a calibration constant shift is actually true excess heat. In particular he proposes that the mechanisms proposed that foster the proposed calibration constant shifts cannot occur as postulated for several reasons. As well, he proposes Shanahan has ignored the extant data proving this. Because this Letter may lend unwarranted support to acceptance of cold fusion claims, these erroneous arguments used by Storms need to be answered.     

The role of emitter quasi-bound state and scattering on intrinsic bistability in resonant tunneling diodes

Usually, numerical self-consistent calculations predict a much larger intrinsic bistability region than actually is measured in resonant tunneling diodes (RTDs). In addition, numerical calculations have shown that scattering in the well reduces bistability. We used a unified treatment of current flowing from continuum states and emitter quasi-bound states to show numerically and analytically that not only the scattering in the quantum well but also the scattering in the emitter reduces bistability. Moreover, within the Hartree approximation, bistability occurs by tunneling resonantly between emitter quasi-bound state and well quasi-bound state as a pitchfork bifurcation.     

Evaluating the equivalence of verbal scales and question stems to be used in English and Japanese noise annoyance questions

Two experiments were conducted to evaluate the equivalence of noise annoyance scales and questions recommended by Team 6 (Community Response to Noise) of ICBEN for English and Japanese, two strikingly different languages. The first experiment was conducted with bilingual subjects in order to test a key assumption of the method established by ICBEN Team 6 for the development of equivalent noise annoyance scales: subjects who speak different languages interpret the concept of “highest degree” of annoyance similarly. The results indicate that English- and Japanese-speaking subjects do interpret the “highest degree” similarly. The second experiment tested for effects of wording differences. English- and Japanese-speaking subjects were presented with noise annoyance questions of one of three format types. The first type was similar to the question format recommended by ICBEN Team 6. It focused on the degree to which a given noise would “bother, disturb, or annoy” the subject. The second asked subjects to evaluate the “bothersome, annoying, or disturbing” quality of the noise. The third asked how much the noise would “worry, irritate, or concern” the subject. No significant difference was found in responses to the three formats when subjects evaluated noise in laboratory conditions.     

Online weighted flow time and deadline scheduling

In this paper we study some aspects of weighted flow time. We first show that the online algorithm Highest Density First is an O(1)-speed O(1)-approximation algorithm for P|r_i,pmtn|∑w_iF_i. We then consider a related Deadline Scheduling Problem that involves minimizing the weight of the jobs unfinished by some unknown deadline D on a uniprocessor. We show that any c-competitive online algorithm for weighted flow time must also be c-competitive for deadline scheduling. We then give an O(1)-competitive algorithm for deadline scheduling.     

Diethoxyphosphinyl acetic acid hydrazide: a uniquely versatile reagent for the preparation of fused [5,5]-, [5,6]-, and [5,7]-3-[(E)-2-(arylvinyl)]-1,2,4-triazoles

Diethoxyphosphinyl acetic acid hydrazide is a unique reagent that provides a convenient and efficient process to prepare fused [5,5]-, [5,6]-, and [5,7]-3-[(E)-2-(arylvinyl)]-1,2,4-triazoles from aldehydes and alkoxyimines. The process involves three steps without isolation of any intermediates to afford 1,2,4-triazoles in modest to excellent overall yield.