A novel deletion mutation in GJB1 causes X-linked Charcot-Marie-Tooth disease in a Han Chinese family.

X-linked Charcot-Marie-Tooth disease CMT (CMTX) is predominantly caused by mutations in the GJB1 gene that encode connexin32. We describe the clinical findings and the identification of a novel mutation in GJB1 in a large Han Chinese family with CMTX. Linkage to GJB1 was determined by genotyping five polymorphic markers flanking GJB1. Sequence alterations were determined by directly sequencing the coding region of the GJB1 gene. The affected members have variable clinical manifestations. Linkage analysis confirmed the cosegregation of the disease with the GJB1 locus. Sequencing of the GJB1 gene revealed a 1-basepair deletion (c.110delT) in the coding region. The frameshift begins at amino acid 37 and generates a premature stop codon at position 83. The shortened peptide is unlikely to be functional, as it lacks most of the functional domains. The CMTX in this family is caused by a novel loss of function mutation.

Biophysical characterization of styryl dye-membrane interactions.

Styryl dyes (also referred to as FM dyes) become highly fluorescent upon binding to membranes and are often used to study synaptic vesicle recycling in neurons. To date, however, no direct comparisons of the fluorescent properties, or time-resolved (millisecond) measurements of dye-membrane binding and unbinding reactions, for all members of this family of probes have been reported. Here, we compare the fluorescence intensities of each member of the FM dye family when bound to membranes. This analysis included SGC5, a new lipophilic fluorescent dye with a unique structure. Fluorescence intensities depended on the length of the lipophilic tail of each dye, with a rank order as follows: SGC5 > FM1-84 > FM1-43 > SynaptoGreen C3 > FM2-10/FM4-64/FM5-95. Stopped-flow measurements revealed that dye hydrophobicity determined the affinity and departitioning rates for dye-membrane interactions. All of the dyes dissociated from membranes on the millisecond timescale, which is orders of magnitude faster than the overall destaining rate (timescale of seconds) of these dyes from presynaptic boutons. Departitioning kinetics were faster at higher temperatures, but were unaffected by pH or cholesterol. The data reported here aid interpretation of dye-release kinetics from single synaptic vesicles, and indicate that these probes dissociate from membranes on more rapid timescales than previously appreciated.

Design, synthesis, and evaluation of multitarget-directed selenium-containing clioquinol derivatives for the treatment of Alzheimer's disease.

A series of selenium-containing clioquinol derivatives were designed, synthesized, and evaluated as multifunctional anti-Alzheimer's disease (AD) agents. In vitro examination showed that several target compounds exhibited activities such as inhibition of metal-induced Aß aggregation, antioxidative properties, hydrogen peroxide scavenging, and the prevention of copper redox cycling. A parallel artificial membrane permeation assay indicated that selenium-containing clioquinol derivatives possessed significant blood-brain barrier (BBB) permeability. Compound 8a, with a propynylselanyl group linked to the oxine, demonstrated higher hydrogen peroxide scavenging and intracellular antioxidant activity than clioquinol. Furthermore, 8a exhibited significant inhibition of Cu(II)-induced Aß1-42 aggregation and was capable of disassembling the preformed Cu(II)-induced Aß aggregates. Therefore, 8a is an excellent multifunctional promising compound for development of novel drugs for AD.

Long tethers binding redox centers to polymer backbones enhance electron transport in enzyme "Wiring" hydrogels.

A redox hydrogel with an apparent electron diffusion coefficient (D(app)) of (5.8 +/- 0.5) x 10(-)(6) cm(2) s(-)(1) is described. The order of magnitude increase in D(app) relative to previously studied redox hydrogels results from the tethering of redox centers to the backbone of the cross-linked redox polymer backbone through 13 atom spacer arms. The long and flexible tethers allow the redox centers to sweep electrons from large-volume elements and to collect electrons of glucose oxidase efficiently. The spacer arms make the collection of electrons from glucose oxidase so efficient that glucose is electrooxidized already at -0.36 V versus Ag/AgCl, the reversible potential of the redox potential of the FAD/FADH(2) centers of the enzyme at pH 7.2. The limiting current density of 1.15 mA cm(-)(2) is reached at a potential as low as -0.1 V versus Ag/AgCl. The novel redox center of the polymer is a tris-dialkylated N,N'-biimidazole Os(2+/3+) complex. Its redox potential, -0.195 V versus Ag/AgCl, is 0.8 V reducing relative to that of Os(bpy)(2+/3+), its 2,2'-bipyridine analogue.

A miniature biofuel cell operating in a physiological buffer.

A glucose-O2 biofuel cell, consisting only of two electrocatalyst coated 7-mum diameter, 2-cm long carbon fibers is reported. The cell operated continuously at 0.52 V at 37 degrees C in a physiological buffer solution for a week, producing 1.9 muW during the first and 1.0 muW during the last day, generating in the period 0.9 J of electrical energy while passing a charge of 1.7 C. If a similar dimension zinc fiber were utilized in a battery at 100% current efficiency, only 0.016 C would have been generated.