The mdx mouse, a model of the human disease Duchenne muscular dystrophy, has skeletal muscle fibres which display incompletely understood impaired contractile function. We explored the possibility that action potential-evoked Ca 2+ release is altered in mdx fibres. Action potential-evoked Ca 2+ -dependent fluorescence transients were recorded, using both low and high affinity Ca 2+ indicators, from enzymatically isolated fibres obtained from extensor digitorum longus (EDL) and flexor digitorum brevis (FDB) muscles of normal and mdx mice. Fibres were immobilized using either intracellular EGTA or N -benzyl-p-toluene sulphonamide, an inhibitor of the myosin II ATPase. We found that the amplitude of the action potential-evoked Ca 2+ transients was significantly decreased in mdx mice with no measured difference in that of the surface action potential. In addition, Ca 2+ transients recorded from mdx fibres in the absence of EGTA also displayed a marked prolongation of the slow decay phase. Model simulations of the action potential-evoked transients in the presence of high EGTA concentrations suggest that the reduction in the evoked sarcoplasmic reticulum Ca 2+ release flux is responsible for the decrease in the peak of the Ca 2+ transient in mdx fibres. Since the myoplasmic Ca 2+ concentration is a critical regulator of muscle contraction, these results may help to explain the weakness observed in skeletal muscle fibres from mdx mice and, possibly, Duchenne muscular dystrophy patients.

Using a two-microelectrode voltage clamp technique, we investigated possible mechanisms underlying the impaired excitation-contraction coupling in skeletal muscle fibres of the mdx mouse, a model of the human disease Duchenne muscular dystrophy. We evaluated the role of the transverse tubular system (T-system) by using the potentiometric indicator di-8 ANEPPS, and that of the sarcoplasmic reticulum (SR) Ca 2+ release by measuring Ca 2+ transients with a low affinity indicator in the presence of high EGTA concentrations under voltage clamp conditions. We observed minimal differences in the T-system structure and the T-system electrical propagation was not different between normal and mdx mice. Whereas the maximum Ca 2+ release elicited by voltage pulses was reduced by ∼67% in mdx fibres, in agreement with previous results obtained using AP stimulation, the voltage dependence of SR Ca 2+ release was identical to that seen in normal fibres. Taken together, our data suggest that the intrinsic ability of the sarcoplasmic reticulum to release Ca 2+ may be altered in the mdx mouse.

Rationale Atrial fibrillation (AF) is a complex disease with multiple interrelating causes culminating in rapid, seemingly disorganized atrial activation. Therapy targeting AF is rapidly changing and improving. Objective The purpose of this review is to summarize current state-of-the-art diagnostic and therapeutic modalities for treatment of atrial fibrillation. The review focuses on reviewing treatment as it relates to the pathophysiological basis of disease and reviews pre-clinical and clinical evidence for potential new diagnostic and therapeutic modalities, including imaging, biomarkers, pharmacologic therapy as well as ablative strategies for AF. Conclusions Current ablation and drug therapy approaches to treating AF are largely based on treating the arrhythmia once the substrate occurs and is more effective in paroxysmal AF rather than persistent or permanent AF. However, there is much research aimed at prevention strategies, targeting AF substrate—so called upstream therapy. Improved diagnostics, using imaging, genetics and biomarkers are needed to better identify sub-types of AF based on underlying substrate/mechanism to allow more directed therapeutic approaches. In addition, novel anti-arrhythmics with more atrial specific effects may reduce limiting pro-arrhythmic side-effects. Advances in ablation therapy are aimed at improving technology to reduce procedure time and in mechanism targeted approaches.

Antibody solutions are typically much more viscous than solutions of globular proteins at equivalent volume fraction. Here we propose that this is due to molecular entanglements that are caused by the elongated shape and intrinsic flexibility of antibody molecules. We present a simple theory in which the antibodies are modeled as linear polymers that can grow via reversible bonds between the antigen binding domains. This mechanism explains the observation that relatively subtle changes to the interparticle interaction can lead to large changes in the viscosity. The theory explains the presence of distinct power law regimes in the concentration dependence of the viscosity as well as the correlation between the viscosity and the charge on the variable domain in our anti-streptavidin IgG 1 model system.

This paper is a short summary of the first real world detection of a backdoor in a military grade FPGA. Using an innovative patented technique we were able to detect and analyse in the first documented case of its kind, a backdoor inserted into the Actel/Microsemi ProASIC3 chips for accessing FPGA configuration. The backdoor was found amongst additional JTAG functionality and exists on the silicon itself, it was not present in any firmware loaded onto the chip. Using Pipeline Emission Analysis (PEA), our pioneered technique, we were able to extract the secret key to activate the backdoor, as well as other security keys such as the AES and the Passkey. This way an attacker can extract all the configuration data from the chip, reprogram crypto and access keys, modify low-level silicon features, access unencrypted configuration bitstream or permanently damage the device. Clearly this means the device is wide open to intellectual property (IP) theft, fraud, reprogramming as well as reverse engineering of the design which allows the introduction of a new backdoor or Trojan. Most concerning, it is not possible to patch the backdoor in chips already deployed, meaning those using this family of chips have to accept the fact they can be easily compromised or will have to be physically replaced after a redesign of the silicon itself.

Disaccharides have a greater effect on the solution viscosity at high protein concentrations compared to monosaccharides. The effect may be explained by commonly accepted mechanisms of interactions between sugar and protein molecules in solution.

No abstract

No abstract