A calcium sensor in the sodium channel modulates cardiac excitability.

Sodium channels are principal molecular determinants responsible for myocardial conduction and maintenance of the cardiac rhythm. Calcium ions (Ca2+) have a fundamental role in the coupling of cardiac myocyte excitation and contraction, yet mechanisms whereby intracellular Ca2+ may directly modulate Na channel function have yet to be identified. Here we show that calmodulin (CaM), a ubiquitous Ca2+-sensing protein, binds to the carboxy-terminal 'IQ' domain of the human cardiac Na channel (hH1) in a Ca2+-dependent manner. This binding interaction significantly enhances slow inactivation-a channel-gating process linked to life-threatening idiopathic ventricular arrhythmias. Mutations targeted to the IQ domain disrupted CaM binding and eliminated Ca2+/CaM-dependent slow inactivation, whereas the gating effects of Ca2+/CaM were restored by intracellular application of a peptide modelled after the IQ domain. A naturally occurring mutation (A1924T) in the IQ domain altered hH1 function in a manner characteristic of the Brugada arrhythmia syndrome, but at the same time inhibited slow inactivation induced by Ca2+/CaM, yielding a clinically benign (arrhythmia free) phenotype.     

Simple scaling relations in geodynamics： the role of pressure in mantle convection and plume formation

Scaling relations are important in extrapolating laboratory experiments to the Earth‘s mantle. In planetary interiors, compression becomes an important parameter and it is useful to explore scalings that involve volume. I use simple volume scaling relations that allow one to extrapolate laboratory experiments and upper mantle behavior, in a thermodynamically self-consistent way, to predict lower mantle behavior. The relations are similar to the quasi-har-monic approximation. Slabs and plates have characteristic dimensions of hundreds of kilometers and time constants of 100 million years, but the volume scalings predict order of magnitude higher values in the deep mantle. The scaling relations imply that the deep mantle is a sluggish system with ancient features. They imply irreversible chemical stratification and do not favor the plume hypothesis.     

Activation of stress signalling pathways enhances tolerance of fungi to chemical fungicides and antifungal proteins

Fungal disease is an increasing problem in both agriculture and human health. Treatment of human fungal disease involves the use of chemical fungicides, which generally target the integrity of the fungal plasma membrane or cell wall. Chemical fungicides used for the treatment of plant disease, have more diverse mechanisms of action including inhibition of sterol biosynthesis, microtubule assembly and the mitochondrial respiratory chain. However, these treatments have limitations, including toxicity and the emergence of resistance. This has led to increased interest in the use of antimicrobial peptides for the treatment of fungal disease in both plants and humans. Antimicrobial peptides are a diverse group of molecules with differing mechanisms of action, many of which remain poorly understood. Furthermore, it is becoming increasingly apparent that stress response pathways are involved in the tolerance of fungi to both chemical fungicides and antimicrobial peptides. These signalling pathways such as the cell wall integrity and high-osmolarity glycerol pathway are triggered by stimuli, such as cell wall instability, changes in osmolarity and production of reactive oxygen species. Here we review stress signalling induced by treatment of fungi with chemical fungicides and antifungal peptides. Study of these pathways gives insight into how these molecules exert their antifungal effect and also into the mechanisms used by fungi to tolerate sub-lethal treatment by these molecules. Inactivation of stress response pathways represents a potential method of increasing the efficacy of antifungal molecules.     

For whom the bell tolls? DING proteins in health and disease

DING proteins, identified mainly by their eponymous N-terminal sequences, are ubiquitous in living organisms. Amongst bacteria, they are common in pseudomonads, and have been characterised with respect to genetics and structure. They form part of a wider family of phosphate-binding proteins, with emerging roles in phosphate acquisition and pathogenicity. Many DING proteins have been isolated in eukaryotes, in which they have been associated with very diverse biological activities, often in the context of possible signalling roles. Disease states in which DING proteins have been implicated include rheumatoid arthritis, lithiasis, atherosclerosis, some tumours and tumour-associated cachexia, and bacterial and viral adherence. Complete genetic and structural characterisation of eukaryotic DING genes and proteins is still lacking, though the phosphate-binding site seems to be conserved. Whether as bacterial proteins related to bacterial pathogenicity, or as eukaryotic components of biochemical signalling systems, DING proteins require further study. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Magnetoelectrics: is CdCr2S4 a multiferroic relaxor?

Materials showing simultaneous ferroelectric and magnetic ordering are attracting a great deal of interest because of their unusual physics and potential applications. Hemberger et al. have reported relaxor-like dielectric properties and colossal magnetocapacitance (in excess of 500%) for the cubic spinel compound CdCr2S4 and related isomorphs, concluding that CdCr2S4 is a multiferroic relaxor. We argue here, however, that their results might also be explained by a conductive artefact.